NZ617991B2 - Novel compounds as diacylglycerol acyltransferase inhibitors - Google Patents
Novel compounds as diacylglycerol acyltransferase inhibitors Download PDFInfo
- Publication number
- NZ617991B2 NZ617991B2 NZ617991A NZ61799112A NZ617991B2 NZ 617991 B2 NZ617991 B2 NZ 617991B2 NZ 617991 A NZ617991 A NZ 617991A NZ 61799112 A NZ61799112 A NZ 61799112A NZ 617991 B2 NZ617991 B2 NZ 617991B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- pyrimido
- amino
- oxazepinone
- indolyl
- alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 237
- 102000002148 EC 2.3.1.20 Human genes 0.000 title abstract description 5
- 108010001348 EC 2.3.1.20 Proteins 0.000 title abstract description 5
- 239000002404 acyltransferase inhibitor Substances 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 208000008589 Obesity Diseases 0.000 claims abstract description 19
- 235000020824 obesity Nutrition 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- -1 dihydroindazolyl Chemical group 0.000 claims description 480
- 125000000217 alkyl group Chemical group 0.000 claims description 98
- 239000011780 sodium chloride Substances 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000005843 halogen group Chemical group 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 150000001408 amides Chemical class 0.000 claims description 28
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 125000004104 aryloxy group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 12
- 125000005842 heteroatoms Chemical group 0.000 claims description 9
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000004609 dihydroquinazolinyl group Chemical group N1(CN=CC2=CC=CC=C12)* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 31
- 201000010099 disease Diseases 0.000 abstract description 16
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 125000001424 substituent group Chemical group 0.000 abstract description 8
- 206010012601 Diabetes mellitus Diseases 0.000 abstract description 7
- 206010022489 Insulin resistance Diseases 0.000 abstract description 6
- 125000002252 acyl group Chemical group 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 5
- 230000001225 therapeutic Effects 0.000 abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 abstract description 5
- 206010062060 Hyperlipidaemia Diseases 0.000 abstract description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 4
- 206010000496 Acne Diseases 0.000 abstract description 3
- 206010058108 Dyslipidaemia Diseases 0.000 abstract description 3
- 241000711549 Hepacivirus C Species 0.000 abstract description 3
- 208000001252 Hyperlipoproteinemias Diseases 0.000 abstract description 3
- 208000006575 Hypertriglyceridemia Diseases 0.000 abstract description 3
- 206010061227 Lipid metabolism disease Diseases 0.000 abstract description 3
- 206010053219 Non-alcoholic steatohepatitis Diseases 0.000 abstract description 3
- 208000006641 Skin Disease Diseases 0.000 abstract description 3
- 208000001756 Virus Disease Diseases 0.000 abstract description 3
- 230000004064 dysfunction Effects 0.000 abstract description 3
- 230000000051 modifying Effects 0.000 abstract description 3
- NITOXUVAYQVUKG-UHFFFAOYSA-N O=C1NC=COC2=NC=NC=C12 Chemical class O=C1NC=COC2=NC=NC=C12 NITOXUVAYQVUKG-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 462
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 139
- 239000000243 solution Substances 0.000 description 128
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 119
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 99
- 229910052938 sodium sulfate Inorganic materials 0.000 description 98
- 235000011152 sodium sulphate Nutrition 0.000 description 98
- 239000000203 mixture Substances 0.000 description 95
- 239000000047 product Substances 0.000 description 94
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 86
- 238000004128 high performance liquid chromatography Methods 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 59
- 235000002639 sodium chloride Nutrition 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
- 238000003818 flash chromatography Methods 0.000 description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
- 239000000543 intermediate Substances 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 50
- 239000003921 oil Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 48
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 46
- 239000008079 hexane Substances 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
- 239000000706 filtrate Substances 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000003153 chemical reaction reagent Substances 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 27
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- OPQARKPSCNTWTJ-UHFFFAOYSA-L Copper(II) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 18
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 17
- 229910052786 argon Inorganic materials 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 16
- 239000003480 eluent Substances 0.000 description 15
- 230000002829 reduced Effects 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- PLECUXAVVVRCNX-UHFFFAOYSA-N 4,6-dichloropyrimidine-2-carbonyl chloride Chemical compound ClC(=O)C1=NC(Cl)=CC(Cl)=N1 PLECUXAVVVRCNX-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000010949 copper Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- XDXFUMZONWWODJ-UHFFFAOYSA-N 2-[tert-butyl(dimethyl)silyl]oxyethanamine Chemical compound CC(C)(C)[Si](C)(C)OCCN XDXFUMZONWWODJ-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000006188 syrup Substances 0.000 description 12
- 235000020357 syrup Nutrition 0.000 description 12
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 150000002431 hydrogen Chemical group 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- 230000002194 synthesizing Effects 0.000 description 10
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 102100007851 DGAT1 Human genes 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- 238000004166 bioassay Methods 0.000 description 8
- 229940079593 drugs Drugs 0.000 description 8
- 125000003367 polycyclic group Chemical group 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N N-Propyl bromide Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000001184 potassium carbonate Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 101700039623 DGAT1 Proteins 0.000 description 5
- SNHMUERNLJLMHN-UHFFFAOYSA-N Iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 125000004429 atoms Chemical group 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 238000005828 desilylation reaction Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- HVJXGFRHCQZURE-UHFFFAOYSA-N (1,2-dihydroxy-4-oxotridecan-3-yl) decanoate Chemical compound CCCCCCCCCC(=O)OC(C(O)CO)C(=O)CCCCCCCCC HVJXGFRHCQZURE-UHFFFAOYSA-N 0.000 description 4
- LWPPASWKWXDDFK-UHFFFAOYSA-N 2-chloro-5H-pyrrolo[3,2-d]pyrimidine Chemical compound ClC1=NC=C2NC=CC2=N1 LWPPASWKWXDDFK-UHFFFAOYSA-N 0.000 description 4
- RDGLADDXPVHWLF-UHFFFAOYSA-N 4-amino-7,8-dihydro-6H-pyrimido[5,4-f][1,4]oxazepin-5-one Chemical compound O1CCNC(=O)C2=C1N=CN=C2N RDGLADDXPVHWLF-UHFFFAOYSA-N 0.000 description 4
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1H-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N Allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 4
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- YGHRJJRRZDOVPD-UHFFFAOYSA-N Isovaleraldehyde Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- UUCHOLIRUIGYGZ-UHFFFAOYSA-N NC1=NC(=NC=2OC(C=NC=21)(C)C)C1=CC=C(C=C1)C1CCC(CC1)CC(=O)O Chemical compound NC1=NC(=NC=2OC(C=NC=21)(C)C)C1=CC=C(C=C1)C1CCC(CC1)CC(=O)O UUCHOLIRUIGYGZ-UHFFFAOYSA-N 0.000 description 4
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- 230000002378 acidificating Effects 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
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- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- VMQMZMRVKUZKQL-UHFFFAOYSA-N cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 4
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 4
- 235000019797 dipotassium phosphate Nutrition 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 150000002475 indoles Chemical class 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- 125000004076 pyridyl group Chemical group 0.000 description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- SANWNNBJJJRVKJ-UHFFFAOYSA-N 2-(5-bromoindol-1-yl)-1,3-thiazole Chemical compound C1=CC2=CC(Br)=CC=C2N1C1=NC=CS1 SANWNNBJJJRVKJ-UHFFFAOYSA-N 0.000 description 3
- MRAYNLYCQPAZJN-BQYQJAHWSA-N 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CCO\C=C\B1OC(C)(C)C(C)(C)O1 MRAYNLYCQPAZJN-BQYQJAHWSA-N 0.000 description 3
- IXNCNQSYKWBWOH-UHFFFAOYSA-N 3-benzyl-2-bromoquinazolin-4-one Chemical compound BrC1=NC2=CC=CC=C2C(=O)N1CC1=CC=CC=C1 IXNCNQSYKWBWOH-UHFFFAOYSA-N 0.000 description 3
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1H-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 description 3
- FQPKKECSRKYXIZ-UHFFFAOYSA-N 6-bromo-3,4-dihydro-2H-isoquinolin-1-one Chemical compound O=C1NCCC2=CC(Br)=CC=C21 FQPKKECSRKYXIZ-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- NCNBBUAONNFJIY-UHFFFAOYSA-N COc1ccc(CNCCO[Si](C)(C)C(C)(C)C)cc1 Chemical compound COc1ccc(CNCCO[Si](C)(C)C(C)(C)C)cc1 NCNBBUAONNFJIY-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical class CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical class C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical class C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000003887 narcotic antagonist Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 239000003901 neurotransmitter uptake inhibitor Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004977 physiological function Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical class CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical class [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical class OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical class [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical class [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001663 sulfanilamide Drugs 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-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
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
This disclosure relates to substituted bicyclolactam, specifically pyrimido[5,4-f][1,4]oxazepin-5-one compounds of formula I where R1 is a bicyclic ring system and the other substituents are as given in the description, which are inhibitors of acyl coenzymeA: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the prevention or treatment of diseases related to DGAT-1 dysfunction or where modulation of DGAT-1 activity may have therapeutic benefit including but not limited to obesity, obesity related disorders, hypertriglyceridemia, hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, hepatitis C virus infection and acne or other skin disorders. ), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the prevention or treatment of diseases related to DGAT-1 dysfunction or where modulation of DGAT-1 activity may have therapeutic benefit including but not limited to obesity, obesity related disorders, hypertriglyceridemia, hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, hepatitis C virus infection and acne or other skin disorders.
Description
PU64642PCT
NOVEL COMPOUNDS AS DIACYLGLYCEROL ACYLTRANSFERASE
INHIBITORS
FIELD OF INVENTION
This invention relates to novel compounds which are inhibitors of acyl
coenzymeA: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions
containing them, to processes for their preparation, and to their use in therapy for the
prevention or treatment of diseases related to DGAT-1 dysfunction or where modulation
of DGAT-1 activity may have therapeutic benefit including but not limited to obesity,
obesity related disorders, hypertriglyceridemia, hyperlipoproteinemia, chylomicronemia,
dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic
syndrome, hepatitis C virus infection and acne or other skin disorders.
BACKGROUND OF THE INVENTION
Obesity is a medical condition that is reaching epidemic proportions among
humans in a number of countries throughout the world. It is a condition that is also
associated with or induces other diseases or conditions that disrupt life activities and
lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions
such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body
weight due to obesity can place a burden on joints, such as knee joints, causing arthritis,
pain, and stiffness.
Because overeating and obesity have become such a problem in the general
population, many individuals are now interested in losing weight, reducing weight, and
maintaining a healthy body weight and desirable lifestyle. One approach to treating
obesity is to reduce food intake and/or hyperlipidemia. It has been suggested that
molecules which are developed to prevent the accumulation of triglyceride would not only
reduce obesity but also have the additional beneficial effect of reducing insulin resistance,
a primary factor contributing to the development of diabetes.
Acyl coenzymeA: diacylglycerol acyltransferase 1 (DGAT-1) is one of two known
DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT-1
is an enzyme that is implicated in the development of both diabetes and insulin resistance.
Studies of DGAT-1 deficient mice show that DGAT-1 deficiency protects against insulin
resistance and obesity, see Chen, H.C. et al., J Clin Invest., 109(8), 1049-1055 (2002).
Therefore, inhibitors of DGAT-1 should be useful for the treatment of metabolic disorders,
PU64642PCT
e.g. obesity, Type 2 diabetes, and insulin resistance syndrome (or metabolic syndrome)
and other associated or related diseases and conditions.
SUMMARY OF THE INVENTION
This invention relates to compounds of Formula (I):
wherein
R is a bicyclic ring system which contains 9 to 11 ring members including 1 to 4 hetero
atoms, in which said bicyclic ring system may be substituted by 1 to 3 groups selected
from the group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo,
1 6 1 6 3 7
hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C -
a 2 a 1
C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy,
3 1 4
in which each R is independently C -C alkyl, substituted C -C alkyl or
a 1 6 1 6
unsubstituted C -C cycloalkyl;
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or C -C alkoxy; and
m is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition comprising a compound of
Formula (I) and a pharmaceutically acceptable carrier.
Also described herein is a method of treating obesity comprising administering to a human
in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof in a pharmaceutical composition.
PU64642PCT
DETAIL DESCRIPTION OF THE INVENTION
This invention relates to compounds of the Formula (I) as defined above.
This invention also relates to compounds of Formula (I)(A):
(I)(A)
wherein A is a 5- or 6-membered heterocyclic ring, which may contain 0 to 3 double
bonds and may be substituted by 1 to 3 groups selected from the group consisting of C -
C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, hydroxyl, oxo, amide, carboxylic
6 1 6 3 7
acid, -C(O)R , -SO R , arylalkyl, -(C -C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy,
a 2 a 1 3 1 4
in which each R is independently C -C alkyl, substituted C -C alkyl or
a 1 6 1 6
unsubstituted C -C cycloalkyl;
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or C -C alkoxy;
R is halo or alkoxy;
X is N or CH; and
m is 0-2;
n is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I)(A), wherein A is a 5-membered
heterocyclic ring, which may contain 0-2 double bonds and may be substituted by 1 to 3
groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -
1 6 1 6 3
C cycloalkyl, halo, hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -
7 a 2 a
(C -C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy,
1 3 1 4
in which each R is independently C -C alkyl, substituted C -C alkyl or
a 1 6 1 6
unsubstituted C -C cycloalkyl;
PU64642PCT
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or C -C alkoxy;
R is halo or alkoxy;
X is N or CH; and
m is 0-2;
n is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I)(A), wherein A is a 6-membered
heterocyclic ring, which may contain 0-3 double bonds and may be substituted by 1 to 3
groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -
1 6 1 6 3
C cycloalkyl, halo, hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -
7 a 2 a
(C -C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy,
1 3 1 4
in which each R is independently C -C alkyl, substituted C -C alkyl or
a 1 6 1 6
unsubstituted C -C cycloalkyl;
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or C -C alkoxy;
R is halo or alkoxy;
X is N or CH; and
m is 0-2;
n is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to any one of the above compounds,
wherein m is 0;
n is 0;
R is hydrogen; and
X is N or CH;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I),
wherein m is 0;
R is hydrogen;
PU64642PCT
R is a bicyclic ring system selected from the group consisting of tetrahydroisoquinolinyl,
tetrahydroquinolinyl, indolyl, dihydroindolyl, indazolyl, dihydroindazolyl,
benzothiophenyl, benzodiazolyl, dihydrobenzodiazolyl, benzimidazolyl, indolinyl,
benzotriazolyl, pyrrolopyridinyl, benzothiazolyl, benzofuranyl, dihydroquinazolinyl, and
pyrrolopyrimidinyl;
wherein said bicyclic ring system may be substituted by 1 to 3 groups selected from the
group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, hydroxyl,
1 6 1 6 3 7
oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C -C alkyl)aryloxy, aryl,
a 2 a 1 3
heteroaryl and C -C alkoxy,
in which each R is independently C -C alkyl, substituted C -C alkyl or unsubstituted C -
a 1 6 1 6 3
C cycloalkyl;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I),
wherein m is 0;
R is hydrogen;
R is a bicyclic ring system selected from the group consisting of tetrahydroisoquinolinyl,
tetrahydroquinolinyl, indolyl, dihydroindolyl, indazolyl, dihydroindazolyl, and
pyrrolopyridinyl;
wherein said bicyclic ring system may be substituted by 1 to 3 groups selected from the
group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, hydroxyl,
1 6 1 6 3 7
oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C -C alkyl)aryloxy, aryl,
a 2 a 1 3
heteroaryl and C -C alkoxy,
in which each R is independently C -C alkyl, substituted C -C alkyl or unsubstituted C -
a 1 6 1 6 3
C cycloalkyl;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I),
wherein m is 0;
R is hydrogen;
R is a bicyclic ring system selected from the group consisting of tetrahydroisoquinolinyl,
tetrahydroquinolinyl, indolyl, dihydroindolyl, indazolyl, dihydroindazolyl,
benzothiophenyl, benzodiazolyl, dihydrobenzodiazolyl, benzimidazolyl, indolinyl,
PU64642PCT
benzotriazolyl, pyrrolopyridinyl, benzothiazolyl, benzofuranyl, dihydroquinazolinyl, and
pyrrolopyrimidinyl;
wherein said bicyclic ring system may be substituted by 1 to 3 groups selected from the
group consisting of aryl and heteroaryl;
or a pharmaceutically acceptable salt thereof.
This invention relates to compounds of Formula (I)(B):
(I)(B)
wherein
R is a bicyclic ring system which contains 9 to 11 ring members including 1 to 4 hetero
atoms, in which said bicyclic ring system may be substituted by 1 to 3 groups selected
from the group consisting of C -C alkyl, substituted C -C alkyl, halo, hydroxyl, oxo,
1 6 1 6
amide, carboxylic acid, and alkoxy;
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or alkoxy; and
m is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I)(C):
(I)(C)
wherein A is a 5- or 6-membered heterocyclic ring, which may contain 0 to 3 double
bonds and may be substituted by 1 to 3 groups selected from the group consisting of C -
C alkyl, substituted C -C alkyl, halo, hydroxyl, oxo, amide, carboxylic acid, and alkoxy;
6 1 6
PU64642PCT
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or alkoxy; and
m is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I)(C), wherein A is a 5-membered
heterocyclic ring, which may contain 0 to 3 double bonds and may be substituted by 1 to 3
groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, halo,
1 6 1 6
hydroxyl, oxo, amide, carboxylic acid, and alkoxy;
each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo,
2 3 1 6 1 6
hydroxyl, amide, carboxylic acid or alkoxy; and
m is 0-2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds of Formula (I), (I)(A), (I)(B) or (I)(C), wherein
m is 0, and R is hydrogen, or a pharmaceutically acceptable salt thereof.
This invention also relates to compounds that are exemplified in the Experimental section.
Specific compounds of this invention include:
2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo-1,2,3,4-
tetrahydroisoquinolinyl)acetic acid;
ethyl 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo-
1,2,3,4-tetrahydroquinolinyl)acetate;
2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo-1,2,3,4-
tetrahydroquinolinyl)acetic acid;
ethyl 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo-
1,2,3,4-tetrahydroisoquinolinyl)acetate;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}methyl-1,2,3,4-
tetrahydroquinolinone;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}methyl-1,2,3,4-
tetrahydroisoquinolinone;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl-1,2,3,4-
tetrahydroisoquinolinone;
PU64642PCT
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl-1,2,3,4-
tetrahydroisoquinolinone;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl-1,2,3,4-
tetrahydroquinolinone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl(prop
enyl)-2,3-dihydro-1H-indazolone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl-2,3-
dihydro-1H-indazolone;
4-amino(1-propyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1-propyl-1H-indazolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin
one;
4-amino(1-benzothiophenyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-1,3-dipropyl-2,3-
dihydro-1H-1,3-benzodiazolone;
4-amino(2-propyl-2H-indazolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1,3-benzothiazolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl-2,3-
dihydro-1H-indole-2,3-dione;
4-amino(1-benzofuranyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1-cyclopropyl-1,2,3,4-tetrahydroquinolinyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(2-propyl-1,2,3,4-tetrahydroisoquinolinyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinolinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
-{4-aminooxo-5H,6H,7H,8H-oxepino[2,3-d]pyrimidinyl}(propanyl)-2,3-
dihydro-1H-indazolone;
-{4-aminooxo-5H,6H,7H,8H-oxepino[2,3-d]pyrimidinyl}(2-methoxyethyl)-2,3-
dihydro-1H-indazolone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}(2,2-
difluoroethyl)-2,3-dihydro-1H-indazolone;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}cyclopropyl-2,3-
dihydro-1H-indazolone;
PU64642PCT
6-amino(1-propyl-1H-1,3-benzodiazolyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin
one;
4-amino(1-propyl-1H-1,3-benzodiazolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(2-propyl-2H-1,2,3-benzotriazolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1-propyl-1H-1,2,3-benzotriazolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(2-methyl-1,3-benzothiazolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin-
-one;
4-amino[1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(cyclopropylmethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
3-(5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-1H-indol
yl)propanoic acid;
4-amino[1-(cyclohexylmethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(pentanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin
one;
4-amino{1-[(4-methoxyphenyl)methyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino{1-[(4-fluorophenyl)methyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino{1-[2-(benzyloxy)ethyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1-benzyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(3-methoxypropyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2,2-difluoroethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1-methyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
PU64642PCT
4-amino[1-(2-methoxyethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(propanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin-
-one;
4-amino(1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1-propyl-2,3-dihydro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(2,3-dihydro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin
one;
4-amino[1-(2-methoxyethyl)-2,3-dihydro-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1,2-dimethyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin
one;
4-amino[1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-propyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-cyclohexyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(propanyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1-methanesulfonyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1-cyclopropyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin
one;
-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl-1H-indole-
2-carboxylic acid;
PU64642PCT
4-amino[1-propyl(trifluoroacetyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-propyl(1,1,1-trifluoromethoxypropanyl)-1H-indolyl]-
5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino(1-phenyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(3-chlorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(2-methoxyphenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino{1-phenyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(3,4-difluorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(2-fluorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino{1-[4-(trifluoromethyl)phenyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-[3-(trifluoromethyl)phenyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
PU64642PCT
4-amino{1-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(1,3-thiazolyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino{1-[6-(trifluoromethyl)pyridinyl]-1H-indolyl}-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(pyridinyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin-
-one;
4-amino[1-(pyridinyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(pyrazinyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino[1-(pyrazinyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin-
-one;
4-amino{1-[5-(trifluoromethyl)pyridinyl]-1H-indolyl}-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-[5-(trifluoromethyl)pyridinyl]-1H-pyrrolo[2,3-b]pyridinyl}-
5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-(1,3-thiazolyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H-
pyrimido[5,4-f][1,4]oxazepinone;
4-amino{1-[6-(trifluoromethyl)pyridinyl]-1H-pyrrolo[2,3-b]pyridinyl}-
5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone;
4-amino[1-phenyl(propanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(2-phenylpropyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(6-fluorophenyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl-3,4-
dihydroquinazolinone;
6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-3,4-
dihydroquinazolinone;
4-amino(1-benzylfluoro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
PU64642PCT
4-amino{5-propyl-5H-pyrrolo[3,2-d]pyrimidinyl}-5H,6H,7H,8H-pyrimido[5,4-
f][1,4]oxazepinone;
4-amino(1-propyl-1H-pyrrolo[3,2-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one;
4-amino(1-(6-methylpyridinyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one;
4-amino(1-(4-(difluoromethyl)phenyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one;
4-amino(1-(4-(difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;
4-amino(1-(4-(trifluoromethyl)pyridinyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;
or a pharmaceutically acceptable salt thereof.
A person of ordinary skills in the art recognizes that compounds of the present
invention may have alternative names when different naming software is used.
The following exemplified compounds have alternative chemical names as
illustrated in table below.
Ex Chemical Name Alternative Chemical Name
2-(6-{4-aminooxo-5H,6H,7H,8H- 2-(6-(4-aminooxo-5,6,7,8-
pyrimido[5,4-f][1,4]oxazepinyl}- tetrahydrooxepino(2,3-d)pyrimidin
1-oxo-1,2,3,4-tetrahydroisoquinolin- yl)methyloxo-1,2,3,4-
2-yl)acetic acid tetrahydronapthalenyl) acetic acid
-{4-aminooxo-5H,6H,7H,8H- 6-(1-allylbenzyloxo-2,3-
pyrimido[5,4-f][1,4]oxazepinyl}- dihydro-1H-indazolyl)amino-
2-benzyl(propenyl)-2,3- 7,8-dihydropyrimido[5,4-
dihydro-1H-indazolone f][1,4]oxazepin-5(6H)-one
-{4-aminooxo-5H,6H,7H,8H- 4-amino(3-oxopropyl-2,3-
pyrimido[5,4-f][1,4]oxazepinyl}- dihydro-1H-indazolyl)-7,8-
1-propyl-2,3-dihydro-1H-indazol dihydropyrimido[5,4-f][1,4]oxazepin-
one 5(6H)-one
4-amino(1-propyl-1H-indolyl)- 4-amino(1-propyl-1H-indolyl)-
12 5H,6H,7H,8H-pyrimido[5,4- 7,8-dihydropyrimido[5,4-
f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino[1-(2,2-difluoroethyl)- 4-amino(1-(2,2-difluoroethyl)-1H-
1H-pyrrolo[2,3-b]pyridinyl]- pyrrolo[2,3-b]pyridinpyridinyl)-
5H,6H,7H,8H-pyrimido[5,4- 7,8-dihydropyrimido[5,4-
f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
PU64642PCT
4-amino{1-cyclopropyl-1H- 4-amino(1-cyclopropyl-1H-
pyrrolo[2,3-b]pyridinyl}- pyrrolo[2,3-b]pyridinpyridinyl)-
5H,6H,7H,8H-pyrimido[5,4- 7,8-dihydropyrimido[5,4-
f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino[1-propyl 4-amino(1-propyl(2,2,2-
(trifluoroacetyl)-1H-indolyl]- trifluoroacetyl)-1H-indolyl)-7,8-
5H,6H,7H,8H-pyrimido[5,4- dihydropyrimido[5,4-f][1,4]oxazepin-
f][1,4]oxazepinone 5(6H)-one
4-amino(1-phenyl-1H-indol 4-amino(1-phenyl-1H-indolyl)-
65 yl)-5H,6H,7H,8H-pyrimido[5,4- 7,8-dihydropyrimido[5,4-
f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino{1-[4- 4-amino(1-(4-
(trifluoromethyl)phenyl]-1H- (trifluoromethyl)phenyl)-1H-
66 pyrrolo[2,3-b]pyridinyl}- pyrrolo[2,3-b]pyridinpyridinyl)-
5H,6H,7H,8H-pyrimido[5,4- 7,8-dihydropyrimido[5,4-
f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino[1-(1,3-thiazolyl)-1H- 4-amino(1-(thiazolyl)-1H-
82 indolyl]-5H,6H,7H,8H- indolyl)-7,8-dihydropyrimido[5,4-
pyrimido[5,4-f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino(1-(6-
4-amino{1-[6-
(trifluoromethyl)pyridinpyridinyl)-
(trifluoromethyl)pyridinyl]-1H-
83 1H-indolyl)-7,8-
indolyl}-5H,6H,7H,8H-
dihydropyrimido[5,4-f][1,4]oxazepin-
pyrimido[5,4-f][1,4]oxazepinone
(6H)-one
4-amino[1-phenyl(propan 4-amino(3-isopropylphenyl-1H-
94 yl)-1H-indolyl]-5H,6H,7H,8H- indolyl)-7,8-dihydropyrimido[5,4-
pyrimido[5,4-f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino(2-phenylpropyl-1H- 4-amino(2-phenylpropyl-1H-
95 indolyl)-5H,6H,7H,8H- indolyl)-7,8-dihydropyrimido[5,4-
pyrimido[5,4-f][1,4]oxazepinone f][1,4]oxazepin-5(6H)-one
4-amino(6-fluorophenyl-1H- 4-amino(6-fluorophenyl-1H-
96 indolyl)-5H,6H,7H,8H- indolyl)-7,8-dihydrooxepino[2,3-
pyrimido[5,4-f][1,4]oxazepinone d]pyrimidin-5(6H)-one
6-{4-aminooxo-5H,6H,7H,8H- 4-amino(3-benzyloxo-3,4-
pyrimido[5,4-f][1,4]oxazepinyl}- dihydroquinazolinyl)-7,8-
3-benzyl-3,4-dihydroquinazolin dihydropyrimido[5,4-f][1,4]oxazepin-
one 5(6H)-one
4-amino(4-oxo-3,4-
6-{4-aminooxo-5H,6H,7H,8H-
dihydroquinazolinyl)-7,8-
98 pyrimido[5,4-f][1,4]oxazepinyl}-
dihydropyrimido[5,4-f][1,4]oxazepin-
3,4-dihydroquinazolinone
(6H)-one
4-amino{5-propyl-5H- 4-amino(5-propyl-5H-pyrrolo[3,2-
pyrrolo[3,2-d]pyrimidinyl}- d]pyrimidinyl)-7,8-
5H,6H,7H,8H-pyrimido[5,4- dihydropyrimido[5,4-f][1,4]oxazepin-
f][1,4]oxazepinone 5(6H)-one
4-amino(1-propyl-1H- 4-amino(1-propyl-1H-pyrrolo[3,2-
pyrrolo[3,2-b]pyridinyl)-7,8- b]pyridinpyridinyl)-7,8-
dihydropyrimido[5,4- dihydropyrimido[5,4-f][1,4]oxazepin-
f][1,4]oxazepin-5(6H)-one 5(6H)-one
PU64642PCT
This invention also relates to compounds of Formula (I), (I)(A), (I)(B), (I)(C), or any of
the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use as a
medicament.
This invention also relates to compounds of Formula (I), (I)(A), (I)(B), (I)(C), or any of
the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use in
the treatment of obesity.
This invention also relates to compounds of Formula (I), (I)(A), (I)(B), (I)(C), or any of
the exemplified compounds, or their pharmaceutically acceptable salts thereof, in the
manufacture of a medicament for the treatment of obesity.
It will be appreciated by those skilled in the art that the compound of the present
invention may also be utilized in the form of a pharmaceutically acceptable salt thereof.
Typically, but not absolutely, the salts of the present invention are
pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically
acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the
disclosed compounds containing a basic amine or other basic functional group may be
prepared by any suitable method known in the art, including treatment of the free base
with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid,
trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid,
pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic
acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino
acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or
cinnamic acid, sulfonic acid, such as ptoluenesulfonic acid, methanesulfonic acid,
ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides,
iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates,
caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates,
fumarates, maleates, butyne1,4dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,
phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, -hydroxybutyrates,
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glycolates, tartrates mandelates, and sulfonates, such as xylenesulfonates,
methanesulfonates, propanesulfonates, naphthalene1sulfonates and
naphthalene2sulfonates.
Salts of the disclosed compounds containing a carboxylic acid or other acidic
functional group can be prepared by reacting with a suitable base. Such a
pharmaceutically acceptable salt may be made with a base which affords a
pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium
and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum
salts and ammonium salts, as well as salts made from physiologically acceptable organic
bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline,
dicyclohexylamine, N,N‟-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-
hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
dehydroabietylamine, N,N‟-bisdehydroabietylamine, glucamine, N-methylglucamine,
collidine, choline, quinine, quinoline, and basic amino acid such as lysine and arginine.
Other salts, which are not pharmaceutically acceptable, may be useful in the
preparation of compounds of this invention and these should be considered to form a
further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in
themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as
intermediates in obtaining the compounds of the invention and their pharmaceutically
acceptable salts.
As used herein, the term “a compound of Formula (I)” or “the compound of
Formula (I)” refers to one or more compounds according to Formula (I). The compound
of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in
crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will
appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-
crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the
crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such
as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl
acetate, or they may involve water as the solvent that is incorporated into the crystalline
lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are
typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as
compositions containing variable amounts of water. The invention includes all such
solvates.
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The skilled artisan will further appreciate that certain compounds of the invention
that exist in crystalline form, including the various solvates thereof, may exhibit
polymorphism (i.e. the capacity to occur in different crystalline structures). These
different crystalline forms are typically known as "polymorphs." The invention includes
all such polymorphs. Polymorphs have the same chemical composition but differ in
packing, geometrical arrangement, and other descriptive properties of the crystalline solid
state. Polymorphs, therefore, may have different physical properties such as shape,
density, hardness, deformability, stability, and dissolution properties. Polymorphs
typically exhibit different melting points, IR spectra, and X-ray powder diffraction
patterns, which may be used for identification. The skilled artisan will appreciate that
different polymorphs may be produced, for example, by changing or adjusting the reaction
conditions or reagents, used in making the compound. For example, changes in
temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph
may spontaneously convert to another polymorph under certain conditions.
The compound of Formula (I) or a salt thereof may exist in stereoisomeric forms
(e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers
(enantiomers and diastereomers) and mixtures of these are included within the scope of the
present invention. Likewise, it is understood that a compound or salt of Formula (I) may
exist in tautomeric forms other than that shown in the formula and these are also included
within the scope of the present invention. It is to be understood that the present invention
includes all combinations and subsets of the particular groups defined hereinabove. The
scope of the present invention includes mixtures of stereoisomers as well as purified
enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be
understood that the present invention includes all combinations and subsets of the
particular groups defined hereinabove.
The subject invention also includes isotopically-labelled compounds, which are
identical to those recited in formula (I) and following, but for the fact that one or more
atoms are replaced by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention and pharmaceutically acceptable salts
thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur,
fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 31P, 32P,
35S, 18F, 36Cl, 123I and 125I.
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Compounds of the present invention and pharmaceutically acceptable salts of said
compounds that contain the aforementioned isotopes and/or other isotopes of other atoms
are within the scope of the present invention. Isotopically-labelled compounds of the
present invention, for example those into which radioactive isotopes such as 3H, 14C are
incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,
3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of
preparation and detectability. 11C and 18F isotopes are particularly useful in PET
(positron emission tomography), and 125I isotopes are particularly useful in SPECT
(single photon emission computerized tomography), all useful in brain imaging. Further,
substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain
therapeutic advantages resulting from greater metabolic stability, for example increased in
vivo half-life or reduced dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labelled compounds of formula I and following of this
invention can generally be prepared by carrying out the procedures disclosed in the
Schemes and/or in the Examples below, by substituting a readily available isotopically
labelled reagent for a non-isotopically labelled reagent.
DEFINITIONS
Terms are used within their accepted meanings. The following definitions are
meant to clarify, but not limit, the terms defined.
As used herein, unless otherwise defined, the term “alkyl” (or “alkylene”) refers to
a straight or branched chain alkyl, preferably having from one to twelve carbon atoms,
which may be saturated or unsaturated included within the present invention. Examples of
“alkyl” as used herein include methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl,
isopentyl, n-pentyl, and the like, as well as substituted versions thereof.
As used herein, unless otherwise defined, the term “substituted alkyl” (or
“alkylene”) refers to a straight or branched chain alkyl, preferably having from one to
twelve carbon atoms, which may be saturated or unsaturated with multiple degrees of
substitution included within the present invention, preferably one, two or three. Suitable
substituents are selected from the group consisting of unsubstituted C -C cycloalkyl,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, difluoromethyl, trifluoromethyl, halo,
amino, substituted amino, urea, cyano, hydroxyl, alkoxy, alkylthio, alkylsulfonyl,
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sulfonamide, carboxylic acid (eg. COOH), carboxylic ester (eg. methyl ester, ethyl ester,
and carboxamide.
As used herein, unless otherwise defined, the term “substituted amino” is meant –
NR‟R” wherein each R‟ and R” is independently selected from a group including
hydrogen, unsubstituted C -C alkyl, acyl, unsubstituted C -C cycloalkyl, wherein at least
1 6 3 7
one of R‟ and R” is not hydrogen. Examples of substituted amino includes, but are not
limited to alkylamino, dialkylaminio, acylamino, and cycloalkylamino.
As used herein, unless otherwise defined, the term “aryloxy” refers to the group –
O-C -C alkylaryl. Examples of –O-C -C alkylaryl includes, but are not limited to
1 6 1 6
phenylmethoxy, naphthylmethoxy.
As used herein, unless otherwise defined, the term “arylalkyl” refers to the group -
C -C alkylaryl. Examples of –C -C alkylaryl includes, but are not limited to
1 6 1 6
phenylmethyl, naphthylmethyl.
As used herein, unless otherwise defined, the term “cycloalkyl” refers to an
unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring, which
optionally includes an alkylene linker through which the cycloalkyl may be attached.
Suitable substituents are defined in the definition of „substituted”. Exemplary “cycloalkyl”
groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like, as well as unsubstituted and substituted versions thereof.
As used herein, unless otherwise defined, the term “alkoxy” refers to the group -
OR , where R is C -C alkyl or cycloalkyl as defined above.
As used herein, unless otherwise defined, the term “amide” refers to the group –
c d c d c
C(O)NR R , wherein R and R are each independently H, or C -C alkyl , or R is the
remaining portion of a natural or un-natural aminoacid.
As used herein, unless otherwise defined, the term “heterocycle” or “heterocyclyl”
or “heterocyclic” refers to unsubstituted and substituted mono- or polycyclic non-aromatic
ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and
S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight-
membered and is either fully saturated or has one or more degrees of unsaturation.
Multiple degrees of substitution are included within the present definition. Examples of
“heterocyclic” groups include, but are not limited to tetrahydrofuranyl, pyranyl, 1,4-
dioxanyl, 1,3-dioxanyl, piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, piperazinyl,
pyrrolidinonyl, piperazinonyl, pyrazolidinyl, and their various tautomers.
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As used herein, unless otherwise defined, the term “aryl”, unless otherwise
defined, is meant aromatic, hydrocarbon, ring system. The ring system may be monocyclic
or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted. A C6 ring
system, i.e. a phenyl ring, is a suitable aryl group. In various embodiments, the polycyclic
ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10. A
naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group. Suitable
substituents for aryl are described below in the definition of “optionally substituted”.
As used herein, unless otherwise defined, the term “heteroaryl”,unless otherwise
defined, is meant an aromatic ring system containing carbon(s) and at least one
heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A
monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic
heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain
fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic
heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and
heteroatoms). Exemplary heteroaryl groups include but are not limited to: benzofuran,
benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole,
and thiophene. Suitable substituents for heteroaryl are described below in the definition of
“optionally substituted”.
As used herein, unless otherwise defined, the term “cyano” refers to the group -
As used herein, unless otherwise defined, the term “acyl” refers to the group -
C(O)R , where R is alkyl, cycloalkyl, or heterocyclyl, as each is defined herein.
As used herein, unless otherwise defined, the term “optionally” means that the
subsequently described event(s) may or may not occur, and includes both event(s) that
occur and event(s) that do not occur.
As used herein, unless otherwise defined, the phrase “substituted” or variations
thereof denote an optional substitution, including multiple degrees of substitution, with
one or more substitutent group, preferably one, two or three. The phrase should not be
interpreted as duplicative of the substitutions herein described and depicted. Suitable
optional substituent groups include acyl, C -C alkyl, substituted C -C alkyl, unsubstituted
1 6 1 6
C -C cycloalkyl, alkylsulfonyl, alkoxy, alkoxycarbonyl, cyano, halo, urea, amide,
hydroxyl, oxo, and nitro.
PU64642PCT
PHARMACEUTICAL COMPOSITIONS
The invention further provides a pharmaceutical composition (also referred to as
pharmaceutical formulation) comprising a compound of Formula I or pharmaceutically
acceptable salt, thereof and one or more excipients (also referred to as carriers and/or
diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being
compatible with the other ingredients of the formulation and not deleterious to the
recipient thereof (i.e., the patient).
In accordance with another aspect of the invention there is provided a process for
the preparation of a pharmaceutical composition comprising mixing (or admixing) a
compound of Formula I or salt thereof with at least one excipient.
Pharmaceutical compositions may be in unit dose form containing a predetermined
amount of active ingredient per unit dose. Such a unit may contain a therapeutically
effective dose of the compound of Formula I or salt thereof or a fraction of a
therapeutically effective dose such that multiple unit dosage forms might be administered
at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage
formulations are those containing a daily dose or sub-dose, as herein above recited, or an
appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical
compositions may be prepared by any of the methods well-known in the pharmacy art.
Pharmaceutical compositions may be adapted for administration by any
appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal,
topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including
subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may
be prepared by any method known in the art of pharmacy, for example, by bringing into
association the active ingredient with the excipient(s).
When adapted for oral administration, pharmaceutical compositions may be in
discrete units such as tablets or capsules; powders or granules; solutions or suspensions in
aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or
water-in-oil liquid emulsions. The compound or salt thereof of the invention or the
pharmaceutical composition of the invention may also be incorporated into a candy, a
wafer, and/or tongue tape formulation for administration as a “quick-dissolve” medicine.
For instance, for oral administration in the form of a tablet or capsule, the active
drug component can be combined with an oral, non-toxic pharmaceutically acceptable
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inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are
prepared by comminuting the compound to a suitable fine size and mixing with a similarly
comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch
or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
Capsules are made by preparing a powder mixture, as described above, and filling
formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica,
talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the
powder mixture before the filling operation. A disintegrating or solubilizing agent such as
agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the
availability of the medicine when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating
agents, and coloring agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners,
natural and synthetic gums such as acacia, tragacanth, sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in
these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without
limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
Tablets are formulated, for example, by preparing a powder mixture, granulating or
slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture
is prepared by mixing the compound, suitably comminuted, with a diluent or base as
described above, and optionally, with a binder such as carboxymethylcellulose, and
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a
resorption accelerator such as a quaternary salt, and/or an absorption agent such as
bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by
wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or
polymeric materials and forcing through a screen. As an alternative to granulating, the
powder mixture can be run through the tablet machine and the result is imperfectly formed
slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet
forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
The lubricated mixture is then compressed into tablets. The compound or salt of the
present invention can also be combined with a free-flowing inert carrier and compressed
into tablets directly without going through the granulating or slugging steps. A clear
opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or
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polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added
to these coatings to distinguish different dosages.
Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit
form so that a given quantity contains a predetermined amount of active ingredient.
Syrups can be prepared by dissolving the compound or salt thereof of the invention in a
suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-
toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or
salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as
ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor
additives such as peppermint oil, natural sweeteners, saccharin, or other artificial
sweeteners, and the like, can also be added.
Where appropriate, dosage unit formulations for oral administration can be
microencapsulated. The formulation can also be prepared to prolong or sustain the release
as, for example, by coating or embedding particulate material in polymers, wax, or the
like.
In the present invention, tablets and capsules are preferred for delivery of the
pharmaceutical composition.
As used herein, the term “treatment” includes prophylaxis and refers to alleviating
the specified condition, eliminating or reducing one or more symptoms of the condition,
slowing or eliminating the progression of the condition, and preventing or delaying the
reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
Prophylaxis (or prevention or delay of disease onset) is typically accomplished by
administering a drug in the same or similar manner as one would to a patient with the
developed disease or condition.
Described herein is a method of treatment in a mammal, especially a human,
suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction,
substance addiction, or a combination thereof. Such treatment comprises the step of
administering a therapeutically effective amount of a compound of Formula I or salt
thereof to said mammal, particularly a human. Treatment can also comprise the step of
administering a therapeutically effective amount of a pharmaceutical composition
containing a compound of Formula I or salt thereof to said mammal, particularly a human.
As used herein, the term "effective amount" means that amount of a drug or
pharmaceutical agent that will elicit the biological or medical response of a tissue, system,
animal, or human that is being sought, for instance, by a researcher or clinician.
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The term “therapeutically effective amount” means any amount which, as
compared to a corresponding subject who has not received such amount, results in
improved treatment, healing, prevention, or amelioration of a disease, disorder, or side
effect, or a decrease in the rate of advancement of a disease or disorder. The term also
includes within its scope amounts effective to enhance normal physiological function. For
use in therapy, therapeutically effective amounts of a compound of Formula I, as well as
salts thereof, may be administered as the raw chemical. Additionally, the active ingredient
may be presented as a pharmaceutical composition.
While it is possible that, for use in therapy, a therapeutically effective amount of a
compound of Formula I or salt thereof may be administered as the raw chemical, it is
typically presented as the active ingredient of a pharmaceutical composition or
formulation.
The precise therapeutically effective amount of a compound or salt thereof of the
invention will depend on a number of factors, including, but not limited to, the age and
weight of the subject (patient) being treated, the precise disorder requiring treatment and
its severity, the nature of the pharmaceutical formulation/composition, and route of
administration, and will ultimately be at the discretion of the attending physician or
veterinarian. Typically, a compound of Formula I or salt thereof will be given for the
treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient,
mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from
about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a
number (such as two, three, four, five, or more) of sub-doses per day such that the total
daily dose is the same. An effective amount of a salt thereof may be determined as a
proportion of the effective amount of the compound of Formula I per se. Similar dosages
should be appropriate for treatment (including prophylaxis) of the other conditions
referred herein for treatment. In general, determination of appropriate dosing can be
readily arrived at by one skilled in medicine or the pharmacy art.
Additionally, the present invention comprises a compound of Formula I or salt
thereof or a pharmaceutical composition thereof with at least one other anti-obesity drug
and/or at least one anti-diabetes drug. Such anti-obesity drugs can include, for example,
Metformin (or glucophage), CB1 receptor antagonists, GLP-1 agonists, opioid antagonists,
and neurotransmitter reuptake inhibitors. When a compound of the invention is employed
in combination with another anti-obesity drug or anti-diabetes drug, it is to be appreciated
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by those skilled in the art that the dose of each compound or drug of the combination may
differ from that when the drug or compound is used alone. Appropriate doses will be
readily appreciated and determined by those skilled in the art. The appropriate dose of the
compound of Formula I or salt thereof and the other therapeutically active agent(s) and the
relative timings of administration will be selected in order to achieve the desired combined
therapeutic effect, and are with the expertise and discretion of the attending doctor or
clinician.
COMPOUNDS PREPARATION
Generic Synthesis Schemes
The compounds of this invention may be made by a variety of methods, including
well-known standard synthetic methods. Illustrative general synthetic methods are set out
below and then specific compounds of the invention are prepared in the working
examples. The skilled artisan will appreciate that if a substituent described herein is not
compatible with the synthetic methods described herein, the substituent may be protected
with a suitable protecting group that is stable to the reaction conditions. The protecting
group may be removed at a suitable point in the reaction sequence to provide a desired
intermediate or target compound. In all of the schemes described below, protecting groups
for sensitive or reactive groups are employed where necessary in accordance with general
principles of synthetic chemistry. Protecting groups are manipulated according to
standard methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting
Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard
to protecting groups). These groups are removed at a convenient stage of the compound
synthesis using methods that are readily apparent to those skilled in the art. The selection
of processes as well as the reaction conditions and order of their execution shall be
consistent with the preparation of compounds of the present invention.
The synthesis of the compounds of the general Formula (I) and pharmaceutically
acceptable derivatives and salts thereof may be accomplished as outlined below in
Schemes 1 – 10 by those skilled in the art. In the following description, the groups are as
defined above for compounds of Formula (I) unless otherwise indicated. Starting
materials are commercially available or are made from commercially available starting
materials using methods known to those skilled in the art.
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Scheme 1. Reagents and conditions: a) NaN , MeSO H, CH Cl , RT; b) NaH,
3 3 2 2
BrCH CO Et, THF, RT; c) Pd(OAc) , Cs CO , X-Phos, Toluene, 120 C; d) THF, Et N,
2 2 2 2 3 3
RT; e) 3%HCl-MeOH, RT; f) CH CN, Et N, 80 C; g) NH , Dioxane, RT; h) LiOH,
3 3 3
Dioxane-H O, RT
Compounds of Formula (I) may be prepared as illustrated in Scheme 1.
Intermediate A can be obtained by rearrangement reaction of 5-bromoindanone with
NaN in MeSO H in solvents such as CH Cl . Alkylation of intermediate A with an
3 3 2 2
appropriate alkyl halide such as ethyl bromoacetate in the presence of a suitable base such
as NaH gives intermediate B. Intermediate A’ can also be similarly alkylated and
progressed similar to that of intermediate A. Intermediate B can then be subjected to
amination under Buchwald conditions using an appropriate amine in the presence of
reagents such as palladium acetate, ligand such as X-Phos and a base such as cesium
carbonate in toluene at 120 °C. Intermediate C thus obtained can then be coupled to the
appropriately substituted acid chloride to afford D. Desilylation of intermediate D under
standard acidic conditions leads to E which is then subjected to ring closure by heating the
reaction mixture in acetonitrile at 80 °C in the presence of a base such as triethylamine to
give F. Substitution of the chloro residue in intermediate F with an amino group by
treatment with ammonia at room temperature results in compounds of Formula (I) (1a).
Hydrolysis of the ester group in compound 1a with base such as LiOH provides another
compound of Formula (I) (1b).
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Scheme 2. Reagents and conditions: a) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-
2 2 2 2 2 3
PHOS, Toluene, 120 C; b) THF, Et N, RT; c) 3% HCl-MeOH, RT; d) CH CN, Et N, 80
3 3 3
C; e) NH , Dioxane, RT.
Compounds of Formula (I) may be also prepared as illustrated in Scheme 2.
Intermediate H can be obtained by the amination of an appropriate bromo substituted
heterocyclic compound G with a suitably protected amine under the standard Buchwald
conditions. Bromide G is available either commercially or is synthesized according to
standard methods of organic synthesis known to those skilled in the art with or without
appropriate protecting groups. Amine intermediate H can then be converted to the tertiary
amide I with an appropriately substituted acid chloride using triethylamine as a base.
Desilylation of intermediate I followed by ring closure of the resulting alcohol J under
heating conditions in acetonitrile affords intermediate K. Substitution of the chloro residue
in intermediate K with an amino group by treatment with ammonia at room temperature
results in compounds of Formula (I) (1c). If necessary, compound 1c can be subjected to a
functional group deprotection reaction under standard conditions to remove the group that
was introduced during the preparation of bromide G.
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Scheme 3. Reagents and conditions: a) NH NH .H O, EtOH, 80 C; b) Allyl bromide,
2 2 2
KOH, NaOH, 100 C; c) Benzyl bromide, NaH, DMF, RT; d) Fe/NH Cl, EtOH-H O, 85
C; e) Br(CH ) OTBDMS, CH CN, K CO , 80 C; f)DCM, Et N, rt; g) 3% HCl-MeOH,
2 2 3 2 3 3
RT; h) CH CN, Et N, 80 C; i) NH , Dioxane, RT; j) 10% Pd/C, H , MeOH, RT.
3 3 3 2
Compounds of Formula (I) may be also prepared as illustrated in Scheme 3.
Commercially available 2-chloronitro benzoic acid L was treated with hydrazine
hydrate in refluxing ethanol to give the indazolone M. Intermediate M was then doubly
protected first with allyl group on the aniline nitrogen to give N and then with a benzyl
group on the lactam nitrogen to afford O. Intermediate O was then reduced to the
corresponding amine P under standard conditions. Aniline P was then alkylated with a
suitable alkyl bromide to afford Q which was then converted to a tertiary amide R using
an appropriately substituted acid chloride. Desilylation of intermediate R followed by ring
closure of the resulting alcohol S under heating conditions in acetonitrile affords
intermediate T. Substitution of the chloro residue in intermediate T with an amino group
by treatment with ammonia at room temperature results in compounds of Formula (I) (1d).
Deprotection of benzyl group on the lactam nitrogen of compound 1d with concomitant
reduction of olefin in the allyl moiety provides another compound of Formula (I) (1e).
Scheme 4. Reagents and conditions: a) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-
2 2 2 2 2 3
Phos, Toluene, 120 C; b) DCM, Et N, RT; c) 3% HCl-MeOH, RT; d) CH CN, Et N, 80
3 3 3
C; e) NH , Dioxane, RT.
Compounds of Formula (I) may be also prepared as illustrated in Scheme 4. An
appropriately substituted indole or a derivative thereof U, can be subjected to amination
under Buchwald conditions using an appropriate amine in the presence of reagents such as
palladium acetate, ligand such as X-Phos and a base such as cesium carbonate in toluene
at 120 °C. Intermediate V thus obtained can then be coupled to an appropriately
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substituted acid chloride to afford W. Desilylation of intermediate W under standard
acidic conditions leads to X which is then subjected to ring closure by heating the reaction
mixture in acetonitrile at 80 °C in the presence of a base such as triethylamine to give Y.
Substitution of the chloro residue in intermediate Y with an amino group by treatment
with ammonia at room temperature results in compounds of Formula (I) (1f).
Scheme 5. Reagents and conditions: a) R -Br/ R -I, Cs CO , DMF, 100 C; b) Cu(I)Br,
4 4 2 3
Cu(OAc) , K CO , NaOH, 140 C; c) Cu(I)Br, Cu(OAc) , K CO , NaOH, DMF, 110 C;
2 2 3 2 2 3
d) R -B(OH) , 2,2‟-bipyridine, Na CO , Cu(OAc) , DCE, 110 C; e) Cs CO , DMF, 100
4 2 2 3 2 2 3
Compounds of Formula (I) may be also prepared via intermediates U, AA & AB as
illustrated in Scheme 5. A suitably substituted indole or a derivative thereof Z is alkylated
or arylated using the appropriate alkyl bromide R -Br (or iodide R -I) or aryl/heteroaryl
boronic acid R -B(OH) respectively under standard conditions to afford the nitrogen-
capped intermediate U. This can be converted to compounds of formula (I) 1g by using
this intermediate U via Scheme 4. Similarly Z can also be arylated under copper catalysed
conditions with copper (I) bromide and cupric acetate using an appropriately substituted
aryl iodide to afford intermediate AA. This intermediate can again be transformed into
compounds of formula (I) 1h via Scheme 4. Intermediate Z can be treated with 2-chloro
substituted heterocycles under heating conditions in the presence of a mild base such as
cesium carbonate. The intermediate AB thus obtained can be transformed into compounds
of Formula (I) 1i via Scheme 4.
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Scheme 6. Reagents and conditions: a) AcOH, 120 °C; b) Cu(I)Br, Cu(OAc) , K CO ,
2 2 3
NaOH, 140 C.
Compounds of Formula (I) may also be synthesized via intermediate AE whose
synthesis is shown in Scheme 6. An appropriately substituted phenyl hydrazine AC is
heated with a suitably α-substituted aldehyde in acetic acid at 120 °C to afford the 3-
substituted indole AD. Intermediate AD then is coupled to an appropriately substituted
aryl or heteroaryl iodide under copper catalysed conditions (similar to that described for
the synthesis of intermediate AA) to afford intermediate AE. This can then be taken
through synthetic sequence similar to that in Scheme 4 to afford compounds of Formula
(I) 1j.
Scheme 7. Reagents and conditions: a) R -B(OH) , AcOH, Pd(OAc) , copper(II) acetate,
2 2
o o o
C; b) R -Br/ R -I, Cs CO , DMF, 25 C; c) BBr , DCM, 0 C; d) Triflic anhydride, Py,
4 4 2 3 3
DCM, 0 C.
Compounds of Formula (I) may also be synthesized via intermediate AJ whose
synthesis is described in Scheme 7. Commercially available 5-methoxy indole AF was
substituted suitably with R moiety using R -substituted boronic acid under palladium
catalysed conditions to afford 2-substituted indole derivative AG. Intermediate AG in turn
is alkylated (or arylated) under standard conditions using a suitable alkylating agent such
as R -bromide (or the corresponding iodide) to afford AH. Demethylation of the methoxy
group with boron tribromide and triflation of the resulting intermediate AI gives the
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appropriately susbstituted indole derivative AJ. This intermediate can then be taken
through the various synthetic steps of Scheme 4 to produce compounds of Formula (I) 1k.
Scheme 8. Reagents and conditions: a) K OBu, DMF, -20 C; b) 10% Pd/C, Ethanol, 27
C; c) R -Br/ R -I, Cu(OAc) , CuBr, K CO , NaOH, DMF, 80 C
4 4 2 2 3
Compounds of Formula (I) may also be synthesized via intermediate AO whose
synthesis is described in Scheme 8. Intermediate AM can be prepared by a cyanomethyl
transfer reacton using an agent such as AL when treated with the substrate AK in the
presence of a strong base such as potassium tert-butoxide. Nitro arene AM can then be
subjected to a reduction using palladium on carbon and the resulting transient aniline
condenses internally to cyclise to form indole AN thereby losing an equivalent of
ammonia. Indole AN can then be suitably alkylated (or arylated) under standard conditions
to afford AO. Fluoro indole AO can be taken through steps similar to those described in
Scheme 7 for intermediate AH, followed by those in Scheme 4 eventually leading to the
synthesis of compounds of Formula (I) 1l.
Scheme 9. Reagents and conditions: a) Br(CH ) OTBDMS, K CO , ACN, 80 C; b)
2 2 2 3
DCM, Et N, RT; c) 3% HCl-MeOH, RT; d) CH CN, Et N, 80 C; e) NH , Dioxane, RT; f)
3 3 3 3
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TFA, anisole, 90 C; g) K PO dibasic, CuI, (1S,2S)-cyclohexane-1,2-diamine, 1,4-
dioxane, 110 C; h) R -Br, Cs CO , DMF, 25 C.
4 2 3
An alternative methodology is described in Scheme 9 towards the synthesis of
compounds of Formula (I). p-Methoxy benzylamine is alkylated with TBS-protected
bromoethanol in acetonitrile using a mild base such as potassium carbonate under heating
conditions to afford secondary amine AQ. Intermediate AQ was converted to the tertiary
amide AR upon treatment with an appropriately substituted acid chloride under standard
conditions. Desilylation of AR under acidic conditions followed by ring closure of the
resultant alcohol AS by heating in acetonitrile afforded PMB-substituted oxazepinone AT.
Conversion of the chloro group in AT to an amine was effected by treatment with
ammonia in dioxane to afford AU. Removal of the PMB group under TFA conditions in
the presence of a scavenger anisole at 90 C afforded the key intermediate AV.
Oxazepinone AV was then coupled to appropriately substituted 5-chloro indole AX under
copper catalysed conditions to afford compounds of Formula (I) 1m. Intermediate AX can
itself be prepared by alkylation of 5-chloro indole AW with a suitable bromide (or iodide)
under standard conditions.
Scheme 10. Reagents and conditions: a) di(cyclopenta-2,4-dienyl)zirconium(IV)
chloride, ethoxyethyne, DCM, RT, b) K PO dibasic, Pd(OAc) , dicyclohexyl(2',6'-
3 4 2 ,
dimethoxy-[1,1'-biphenyl]yl)phosphine, ACN, water, 80 C ; c), AcOH, 140 C.
Compounds of Formula (I) can also be synthesized via intermediates such as AW
as described in Scheme 10. Various substituted indoles represented by AW can be
synthesized starting from ethoxy vinyl boronate AZ which itself is prepared by treatment
of pinacolate borane AY with ethoxyethyne in the presence of a zirconium catalyst at
room temperature. Intermediate AZ is then treated with 2, 4-dichloro substituted aniline
under palladium catalysed conditions using a suitable ligand and base such as potassium
phosphate dibasic to afford aniline BA. Intermediate BA is then heated in acetic acid at
140 C to give indole AW. Intermediate AW can then be carried over through appropriate
synthetic steps described in Scheme 9 to finally afford compounds of Formula (I) 1n.
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EXPERIMENTALS
The following examples illustrate the invention. These examples are not intended
to limit the scope of the present invention, but rather to provide guidance to the skilled
artisan to prepare and use the compounds, compositions, and methods of the present
invention. While particular embodiments of the present invention are described, the
skilled artisan will appreciate that various changes and modifications can be made without
departing from the spirit and scope of the invention. Unless otherwise noted, reagents are
commercially available or are prepared according to procedures in the literature. The
symbols and conventions used in the descriptions of processes, schemes, and examples are
consistent with those used in the contemporary scientific literature, for example, the
Journal of the American Chemical Society or the Journal of Biological Chemistry.
In the Examples:
Chemical shifts are expressed in parts per million (ppm) units. Coupling constants
(J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are
designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double
triplet), m (multiplet), br (broad).
Flash column chromatography was performed on silica gel.
The naming programs used are ACDLABs 11.0 Namebatch, ACD IUPAC or
Chem Draw.
Abbreviations:
Ac acetyl
ACN acetonitrile
AcOH acetic acid
BBr boron tribromide
CH Cl dichloromethane
CH CN acetonitrile
Cs CO cesium carbonate
Cu(I)Br copper (I) bromide
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Cu(OAc) copper (II) acetate
DCE dichloroethane
DCM dichloromethane
DMF dimethylformamide
DMSO dimethylsulfoxide
Et N triethylamine
g grams
h hours
LiOH lithium hydroxide
K CO potassium carbonate
K OBu potassium tert-butoxide
KOH potassium hydroxide
m/z mass to charge ratio
MeOH methanol
MeSO H methyl sulfonic acid
mmol millimoles
Na CO sodium carbonate
NaH sodium hydride
NaN sodium azide
NaOH sodium hydroxide
NMR nuclear magnetic resonance
Pd palladium
Pd/C palladium on carbon
Pd(OAc) palladium (II) acetate
Py pyridine
rt room temperature
TBAF tetrabutyl ammonium fluoride
TBDMS (TBS) tert-butyl dimethylsilyl
Tf O triflic anhydride
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
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Example 1: 2-(6-(4-Aminooxo-5,6,7,8-tetrahydrooxepino(2,3-d)pyrimidinyl)
methyloxo-1,2,3,4-tetrahydronapthalenyl) acetic acid:
Reagents and conditions: a) NaN , MeSO H, CH Cl , RT, 8h; b) NaH, BrCH CO Et,
3 3 2 2 2 2
THF, RT, 5h; c) NH (CH ) OTBDMS, Pd(OAC) , Cs CO , X-PHOS, Toluene, 120 C,
2 2 2 2 2 3
24h; d) THF, Et N, RT, 16h; e) 3%HCl-MeOH, RT, 4h; f) CH CN, Et N, 80 C, 16h; g)
3 3 3
NH , Dioxane, RT, 16h; h) LiOH, Dioxane-H O, RT, 16h.
Procedures:
2-(6-(4-Aminooxo-5,6,7,8-tetrahydrooxepino(2,3-d)pyrimidinyl)methyl
oxo-1,2,3,4-tetrahydronapthalenyl) acetic acid:
6-Bromo-3,4-dihydroisoquinolin-1(2H)-one (1A):
NaN (6.2 g, 94.78 mmol) was added to a solution of 5-bromoindanone (10 g, 47.39
mmol) in 40 mL mixture of methane sulphonic acid and dichloromethane (1:1) in portion
wise at 0 C-5 C. The resulting mixture was stirred for 8 h at room temperature. The
reaction mixture was cooled to 0 C in ice bath, neutralized with 5 % aq. NaOH solution,
and the aqueous layer with extracted with ethyl acetate (2x100 mL). The combined
organic layer was washed with water and brine solution, dried over sodium sulphate,
filtered and concentrated under vacuum. The residue was purified by silica gel flash
column chromatography by eluting with 30 % ethyl acetate in hexane to afford title
compound (6.4 g, 60%) as solid. H NMR (400 MHz, CDCl ): 7.95 (d, J = 8.4 Hz, 1H),
7.5 (d, J = 8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J = 6.8 Hz, 2H), 3.0 (t, J = 6.4 Hz,
2H).
Ethyl 2-(6-bromooxo-3,4-dihydroquinolin-1(2H)-yl) acetate (1B):
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Sodium hydride (0.63 g, 26.25 mmol) was added portion wise to an ice cold solution of
product of Example 1A (3 g, 13.3 mmol) in THF (40 mL), and the mixture was stirred for
min. Ethyl bromo acetate (3.3 g, 19.9 mmol) was now added slowly, and the mixture
was stirred at room temperature for 5 h. The reaction was then cooled to 0 C, excess NaH
quenched with ice water, and the aqueous layer was extracted twice with ethyl acetate
(2x50 mL). The combined organic layers were washed with water followed by brine
solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue
was purified using flash column chromatography by eluting with 15% ethyl acetate in
hexane to afford title compound (2 g, 48%) as solid. H NMR (300 MHz, CDCl ): 7.4
(m, 2H), 6.6 (m, 1H), 4.6 (s, 2H), 4.2 (q, J = 6.9 Hz, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 1.2 (t,
J = 6.9 Hz, 3H).
Ethyl 2-(6-(2-(tert-butyldimethylsilyloxy)ethylamino)oxo-3,4-dihydroisoquinolin-
2(1H)-yl)acetate (1C):
A mixture of product of Example 1B (1.5 g, 4.8 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (1.0 g, 5.71 mmol), cesium carbonate (1.87 g, 5.73
mmol), palladium acetate (0.11 g, 0.47 mmol) and X-PHOS (0.23 g, 0.47 mmol) in
toluene (15 mL) under argon was refluxed at 120 C for 24 h. The reaction was cooled, the
mixture was diluted into ethyl acetate and washed with water (2x10 mL) and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
to obtain dark oil. The residue was purified by flash chromatography using 10% ethyl
acetate in hexane to afford title compound (0.95 g, 48%) as solid. H NMR (300 MHz,
CDCl ): 7.89 (d, J = 8.4 Hz, 1H), 6.51 (m, 1H), 6.32 (s, 1H), 4.4 (m, 1H), 4.29 (s, 2H),
4.2 (q, J = 6.9 Hz, 2H), 3.81 (t, J = 5.1 Hz, 2H), 3.59 (t, J = 6.3 Hz, 2H), 3.25 (q, J = 5.7
Hz, 2H), 2.94 (t, J = 6.9 Hz, 2H), 1.27 (t, J = 6.9 Hz, 3H), 0.9 (s, 9H), 0.06 (s, 6H); ESI-
MS m/z = 407 (M+H) .
Ethyl 2-(6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine
carboxamido)oxo-3,4-dihydroisoquinolin-2(1H)-yl)acetate (1D):
To a stirred, cooled (0 C) solution of product of Example 1C (0.95 g, 2.33 mmol) and
TEA (1.18 g, 11.67 mmol) in THF (15 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.74 g, 3.5 mmol) in THF (5 mL). After 16 h, the
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reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x10 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in hexane as eluent to afford title compound
(0.75 g, 55%) as an solid. H NMR (300 MHz, CDCl ): 8.6 (s, 1H), 7.95 (d, J = 8.4 Hz,
1H), 7.34 (dd, J = 1.2 Hz, J = 7.5 Hz, 1H), 7.29 (s, 1H), 4.34 (s, 2H), 4.21 (q, J = 6.9 Hz,
2H), 4.03 (t, J = 5.7 Hz, 2H), 3.93 (t, J = 4.8 Hz, 2H), 3.6 (t, J = 6.3 Hz, 2H), 2.94 (t, J =
7.2 Hz, 2H), 1.27 (t, J = 7.8 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H); ESI-MS m/z = 581
(M+H) .
Ethyl 2-(6-(4,6-dichloro-N-(2-hydroxyethyl)pyrimidinecarboxamido)oxo-3,4-
dihydroisoquinolin-2(1H)-yl)acetate (1E):
A solution of product of Example 1D (0.75 g, 1.29 mmol), in a methanolic solution of HCl
(3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at room temperature
for 4 h. Methanol was removed in vacuo. The residue was dissolved in ethyl acetate, and
washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The
organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford
title compound (0.45 g, 75%) as solid, which was carried on to the next step without
further purification. H NMR (400 MHz, CDCl ): 8.62 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H),
7.36 (m, 1H), 7.31 (s, 1H), 4.28 (s, 2H), 4.2 (q, J = 7.2 Hz, 2H), 4.1 (m, 2H), 3.96 (m, 2H),
3.62 (t, J = 6.4 Hz, 2H), 3.0 (t, J = 6.4 Hz, 2H), 2.1 (t, J = 5.6 Hz, 1H), 1.28 (t, J = 7.2 Hz,
3H); ESI-MS m/z = 467 (M+H) .
Ethyl 2-(6-(4-chlorooxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)oxo-
3,4-dihydroisoquinolin-2(1H)-yl)acetate (1F):
A slurry of product of Example 1E (0.4 g, 0.85 mmol) and TEA (0.43 g, 4.28 mmol) in
acetonitrile (10 mL) was stirred at 80 C for 16 h. The reaction was cooled, concentrated
in vacuo, and diluted with ethyl acetate. The mixture was washed with water and
saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.35 g, 95%) as a white solid. H NMR
(400 MHz, CDCl ): 8.78 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.29 (dd, J =
2.8 Hz, J = 8.8 Hz, 1H), 4.78 (t, J = 4.8 Hz, 2H), 4.34 (s, 2H), 4.23 (q, J =7.6 Hz, 2H),
4.1 (t, J = 4.8 Hz, 2H), 3.7 (t, J = 6.8 Hz, 2H), 3.1 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H); ESI-
MS m/z = 431 (M+H) .
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Ethyl 2-(6-(4-aminooxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)oxo-
3,4-dihydroisoquinolin-2(1H)-yl)acetate (1G):
A solution of product of Example 1F (0.3 g, 0.697 mmol) in 0.5M ammonia in p-dioxane
(10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated
in vacuo and diluted with ethyl acetate. The organic layer was washed with water,
saturated aqueous brine, dried over sodium sulfate, filtered and concentrated in vacuo to
afford title compound (0.22 g, 70%) as an white solid. H NMR (300 MHz, CDCl ): 8.3
(s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.2 (m, 2H), 4.71 (t, J = 4.2 Hz, 2H), 4.34 (s, 2H), 4.23
(q, J = 6.9 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 3.69 (m, 2H), 3.1 (t, J = 6.3 Hz, 2H), 1.29 (t,
J = 6.9 Hz, 3H); LC-MS: 91% pure, m/z = 412 (M+H) .
2-(6-(4-Aminooxo-5,6,7,8-tetrahydrooxepino(2,3-d)pyrimidinyl)methyl
oxo-1,2,3,4-tetrahydronapthalenyl) acetic acid (1):
A solution of product of Example 1G (0.18 g, 0.43 mmol) and lithium hydroxide (0.055 g,
1.309 mmol) in 5 mL of p-dioxane-water (4:1) mixture was stirred at room temperature for
16 h. After the solvent was removed in vacuo, the residue was dissolved in water and
washed with ethyl acetate. The aqueous layer was acidified using 2N aqueous solution of
HCl until pH 2 was attained. The resulting solution was cooled to 0 C, and resulting
solids were filtered off and dried in vacuo to afford title compound (0.12 g, 72%) as a
white solid. H NMR (300 MHz, DMSO-d ): 12.8 (bs, 1H), 8.45 (bs, 2H), 8.36 (s, 1H),
7.9 (d, J = 9.0 Hz, 1H), 7.4 (m, 2H), 4.7 (m, 2H), 4.21 (m, 2H), 4.13 (m, 2H), 3.64 (t, J =
6.3 Hz, 2H), 3.03 (t, J = 5.7 Hz, 2H); HPLC purity: 99%, m/z = 384 (M+H) .
Examples 2 - 9 were prepared by the method described above for Example 1 or routine
variations thereof starting from the requisite halo-quinolinone.
Ex Structure Analytical Data Mass/Purity
2 ESI-MS m/z
H NMR (300 MHz, DMSO-d ):
= 412
8.17 (s, 1H), 7.61 (bs, 2H), 7.29
(M+H) ; LC-
(m, 1H), 7.23 (dd, J = 2.1 Hz, J
MS purity:
= 8.1 Hz, 1H), 7.0 (d, J = 9.0 Hz,
97%.
1H), 4.67 (s, 2H), 4.6 (t, J = 4.2
Hz, 2H), 4.15 (q, J = 7.8 Hz, 2H),
3.96 (t, J = 4.2 Hz, 2H), 2.91 (t, J
= 6.9 Hz, 2H), 2.6 (t, J = 7.8 Hz,
2H), 1.21 (t, J = 7.5 Hz, 3H).
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3 ESI-MS m/z
H NMR (400 MHz, DMSO-d ):
= 384
13.0 (bs, 1H), 8.17 (s, 1H), 7.61
(M+H) ; LC-
(bs, 2H), 7.28 (s, 1H), 7.23 (d, J =
MS purity:
8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz,
99%.
1H), 4.6 (m, 4H), 3.96 (m, 2H),
2.9 (t, J = 6.8 Hz, 2H), 2.59 (t, J =
7.2 Hz, 2H).
4 ESI-MS m/z
H NMR (300 MHz, CDCl ):
= 412
8.3 (s, 1H), 8.18 (d, J = 7.8 Hz,
(M+H) ;LC-
1H), 7.2 (m, 2H), 4.71 (t, J = 4.2
MS purity:
Hz, 2H), 4.34 (s, 2H), 4.23 (q, J =
91%.
6.9 Hz, 2H), 4.04 (t, J = 4.8 Hz,
2H), 3.69 (m, 2H), 3.1 (t, J = 6.3
Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H).
H NMR (400 MHz, DMSO-d ): ESI-MS m/z
= 340
8.17 (s, 1H), 7.62 (bs, 2H), 7.25
(M+H) ;HPL
(m, 1H), 7.12 (m, 1H), 4.6 (t, J =
C purity:
4.0 Hz, 2H), 3.95 (t, J = 4.4 Hz,
96%.
2H), 3.27 (s, 3H), 2.88 (t, J = 7.2
Hz, 2H), 2.55 (t, J = 8.4 Hz, 2H).
6 H NMR (300 MHz, DMSO-d ): ESI-MS m/z
= 340
8.18 (s, 1H), 7.9 (d, J = 9.0 Hz,
(M+H) ; LC-
1H), 7.62 (bs, 2H), 7.35 (m, 2H),
MS purity:
4.6 (t, J = 4.2 Hz, 2H), 4.02 (t, J =
96.6 %.
4.8 Hz, 2H), 3.56 (t, J = 6.3 Hz,
2H), 2.99 (m, 5H).
7 H NMR (400 MHz, DMSO-d ): ESI-MS m/z
= 416
8.18 (s, 1H), 7.97 (d, J = 8.4
(M+H) ;
Hz, 1H), 7.62 (bs, 2H), 7.41-7.27
HPLC purity:
(m, 6H), 7.15 (s, 1H), 4.72 (s,
97%.
2H), 4.61 (t, J = 4.4 Hz, 2H), 4.02
(t, J = 4.4 Hz, 2H), 3.5 (t, J = 6.4
Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H).
8 ESI-MS m/z
H NMR (400 MHz, DMSO-d ):
= 368
8.18 (s, 1H), 7.9 (d, J = 9.2 Hz,
(M+H) ;
1H), 7.62 (bs, 2H), 7.35 (m, 2H),
HPLC purity:
4.6 (t, J = 4.0 Hz, 2H), 4.02 (t, J =
97%.
4.4 Hz, 2H), 3.55 (m, 2H), 3.44
(t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.4
Hz, 2H), 1.58 (m, 2H), 0.87 (t, J
= 7.6 Hz, 3H).
9 ESI-MS m/z
H NMR (400 MHz, DMSO-d ):
= 368
8.17 (s, 1H), 7.61 (bs, 2H), 7.21
(M+H) ;
(m, 3H), 4.6 (t, J = 4.4 Hz, 2H),
HPLC purity:
3.96 (t, J = 4.4 Hz, 2H), 3.8 (t, J =
99%.
7.6 Hz, 2H), 2.86 (t, J = 6.8 Hz,
2H), 2.55 (t, J = 7.6 Hz, 2H),
1.55 (m, 2H), 0.88 (t, J = 7.2 Hz,
3H).
PU64642PCT
Example 10: 6-(1-Allylbenzyloxo-2,3-dihydro-1H-indazolyl)amino-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
Example 11: 4-Amino(3-oxopropyl-2,3-dihydro-1H-indazolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) NH NH .H O, EtOH, 80 C, 16h; b) Allyl bromide, KOH,
2 2 2
NaOH, 100 C, 3h; c) Benzyl bromide, NaH, DMF, RT, 16h; d) Fe/NH Cl, EtOH-H O, 85
C, 3h; e) Br(CH ) OTBDMS, CH CN, K CO , 80 C, 24h; f) DCM, Et N, rt, 6h; g)
2 2 3 2 3 3
3%HCl-MeOH, RT, 1h; h) CH CN, Et N, 80 C, 16h; i) NH , Dioxane, RT, 2h; j) 10%
3 3 3
Pd/C, H , MeOH, RT, 2h.
Procedures:
-nitro-1H-indazol-3(2H)-one (11A):
Hydrazine hydrate (4 mL, 124 mmol) was added to a solution of 2-chloronitro benzoic
acid (5 g, 24.8 mmol) in absolute ethanol (30 mL), and the resulting mixture was refluxed
for 16 h. The reaction mixture was concentrated under reduced pressure. Residue was
trituated with methanol to give 6.5 g of crude intermediate. 2N aq. HCl (40 mL) was
added to the crude product, and the mixture was refluxed for 8 h. Reaction mixture was
cooled to 0 C, solids were collected via filtration, washed with cold water and dried under
vacuum. Residue was purified by flash chromatography using 1% methanol in chloroform
as eluent to afford title compound (2 g, 27%) as a solid. H NMR (400 MHz, DMSO-d ):
12.4 (bs, 1H), 11.3 (bs, 1H), 8.67 (s, 1H), 8.12 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.5 (d, J
= 9.0 Hz, 1H); ESI-MS m/z: 179 ( M+H) .
PU64642PCT
1-Allylnitro-1H-indazol-3(2H)-one (11B):
Allyl bromide (2.7 g, 22.34 mmol) was added to a mixture of product of Example 11A (4
g, 22.34 mmol) and 1N aqueous KOH solution (25 mL), and the mixture was refluxed for
2h. 15% NaOH (2 mL) and allyl bromide (0.54 mg, 0.04 mmol) were added, and again
the mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature
and neutralized using 3N aqueous HCl solution. Resulting solids were collected via
filtration, washed with water and dried under vacuum to afford title product (4.5 g, 92%)
as solid. H NMR (300 MHz, DMSO-d ): 11.5 (bs, 1H), 8.67 (s, 1H), 8.15 (dd, J = 2.1
Hz, J = 9.9 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 5.96 (m, 1H), 5.13 (m, 2H), 4.93 (d, J = 5.7
Hz, 2H).
1-Allylbenzylnitro-1H-indazol-3(2H)-one (11C):
Sodium hydride (0.55 g, 13.68 mmol) was added portion wise to an ice cold solution of
product of Example 11B (2.5 g, 11.4 mmol) in DMF (20 mL), and the mixture was stirred
for 30 min. Benzyl bromide (3.9 g, 22.8 mmol) was now added slowly, and the mixture
was stirred at room temperature for 16 h. The reaction was then cooled to 0 C and
quenched with ice water. The aqueous layer was extracted twice with ethyl acetate (2x50
mL). The combined organic layers were washed with water followed by brine solution,
dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified
by flash column chromatography using 5% ethyl acetate in hexane as eluent to afford title
compound (2.2 g, 62%) as solid. H NMR (400 MHz, DMSO-d ): 8.57 (d, J = 2.0 Hz,
1H), 8.23 (dd, J = 2.0 Hz, J = 9.2 Hz, 1H), 7.7 (d, J = 9.2 Hz, 1H), 7.5 (d, J = 5.7 Hz,
2H), 7.4 (m, 3H), 5.98 (m, 1H), 5.44 (s, 2H), 5.2 – 5.07 (m, 2H), 4.98 (d, J = 5.2 Hz, 2H).
1-Allylaminobenzyl-1H-indazol-3(2H)-one (11D):
Iron powder (0.77 g, 14.22 mmol) was added to a solution of product of Example 11C (2.2
g, 7.11 mmol) in 80 mL of ethanol-water mixture (4:1) followed by NH Cl (0.19 g, 3.55
mmol), and the mixture was refluxed for 4 h. The solvent was removed under reduced
pressure, and residue was partitioned between ethyl acetate and water. The organic layer
was dried over sodium sulphate, filtered and removed in vacuo. Residue was purified by
flash chromatography using 20% ethyl acetated in hexane as eluent to afford title
compound as solid (1.6 g, 66%). H NMR (300 MHz, DMSO-d ): 7.5 (m, 2H), 7.39 (m,
3H), 7.19 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 2.1 Hz, J = 9.3 Hz, 1H), 6.64 (m, 1H), 5.9
(m, 1H), 5.3 (s, 2H), 5.06 (m ,2H), 4.73 (m, 2H); ESI-MS m/z = 280 (M+H) .
PU64642PCT
1-Allylbenzyl(2-(tert-butyldimethylsilyloxy)ethylamino)-1H-indazol-3(2H)-one
(11E):
Potassium carbonate (2.6 g, 19.32 mmol) was added to a mixture of (2-bromoethoxy)(tert-
butyl)dimethylsilane (0.92 g, 3.87 mmol) and product of Example 11D (0.9 g, 3.22 mmol)
in acetonitrile (70 mL), and the mixture was refluxed for 24 h. Reaction mixture was
cooled to room temperature and partitioned between ethyl acetate and water. Separated
organic layer was washed with brine solution, dried over sodium sulfate, filtered and
concentrated under vacuum. Residue was purified by flash chromatography using 15%
ethyl acetate in hexane as eluent to afford title compound (0.35 g, 25%) as solid. H NMR
(400 MHz, DMSO-d ): 7.48 (m, 2H), 7.34 (m, 3H), 7.21 (d, J = 8.8 Hz, 1H), 6.84 (dd, J
= 2.0 Hz, J = 9.6 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 5.86 (m, 1H), 5.28 (s, 2H), 5.21 (t, J
= 6.0 Hz, 1H), 5.05 (m, 2H), 4.72 (d, J = 5.2 Hz, 2H), 3.69 (t, J = 6.4 Hz, 2H), 3.11 (q, J =
.6 Hz, 2H), 0.82 (s, 9H), 0.03 (s ,6H).
N-(1-Allylbenzyloxo-2,3-dihydro-1H-indazolyl)-N-(2-(tert-
butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidinecarboxamide (11F):
To a stirred, cooled (0 C) solution of product of 11E (0.55 g, 1.23 mmol) and TEA (0.5 g,
.0 mmol) in DCM (12 mL) was added drop wise a solution of 4,6-dichloropyrimidine
carbonyl chloride (0.26 g, 1.23 mmol) in DCM (5 mL). After 6 h, the reaction was
concentrated in vacuo, diluted with ethyl acetate, and washed with water (2x10 mL) and
saturated aqueous brine. The organic layer was dried over sodium sulphate, filtered and
concentrated in vacuo to afford oil. The residue was purified by flash chromatography
using 12% ethyl acetate in hexane as eluent to afford title compound (0.35 g, 46%) as an
oil. H NMR (400 MHz, DMSO-d ): 8.75 (s, 1H), 7.75 (s, 1H), 7.46 (m, 3H), 7.36 (m,
4H), 5.94 (m, 1H), 5.34 (s, 2H), 5.08 (m, 1H), 4.96 (m ,1H), 4.82 (m, 2H), 4.0 (m, 2H),
3.77 (t, J = 4.8 Hz, 2H), 0.8 (s, 9H), 0.01 (s, 6H); ESI-MS m/z = 611 (M+H) .
N-(1-Allylbenzyloxo-2,3-dihydro-1H-indazolyl)-4,6-dichloro-N-(2-
hydroxyethyl)pyrimidinecarboxamide (11G):
PU64642PCT
A solution of product of Example 11F (0.35 g, 0.57 mmol) in a methanolic solution of HCl
(3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at room temperature
for 1 h. Methanol was removed in vacuo. The residue was dissolved in ethyl acetate,
washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The
organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford
title compound (0.25 g, 88%) as an oil, which was carried on to the next step without
further purification. H NMR (400 MHz, DMSO-d ): 8.75 (s, 1H), 7.75 (s, 1H), 7.46 (m,
3H), 7.36 (m, 4H), 5.94 (m, 1H), 5.34 (s, 2H), 5.12 (m, 1H), 5.03 (m ,1H), 4.86 (m, 2H),
3.9 (t, J = 6.0 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H); ESI-MS m/z = 498 (M+H) .
6-(1-Allylbenzyloxo-2,3-dihydro-1H-indazolyl)chloro-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (11H):
A slurry of product of Example 11G (0.25 g, 0.5 mmol) and TEA (0.22 g, 2.2 mmol) in
acetonitrile (20 mL) was stirred at 80 C for 16 h. The reaction was cooled, concentrated
in vacuo, and diluted with ethyl acetate. The organic layer was washed with water and
saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.22 g, 94%) as a white solid. H NMR
(300 MHz, DMSO-d ): 8.8 (s, 1H), 7.68 (s, 1H), 7.55 (m, 3H), 7.38 (m, 4H), 5.94 (m,
1H), 5.4 (s, 2H), 5.17 (m, 1H), 5.05 (m, 1H), 4.93 (d, J = 4.8 Hz, 2H), 4.76 (t, J = 4.0 Hz,
2H), 4.15 (t, J = 4.8 Hz, 2H); ESI-MS m/z = 462 (M+H) .
6-(1-Allylbenzyloxo-2,3-dihydro-1H-indazolyl)amino-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (10):
A solution of product of Example 11H (0.22 g, 0.46 mmol) in 0.5M ammonia in p-dioxane
(40 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated in
vacuo and diluted with ethyl acetate. The organic layer was washed with water and
saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.17 g, 82%) as an white solid. H NMR
(400 MHz, DMSO-d ): 8.16 (s, 1H), 7.62 (s, 1H), 7.55 (m, 3H), 7.38 (m, 4H), 7.19 (bs,
2H), 5.97 (m, 1H), 5.39 (s, 2H), 5.16 (m, 1H), 5.09 (m, 1H), 4.91 (d, J = 5.6 Hz, 2H), 4.65
(t, J = 4.4 Hz, 2H), 3.98 (t, J = 4.4 Hz, 2H); LC-MS purity: 94%, m/z = 443 (M+H) .
4-Amino(3-oxopropyl-2,3-dihydro-1H-indazolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (11):
PU64642PCT
Excess 10% Pd/C (0.15 g) was added to a solution of product of Example 10 (0.15 g,
0.226 mmol) in 120 mL of methanol, and the mixture was stirred at room temperature for
2 h. The reaction mixture was filtered over celite bed, filtrate was concentrated under
reduced pressure, and the residue partitioned between ethyl acetate and water. The organic
layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude
product was triturated with ethyl acetate to afford title compound (0.09 g, 75%) as brown
solid. H NMR (300 MHz, DMSO-d ): 10.5 (bs, 1H), 8.17 (s, 1H), 7.63 (bs, 2H), 7.56
(m, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.3 (dd, J = 1.2 Hz, J = 9.0 Hz, 1H), 4.63 (t, J = 4.2
Hz, 2H), 4.1 (t, J = 7.2 Hz, 2H), 3.98 (t, J = 4.2 Hz, 2H), 1.76 (m, 2H), 0.81 (t, J = 7.2 Hz,
3H); HPLC purity: 95%, ESI-MS m/z = 355 (M+H) .
Example 12: 4-Amino(1-propyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) n-propyl bromide, Cs CO , DMF, 100 C, 2h; b)
NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 120 C, 2.5h; c) DCM,
2 2 2 2 2 3
Et N, RT, 1h; d) 3%HCl-MeOH, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH , Dioxane,
3 3 3 3
RT, 2h.
Procedures:
4-Amino(1-propyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one:
-bromopropyl-1H-indole (12A):
PU64642PCT
1-Bromopropane (1.25 g, 10.2 mmol) was added to a solution of 5-bromo indole (2 g, 10.2
mmol) in DMF (30 mL) followed by cesium carbonate (6.63 g, 20.4 mmol), and the
mixture was stirred at 100 C for 2 h. Insoluble solids were filtered off, and filtrate was
concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was
separated, washed with brine, dried over sodium sulphate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography using 5% ethyl acetate in
hexane as eluent to afford title compound (1.8 g, 74%) as oil. H NMR (400 MHz,
CDCl ): 7.74 (d, J = 1.6 Hz, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.09 (d, J = 3.2 Hz, 1H),
6.41 (d, J = 2.4 Hz, 1H), 4.05 (t, J = 7.2 Hz, 2H), 1.87 (m, 2H), 0.9 (t, J = 7.2 Hz, 3H);
ESI-MS m/z = 238 (M+H) .
N-(2-(tert-Butyldimethylsilyloxy)ethyl)propyl-1H-indolamine (12B):
A mixture of product of Example 12A (2 g, 8.4 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (1.5 g, 8.4 mmol), cesium carbonate (4.09 g, 12.6
mmol), palladium acetate (0.18 g, 0.84 mmol) and X-PHOS (0.4 g, 0.84 mmol) in Toluene
(25 mL) under Argon was refluxed at 120 C for 2.5 h. The reaction was cooled, diluted
with ethyl acetate, and washed with water (2x10 mL) and saturated aqueous brine. The
organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark oil.
The residue was purified by flash chromatography using 10% ethyl acetate in hexane to
afford title compound (1.5 g, 53%) as oil. H NMR (400 MHz, CDCl ): 7.16 (d, J = 8.8
Hz, 1H), 7.0 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.08 Hz, 1H), 6.68-6.65 (dd, J = 2.0 Hz, J
= 8.4 Hz, 1H), 6.30 (d, J = 3.2 Hz, 1H), 4.01 (t, J = 7.2 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H),
3.25 (t, J = 5.2 Hz, 2H), 1.86-1.81 (m, 2H), 0.93 (t, J = 5.6 Hz, 3H), 0.91 (s, 9H), 0.07(s,
6H); ESI-MS m/z = 333 (M+H) .
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-propyl-1H-indol
yl)pyrimidinecarboxamide (12C):
To a stirred, cooled (0 C) solution of product of Example 12B (1.5 g, 4.51 mmol) and
TEA (1.82 g, 18 mmol) in DCM (30 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.95 g, 4.5 mmol) in DCM (5 mL). After 1 h, the
reaction was concentrated in vacuo, diluted into ethyl acetate, and washed with water
(2x10 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in hexane as eluent to afford title compound (1 g,
43%) as a syrup. H NMR (400 MHz, CDCl ): 8.46 (s, 1H), 7.66 (m, 1H), 7.21-7.13 (m,
PU64642PCT
2H), 7.09 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 4.01 (t, J
= 7.2 Hz, 2H), 3.91 (t, J = 5.6 Hz, 2H), 1.84-1.78 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.88
(s, 9H), 0.06 (s, 6H); ESI-MS m/z = 507 (M+H) .
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-propyl-1H-indolyl)pyrimidine
carboxamide (12D):
A solution of product of Example 12C (1 g, 1.97 mmol), in 15 mL of methanolic solution
of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at room
temperature for 1 h. Methanol was removed in vacuo, the residue dissolved in ethyl
acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous
brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo
to afford title compound (0.6 g, 77%) as solid, which was carried on to the next step
without further purification. H NMR (400 MHz, DMSO-d ): 8.49 (s, 1H), 7.65 (s, 1H),
7.17 (m, 2H), 7.11 (d, J = 2.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.15 (t, J = 5.2 Hz, 2H),
4.02 (t, J = 6.8 Hz, 2H), 3.93 (q, J = 4.8 Hz, 2H), 1.84-1.77 (m, 2H), 0.90 (t, J = 7.6 Hz,
3H); ESI-MS m/z = 393 (M+H) .
4-Chloro(1-propyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one (12E):
A slurry of product of Example 12D (0.6 g, 1.68 mmol) and TEA (1.36 g, 13.44 mmol) in
acetonitrile (25 mL) was stirred at 80 C for 16 h. The reaction was cooled, concentrated
in vacuo, diluted with ethyl acetate and washed with water and saturated aqueous brine.
The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to
afford title compound (0.3 g, 55%) as a white solid. H NMR (300MHz, DMSO-d ):
8.82 (s, 1H), 7.57 (m, 2H), 7.46 (d, J = 3.0 Hz, 1H), 7.13 (dd, J = 2.1 Hz, J = 8.7 Hz,
1H), 6.48 (d, J = 3.0 Hz, 1H), 4.75 (t, J = 4.5 Hz, 2H), 4.16 (m, 4H), 1.82 (m, 2H), 0.84 (t,
J = 7.5 Hz, 3H); ESI-MS m/z = 357 (M+H) .
4-Amino(1-propyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one (12):
PU64642PCT
A solution of product of Example 12E (0.3 g, .84 mmol) in 0.5M ammonia in p-dioxane
(15 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in
vacuo, diluted with ethyl acetate, and washed with water and saturated aqueous brine. The
organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford
title compound (0.2 g, 71%) as an white solid. H NMR (400MHz, DMSO-d ): 8.17 (s,
1H), 7.61 (bs, 2H), 7.52 (s, 1H), 7.5 (m, 1H), 7.42 (d, J = 3.2 Hz, 1H), 7.09 (dd, J = 2.0
Hz, J = 8.8 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 4.63 (t, J = 3.6 Hz, 2H), 4.15 (t, J = 6.8 Hz,
2H), 3.98 (t, J = 4.4 Hz, 2H), 1.76 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); ESI-MS m/z = 338
(M+H) ; HPLC purity: 92.5%.
Examples 13 – 31 were prepared by the method described above for Example 12 or
routine variations thereof using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
13 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
339 (M+H) ;
8.18 (s, 1H), 8.08 (s, 1H),
HPLC purity:
7.74 (m, 2H), 7.6 (bs, 2H), 7.38
99%.
(d, J = 1.8 Hz, 1H), 4.65 (t, J =
4.2 Hz, 2H), 4.39 (t, J = 6.9 Hz,
2H), 4.01 (t, J = 4.5 Hz, 2H),
1.9-1.83 (m, 2H), 0.82 (t, J =
7.5 Hz, 3H).
14 ESI-MS m/z =
H NMR (300MHz, DMSO-d ):
313 (M+H) .
8.18 (s, 1H), 8.05 (d, J = 8.7
HPLC purity:
Hz, 1H), 7.9 (m, 1H), 7.84 (d, J
94%,
= 5.7 Hz, 1H), 7.64 (bs, 2H),
7.47 (d, J = 5.4 Hz, 1H), 7.38
(dd, J = 2.1 Hz, J = 8.7 Hz,
1H), 4.65 (t, J = 4.2 Hz, 2H),
4.04 (t, J = 4.5 Hz, 2H).
ESI-MS m/z =
H NMR (400MHz, DMSO-d ):
397 (M+H) ;
8.17 (s, 1H), 7.62 (bs, 2H),
LCMS purity:
7.24 (m, 2H), 7.02 (d, J = 7.6
98%.
Hz, 1H), 4.63 (m, 2H), 3.97 (m,
2H), 3.83-3.56 (q, J = 7.2 Hz,
4H), 1.68-1.65 (m, 4H), 0.86 (t,
J = 6.8 Hz, 6H).
16 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
339 (M+H) ;
8.4 (s, 1H), 8.17 (s, 1H), 7.67
HPLC purity:
(d, J = 2.1 Hz, 1H), 7.63 (d, J =
96%.
9.0 Hz, 1H), 7.19 (dd, J = 2.1
Hz, J = 9.0 Hz, 1H), 7.15 (bs,
PU64642PCT
2H), 4.64 (t, J = 4.2 Hz, 2H),
4.39 (t, J = 7.2 Hz, 2H), 4.0 (t, J
= 4.2 Hz, 2H), 2.0 (m, 2H), 0.83
(t, J = 7.5 Hz, 3H).
17 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
314 (M+H) ;
9.43 (s, 1H), 8.23 (d, J = 1.5
HPLC purity:
Hz, 1H), 8.19 (s, 1H), 8.12 (d, J
96%.
= 8.7 Hz, 1H), 7.9 (bs, 2H),
7.57 (dd, J = 1.8 Hz, J = 8.7
Hz, 1H), 4.66 (t, J = 4.5 Hz,
2H), 4.07 (t, J = 4.5 Hz, 2H).
18 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
368 (M+H) ;
8.16 (s, 1H), 7.66 (bs, 2H),
HPLC purity:
7.63 (m, 2H), 7.26 (d, J = 8.1
93%.
Hz, 1H), 4.64 (t, J = 4.5 Hz,
2H), 3.97 (t, J = 4.5 Hz, 2H),
3.65 (t, J = 7.2 Hz, 2H), 1.64
(m, 2H), 0.92 (t, J = 7.2 Hz,
2H).
19 H NMR (400MHz, DMSO-d ): ESI-MS m/z:
297 (M+H) ;
8.18 (s, 1H), 8.05 (d, J = 2.0
HPLC purity:
Hz, 1H), 7.66-7.63 (m, 3H),
97%.
7.30 (dd, J = 2.0 Hz, J =
8.4Hz, 1H), 7.1 (bs, 2H), 4.65
(t, J = 4.4 Hz, 2H), 4.01 (t, J =
4.8 Hz, 2H).
H NMR (300MHz, DMSO-d ): ESI-MS m/z =
352 (M+H) ;
HPLC purity:
7.04 (d, J = 8.7 Hz, 1H), 7.0
99.2%.
(dd, J = 2.4 Hz, J = 8.7 Hz,
1H), 6.89 (d, J = 2.7 Hz, 1H),
4.57 (t, J = 4.8 Hz, 2H), 3.88 (t,
J = 4.5 Hz, 2H), 3.20 (t, J = 5.4
Hz, 2H), 2.67 (t, J = 6.3 Hz,
2H), 2.28 (m, 1H), 1.84 (m,
2H), 0.80 (m, 2H), 0.53 (m,
2H).
21 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
354 (M+H) ;
HPLC purity:
7.24 (m, 3H), 4.60 (m, 2H),
95%.
4.12 (s, 2H), 3.97 (m, 2H),
3.31-3.25 (m, 2H), 3.0 (m, 2H),
2.82 (m, 2H), 1.73 (m, 2H),
0.84 (t, J = 6.8 Hz, 3H).
PU64642PCT
22 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
376 (M+H) ;
HPLC purity:
6.94 (dd, J = 2.4 Hz, J = 8.4
Hz, 1H), 6.89 (d, J = 2.0 Hz, 98.24%.
1H), 6.71 (d, J = 8.0 Hz, 1H),
6.21 (tt, J = 4.0 Hz, J = 55.2
Hz, 1H), 4.56 (t, J = 4.8 Hz,
2H), 3.87 (t, J = 4.4 Hz, 2H),
3.70 (dt, J = 3.6 Hz, J = 15.6
Hz, 2H), 3.37 (m, 2H), 2.70 (t, J
= 6.0 Hz, 2H), 1.85 (m, 2H).
23 H NMR (400MHz, DMSO- ESI-MS m/z =
354 (M+H) ;
D O):
HPLC purity:
J = 1.2 Hz, 1H), 7.52 (d, J =
96.4%.
8.8 Hz, 1H), 7.28 (dd, J = 1.6
Hz, J = 8.8 Hz, 1H), 4.76 (m,
1H), 4.64 (t, J = 4.8 Hz, 2H),
3.99 (t, J = 4.4 Hz, 2H), 1.38 (d,
J = 6.8 Hz, 6H).
24 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
370 (M+H) ;
10.65 (bs, 1H), 8.17 (s, 1H),
HPLC purity:
7.64 (bs, 2H), 7.55 (s, 1H), 7.49
(d, J = 9.3 Hz, 1H), 7.29 (m, 95.2%.
1H), 4.63 (m, 2H), 4.30 (m,
2H), 3.99 (m, 2H), 3.66 (m,
2H), 3.19 (s, 3H).
H NMR (300MHz, DMSO-d ): ESI-MS m/z =
377 (M+H) ;
10.85 (bs, 1H), 8.17 (s, 1H),
HPLC purity:
7.64 (bs, 2H), 7.6-7.56 (m, 2H),
7.37 (dd, J = 1.8 Hz, J = 8.7 97%.
Hz, 1H), 6.50 (tt, J = 3.3 Hz, J
= 54.9 Hz, 1H), 4.74-4.58 (m,
4H), 4.0 (t, J = 4.5 Hz, 2H).
26 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
353 (M+H) ,
HPLC purity:
7.63 (bs, 2H), 7.58 (d, J = 1.5
93%.
Hz, 1H), 7.46 (d, J = 9.0 Hz,
1H), 7.32 (dd, J = 2.1 Hz, J =
9.0 Hz, 1H), 4.61 (t, J = 3.9 Hz,
2H), 3.96 (t, J = 4.2 Hz, 2H),
3.38 (m, 1H), 0.99 (d, J = 5.4
Hz, 4H).
27 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
δ 8.29 (s, 1H), 8.18 (s, 1H), 7.7- 337 (M+H) ;
7.6 (m, 4H), 7.23 (dd, J = 1.6 LCMS purity:
Hz, J = 8.4 Hz, 1H), 4.66 (t, J 95%.
= 4.4 Hz, 2H), 4.20 (t, J = 6.8
Hz, 2H), 4.02 (t, J = 4.4 Hz,
PU64642PCT
2H), 1.81 (m, 2H), 0.86 (t, J =
7.2 Hz, 3H).
28 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
δ 8.28 (s, 1H), 8.18 (s, 1H), 7.7- 339 (M+H) ;
7.6 (m, 4H), 7.18 (dd, J = 1.6 LCMS purity:
Hz, J = 8.4 Hz, 1H), 4.66 (t, J 99%.
= 4.4 Hz, 2H), 4.2 (t, J = 6.8
Hz, 2H), 4.02 (t, J = 4.4 Hz,
2H), 1.81 (m, 2H), 0.85 (t, J =
7.2 Hz, 3H).
29 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
340 (M+H) ;
8.18 (s, 1H), 7.97-7.93 (m,
HPLC Purity:
2H), 7.67 (bs, 2H), 7.44 (dd, J
= 1.8 Hz, J = 9.3 Hz, 1H), 4.72 98%.
(t, J = 6.9 Hz, 2H), 4.66 (t, J =
4.2 Hz, 2H), 4.06 (t, J = 4.5 Hz,
2H), 2.04 (m, 2H), 0.86 (t, J =
7.5 Hz, 3H).
H NMR (400MHz, DMSO-d ): ESI-MS m/z =
340 (M+H) ;
8.19 (s, 1H), 8.06 (d, J = 8.8
HPLC Purity:
Hz, 1H), 7.99 (d, J = 1.6 Hz,
97%.
1H), 7.66 (bs, 2H), 7.43 (dd, J
= 1.6 Hz, J = 8.8 Hz, 1H), 4.67
(m, 4H), 4.09 (t, J = 4.4 Hz,
2H), 1.95 (m, 2H), 0.88 (t, J =
7.6 Hz, 3H).
31 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
328 (M+H) ;
J = 8.8
HPLC purity:
Hz, 1H), 7.94 (d, J = 2.0 Hz,
92%.
1H), 7.65 (bs, 2H), 7.42 (dd, J
= 1.2 Hz, J = 8.0 Hz, 1H), 4.66
(t, J = 4.4 Hz, 2H), 4.05 (t, J =
4.4 Hz, 2H), 2.82 (s, 3H).
Example 33: 4-Amino(1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
PU64642PCT
Reagents and conditions: a) 1,1-Difluoroiodoethane, Cs CO , DMF, 70 C, 1h; b)
NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 110 C, 3h; c) DCM, Et N,
2 2 2 2 2 3 3
RT, 1h; d) 3% HCl-MeOH, RT, 1h; e) CH CN, Et N, 70 C, 4h; f) NH , Dioxane, RT, 2h.
3 3 3
Procedures:
4-Amino(1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
-Bromo(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (33A):
1,1-Difluoroiodoethane (2.19 g, 11.42 mmol) was added to a solution of 5-bromo,7-
azaindole (1.5 g, 7.61 mmol) in DMF (30 mL) followed by cesium carbonate (4.96 g, 15.2
mmol), and the mixture was stirred at 70 C for 1 h. Insoluble solids were filtered off, and
filtrate was concentrated. Residue was partitioned between ethyl acetate and water.
Organic layer was separated, washed with brine, dried over Na SO and filtered. The
filtrate was concentrated in reduced pressure and purified by flash chromatography using
% ethyl acetate in hexane to afford title compound (1.3 g, 65%) as oil. H NMR (300
MHz, CDCl ): 8.33 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.1 Hz,
1H), 6.46 (d, J = 3.6 Hz, 1H), 6.28-5.88 (tt, J = 3.9 Hz, J = 55.8 Hz, 1H), 4.60 (dt, J =
1 2 1
4.2 Hz, J = 14.1 Hz, 2H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)(2,2-difluoroethyl)-1H-pyrrolo[2,3-
b]pyridinamine (33B):
A mixture of product of Example 33A (1.3 g, 8.4 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (1.0 g, 5.98 mmol), cesium carbonate (3.24 g, 9.96
mmol), palladium acetate (0.11 g, 0.49 mmol) and X-PHOS (0.23 g, 0.49 mmol) in
toluene (25 mL) under Argon was refluxed at 110 C for 3 h. The reaction was cooled,
diluted with ethyl acetate, and washed with water (2x15 mL) and saturated aqueous brine.
PU64642PCT
The organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark
oil. The residue was purified by flash chromatography using 10% ethyl acetate in hexane
to afford title compound (0.61 g, 34.5%) as oil. H NMR (400 MHz, CDCl ): 7.87 (d, J =
2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 3.2 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H),
6.23-5.92 (tt, J = 4.4 Hz, J = 55.6 Hz, 1H), 4.54 (dt, J = 4.0 Hz, J = 14.0 Hz, 2H), 3.94
1 2 1 2
(bs, 1H), 3.85 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 4.8 Hz, 1H), 0.91 (s, 9H), 0.08 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(2,2-difluoroethyl)-1H-
pyrrolo[2,3-b]pyridinyl)pyrimidinecarboxamide (33C):
To a stirred, cooled (0 C) solution of product of Example 33B (0.61 g, 1.71 mmol) and
TEA (0.52 g, 5.15 mmol) in DCM (25 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.43 g, 2.05 mmol) in DCM (5 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x10 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in hexane as eluent to afford title compound
(0.67 g, 73%) as a syrup. H NMR (300MHz, CDCl ): J = 2.4
Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 3.9 Hz, 1H), 6.24-
.84 (tt, J = 4.2 Hz, J = 55.5 Hz, 1H), 4.55 (dt, J = 4.2 Hz, J = 14.1 Hz, 2H), 4.06 (t, J
1 2 1 2
= 5.1 Hz, 2H), 3.94 (t, J = 4.8 Hz, 2H), 0.86 (s, 9H), 0.058 (s, 6H).
4,6-Dichloro-N-(1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl)-N-(2-
hydroxyethyl)pyrimidinecarboxamide (33D):
A solution of product of Example 33C (0.67 g, 1.26 mmol), in 20 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 1 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous brine. The organic layer was dried over Na SO and filtered. The
filtrate was concentrated in reduced pressure to afford title compound (0.4 g, 76%) as
solid, which was carried to the next step without further purification. H NMR (300MHz,
CDCl ): 8.55 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 3.6
Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 6.25-5.85 (tt, J = 4.2 Hz, J = 55.5 Hz, 1H), 4.56 (dt, J
1 2 1
= 4.2 Hz, J = 14.1 Hz, 2H), 4.14 (t, J = 4.8 Hz, 2H), 3.96 (t, J = 4.8 Hz, 2H).
PU64642PCT
4-Chloro(1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (33E):
A slurry of product of Example 33D (0.4 g, 0.96 mmol) and TEA (0.19 g, 1.92 mmol) in
acetonitrile (20 mL) was stirred at 70 C for 4 h. The reaction was cooled, concentrated in
vacuo, diluted with ethyl acetate, and washed with water and saturated aqueous brine. The
organic layer was dried over Na SO and filtered. The filtrate was concentrated in reduced
pressure to afford title compound (0.3 g, 82%) as a white solid. H NMR (300MHz,
CDCl ): J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.35 (d, J =
3.9 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 6.31-5.91 (tt, J = 3.9 Hz, J = 56.1 Hz, 1H), 4.81 ( t,
J = 4.5 Hz, 2H), 4.66 (dt, J = 3.9 Hz, J = 13.8 Hz, 2H), 4.10 (t, J = 4.8 Hz, 2H).
4-Amino(1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (33):
A solution of product of Example 33E (0.3 g, 0.79 mmol) in 0.5M ammonia in p-dioxane
(15 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in
vacuo, diluted with ethyl acetate, and washed with water and saturated aqueous brine. The
organic layer was dried over Na SO and filtered. The filtrate was concentrated in reduced
pressure to afford title compound (0.25 g, 86%) as an off-white solid. H NMR (300MHz,
CDCl ): 8.30 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.20 (bs, 1H), 7.84 (d, J = 2.4 Hz, 1H),
7.33 (d, J = 3.3 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 6.31-5.91 (tt, J = 4.5 Hz , J = 55.8 Hz,
1H), 5.67 (bs, 1H), 4.75 (t, J = 4.5 Hz, 2H), 4.65 (dt, J = 3.9 Hz, J = 13.8 Hz, 2H), 4.07
(t, J = 4.5 Hz, 2H) ; ESI-MS m/z = 361 (M+H) . HPLC purity: 98.14%.
Example 34: 4-Amino(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
PU64642PCT
Reagents and conditions: a) Cyclopropyl boronic acid, 2,2‟-bipyridine, Na CO ,
Cu(OAc) , DCE, 110 C, 8h; b) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS,
2 2 2 2 2 2 3
Toluene, 120 C, 2.5h; c) DCM, Et N, RT, 1h; d) TBAF, THF, RT, 1h; e) CH CN, Et N,
3 3 3
80 C, 16h; f) NH , Dioxane, RT, 2h.
Procedures:
4-Amino(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
-Bromocyclopropyl-1H-pyrrolo[2,3-b]pyridine (34A):
Cyclopropylboronic acid (0.872 g, 10.15 mmol) was added to a solution of 5-bromo-1H-
pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol), Na CO (1.076 g, 10.15 mmol), copper(II)acetate
(0.922 g, 5.08 mmol) and 2,2‟-bipyridine (0.793 g, 5.08 mmol) in dichloroethane (20 mL),
and the mixture was stirred at 110 C for 8h. The reaction mixture was concentrated, and
then diluted with ethyl acetate and water. Organic layer was separated, washed with brine,
dried over Na SO and filtered. The filtrate was concentrated in reduced pressure and
purified by flash chromatography using 10% ethyl acetate in pet ether to afford title
compound (0.38 g, 31.3%) as oil. H NMR (300 MHz, CDCl ): 8.38 (d, J = 2.1 Hz, 1H),
7.99 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 3.3 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 3.5 (m, 1H),
1.15 (m, 2H), 1.03 (m, 2H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)cyclopropyl-1H-pyrrolo[2,3-b]pyridin
amine (34B):
A mixture of product of Example 34A (0.38 mg, 1.603 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.337 g, 1.923 mmol), cesium carbonate (0.783 g,
PU64642PCT
2404 mmol), palladium acetate (0.036 g, 0.160 mmol) and X-PHOS (0.076 g, 0.160
mmol) in Toluene (15 mL) under Argon was refluxed at 120 C for 12 h. The reaction was
cooled, diluted with ethyl acetate, and washed with water (2x5 mL) and saturated aqueous
brine. The organic layer was dried over Na SO and filtered. The filtrate was concentrated
in reduced pressure and purified by flash chromatography using 10% ethyl acetate in
hexane to afford title compound (0.25 g, 40.5%) as oil. H NMR (400 MHz, CDCl ):
7.94 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.22 (d, J = 3.2
Hz, 1H), 3.84 (t, J = 5.2 Hz, 2H), 3.46 (m, 1H), 3.24 (t, J = 5.2 Hz, 2H), 1.1 (m, 2H), 1.01
(m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-cyclopropyl-1H-
pyrrolo[2,3-b]pyridinyl)pyrimidinecarboxamide (34C):
To a stirred, cooled (0 C) solution of product of Example 34B (0.25 g, 0.754 mmol) and
TEA (0.315 mL, 2.262 mmol) in DCM (10 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.191 g, 0.905 mmol) in DCM (5 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x5 mL) and saturated aqueous brine. The organic layer was dried over sodium sulphate,
filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in pet ether to afford title compound (0.25 g,
60.2%) as a syrup. H NMR (400 MHz, CDCl ): 8.53 (s, 1H), 8.37 (s, 1H), 8.0 (s, 1H),
7.22 (d, J = 3.6 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 4.05 (t, J = 5.6 Hz, 2H), 3.92 (t, J = 5.2
Hz, 2H), 3.45 (m, 1H), 1.13 (m, 2H), 1.0 (m, 2H), 0.86 (s, 9H), 0.05 (s, 6H).
4,6-Dichloro-N-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl)-N-(2-
hydroxyethyl)pyrimidinecarboxamide (34D):
TBAF (0.387 g, 1.481 mmol) was added to a solution of Example 34C (0.25 g, 0.494
mmol) in THF (10 mL), and the mixture was stirred at room temperature for 1 h. THF was
removed in vacuo, the residue dissolved in ethyl acetate, and washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous brine. The organic layer was
dried over sodium sulfate, filtered and concentrated in vacuo to afford title compound
(0.19 g, 91%) as solid, which was carried on to the next step without further purification.
H NMR (400 MHz, CDCl ): J = 3.2
Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 4.15 (m, 2H), 3.97 (q, J = 4.8 Hz, 2H), 3.45 (m, 1H),
2.11 (t, J = 5.2 Hz, 1H), 1.12 (m, 2H), 1.01 (m, 2H).
PU64642PCT
4-Chloro(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (34E):
A slurry of product of Example 34D (0.19 g, 0.484 mmol) and TEA (0.203 mL, 1.453
mmol) in acetonitrile (15 mL) was stirred at 80 C for 6 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.17 g, 98%) as a white solid. H NMR (300MHz,
CDCl ): J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.30 (d, J =
3.9 Hz, 1H), 6.45 (d, J = 3.3 Hz, 1H), 4.8 (t, J = 4.8 Hz, 2H), 4.09 (t, J = 4.5 Hz, 2H), 3.56
(m, 1H), 1.16 (m, 2H), 1.08 (m, 2H).
4-Amino(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (34):
A solution of product of Example 34E (0.17 g, 0.478 mmol) in 0.5M ammonia in p-
dioxane (15 mL) was stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.1 g, 60.4%) as an white solid. H NMR (300MHz,
DMSO-d ): J = 2.1 Hz, 1H), 8.18 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.65 (bs,
2H), 7.54 (d, J = 3.6 Hz, 1H), 6.46 (d, J = 3.3 Hz, 1H), 4.67 (t, J = 3.6 Hz, 2H), 4.02 (t, J
= 4.2 Hz, 2H), 3.62 (m, 1H), 1.1-1.0 (m, 4H); ESI-MS m/z = 337 (M+H) ; HPLC purity:
97%.
Examples 35 – 62 were prepared by the procedures analogous to those described in
Example 33 or Example 34 using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
H NMR (400MHz, DMSO-d ): ESI-MS m/z =
350 (M+H) ;
8.17 (s, 1H), 7.61 (bs, 2H),
HPLC purity:
7.55 (d, J = 8.0 Hz, 1H), 7.49
98.7%.
(m, 2H), 7.08 (dd, J = 2.0 Hz, J
= 8.4 Hz, 2H), 6.52 (d, J = 3.2
Hz, 1H), 4.64 (t, J = 4.4 Hz,
2H), 4.06 (d, J = 6.8 Hz, 2H),
3.98 (t, J = 4.8 Hz, 2H), 1.25 (m,
PU64642PCT
1H), 0.52 (m, 2H), 0.38 (m, 2H).
36 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
366 (M-H)-;
HPLC purity:
7.61 (bs, 2H), 7.54 (d, J = 8.8
97.7%.
Hz, 1H), 7.49 (d, J = 1.6 Hz,
1H), 7.41 (d, J = 3.6 Hz, 1H),
7.09 (dd, J = 1.6 Hz, J = 10.8
Hz, 1H), 6.44 (d, J = 3.6 Hz,
1H), 4.63 (t, J = 4.4 Hz, 2H),
4.41 (t, J = 6.8 Hz, 2H), 3.98 (t,
J = 4.4 Hz, 2H), 2.75 (t, J = 6.4
Hz, 2H)
37 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
392 (M+H) ;
HPLC purity:
7.52 (m, 2H), 7.38 (d, J = 3.3
97%.
Hz, 1H), 7.06 (dd, J = 2.1 Hz, J
= 10.8 Hz, 1H), 6.44 (d, J = 2.7
Hz, 1H), 4.63 (t, J = 3.9 Hz, 2H),
4.04 (m, 4H), 1.79 (m, 1H), 1.7-
1.45 (m, 5H), 1.2-0.9 (m, 5H).
38 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
366 (M+H) ;
HPLC purity:
7.57 (d, J = 8.8 Hz, 1H), 7.49
96%.
(m, 2H), 7.05 (dd, J = 1.6 Hz,
J = 7.2 Hz, 1H), 6.52 (d, J = 2.4
Hz, 1H), 4.63 (t, J = 4.0 Hz, 2H),
4.27 (m, 1H ), 4.0 (t, J = 3.6 Hz,
2H), 1.86 (m, 4H), 0.66 (t, J =
7.2 Hz, 6H).
39 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
416 (M+H) ;
HPLC purity:
7.55 (d, J = 3.3 Hz, 1H), 7.49
96%.
(m, 2H), 7.2 (d, J = 8.4 Hz, 2H),
7.04 (dd, J = 1.8 Hz, J = 8.7
Hz, 1H), 6.88 (d, J = 8.4 Hz,
2H), 6.48 (d, J = 3.0 Hz, 1H),
.35 (s, 2H), 4.61 (t, J = 3.9 Hz,
2H ), 3.96 (t, J = 4.5 Hz, 2H),
3.69 (s, 3H).
40 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
404 (M+H) ;
HPLC purity:
7.52 (m, 2H), 7.28-7.25 (m, 2H),
97%.
7.22-7.0 (m, 3H), 6.51 (d, J = 3.3
Hz, 1H), 5.43 (s, 2H), 4.62 (t, J
= 4.5 Hz, 2H), 3.97 (t, J = 4.5
Hz, 2H).
PU64642PCT
41 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
430 (M+H) ;
HPLC purity:
7.56-7.5 (m, 2H), 7.44 (d, J = 2.8
Hz, 1H), 7.32-7.16 (m, 4H), 7.09 99 %.
(d, J = 8.8 Hz, 1H), 6.46 (d, J
=2.8 Hz, 1H), 4.64 (t, J = 4.0 Hz,
2H), 4.45 (s, 2H), 4.41 (t, J = 4.8
Hz, 2H), 3.98 (t, J = 4.4 Hz,
2H), 3.75 (t, J = 4.8 Hz, 2H).
42 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
386 (M+H) ;
HPLC purity:
7.58 (d, J = 2.8 Hz, 1H), 7.51 (d,
98%.
J = 1.6 Hz, 1H), 7.48 (d, J = 8.8
Hz, 1H), 7.33-7.29 (m, 1H),
7.26-7.20 (m, 4H), 7.06 (dd, J =
2.0 Hz, J = 8.8 Hz, 1H), 6.51 (d,
J = 3.2 Hz, 1H), 5.44 (s, 2H),
4.61 (t, J = 4.4 Hz, 2H), 3.97 (t,
J = 4.4 Hz, 2H).
43 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
368 (M+H) ;
HPLC purity:
7.50 (m, 2H), 7.40 (d, J = 2.8
Hz, 1H), 7.1 (d, J = 8.8 Hz, 1H), 99%.
6.46 (d, J = 2.4 Hz, 1H), 4.63
(m, 2H), 4.24 (t, J = 6.8 Hz, 2H),
3.98 (m, 2H), 3.24 (m, 5H), 1.97
(m, 2H).
44 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
360 (M+H) ;
HPLC purity:
7.58-7.53 (m, 2H), 7.43 (d, J =
95%.
2.8 Hz, 1H), 7.13 (d, J = 8.0 Hz,
1H), 6.52 (d, J = 3.2 Hz, 1H),
6.5-6.2 (m, 1H), 4.76-4.6 (m,
4H), 4.0 (t, J = 4.4 Hz, 2H).
45 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
310 (M+H) ;
HPLC purity:
7.51 (d, J = 1.8 Hz, 1H), 7.46 (d,
92%.
J = 9.0 Hz, 1H), 7.38 (d, J = 3.0
Hz, 1H), 7.12 (dd, J = 1.8 Hz, J
= 8.4 Hz, 1H), 6.44 (d, J = 3.0
Hz, 1H), 4.64 (t, J = 4.2 Hz, 2H),
3.98 (t, J = 4.5 Hz, 2H ), 3.8 (s,
3H).
PU64642PCT
46 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
354 (M+H) ;
HPLC purity:
7.50 (m, 2H), 7.41 (d, J = 2.8
Hz, 1H), 7.08 (dd, J = 2.0 Hz, J 99%.
= 8.8 Hz, 1H), 6.44 (d, J = 2.8
Hz, 1H), 4.64 (t, J = 4.4 Hz, 2H),
4.35 (t, J = 5.2 Hz, 2H), 3.98 (t,
J = 4.4 Hz, 2H), 3.65 (t, J = 5.2
Hz, 2H), 3.22 (s, 3H)
47 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
338 (M+H) ;
HPLC purity:
7.56-7.49 (m, 2H), 7.5 (d, J = 1.8
96%.
Hz, 1H), 7.08 (dd, J = 1.8 Hz, J
= 8.7 Hz, 1H), 6.48 (d, J = 3.0
Hz, 1H), 4.77 (m, 1H), 4.63 (t, J
= 4.2 Hz, 2H), 3.98 (t, J = 4.5
Hz, 2H), 1.46 (d, J = 6.9 Hz,
6H).
48 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
296 (M+H) ;
), 8.17 (s, 1H),
HPLC purity:
7.60 (bs, 2H), 7.49 (d, J = 1.6
93%.
Hz, 1H), 7.40 (m, 2H), 7.04 (dd,
J = 2.0 Hz, J = 8.8 Hz, 1H),
6.44 (m, 1H), 4.63 (t, J = 4.4 Hz,
2H), 3.97 (t, J = 4.8 Hz, 2H).
49 H NMR (400 MHz, DMSO-d ): ESI-MS m/z =
340 (M+H) ;
8.15 (s, 1H), 7.57 (bs, 2H),
LCMS Purity:
6.98 (s, 1H), 6.92 (dd, J = 2.0
99%.
Hz, J = 8.4 Hz, 1H), 6.47 (d, J =
8.4 Hz, 1H), 4.57 (t, J = 4.4 Hz,
2H), 3.86 (t, J = 4.8 Hz, 2H),
3.33 (t, J = 8.0 Hz, 2H), 3.0 (t, J
= 7.6 Hz, 2H), 2.89 (t, J = 8.4
Hz, 2H), 1.55 (m, 2H), 0.93 (t, J
= 7.6 Hz, 3H).
50 H NMR (400 MHz, DMSO-d ): ESI-MS m/z =
298 (M+H) ;
8.15 (s, 1H), 7.57 (bs, 2H),
HPLC Purity:
6.98 (s, 1H), 6.84 (dd, J = 1.6
94%.
Hz, J = 8.0 Hz, 1H), 6.49 (d, J =
8.4 Hz, 1H), 5.58 (bs, 1H), 4.57
(t, J = 4.4 Hz, 2H), 3.86 (t, J =
4.4 Hz, 2H), 3.44 (t, J = 8.4 Hz,
2H), 2.91 (t, J = 8.0 Hz, 2H).
PU64642PCT
51 H NMR (400 MHz, DMSO-d ): ESI-MS m/z =
356 (M+H) ;
8.15 (s, 1H), 7.58 (bs, 2H),
HPLC Purity:
6.98 (s, 1H), 6.92 (dd, J = 2.4
Hz, J = 8.4 Hz, 1H), 6.50 (d, J = 97%.
8.4 Hz, 1H), 4.57 (t, J = 4.4 Hz,
2H), 3.87 (t, J = 4.4 Hz, 2H),
3.53 (t, J = 6.0 Hz, 2H), 3.41 (t,
J = 8.0 Hz, 2H), 3.28 (s, 3H),
3.23 (t, J = 5.6 Hz, 2H), 2.89 (t,
J = 8.4 Hz, 2H).
52 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
324 (M+H) ;
HPLC purity:
7.02-6.98 (m, 2H), 7.01 (dd, J =
96%.
2.0 Hz, J = 8.8 Hz, 1H), 6.23 (s,
1H), 4.63 (t, J = 4.0 Hz, 2H),
3.96 (t, J = 4.4 Hz, 2H), 3.67 (s,
3H), 2.87 (s, 3H).
53 H NMR (400MHz, CDCl ): ESI-MS m/z =
351 (M+H) ;
8.30 (s, 1H), 8.22 (d, J = 2.0 Hz,
HPLC purity:
1H), 7.81 (d, J = 1.6 Hz, 1H),
96%.
7.41 (d, J = 3.2 Hz, 1H), 6.50 (d,
J = 3.6 Hz, 1H), 5.64 (bs, 1H),
4.75 (t, J = 4.0 Hz, 2H), 4.17 (d,
J = 6.8 Hz, 2H), 4.07 (t, J = 4.4
Hz, 2H), 1.29 (m, 1H), 0.61 (q, J
= 6.0 Hz, 2H), 0.42 (q, J = 4.8
Hz, 2H).
54 ESI-MS m/z =
H NMR (400MHz, CDCl ):
339 (M+H) ;
8.30 (s, 1H), 8.22 (d, J = 2.4 Hz,
1H), 7.81 (d, J = 2.4 Hz, 1H), HPLC purity:
93.5%.
7.29 (d, J = 3.6 Hz, 1H), 6.48 (d,
J = 3.6 Hz, 1H), 5.64 (bs, 1H),
4.75 (t, J = 4.4 Hz, 2H), 4.26 (t,
J = 6.8 Hz, 2H), 4.07 (t, J = 4.4
Hz, 2H), 1.91 (m, 2H), 0.95 (t, J
= 7.6 Hz, 3H);
55 ESI-MS m/z =
H NMR (400MHz, CDCl ):
355 (M+H) ;
8.30 (s, 1H), 8.22 (d, J = 2.0 Hz,
HPLC purity:
1H), 7.81 (d, J = 2.0 Hz, 1H),
91.63%.
7.40 (d, J = 3.6 Hz, 1H), 6.48 (d,
J = 3.6 Hz, 1H), 5.71 (bs, 1H),
4.75 (t, J = 4.4 Hz, 2H), 4.48 (t,
J = 5.2 Hz, 2H), 4.06 (t, J = 4.4
Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H),
3.33 (s, 3H);
PU64642PCT
56 H NMR (400MHz, CDCl ESI-MS m/z =
393 (M+H) ;
J = 2.0
HPLC purity:
Hz, 1H), 7.80 (d, J = 2.0 Hz,
1H), 7.25 (d, J = 3.6 Hz, 1H), 98.7%.
6.46 (d, J = 3.2 Hz, 1H), 5.65
(bs, 1H), 4.75 (t, J = 4.4 Hz,
2H), 4.12 (d, J = 7.2 Hz, 2H)
4.07 (t, J = 4.4 Hz, 2H), 1.93 (m,
1H), 1.7-1.6 (m, 4H), 1.25-1.14
(m, 3H), 1.03 (m, 2H).
57 H NMR (300MHz, CDCl ): ESI-MS m/z =
379 (M+H) ;
J =
HPLC purity:
2.1 Hz, 1H), 7.8 (d, J = 2.1 Hz,
92.8%.
1H), 7.39 (d, J = 3.3 Hz, 1H),
6.48 (d, J = 3.3 Hz, 1H), 5.65
(bs, 1H), 4.84-4.7 (m, 3H), 4.06
(t, J = 4.5 Hz, 2H), 2.18-2.04 (m,
2H), 1.95-1.88 (m, 2H), 1.8-1.6
(m, 4H), 1.4-1.2 (m, 2H).
58 H NMR (300MHz, DMSO d ): ESI-MS m/z =
339 (M+H) ;
J = 2.1 Hz, 1H), 8.18
HPLC purity:
(s, 1H), 7.96 (d, J = 1.8 Hz, 1H),
7.73 (d, J = 3.6 Hz, 1H), 7.65 97%.
(bs, 2H), 6.52 (d, J = 3.3 Hz,
1H), 5.07 (m, 1H), 4.67 (t, J =
4.2 Hz, 2H), 4.02 (t, J = 4.5 Hz,
2H), 1.48 (d, J = 6.3 Hz, 6H).
59 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
341 (M+H) .
J = 2.4 Hz, 1H), 8.18
(s, 1H), 7.97 (d, J = 2.1 Hz, 1H), HPLC purity:
95%.
7.64 (bs, 2H), 7.61 (d, J = 3.3
Hz, 1H), 6.48 (d, J = 3.3 Hz,
1H), 4.92 (t, J = 5.4 Hz, 1H),
4.67 (t, J = 5.1 Hz, 2H), 4.32 (t,
J = 5.7 Hz, 2H), 4.02 (t, J = 4.5
Hz, 2H), 3.75 (q, J = 5.7 Hz,
2H).
60 H NMR (300MHz, DMSO-d - ESI-MS m/z =
374 (M+H) ;
D O): J
HPLC purity:
= 8.7 Hz, 1H), 7.7 (d, J = 2.1 Hz,
98%.
1H), 7.65 (d, J = 3.6 Hz, 1H),
7.38 (dd, J = 2.1 Hz, J = 8.7
Hz, 1H), 6.87 (d, J = 3.6 Hz,
1H), 4.66 (t, J = 4.2 Hz, 2H),
4.02 (t, J = 4.5 Hz, 2H), 3.46 (s,
3H).
PU64642PCT
61 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
336 (M+H) ;
HPLC purity:
7.58 (d, J = 8.4 Hz, 1H), 7.50 (d,
J = 1.8 Hz, 1H), 7.38 (d, J = 3.3 94%.
Hz, 1H), 7.13 (dd, J = 1.8 Hz, J
= 10.8 Hz, 1H), 6.42 (d, J = 3.0
Hz, 1H), 4.63 (t, J = 3.9 Hz, 2H),
3.98 (t, J = 4.8 Hz, 2H), 3.45 (m,
1H), 1.08 (m, 2H), 0.95 (m, 2H).
62 H NMR (400MHz, DMSO-d ): ESI-MS m/z =
382 (M+H) .
HPLC purity:
7.68-7.6 (m, 4H), 7.29 (d, J =
98%.
.4 Hz, 1H), 7.23 (s, 1H), 4.64
(t, J = 4.4 Hz, 2H), 4.56 (t, J =
7.6 Hz, 2H), 4.0 (t, J = 4.4 Hz,
2H), 1.72 (m, 2H), 0.83 (t, J =
7.6 Hz, 3H).
Example 63: 4-Amino(1-propyl(2,2,2-trifluoroacetyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) TFAA, Et N, DCM, RT, 1h; b) NH (CH ) OTBDMS,
3 2 2 2
Pd(OAc) , Cs CO , X-PHOS, Toluene, 120 C, 2.5h; c) DCM, Et N, RT, 1h; d) 3% HCl-
2 2 3 3
MeOH, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH , Dioxane, RT, 2h.
3 3 3
Procedures:
4-Amino(1-propyl(2,2,2-trifluoroacetyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
1-(5-Bromopropyl-1H-indolyl)-2,2,2-trifluoroethanone (63A):
PU64642PCT
TFAA (5.0 mL, 35.4 mmol) was added to a solution of product of Example 12A (2.5 g,
.5 mmol) in DCM (10 mL) followed by TEA (2.5 mL, 17.94 mmol) at 0 °C, and the
mixture was stirred at 25 C for 1 h. The reaction mixture was diluted with DCM and
quenched with water. Organic layer was separated, washed with brine, dried over sodium
sulphate, filtered and concentrated in vacuo. The crude product was purified by flash
chromatography using 5% ethyl acetate in hexane to afford title compound (2.0 g, 57%) as
a yellow solid. H NMR (300 MHz, CDCl ): 8.57 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 1.5
Hz, 1H), 7.49-7.45 (dd, J = 1.8 Hz, J = 9.0 Hz, 1H), 7.09 (m, 1H), 4.16 (t, J = 6.9 Hz,
2H), 1.98-1.91 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); ESI-MS m/z = 238 (M+H) .
1-(5-(2-(tert-Butyldimethylsilyloxy)ethylamino)propyl-1H-indolyl)-2,2,2-
trifluoroethanone (63B):
A mixture of product of Example 63A (1.25 g, 3.74 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.656 g,3.74 mmol), cesium carbonate (1.463 g, 4.49
mmol), palladium acetate (0.084 g, 0.374 mmol) and X-PHOS (0.178 g, 0.374 mmol) in
toluene (20 mL) under Argon was refluxed at 110 C for 2 h. The reaction mixture was
cooled, diluted with ethyl acetate, and washed with water (2x15 mL) and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and oncentrated
to obtain dark oil. The residue was purified by flash chromatography using 10% ethyl
acetate in hexane to afford title compound (0.7 g, 43.7%) as an oil. H NMR (300 MHz,
CDCl ): 7.78 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.20 (d, J =.9.0 Hz, 1H),
6.75-6.72 (dd, J = 2.4 Hz, J = 8.7 Hz, 1H), 4.17 (bs, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.87 (t,
J = 5.1 Hz, 2H), 3.30 (t, J = 7.5 Hz, 1H), 1.96-1.89 (m, 2H), 0.97(t, J = 7.2 Hz, 3H),
0.91(s, 9H), 0.07 (s, 6H ); ESI-MS m/z = 429 (M+H) .
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-propyl(2,2,2-
trifluoroacetyl)-1H-indolyl)pyrimidinecarboxamide (63C):
To a stirred, cooled (0 C) solution of product of Example 63B (0.7 g, 1.633 mmol) and
TEA (1.138 g, 8.17 mmol) in DCM (20 mL) was added drop wise a solution of 4,6-
PU64642PCT
dichloropyrimidinecarbonyl chloride (0.345 g, 1.633 mmol) in DCM (5 mL). After 1 h,
the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and washed
with water (2x15 mL) and saturated aqueous brine. The organic layer was dried over
sodium sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified
by flash chromatography using 12% ethyl acetate in hexane as eluent to afford title
compound (0.6 g, 60.9%) as a syrup. H NMR (400 MHz, CDCl ): 8.49 (s, 1H), 8.46 (d,
J = 1.6 Hz , 1H), 7.91 (d, J =1.2 Hz, 1H),7.45-7.43 (dd, J = 2.0 Hz J =8.8 Hz ,1H),
7.26(m, 1H), 4.13-4.10 (m, 4H), 3.92 (t, J = 5.6 Hz, 2H),1.93-1.88 (q, J =7.6 Hz , 2H),
0.98 (t, J = 7.2 Hz, 3H), 0.83 (s, 9H), 0.045(s, 6H ); ESI-MS m/z = 605 (M+H) .
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-propyl(2,2,2-trifluoroacetyl)-1H-indol
yl)pyrimidinecarboxamide (63D):
A solution of product of Example 63C (0.6 g, 0.994 mmol), in 10 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 1 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.4 g, 82%) as a solid, which was carried on to the next
step without further purification. H NMR (400 MHz, CDCl ): 1H), 8.50 (d, J
= 1.6 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.45-7.42 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.29(
m, 1H), 4.18 (t, J = 5.2 Hz, 2H), 4.11 (t, J = 7.2 Hz, 2H), 3.95(t, 2H), 1.92 (q, J =7.6 Hz,
2H), 0.98 (t, J = 8.0 Hz, 3H); ESI-MS m/z = 490 (M+H) .
4-Chloro(1-propyl(2,2,2-trifluoroacetyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (63E):
A slurry of product of Example 63D (0.4 g, 0.818 mmol) and TEA (0.57 mL, 4.09 mmol)
in acetonitrile (15 mL) was stirred at 80 C for 16 h. The reaction mixture was cooled and
concentrated in vacuo. The residue was diluted with ethyl acetate, and washed with water
and saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.25 g, 67.5%) as a white solid. H NMR
(300MHz, DMSO-d ): 1H), 8.35(s , 1H), 7.99 (d, J = 0.9 Hz, 1H), 7.50-7.48
(m , 2H), 4.82(t, J = 7.8 Hz, 2H), 4.21 (t, J = 7.2 Hz , 2H), 4.15 (t, J = 4.8 Hz, 2H), 2.04-
1.96 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H),; ESI-MS m/z = 453 (M+H) .
PU64642PCT
4-Amino(1-propyl(2,2,2-trifluoroacetyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (63):
A solution of product of Example 63E (0.25 g, 0.552 mmol) in 0.5M ammonia in p-
dioxane (10 mL) was stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo, diluted water ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (70 mg, 27.2%) as a white solid. H NMR (400MHz,
DMSO-d ): J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.82 (d, J
= 8.8 Hz, 1H), 7.65 (bs, 2H), 7.40-7.38 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 4.63 (t, J = 3.6
Hz, 2H), 4.37 (t, J = 6.8 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 1.87-1.82 (m, 2H), 0.870 (t, J =
7.2 Hz, 3H); ESI-MS m/z = 434 (M+H) ; LCMS purity: 92%.
Example 64 was prepared by the procedures analogous to those described in Example 63
using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
64 H NMR (300MHz, DMSO-d ): ESI-MS m/z =
464 (M+H) ;
-7.54 (m,
HPLC purity:
3H), 7.15 (dd, J = 2.1 Hz, J =
90%.
9.0 Hz, 1H), 7.03 (bs, 2H), 4.59
(t, J = 4.2 Hz, 2H), 4.17 (t, J =
6.9 Hz, 2H), 4.0 (t, J = 4.5 Hz,
2H), 3.12 (s, 3H), 1.83-1.7 (m,
5H), 0.83 (t, J = 7.2 Hz, 3H).
Example 65: 4-Amino(1-phenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
PU64642PCT
Reagents and conditions: a) Iodo benzene, CuBr, Cu(OAc) , K CO , NaOH, 140 C, 9h;
2 2 3
b) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 120 C, 2.5h; c) DCM,
2 2 2 2 2 3
Et N, RT, 1h; d) 3%HCl-MeOH, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH , Dioxane,
3 3 3 3
RT, 2h.
Procedures:
4-Amino(1-phenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one:
-bromophenyl-1H-indole (65A):
Copper(I) bromide (0.073 g, 0.509 mmol) was added to a solution of 5-bromo indole (1 g,
.2 mmol) in iodo benzene (13.5 g, 66.2 mmol) followed by potassium carbonate (2.7 g,
19.54 mmol), and the mixture was stirred at 100 C for 10 min. NaOH (150 mg, 3.75
mmol) and copper(II) acetate (0.01g, 0.055 mmol) was added at 140 C, and the mixture
was stirred for 9 h. Insoluble solids were filtered off, filtrate was concentrated and
partitioned between ethyl acetate and water. Organic layer was separated, washed with
brine, dried over sodium sulphate and filtered. The filtrate was concentrated under reduced
pressure and purified by flash chromatography using 8% ethyl acetate in pet ether to
afford title compound (0.5 g, 36%) as an oil. H NMR (300MHz, CDCl ): 7.80 (m, 1H),
7.60-7.45 (m, 4H), 7.42-7.38 (m, 2H), 7.35-7.25 (m, 2H), 6.62 (d, J = 3.3 Hz, 1H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)phenyl-1H-indolamine (65B):
PU64642PCT
A mixture of product of Example 65A (1.7 g, 6.25 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (1.095 g, 6.25 mmol), cesium carbonate (3.05 g, 9.37
mmol), palladium acetate (0.14 g, 0.625 mmol) and X-PHOS (0.298 g, 0.625 mmol) in
toluene (30 mL) under argon was refluxed at 120 C for 16 h. The reaction was cooled,
diluted with ethyl acetate, and washed with water (2x10 mL) and saturated aqueous brine.
The organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark
oil. The residue was purified by flash chromatography using 10% ethyl acetate in hexane
to afford title compound (0.8 g, 34.9%) as an oil. H NMR (400MHz, CDCl ): 7.55-7.48
(m, 4H), 7.45-7.39 (m, 2H), 7.3 (m, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 2.0 Hz, J
= 8.8 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 3.94 (bs, 1H), 3.86 (t, J = 5.2 Hz, 2H), 3.27 (t, J =
.2 Hz, 2H), 0.92 (s, 9H), 0.08 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-phenyl-1H-indol
yl)pyrimidinecarboxamide (65C):
To a stirred, cooled (0 C) solution of product of Example 65B (0.8 g, 2.182 mmol) and
TEA (1.521 mL, 10.91 mmol) in DCM (30 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.461 g, 2.182 mmol) in DCM (5 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x10 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in hexane as eluent to afford title compound
(0.65 g, 5%) as a syrup. H NMR (400MHz, CDCl ): 8.5 (s, 1H), 7.74 (d, J = 2.0 Hz,
1H), 7.51 (t, J = 8.0 Hz, 2H), 7.41-7.33 (m, 5H), 7.22 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H),
6.59 (d, J = 3.2 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 0.92 (s, 9H),
0.08 (s, 6H).
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-phenyl-1H-indolyl)pyrimidine
carboxamide (65D):
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A solution of product of Example 65C (0.65 g, 1.2 mmol), in 20.5 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 1 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.45 g, 72.8%) as a solid, which was carried on to the
next step without further purification. H NMR (400MHz, CDCl ): 8.52 (s, 1H), 7.73
(d, J = 2.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.40-7.38 (m, 4H), 7.36 (d, J = 3.6 Hz, 1H),
7.23 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H),
3.95 (t, J = 5.2 Hz, 2H).
4-Chloro(1-phenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one (65E):
A slurry of product of Example 65D (0.45 g, 1.053 mmol) and TEA (0.734 mL, 5.27
mmol) in acetonitrile (20 mL) was stirred at 80 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.3 g, 67.1%) as a white solid. H NMR (400MHz,
CDCl ): J = 2.0 Hz, 1H), 7.6 (d, J = 8.8 Hz, 1H), 7.56-7.47 (m,
4H), 7.41-7.38 (m, 2H), 7.20 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H),
4.18 (t, J = 4.4 Hz, 2H), 4.10 (t, J = 4.8 Hz, 2H).
4-Amino(1-phenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-
one (65):
A solution of product of Example 65E (0.3 g, 0.768 mmol), in 0.5M ammonia in p-
dioxane (15 mL) was stirred at room temperature for 2 h. The reaction mixture was
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concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.22 g, 73.3%) as a white solid. H NMR (400MHz,
DMSO-d ): J = 3.6 Hz, 1H), 7.64-7.56 (m, 5H), 7.45 (m, 1H),
7.18-7.15 (m, 4H), 6.73 (d, J = 3.2 Hz, 1H), 4.65 (t, J = 4.4 Hz, 2H), 4.01 (t, J = 4.4 Hz,
2H); ESI-MS m/z = 372 (M+H) ; HPLC purity: 95%.
Example 66: 4-Amino(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin
yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) 1-Iodo(trifluoromethyl)benzene, CuBr, Cu(OAc) ,
K CO , NaOH, DMF, 110 C, 16h; b) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-
2 3 2 2 2 2 2 3
PHOS, Toluene, 120 C, 12h; c) DCM, Et N, RT, 1h; d) TBAF, THF, RT, 1h; e) CH CN,
Et N, 80 C, 16h; f) NH , Dioxane, RT, 2h.
Procedures:
4-Amino(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
-Bromo(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (66A):
1-Iodo(trifluoromethyl)benzene (1.657 g, 6.09 mmol) was added to a solution of 5-
bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol) and Copper(I) bromide (0.073 g, 0.508
mmol) in DMF (10 mL ) followed by potassium carbonate (1.75 g, 12.69 mmol), and the
mixture was stirred at 100 C for 10 min. NaOH (150 mg, 3.75 mmol) and copper(II)
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acetate (4.61 mg, 0.025 mmol) were added to the reaction mixture at 110 C, and the
mixture was stirred for 16 h. Insoluble solids were filtered off, and the filtrate was
concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was
separated, washed with brine, dried over sodium sulphate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate
in pet ether to afford title compound (0.4 g, 22%) as a off-white solid. H NMR (400MHz,
CDCl ): J = 2.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H),
7.78 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)(4-(trifluoromethyl)phenyl)-1H-
pyrrolo[2,3-b]pyridinamine (66B):
A mixture of product of Example 66A (0.4 g, 1.173 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.247 g, 1.407 mmol), cesium carbonate (0.573 g,
1.759 mmol), palladium acetate (26.3 mg, 0.117 mmol) and X-PHOS (0.0559 g, 0.117
mmol) in Toluene (15 mL) under Argon was refluxed at 120 C for 2.5 h. The reaction
was cooled, diluted with ethyl acetate, and washed with water (2x5 mL) and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
to obtain dark oil. The residue was purified by flash chromatography using 10% ethyl
acetate in hexane to afford title compound (0.3 g, 50.5%) as an oil. H NMR (400MHz,
CDCl ): J = 8.0 Hz, 2H), 7.93 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H),
7.47 (d, J = 4.0 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 4.0 Hz, 1H), 3.88 (t, J = 5.2
Hz, 2H), 3.27 (t, J = 5.6 Hz, 2H), 0.92 (s, 9H), 0.07 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(4-
(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)pyrimidinecarboxamide
(66C):
To a stirred, cooled (0 C) solution of product of Example 66B (0.3 g, 0.689 mmol) and
TEA (0.288 mL, 2.06 mmol) in DCM (10 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.175 g, 0.827 mmol) in DCM (2 mL). After 1 h,
the reaction mixturewas concentrated in vacuo, diluted with ethyl acetate, and washed
with water (2x5 mL) and saturated aqueous brine. The organic layer was dried over
sodium sulphate, filtered and concentrated in vacuo to afford an oil. The residue was
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purified by flash chromatography using 12% ethyl acetate in pet ether to afford title
compound (0.28 g, 62.6%) as a syrup. H NMR (400MHz, CDCl ): 8.54 (s, 1H), 8.40 (d,
J = 2.4 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz,
2H), 7.58 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H), 4.09 (t, J = 5.2 Hz, 2H), 3.97 (t, J =
.2 Hz, 2H), 0.87 (s, 9H), 0.06 (s, 6H).
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-
b]pyridinyl)pyrimidinecarboxamide (66D):
TBAF (0.3 g, 1.147 mmol) was added to a solution of Example 66C (0.28 g, 0.459 mmol)
in THF (10 mL), and the mixture was stirred at room temperature for 1 h. THF was
removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous brine. The organic layer was
dried over sodium sulfate, filtered and concentrated in vacuo to afford title compound (0.2
g, 86%) as a solid, which was carried on to the next step without further purification. H
NMR (400MHz, CDCl ): J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz,
1H), 7.88 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.6 (d, J = 4.0 Hz, 1H), 6.66 (d, J =
3.2 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 3.98 (q, J = 4.8 Hz, 2H).
4-Chloro(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (66E):
A slurry of product of Example 66D (0.2 g, 0.403 mmol) and TEA (0.169 mL, 1.209
mmol) in acetonitrile (15 mL) was stirred at 80 C for 6 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.16 g, 83%) as a white solid. H NMR (400MHz,
CDCl ): J = 2.4 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.96 (d, J =
8.8 Hz, 2H), 7.8 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H ),
4.81 (t, J = 5.2 Hz, 2H), 4.12 (t, J = 4.8 Hz, 2H).
PU64642PCT
4-Amino(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (66):
A solution of product of Example 66E (0.16 g, 0.348 mmol) in 0.5M ammonia in p-
dioxane (12 mL) was stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.1 g, 64.6%) as a white solid. H NMR (300MHz,
DMSO-d ): J = 2.4 Hz, 1H), 8.23 (d, J = 8.0 Hz, 2H), 8.19 (s, 1H), 8.16 (d, J
= 2.0 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.66 (bs, 2H), 6.87 (d, J
= 4.0 Hz, 1H), 4.71 (t, J = 4.0 Hz, 2H), 4.07 (t, J = 3.6 Hz, 2H); ESI-MS m/z = 441
(M+H) ; HPLC purity: 99%.
Examples 67 – 81 were prepared by the procedures analogous to those described in
Example 65 or Example 66 using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
67 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 391
J = 2.0 Hz, 1H), 8.19
(s, 1H), 8.11 (d, J = 2.0 Hz, 1H), (M+H) ;
HPLC purity:
8.0 (d, J = 4.0 Hz, 1H), 7.94-7.91
97%.
(m, 2H), 7.66 (bs, 2H), 7.41 (t, J
= 8.8 Hz, 2H), 6.76 (d, J = 4.0
Hz, 1H), 4.69 (t, J = 4.4 Hz, 2H),
4.06 (t, J = 4.4 Hz, 2H).
68 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 407
J = 2.4 Hz, 1H), 8.19
(M+H) ;
(s, 1H), 8.16-8.10 (m, 3H), 7.95
HPLC purity:
(dd, J = 1.6 Hz, J = 8.4 Hz, 1H),
97%.
7.67 (bs, 2H), 7.59 (t, J = 8.4 Hz,
1H), 7.43 (d, J = 8.0 Hz, 1H), 6.8
(d, J = 3.6 Hz, 1H), 4.69 (t, J =
4.0 Hz, 2H), 4.06 (t, J = 4.4 Hz,
2H).
69 H NMR (300MHz, DMSO-d ): ESI-MS m/z
= 406
J = 3.3
(M+H) ;
Hz, 1H), 7.7 (bs, 2H), 7.66-7.58
HPLC purity:
(m, 5H), 7.48 (m, 1H), 7.22 (dd,
95%.
J = 2.1 Hz, J = 9.0 Hz, 1H),
6.76 (d, J = 3.3 Hz, 1H), 4.65 (t,
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J = 3.6 Hz, 2H), 4.01 (t, J = 4.5
Hz, 2H).
70 H NMR (300MHz, DMSO-d ): ESI-MS m/z
= 403 (M+H)
J = 2.1
; HPLC
Hz, 1H), 7.66 (bs, 2H), 7.46 (d, J
purity: 92%.
= 7.8 Hz, 2H), 7.27 (d, J = 8.1
Hz, 1H), 7.12 (t, J = 6.3 Hz, 2H),
6.66 (d, J = 3.9 Hz, 1H), 4.67 (t, J
= 4.5 Hz, 2H), 4.04 (t, J = 4.5 Hz,
2H), 3.74 (s, 3H).
71 H NMR (300MHz, DMSO-d ): ESI-MS m/z
= 402
8.18 (s, 1H), 7.62 (bs, 2H), 7.59
(M+H) ;
(s, 1H), 7.54-7.46 (m, 2H), 7.39
HPLC purity:
(d, J = 6.9 Hz, 1H), 7.30 (d, J =
92%.
8.1 Hz, 1H), 7.2-7.05 (m, 3H),
6.66 (d, J = 3.0 Hz, 1H), 4.64 (t, J
= 4.5 Hz, 2H), 4.0 (t, J = 4.5 Hz,
2H), 3.77 (s, 3H).
72 H NMR (300MHz, CDCl ESI-MS m/z
= 373
J = 2.4
Hz, 1H), 8.20 (bs, 1H), 7.90 (d, J (M+H) ;
HPLC purity:
= 2.4 Hz, 1H), 7.74 (m, 2H), 7.6
99%.
(d, J = 3.6 Hz, 1H), 7.54 (t, J =
7.8 Hz, 2H), 7.37 (t, J = 7.5 Hz,
1H), 6.66 (d, J = 3.3 Hz, 1H),
.70 (bs, 1H), 4.76 (t, J = 4.2 Hz,
2H), 4.08 (t, J = 4.5 Hz, 2H).
73 ESI-MS m/z
H NMR (300MHz, CDCl ):
= 391
J = 2.4
(M+H) ;
Hz, 1H), 8.20 (bs, 1H), 7.90 (d, J
HPLC purity:
= 2.4 Hz, 1H), 7.69 (dt, J = 1.5
96%.
Hz, J = 7.5 Hz, 1H), 7.49 (m,
1H), 7.46-7.38 (m, 1H), 7.34-7.27
(m, 2H), 6.68 (d, J = 3.3 Hz, 1H),
.75 (bs, 1H), 4.75 (t, J = 4.5 Hz,
2H), 4.08 (t, J = 4.5 Hz, 2H).
74 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 408
M+H) ;
7.73 (d, J = 3.2 Hz, 1H), 7.70-
7.58 (m, 5H), 7.50 (m, 1H), 7.20 HPLC purity:
96%.
(dd, J = 2.0 Hz, J = 8.8 Hz, 2H),
6.75 (d, J = 3.2 Hz, 1H), 4.65 (t, J
= 4.4 Hz, 2H), 4.0 (t, J = 4.4 Hz,
2H).
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75 H NMR (300MHz, DMSO-d ESI-MS m/z
= 409
J = 2.1 Hz, 1H), 8.18
(M+H) ;
(s, 1H), 8.13 (m, 2H), 8.08 (d, J =
3.9 Hz, 1H), 7.85 (m, 1H), 7.70- HPLC purity:
90%.
7.60 (m, 3H), 6.80 (d, J = 3.3 Hz,
1H), 4.69 (t, J = 3.9 Hz, 2H), 4.06
(t, J = 4.2 Hz, 2H).
76 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 390 (M+H)
-7.60 (m,
; LCMS
5H), 7.55 (m, 2H), 7.43 (m, 1H),
purity: 98%.
7.24 (d, J = 8.4, 1H), 7.16 (d, J =
8.8 Hz, 1H), 6.76 (d, J = 2.8 Hz,
1H), 4.65 (t, J = 4.4 Hz, 2H), 4.01
(t, J = 4.4 Hz, 2H).
78 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 440 (M+H)
J = 8.0
; HPLC
Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H),
purity: 99%.
7.84 (d, J = 2.8 Hz, 1H), 7.71-7.6
(m, 4H), 7.22 (d, J = 8.8 Hz, 1H),
6.81 (d, J = 3.2 Hz, 1H), 4.65 (t, J
= 4.0 Hz, 2H), 4.02 (t, J = 4.4 Hz,
2H).
79 ESI-MS m/z
H NMR (300MHz, DMSO-d ):
= 407
J = 2.1 Hz, 1H), 8.19
(M+H);
(s, 1H), 8.13 (d, J = 1.8 Hz, 1H),
8.05 (d, J = 3.6 Hz, 1H), 7.99 (d, HPLC
purity: 94%.
J = 8.4 Hz, 2H), 7.7-7.6 (m, 4H),
6.79 (d, J = 3.3 Hz, 1H), 4.68 (t, J
= 4.2 Hz, 2H), 4.06 (t, J = 4.5 Hz,
2H).
80 H NMR (400MHz, DMSO-d ESI-MS m/z
= 440 (M+H)
8.10 (s, 1H), 7.91-7.84 (m, 2H),
; HPLC
7.8-7.68 (m, 3H), 7.59 (d, J = 2.0
purity: 93%.
Hz, 1H), 7.55 (bs, 2H), 7.52 (d, J
= 8.8 Hz, 1H), 7.14 (dd, J = 2.0
Hz, J = 8.8 Hz, 1H), 6.71 (d, J=
3.6 Hz, 1H), 4.58 (t, J = 4.8 Hz,
2H), 3.94 (t, J = 4.4 Hz, 2H).
81 ESI-MS m/z
H NMR (400MHz, DMSO-d ):
= 441 (M+H)
8.43 (s, 1H), 8.39 (d, J = 2.4 Hz,
; HPLC
1H), 8.27 (d, J = 8.0 Hz, 1H),
purity: 97%.
8.19 (m, 2H), 8.15 (d, J = 2.0 Hz,
1H), 7.81 (t, J = 7.6 Hz, 1H), 7.72
(d, J = 8.0 Hz, 1H), 7.67 (bs,
2H), 6.83 (d, J = 3.6 Hz, 1H),
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4.70 (t, J = 4.0 Hz, 2H), 4.07 (t, J
= 4.4 Hz, 2H).
Example 82: 4-Amino(1-(thiazolyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) 2-Bromo thiazole, Cs CO , DMF, 100 C, 2h; b)
NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 120 C, 2.5h; c) DCM,
2 2 2 2 2 3
Et N, RT, 1h; d) 3% HCl-MeOH, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH , Dioxane,
3 3 3 3
RT, 2h.
Procedures:
4-Amino(1-(thiazolyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-
(6H)-one:
2-(5-Bromo-1H-indolyl)thiazole (82A):
2-Bromo thiazole (0.837 g, 5.10 mmol) was added to a solution of 5-bromo indole (1 g,
.10 mmol) in DMF (15 mL) followed by cesium carbonate (3.32 g, 10.20 mmol), and the
mixture was stirred at 90 C for 12 h. Insoluble solids were filtered off, the filtrate was
concentrated and partitioned between ethyl acetate and water. Organic layer was
separated, washed with brine, dried over sodium sulphate, and filtered. The filtrate was
concentrated under reduced pressure and purified by flash chromatography using 5% ethyl
acetate in pet ether to afford title compound (0.75 g, 52.7%) as a white solid. H NMR
(400MHz, CDCl ): 8.24 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 3.2
Hz, J = 10.4 Hz, 2H), 7.45 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H),
2 1 2
6.66 (d, J = 4.0 Hz, 1H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)(thiazolyl)-1H-indolamine (82B):
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A mixture of product of Example 82A (0.75 g, 2.69 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.471 g, 2.69 mmol), cesium carbonate (1.751 g, 5.37
mmol), palladium acetate (0.060 g, 0.269 mmol) and X-PHOS (0.128 g, 0.269 mmol) in
Toluene (15 mL) under Argon was refluxed at 120 C for 4 h. The reaction was cooled,
diluted with ethyl acetate, and washed with water (2x15 mL) and saturated aqueous brine.
The organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark
oil. The residue was purified by flash chromatography using 10% ethyl acetate in hexane
to afford title compound (0.4 g, 40%) as an oil. H NMR (300MHz, CDCl ): 8.11 (d, J =
9.0 Hz, 1H), 7.56 (dd, J = 3.6 Hz, J = 9.9 Hz, 2H), 6.99 (d, J = 2.4 Hz, 1H), 6.84 (d, J =
2.1 Hz, 1H), 6.76 (dd, J = 2.1 Hz, J = 8.7 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 4.03 (bs,
1H), 3.86 (t, J = 4.8 Hz, 2H), 3.27 (t, J = 5.4 Hz, 2H), 0.92 (s, 9H), 0.07 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(thiazolyl)-1H-indol
yl)pyrimidinecarboxamide (82C):
To a stirred, cooled (0 C) solution of product of Example 82B (0.4 g, 1.071 mmol) and
TEA (0.746 mL, 5.35 mmol) in DCM (15 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.226 g, 1.071 mmol) in DCM (5 mL). After 1 h,
the reaction was concentrated in vacuo, diluted into ethyl acetate, and washed with water
(2x15 mL) and saturated aqueous brine. The organic layer was dried over sodium sulphate,
filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 12% ethyl acetate in hexane to afford title compound (0.35 g,
59.6%) as a syrup. H NMR (300MHz, CDCl ): 8.49 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H),
7.73 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 3.3 Hz, 1H), 7.59 (d, J = 3.9 Hz, 1H), 7.38 (dd, J =
2.4 Hz, J = 9.0 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 4.07 (t, J = 5.4
Hz, 2H), 3.93 (t, J = 5.4 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H).
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(thiazolyl)-1H-indolyl)pyrimidine
carboxamide (82D):
PU64642PCT
TBAF (1.276 mL, 1.276 mmol) was added to a solution of Example 82C (0.35 g, 0.638
mmol) in THF (10 mL), and the mixture was stirred at room temperature for 1 h. THF was
removed in vacuo, the residue was dissolved in ethyl acetate, and washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous brine. The organic layer was
dried over sodium sulfate, filtered and concentrated in vacuo to afford title compound
(0.25 g, 90%) as a solid, which was carried on to the next step without further purification.
ESI-MS m/z = 434 (M+H) ; LCMS purity: 88%.
4-Chloro(1-(thiazolyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-
(6H)-one (82E):
A slurry of product of Example 82D (0.25 g, 0.576 mmol) and TEA (0.080 mL, 0.576
mmol) in acetonitrile (12 mL) was stirred at 90 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate and concentrated in vacuo
to afford title compound (0.377 g, 65.5%) as a white solid. H NMR (300MHz, DMSO-
d ): J = 9.0 Hz, 1H), 7.73 (d, J = 3.6 Hz, 1H), 7.67 (d, J = 1.8 Hz,
1H), 7.64 (d, J = 3.9 Hz, 1H), 7.34 (dd, J = 1.8 Hz, J = 8.7 Hz, 1H), 7.11 (d, J = 3.6 Hz,
1H), 6.75 (d, J = 3.6 Hz, 1H), 4.81 (t, J = 4.5 Hz, 2H), 4.11 (t, J = 5.1 Hz, 2H).
4-Amino(1-(thiazolyl)-1H-indolyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-
(6H)-one (82):
A solution of product of Example 82E (0.15 g, 0.377 mmol) in 0.5M ammonia in p-
dioxane (10 mL) was stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.09 g, 58%) as a white solid. H NMR (400MHz,
DMSO-d ): J = 8.8 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.72 (d, J
PU64642PCT
= 3.6 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.63 (bs, 2H), 7.57 (d, J = 3.2 Hz, 1H), 7.35 (dd,
J = 2.0 Hz, J = 8.8 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 4.82 (t, J = 4.4 Hz, 2H), 4.11 (t, J =
4.8 Hz, 2H); ESI-MS m/z = 379 (M+H) ; HPLC purity: 92%.
Example 83: 4-Amino(1-(6-(trifluoromethyl)pyridinyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) 5-Bromo(trifluoromethyl)pyridine, CS CO DMF, 90
2 3,
°C,15h; b) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 120 C, 12h; c)
2 2 2 2 2 3
DCM, Et N, RT, 1h; d) TBAF, THF, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH ,
3 3 3 3
Dioxane, RT, 2h.
Procedures:
4-Amino(1-(6-(trifluoromethyl)pyridinyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
-Bromo(6-(trifluoromethyl)pyridinyl)-1H-indole (83A):
-Bromo(trifluoromethyl)pyridine (2.075 g, 9.18 mmol) was added to a solution of 5-
bromo-1H-indole (1.5 g, 7.65 mmol) and in DMF (20 mL) followed by cesium carbonate
(7.48 g, 22.95 mmol), and the mixture was stirred at 90 C for 15 min. Insoluble solids
were filtered, filtrate was concentrated and partitioned between ethyl acetate and water.
Organic layer was separated, washed with brine, dried over sodium sulphate and filtered.
The filtrate was concentrated in vacuo and purified by flash chromatography using 5%
ethyl acetate in pet ether to afford title compound (1.1 g, 42.1%) as an off-white solid. H
PU64642PCT
NMR (300 MHz, DMSO-d ): J = 2.4 Hz, 1H), 8.37 (dd, J = 2.4 Hz, J = 8.4
6 1 2
Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.91 (m, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 1.8
Hz, J = 8.4 Hz, 1H), 6.82 (d, J = 3.0 Hz, 1H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)(6-(trifluoromethyl)pyridinyl)-1H-indol-
-amine (83B):
A mixture of product of Example 83A (0.3 g, 0.879 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.231 g, 1.319 mmol), cesium carbonate (0.86 g, 2.64
mmol), palladium acetate (19 mg, 0.088 mmol) and X-PHOS (0.042 g, 0.088 mmol) in
Toluene (25 mL) under Argon was refluxed at 110 C for 12 h. The reaction was cooled,
diluted with ethyl acetate, and washed with water (2x15 mL) and saturated aqueous brine.
The organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark
oil. The residue was purified by flash chromatography using 7% ethyl acetate in hexane to
afford title compound (0.15 g, 39.2%) as a pale yellow solid. H NMR (400MHz, DMSO-
d ): 9.04 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz,
6 1 2
1H), 7.70 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.68 (dd,
J = 2.0 Hz, J = 8.8 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 5.22 (t, J = 6.0 Hz, 1H) 3.76 (t, J =
6.0 Hz, 2H), 3.18 (q, J = 6.0, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(6-
(trifluoromethyl)pyridinyl)-1H-indolyl)pyrimidinecarboxamide (83C):
To a stirred, cooled (0 C) solution of product of Example 83B (0.5 g, 1.148 mmol) and
TEA (0.8 mL, 5.74 mmol) in DCM (10 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.362 g, 1.72 mmol) in DCM (3 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x5 mL) and saturated aqueous brine. The organic layer was dried over sodium sulphate,
filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 10% ethyl acetate in hexane as eluent to afford title compound (0.5
g, 57.5%) as pale yellow solid. H NMR (400MHz, DMSO-d ): 9.02 (d, J = 2.0 Hz, 1H),
8.75 (s, 1H), 8.31 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.90 (d, J =
3.6 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 1.2 Hz, J =
PU64642PCT
8.8 Hz, 1H), 6.80 (d, J = 3.2 Hz, 1H), 4.01 (t, J = 4.4 Hz, 2H) 3.79 (t, J = 5.6 Hz, 2H), 0.8
(s, 9H), 0.04 (s, 6H).
4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(6-(trifluoromethyl)pyridinyl)-1H-indol
yl)pyrimidinecarboxamide (83D):
A solution of product of Example 83C (0.5 g, 0.819 mmol), in 15 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 3 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.3 g, 67.5%) as a white solid, which was carried on to
the next step without further purification. H NMR (400MHz, DMSO-d ): 9.03 (d, J =
1.6 Hz, 1H), 8.74 (s, 1H), 8.33 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H),
7.90 (d, J = 3.2 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.30 (dd, J =
2.0 Hz, J = 8.8 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 4.87 (m, 1H) 3.95 (t, J = 6.4 Hz, 2H),
3.63 (m, 2H).
4-Chloro(1-(6-(trifluoromethyl)pyridinyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (83E):
A slurry of product of Example 83D (0.3 g, 0.605 mmol) and TEA (0.42 mL, 3.02 mmol)
in acetonitrile (25 mL) was stirred at 80 C for 12 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.2 g, 69.4%) as a white solid. H NMR (400MHz,
DMSO-d ): 9.12 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.40 (dd, J = 2.4 Hz, J = 8.8 Hz,
6 1 2
1H), 8.13 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 3.6 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 2.4 Hz,
2H), 7.30 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 4.78 (t, J = 5.2 Hz,
2H), 4.19 (t, J = 4.8 Hz, 2H).
4-Amino(1-(6-(trifluoromethyl)pyridinyl)-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (83):
PU64642PCT
A solution of product of Example 83E (0.21 g, 0.457 mmol) in 0.5M ammonia in p-
dioxane (10 mL) was stirred at room temperature for 4 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.135 g, 65.6%) as a white solid. H NMR (400MHz,
DMSO-d ): 9.12 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 8.18 (s,
6 1 2
1H), 8.12 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.69 (d, J
= 2.0 Hz, 1H), 7.64 (bs, 2H), 7.25 (dd, J = 1.6 Hz, J = 8.8 Hz, 1H), 6.86 (d, J = 2.8 Hz,
1H), 4.66 (t, J = 4.0 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H). ESI-MS m/z: 441 (M+H) ; HPLC
purity: 97%.
Examples 84 – 93 were prepared by the procedures analogous to those described in
Example 82 or Example 83 using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
84 H NMR (400 MHz, DMSO-d ): ESI-MS m/z
= 373 (M+H)
J = 3.2 Hz, 1H), 8.44
; HPLC
(d, J = 8.8 Hz, 1H), 8.19 (s, 1H),
purity: 98%.
8.11 (d, J = 3.2 Hz, 1H), 8.01 (dt,
J = 1.6 Hz, J = 8.4 Hz, 1H), 7.80
(d, J = 8.0 Hz, 1H), 7.64 (m, 3H),
7.33 (m, 1H), 7.26 (dd, J = 2.0
Hz, J = 8.8 Hz, 1H), 6.79 (d, J =
3.6 Hz, 1H), 4.66 (t, J = 3.6 Hz,
2H), 4.03 (t, J = 4.4 Hz, 2H).
85 ESI-MS m/z
H NMR (400MHz, CDCl ):
8.86 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 374
(M+H) ;
= 3.6 Hz, 1H), 8.45 (d, J = 4.0 Hz,
HPLC purity:
1H), 8.32 (m, 2H), 8.20 (bs, 1H),
98%.
7.88 (dt, J = 2.0 Hz, J = 8.8 Hz,
2H), 7.20 (m, 1H), 6.67 (d, J = 4.0
Hz, 1H), 5.70 (bs, 1H), 4.77 (t, J
= 4.4 Hz, 2H), 4.10 (t, J = 4.4 Hz,
2H).
86 H NMR (300MHz, DMSO-d ): ESI-MS m/z
= 375 (M+H)
J = 1.2 Hz, 1H), 8.64-
; HPLC
8.6 (m, 2H), 8.49 (d, J = 2.4 Hz,
purity: 98%.
1H), 8.40 (d, J = 3.9 Hz, 1H), 8.20
(m, 2H), 7.68 (bs, 2H), 6.91 (d, J =
4.2 Hz, 1H), 4.71 (t, J = 3.6 Hz,
2H), 4.09 (t, J = 4.5 Hz, 2H).
PU64642PCT
87 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 374 (M+H)
; HPLC
(d, J = 2.4 Hz, 1H), 8.48 (d, J =
purity: 98%.
8.8 Hz, 1H), 8.26 (d, J = 3.6 Hz,
1H), 8.19 (s, 1H), 7.67 (d, J = 1.6
Hz, 1H), 7.63 (bs, 2H), 7.30 (dd,
J = 2.0 Hz, J = 8.8 Hz, 1H), 6.87
(d, J = 3.6 Hz, 1H), 4.66 (t, J = 4.4
Hz, 2H), 4.03 (t, J = 5.2 Hz, 2H).
88 ESI-MS m/z
H NMR (300MHz, DMSO-d ):
= 441 (M+H)
8.9 (s, 1H), 8.59 (d, J = 9.0 Hz,
; HPLC
1H), 8.39 (dd, J = 2.4 Hz, J = 9.0
purity: 94%.
Hz, 1H), 8.24 (d, J = 3.3 Hz, 1H),
8.19 (s, 1H), 8.05 (d, J = 8.4 Hz,
1H), 7.67 (d, J = 1.8 Hz, 1H), 7.63
(bs, 2H), 7.32 (dd, J = 1.8 Hz, J
= 8.7 Hz, 1H), 6.88 (d, J = 3.3 Hz,
1H), 4.66 (t, J = 4.2 Hz, 2H), 4.04
(t, J = 4.2 Hz, 2H).
89 H NMR (400MHz, DMSO-d ): ESI-MS m/z
= 442 (M+H)
J = 8.8 Hz, 1H), 8.94
; HPLC
(s, 1H), 8.85 (s, 1H), 8.53 (m, 2H),
purity: 98%.
8.49 (dd, J = 2.0 Hz, J = 8.8 Hz,
1H), 8.28 (d, J = 2.4 Hz, 1H), 6.93
(d, J = 4.0 Hz, 1H), 4.82 (t, J = 4.4
Hz, 2H), 4.27 (t, J = 4.8 Hz, 2H).
90 H NMR (300MHz, DMSO-d ): ESI-MS m/z
= 380
J = 2.1 Hz, 1H), 8.37
(M+H) ;
(d, J = 3.9 Hz, 1H), 8.22 (d, J =
2.4 Hz, 1H) 8.19 (s, 1H), 7.69 (m, HPLC purity:
95%.
3H), 7.58 (d, J = 3.6 Hz, 1H), 6.90
(d, J = 3.6 Hz, 1H), 4.71 (t, J = 4.2
Hz, 2H), 4.09 (t, J = 4.2 Hz, 2H).
93 ESI-MS m/z:
H NMR (300MHz, DMSO-d ):
442 (M+H) ;
9.46 (d, J = 1.8 Hz, 1H), 8.8 (dd,
HPLC purity:
J = 2.1 Hz, J = 8.4 Hz, 1H), 8.42
96%.
(d, J = 2.1 Hz, 1H), 8.28 (d, J =
3.6 Hz, 1H), 8.19 (m, 2H), 8.14 (d,
J = 8.4 Hz, 2H), 7.68 (bs, 2H),
6.91 (d, J = 3.9 Hz, 1H), 4.71 (t, J
= 4.2 Hz, 2H), 4.07 (t, J = 4.2 Hz,
2H).
Example 94: 4-Amino(3-isopropylphenyl-1H-indolyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
PU64642PCT
Reagents and conditions: a) Iso-valeraldehyde, AcOH, 120 C, 3h b) Iodobenzene, CuBr,
Cu(OAc) , K CO , NaOH, 140 C, 9h; c) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-
2 2 3 2 2 2 2 2 3
PHOS, Toluene, 120 C, 2.5h; d) DCM, Et N, RT, 1h; e) 3% HCl-MeOH, RT, 1h; f)
CH CN, Et N, 80 C, 16h; g) NH , Dioxane, RT, 2h.
3 3 3
Procedures:
4-Amino(3-isopropylphenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
-Bromoisopropyl-1H-indole (94A):
3-Methylbutanal (0.921 g, 10.69 mmol) was added to a solution of (4-
bromophenyl)hydrazine (2 g, 10.69 mmol) in acetic acid (100 mL) at 80 C, and the
mixture was stirred for 3 h at 120 C. The reaction mixture was concentrated to get the
residue, and the residue was partitioned between ethyl acetate and water. Organic layer
was separated, washed with saturated bicarbonate solution and brine, dried over sodium
sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash
chromatography using 2% ethyl acetate in pet ether to afford title compound (1.1 g,
38.4%) as an oil. H NMR (400MHz, CDCl ): 7.91 (bs, 1H), 7.76 (m, 1H), 7.25-7.20 (m,
2H), 6.95 (d, J = 2.4 Hz, 1H), 3.18-3.11 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).
-Bromoisopropylphenyl-1H-indole (94B):
PU64642PCT
Copper(I) bromide (66 mg, 0.462 mmol) was added to a solution of 94A (1.1 g, 4.62
mmol) in iodo benzene (3.77g, 18.48 mmol) followed by potassium carbonate (2.55 g,
18.48 mmol), and the mixture was stirred at 100 C for 10 min. NaOH (150 mg, 3.75
mmol) and copper(II) acetate (10 mg, 0.055 mmol) was added at 140 C, and the mixture
was stirred for 9 h. Insoluble solids were filtered, the filtrate was concentrated and
partitioned between ethyl acetate and water. Organic layer was separated, washed with
brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and
purified by flash chromatography using 8% ethyl acetate in hexane to afford title
compound (1.0 g, 68.9%) as an oil. H NMR (300MHz, CDCl ): 7.80 (d, J = 2.1 Hz,
1H), 7.54-7.42 (m , 5H), 7.4-7.28 (m, 2H), 7.21-7.08 (m, 2H), 3.19 (m, 1H), 1.38 (d, J =
6.9 Hz, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)isopropylphenyl-1H-indolamine
(94C):
A mixture of product of Example 94B (1 g, 3.18 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.558 g, 3.18 mmol), cesium carbonate (2.074 g, 6.36
mmol), palladium acetate (0.071 g, 0.318 mmol) and X-PHOS (0.152 g, 0.318 mmol) in
Toluene (20 mL) under Argon was refluxed at 120 C for 2.5 h. The reaction was cooled,
diluted with ethyl acetate, and washed with water (2x15 mL) and saturated aqueous brine.
The organic layer was dried over sodium sulfate, filtered and concentrated to obtain dark
oil. The residue was purified by flash chromatography using 10% ethyl acetate in hexane
to afford title compound (0.6 g, 46.1%) as an oil. H NMR (400 MHz, CDCl ): 7.47-7.46
(m, 4H), 7.28 (m, 1H), 7.18 (m, 1H), 7.05 (s, 1H), 6.94 (m, 1H), 6.70 (dd, J = 2.0 Hz, J =
1 2
8.0 Hz, 1H), 3.87 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5. 6 Hz, 2H), 3.18 (m, 1H), 1.38 (d, J =
7.2 Hz, 6H), 0.92 (s, 9H), 0.09 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(3-isopropylphenyl-1H-
indolyl)pyrimidinecarboxamide (94D):
To a stirred, cooled (0 C) solution of product of Example 94C (0.6 g, 1.468 mmol) and
TEA (1.023 mL, 7.34 mmol) in DCM (15 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.31 g, 1.468 mmol) in DCM (5 mL). After 1 h,
the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and washed
with water (2x10 mL) and saturated aqueous brine. The organic layer was dried over
sodium sulphate, filtered and concentrated in vacuo to afford an oil. The residue was
PU64642PCT
purified by flash chromatography using 12% ethyl acetate in hexane to afford title
compound (0.4 g, 46.7%) as a syrup.
4,6-Dichloro-N-(2-hydroxyethyl)-N-(3-isopropylphenyl-1H-indolyl)pyrimidine-
-carboxamide (94E):
TBAF (0.358 g, 1.371 mmol) was added to a solution of Example 94D (0.4 g, 0.685
mmol) in THF (15 mL), and the mixture was stirred at room temperature for 1 h. THF was
removed in vacuo, the residue was dissolved in ethyl acetate, and washed with saturated
aqueous sodium bicarbonate and saturated aqueous brine. The organic layer was dried
over sodium sulfate, filtered and concentrated in vacuo to afford title compound (0.2 g,
62.2%) as a solid, which was carried on to the next step without further purification.
4-Chloro(3-isopropylphenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (94F):
A slurry of product of Example 94E (0.2 g, 0.426 mmol) and TEA (0.297 mL, 2.131
mmol) in acetonitrile (15 mL) was stirred at 80 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.1 g, 54.2%) as a white solid. H NMR (300MHz,
CDCl ): 8.77 (s, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.60-7.48 (m, 5H), 7.4-7.3 (m, 1H),
7.19-7.12 (m, 2H), 4.95 (t, J = 3.9 Hz, 1H), 4.02 (t, J = 4.5 Hz, 2H), 3.25-3.21 (m, 1H),
1.36 (d, J = 7.2 Hz, 6H).
4-Amino(3-isopropylphenyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (94):
A solution of product of Example 94F (0.1 g, 0.231 mmol) in 0.5M ammonia in p-dioxane
(10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in
vacuo, diluted with ethyl acetate, and washed with water and saturated aqueous brine. The
PU64642PCT
organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford
title compound (0.06 g, 61.6%) as a white solid. H NMR (300MHz, DMSO-d ):
(s, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.66-7.54 (m, 6H), 7.47 (m, 1H), 7.38 (m, 1H), 7.14 (bs,
2H), 4.65 (t, J =3.9 Hz, 2H), 4.02 (t, J = 4.5 Hz, 2H), 3.20 (m, 1H), 1.36 (d, J = 7.2 Hz,
6H); ESI-LC MS m/z = 414 (M+H) ; HPLC purity: 98.30%.
Example 95: 4-Amino(2-phenylpropyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) Phenyl boronic acid, AcOH, Pd(OAc) , copper(II) acetate,
o o o
C 12h; b) Cs CO , DMF, 25 C, 12h; c) BBr , DCM, 0 C, 1h; d) Triflic anhydride,
2 3 3
Py, DCM, 0 C, 1h; e) NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 110
2 2 2 2 2 3
o o o o
C, 4h; f) Et N, DCM, 0 C, 1h; g) MeOH/HCl, 25 C, 2h; h) Et N, ACN, 70 C, 24h; i)
NH gas, Dioxane, 25 C, 3h.
Procedures:
4-Amino(2-phenylpropyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
-methoxyphenyl-1H-indole (95A):
Pd(OAc) (0.031 g, 0.136 mmol) was added to a solution of 5-methoxy-1H-indole (0.2g,
1.359 m mol) and phenylboronic acid (0.249 g, 2.038 mmol) in acetic acid (2 mL)
followed by copper (II) acetate (0.025 g, 0.138 mmol), and the mixture was stirred at 25
C for 2 h under oxygen atmosphere. Insoluble solids were filtered off, and filtrate was
concentrated. Residue was partitioned between ethyl acetate and water. Organic layer
was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate
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in hexane to afford title compound (0.08 g, 24%) as a solid. H NMR (400 MHz, DMSO-
d ): 11.3 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.32-7.26 (m, 2H),
7.02 (d, J = 2.4 Hz 1H), 6.81 (d, J = 1.2 Hz, 1H), 6.74 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H)
3.78 (s ,3H).
-Methoxyphenylpropyl-1H-indole (95B):
1-Bromopropane (0.248 g, 2.015 mmol) was added to a solution of 95A (0.15 g, 0.672
mmol) in DMF (5 mL) followed by cesium carbonate (0.657 g, 2.015 mmol), and the
mixture was stirred at 25 C for 12 h. Insoluble solids were filtered off, and filtrate was
concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was
separated, washed with brine, dried over sodium sulphate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography using 3% ethyl acetate in
hexane as eluent to afford title compound (0.1 g, 56.1%) as a solid. H NMR (400MHz,
DMSO-d ): 7.54-7.5 (m, 4H), 7.46-7.39 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.8 (dd, J =
2.4 Hz, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.12 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.54 (m , 2H),
0.63 (t, J = 7.2 Hz).
2-Phenylpropyl-1H-indolol (95C):
BBr (0.107 mL, 1.131 mmol) was added to a solution of Example 95B (0.1g, 0.398
mmol) in DCM (20 mL) at 0 C, and the mixture was stirred for 1 h. The reaction mixture
was quenched with saturated bicarbonate solution and extracted with DCM (2x30 mL).
Organic layer was separated, washed with water and brine. The organic layer was dried
over sodium sulphate, filtered and concentrated in vacuo. The crude product was triturated
with diethyl ether to afford title compound (0.05 g, 52.8%) as white solid. H NMR
(400MHz, DMSO–d ): 8.72 (s, 1H), 7.5 (m, 4H), 7.42 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H),
6.86 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 6.32 (s, 1H), 4.07 (t, J =
7.2 Hz, 2H), 1.53 (m, 2H), 0.64 (t, J = 7.2 Hz, 3H).
2-Phenylpropyl-1H-indolyl trifluoromethanesulfonate (95D):
Triflic anhydride (0.112 g, 0.398 mmol) was added to an ice cold solution of product of
Example 95C (0.1 g, 0.398 mmol) and pyridine (0.048 mL, 0.597 mmol) in
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dichloromethane (20 mL), and the mixture was stirred at 0 C for 1 h. The reaction
mixture was diluted with dichloromethane (10 mL) and extracted with saturated aqueous
solution of NaCl (45 mL). The organic layer was dried over sodium sulphate, filtered and
evaporated under reduced pressure. The crude product was purified by flash
chromatography using 6% ethyl acetate in hexanes to give the title compound (0.08 g, 52.4
%) as a solid. H NMR (300MHz, DMSO-d ): δ 7.73 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 2.7
Hz, 1H), 7.58-7.46 (m, 5H), 7.22 (dd, J = 2.7 Hz, J = 8.7 Hz, 1H), 6.65 (s, 1H), 4.20 (t, J
= 6.9 Hz, 2H), 1.56 (m, 2H), 0.65 (t, J = 7.8 Hz, 3H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)phenylpropyl-1H-indolamine (95E):
A mixture of product of Example 95D (0.2 g, 0.522 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.183 g, 1.043 mmol), cesium carbonate (0.510 g,
1.565 mmol), palladium acetate (0.012 g, 0.052 mmol) and X-PHOS (0.0025 g, 0.052
mmol) in Toluene (20 mL) under Argon was refluxed at 111 C for 4 h. The reaction was
cooled, diluted with ethyl acetate, and washed with water (2x10 mL) and saturated
aqueous brine The organic layer was dried over sodium sulfate, filtered and concentrated
to obtain dark oil. The residue was purified by flash chromatography using 15% ethyl
acetate in hexane to afford title compound (1.5 g, 53%) as a solid. H NMR (400MHz,
DMSO-d ): δ 7.50 (m, 4H), 7.4 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 1.6 Hz, 1H),
6.61 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 6.27 (s, 1H), 4.91 (t, J = 6.0 Hz, 1H), 4.05 (t, J =
6.8 Hz, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.16 (q, J = 6.0 Hz, 2H), 1.52 (m, 2H), 0.87 (s, 9H),
0.63 (t, J = 7.2 Hz, 3H), 0.059 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(2-phenylpropyl-1H-indol-
-yl)pyrimidinecarboxamide (95F):
To a stirred, cooled (0 C) solution of product of Example 95E (0.04 g, 0.98 mmol) and
TEA (0.041 mL, 0.294 mmol) in DCM (10 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.030 g, 0.14 mmol) in DCM (3 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x10 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 20% ethyl acetate in hexane as eluent to afford title compound
(0.031 g, 32.1%) as a solid. H NMR (400MHz, DMSO-d ): J =
2.0 Hz, 1H), 7.54-7.44 (m, 6H), 7.18 (dd, J = 2.0, J = 8.8 Hz, 1H), 6.48 (s, 1H), 4.09 (t, J
PU64642PCT
= 7.2 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.8 (t, J = 5.6 Hz, 2H), 1.46 (m, 2H), 0.85 (s, 9H),
0.59 (t, J = 7.2 Hz, 3H), 0.04 (s, 6H).
4,6-Dichloro-N-(2-hydroxyethyl)-N-(2-phenylpropyl-1H-indolyl)pyrimidine
carboxamide (95G):
A solution of product of Example 95F (0.35 g, 0.6 mmol), in 20 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 2 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.225 g, 76%) as a solid, which was
carried on to the next step without further purification. H NMR (400MHz, DMSO-d ):
J = 2.0 Hz, 1H), 7.53-7.43 (m, 6H), 7.20 (dd, J = 2.0 Hz, J = 8.4
Hz, 1H), 6.51 (s, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.09 (t, J = 7.6 Hz, 2H), 3.93 (t, J = 6.4 Hz,
2H), 3.63 (q, J = 6.0 Hz, 2H), 1.49 (m, 2H), 0.6 (t, J = 7.2 Hz, 3H).
4-Chloro(2-phenylpropyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (95H):
A slurry of product of Example 95G (0.225 g, 0.479 mmol) and TEA (0.334 mL, 2.397
mmol) in acetonitrile (15 mL) was stirred at 80 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.15 g, 72.3%) as a white solid. H NMR (400MHz,
DMSO-d ): J = 8.8 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.58-7.44
(m, 5H), 7.19 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 6.58 (s, 1H), 4.77 (t, J = 5.2 Hz, 2H),
4.22-4.15 (m, 4H), 1.58 (m, 2H), 0.66 (t, J = 7.6 Hz, 3H).
4-Amino(2-phenylpropyl-1H-indolyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (95):
PU64642PCT
A solution of product of Example 95H (0.15 g, 0.346 mmol) in 0.5M ammonia in p-
dioxane (20 mL) was stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.105 g, 71.1%) as a white solid. H NMR (400MHz,
DMSO-d ): -7.44 (m, 9H), 7.15 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H),
4.65 (m, 2H), 4.19 (t, J = 6.8 Hz, 2H), 4.01 (m, 2H), 1.58 (m, 2H), 0.68 (t, J =7.6 Hz, 3H);
ESI-MS m/z = 414.0 (M+H) ; HPLC purity: 97%.
Example 96: 4-Amino(6-fluorophenyl-1H-indolyl)-7,8-dihydrooxepino[2,3-
d]pyrimidin-5(6H)-one:
t o o
Reagents and conditions: a)K Obu, DMF, -20 C, 1h; b) 10% Pd/C, Ethanol, 27 C, 3h;
c) Cu(OAc) , CuBr, K CO , NaOH, DMF, 80 C, 16h; d) Py/HCl, 180 C, 4h; e) Tf O,
2 2 3 2
Pyridine, DCM, 0 C, 0.5 h; f) Pd(OAc) NH (CH ) OTBDMS, Cs CO , X-PHOS,
2, 2 2 2 2 3
Toluene, 100 C, 4h; g) DCM, Et N, RT, 3h; h) 3% HCl-EtOH, RT, 1h; i) CH CN, Et N,
3 3 3
80 C, 16h; j) NH , Dioxane, RT, 6h.
Procedures:
4-Amino(6-fluorophenyl-1H-indolyl)-7,8-dihydrooxepino[2,3-d]pyrimidin-
(6H)-one:
1-Fluoro(isocyanomethyl)methoxynitrobenzene (96A):
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Potassium t-butoxide (15.74 g, 140 mmol) in DMF (50 mL) was added to a solution of 2-
fluoromethoxynitrobenzene (12 g, 70.1 mmol) and 2-(4-chlorophenoxy)acetonitrile
(11.75 g, 70.1 mmol) in DMF (100 mL) at -20 C. The reaction mixture was stirred for 1 h
and then quenched with water. The aqueous layer was extracted with ethyl acetate.
Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and
concentrated in vacuo. The crude product was purified by flash chromatography using 3%
ethyl acetate in hexane to afford title compound (3.6 g, 23.21%) as a solid. H NMR
(400MHz, CDCl ): 8.05 (d, J = 10.84 Hz, 1H), 7.27-7.23 (m, 1H), 4.28 (s, 2H), 4.05 (s,
3H); ESI-MS m/z = 209 (M-H) ; LCMS Purity: 95%
6-Fluoromethoxy-1H-indole (96B):
Palladium on carbon (1 g, 0.940 mmol) was added to a solution of product of Example
96A (3.5 g, 16.65 mmol) in ethanol (40 mL) under hydrogen atmosphere, and the mixture
was stirred for 4 h. Insoluble solids were filtered off, and filtrate was concentrated to
afford title compound (2.2 g, 78%) as a solid. H NMR (400MHz, CDCl ): 8.05 (bs,
1H), 7.20-7.11 (m, 3H), 6.48 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H).
6-Fluoromethoxyphenyl-1H-indole (96C):
Iodo benzene (1.729 g, 8.48 mmol) was added to a solution of product of Example 96B
(1.4 g, 8.48 mmol) and Copper(I) bromide (10.46 mg, 0.073 mmol) in DMF (10 mL )
followed by potassium carbonate (3.51 g, 25.4 mmol), and the mixture was stirred at 100
C for 10 min. NaOH (210 mg, 5.25 mmol) and copper(II) acetate (14 mg, 0.077 mmol)
was added, and the mixture was stirred at 110 C for 16 h. Insoluble solids were filtered
off, and filtrate was concentrated. Residue was partitioned between diethyl ether and
water. Organic layer was separated, washed with brine, dried over sodium sulphate,
filtered and concentrated in vacuo. The crude product was purified by flash
chromatography using 10% ethyl acetate in hexane as eluent to afford title compound
(1.45 g, 67.4%) as off-white solid. H NMR (300MHz, CDCl ): -7.44 (m, 4H),
7.38-7.26 (m, 3H), 7.19 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 3.95 (s, 3H).
6-Fluorophenyl-1H-indolol (96D):
PU64642PCT
A mixture of product of Example 96C (1.1 g, 4.56 mmol) and pyridine-hydrochloride
(0.527 g, 4.56 mmol) was stirred at 160 C in seal tube for 6 h. The mixture was dissolved
in ethyl acetate, washed with water and saturated aqueous brine, dried over sodium sulfate
and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography
using 12% ethyl acetate in hexane to afford title compound (0.37 g, 32.5%) as a pale
brown solid. H NMR (400MHz, CDCl ): J = 6.8 Hz, 1H), 7.58-7.53 (m, 2H),
7.48-7.34 (m, 5H), 6.7 (d, J = 3.6 Hz, 1H).
6-Fluorophenyl-1H-indolyl trifluoromethanesulfonate (96E):
Triflic anhydride (0.372 g, 2.2 mmol) was added to an ice cold solution of product of
Example 96D (0.5 g, 2.2 mmol) and pyridine (0.087 mg, 1.1 mmol) in dichloromethane
(10 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture
was diluted with dichloromethane (20 mL) and extracted with saturated aqueous solution
of NaCl (15 mL). The organic layer dried over sodium sulphate, filtered and the filtrate
was concentrated under reduced pressure to afford title compound (0.7 g, 89%) as an oil.
ESI-MS m/z = 360 (M+H) ; LCMS Purity: 85%.
N-(2-(tert-Butyldimethylsilyloxy)ethyl)fluorophenyl-1H-indolamine (96F):
A mixture of product of Example 96E (0.1 g, 0.278 mmol), 2-(t-
butyldimethylsilyloxy)ethanamine (0.048 g, 0.278 mmol), cesium carbonate (0.136 g,
0.417 mmol), palladium acetate (6.25 mg, 0.028 mmol) and X-PHOS (13.27 mg, 0.028
mmol) in toluene (10 mL) under Argon was refluxed at 120 C for 2.5 h. The reaction was
cooled, diluted with ethyl acetate, and washed with water (2x5 mL) and saturated aqueous
brine. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain
dark oil. The residue was purified by flash chromatography using 10% ethyl acetate in
hexane to afford title compound (0.03 g, 25%) as an off-white solid. H NMR (300MHz,
CDCl ): 7.6-7.5 (m, 5H), 7.4-7.25 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 3.0 Hz,
1H), 4.75 (m, 1H), 3.81 (t, J = 5.7 Hz, 2H), 3.25 (q, J = 5.7 Hz, 2H), 0.88 (s, 9H), 0.05 (s,
6H).
PU64642PCT
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(6-fluorophenyl-1H-indol-
-yl)pyrimidinecarboxamide (96G):
To a stirred, cooled (0 C) solution of product of Example 96F(0.18 g, 0.468 mmol) and
TEA (0.065 mL, 0.468 mmol) in DCM (8 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.098 g, 0.468 mmol) in DCM (2 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x5 mL) and saturated aqueous brine. The organic layer was dried over sodium sulphate,
filtered and concentrated in vacuo to afford oil. The residue was purified by flash
chromatography using 20% ethyl acetate in hexane to afford title compound (100 mg,
38%) as a pale yellow oil.
4,6-Dichloro-N-(6-fluorophenyl-1H-indolyl)-N-(2-hydroxyethyl)pyrimidine
carboxamide (96H):
A solution of product of Example 96G (100 mg, 0.179 mmol), in 10 mL of ethanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of ethanol) was stirred at room
temperature for 1 h. Ethanol was removed in vacuo, the residue was dissolved in ethyl
acetate, and washed with saturated aqueous sodium bicarbonate and saturated aqueous
brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo
to afford title compound (0.07 g, 77%) as an oil, which was carried on to the next step
without further purification.
4-Chloro(6-fluorophenyl-1H-indolyl)-7,8-dihydrooxepino[2,3-d]pyrimidin-
(6H)-one (96I):
A slurry of product of Example 96H (0.07 g, 0.157 mmol) and TEA (0.022 mL, 0.157
mmol) in acetonitrile (8 mL) was stirred at 80 C for 16 h. The reaction mixture was
cooled, concentrated in vacuo, diluted with ethyl acetate, and washed with water and
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saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.067 g, 87%) as a pale yellow solid. H
NMR (400MHz, CDCl ): J = 7.2 Hz, 1H), 7.6-7.3 (m, 7H), 6.7
(d, J = 2.8 Hz, 1H), 4.84 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H).
4-Amino(6-fluorophenyl-1H-indolyl)-7,8-dihydrooxepino[2,3-d]pyrimidin-
(6H)-one (96):
A solution of product of Example 96I (0.06 g, 0.147 mmol), in 0.5M ammonia in p-
dioxane (8 mL) was stirred at room temperature for 1 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.03 g, 48.8%) as a pale yellow solid. H NMR
(400MHz, DMSO-d ): H NMR (400 MHz, DMSO-d ): -7.56 (m,
7H), 7.5-7.4 (m, 3H), 6.76 (d, J = 2.8 Hz, 1H), 4.64 (t, J = 4.0 Hz, 2H), 4.0 (t, J = 4.0 Hz,
2H); ESI-MS m/z = 390 (M+H) ; HPLC purity: 93%.
Example 97: 4-Amino(3-benzyloxo-3,4-dihydroquinazolinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Example 98: 4-Amino(4-oxo-3,4-dihydroquinazolinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) benzyl bromide, NaH, DMF, 80 C, 4h; b)
NH (CH ) OTBDMS, Pd(OAc) , Cs CO , X-PHOS, Toluene, 110 C, 16h; c) DCM, Et N,
2 2 2 2 2 3 3
RT, 1h; d) 3% HCl-MeOH, RT, 1h; e) CH CN, Et N, 80 C, 16h; f) NH , Dioxane, RT,
3 3 3
Procedures:
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3-Benzylbromoquinazolin-4(3H)-one (97A):
Benzyl bromide (0.264 mL, 2.22 mmol) was added to a solution of 6-bromoquinazolin-
4(3H)-one (0.5 g, 2.22 mmol) and NaH (0.08 g, 3.33 mmol) in DMF (5 mL) at 0 C. The
reaction mixture was heated to 80 C for 4 h. The reaction mixture was partitioned
between ethyl acetate and water. Organic layer was separated, washed with brine, dried
over sodium sulphate, filtered and concentrated in vacuo to afford title compound (0.4 g,
48.1%) as pale yellow solid. H NMR (400MHz, CDCl ): 8.46 (d, J = 1.6 Hz, 1H), 8.09
(s, 1H), 7.83 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.4-7.2 (m, 5H),
.2 (s, 2H); ESI-MS m/z = 315 (M+H) ; LCMS purity: 84.2%
3-Benzyl(2-(tert-butyldimethylsilyloxy)ethylamino)quinazolin-4(3H)-one (97B):
A mixture of product of Example 97A (0.4 g, 1.269 mmol), 2-(tert-
butyldimethylsilyloxy)ethanamine (0.267 g, 1.523 mmol), cesium carbonate (1.241 g, 3.81
mmol), palladium acetate (0.014 g, 0.063 mmol) and X-PHOS (0.03 g, 0.063 mmol) in
Toluene (10 mL) under Argon was refluxed at 110 C for 16 h. The reaction mixture was
cooled, diluted with ethyl acetate, and washed with water (2x15 mL) and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
to obtain dark oil. The residue was purified by flash chromatography using 20% ethyl
acetate in hexane to afford title compound (0.2 g, 31.9%) as an off-white solid.
N-(3-Benzyloxo-3,4-dihydroquinazolinyl)-N-(2-(tert-
butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidinecarboxamide (97C):
To a stirred, cooled (0 C) solution of product of Example 97B (1.2 g, 2.93 mmol) and
TEA (1.225 mL, 8.79 mmol) in DCM (20 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (0.61 g, 2.92 mmol) in DCM (5 mL) at -30 C.
After 1 h, the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed
with water (2x15 mL) and saturated aqueous brine, The organic layer was dried over
sodium sulphate, filtered and concentrated in vacuo to afford title compound (0.9 g,
.8%) as a yellow solid.
N-(3-Benzyloxo-3,4-dihydroquinazolinyl)-4,6-dichloro-N-(2-
hydroxyethyl)pyrimidinecarboxamide (97D):
PU64642PCT
A solution of product of Example 97C (0.9 g, 1.54 mmol), in 10 mL of methanolic
solution of HCl (3 mL concentrated aqueous HCl in 97 mL of methanol) was stirred at
room temperature for 1 h. Methanol was removed in vacuo, the residue was dissolved in
ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo to afford title compound (0.5 g, 38%) as a solid, which was used in
the next step without further purification.
6-(3-Benzyloxo-3,4-dihydroquinazolinyl)chloro-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (97E):
A slurry of product of Example 97D (0.5 g, 1.063 mmol) and TEA (0.445 g, 3.19 mmol)
in acetonitrile (10 mL) was stirred at 80 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.2 g, 38.8%) as a yellow solid. H NMR (300MHz,
DMSO-d ): J = 2.4 Hz, 1H), 7.93 (dd, J = 2.1 Hz,
J = 8.7 Hz, 1H), 7.8 (d, J = 8.4 Hz, 1H), 7.4-7.2 (m, 5H), 5.23 (s, 2H), 4.77 (t, J = 4.5
Hz, 2H), 4.27 (t, J = 4.2 Hz, 2H).
4-Amino(3-benzyloxo-3,4-dihydroquinazolinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (97):
A solution of product of Example 97E (0.18 g, 0.415 mmol) in 0.5M ammonia in p-
dioxane (10 mL) was stirred at room temperature for 5 h. The reaction mixture was
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (0.14 g, 76%) as a white solid. H NMR (300MHz,
DMSO-d ): J = 2.1 Hz, 1H), 7.87 (dd, J = 2.1 Hz,
J = 8.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.67 (bs, 2H), 7.4-7.2 (m, 5H), 5.22 (s, 2H),
4.63 (t, J = 4.5 Hz, 2H), 4.08 (t, J = 4.2 Hz, 2H). ESI-MS m/z = 415 (M+H) ; LCMS
purity: 93%.
PU64642PCT
4-Amino(4-oxo-3,4-dihydroquinazolinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (98):
Pd/C (0.0514 g, 0.048 mmol) was added to a solution of Example 97 (0.1 g, 0.241 mmol)
and ammonium formate (76 mg, 1.207 mmol) in ethanol (5 mL) at 25 C. The reaction
mixture was heated to 80 C for 16 h. Insoluble solids were filtered off, and filtrate was
concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was
separated, washed with brine, dried over sodium sulphate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography using 60% ethyl acetate
in hexane to afford title compound (0.02 g, 23.51%) as a solid. H NMR (300MHz,
DMSO-d ): J = 3.0 Hz, 1H), 8.08 (d, J = 1.8 Hz,
1H), 7.83 (dd, J = 1.8 Hz, J = 8.4 Hz, 1H), 7.75-7.65 (m, 3H), 4.64 (m, 2H), 4.08 (m,
2H); ESI-MS m/z = 325 (M+H) ; LCMS purity: 93%.
Example 99 was prepared by the methods described above for Example 96 or routine
variations thereof starting from the requisite halo-substituted heterocycle ring system.
Ex Structure Analytical Data Mass/Purity
99 H NMR (400 MHz, CDCl ): ESI-MS m/z =
404 (M+H) ;
J = 6.8
HPLC purity:
Hz, 1H), 7.35-7.28 (m, 5H),
90.84%.
7.18 (d, J = 3.2 Hz, 1H), 7.15-
7.07 (m, 3H), 6.55 (d, J = 3.2
Hz, 1H), 5.27 (s, 2H), 4.75 (t, J
= 4.0 Hz, 2H), 3.99 (t, J = 4.8
Hz, 2H).
Example 100: 4-Amino(5-propyl-5H-pyrrolo[3,2-d]pyrimidinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) Br(CH ) OTBDMS, K CO , ACN, 80 C,16h; b) DCM,
2 2 2 3
Et N, -78 C; c) 3% HCl-EtOH, RT, 1h; d) CH CN, Et N, 80 C, 16h; e) NH , Dioxane,
3 3 3 3
RT, 2h, f) TFA, anisole, 90 C, 16h.
Procedures:
PU64642PCT
2-(tert-Butyldimethylsilyloxy)-N-(4-methoxybenzyl)ethanamine (100A):
(2-bromoethoxy)(tert-butyl)dimethylsilane (20 g, 84 mmol) was added to a solution of (4-
methoxyphenyl) methanamine (11.47 g, 84 mmol) in acetonitrile (200 mL) followed by
K CO (57.8 g, 418 mmol), and the mixture was stirred at 80 C for 16 h. Insoluble solids
were filtered off, filtrate was concentrated and partitioned between ethyl acetate and water.
Organic layer was separated, washed with brine, dried over sodium sulphate and filtered.
The filtrate was concentrated in vacuo and purified by flash chromatography using 30%
ethyl acetate in hexane to afford title compound (19 g, 77%) as an oil. H NMR (300
MHz, DMSO-d ): 7.22 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.62
(m, 4H), 2.56 (t, J = 5.7 Hz, 2H), 2.5 (m, 1H), 0.85 (s, 9H), 0.02 (s, 6H).
N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(4-methoxybenzyl)pyrimidine-
-carboxamide (100B):
To a stirred, cooled (0 C) solution of product of Example 100A (7.66 g, 25.9 mmol) and
TEA (5.42 mL, 38.9 mmol) in DCM (80 mL) was added drop wise a solution of 4,6-
dichloropyrimidinecarbonyl chloride (5.46 g, 25.90 mmol) in DCM (10 mL). After 1 h,
the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water
(2x60 mL) and saturated aqueous brine. The organic layer was dried over sodium
sulphate, filtered and concentrated in vacuo to afford title compound (9.0 g, 48.4%) as a
pale yellow solid.
4,6-Dichloro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)pyrimidinecarboxamide
(100C):
PU64642PCT
A solution of product of Example 100B (9 g, 9.13 mmol) in 60 mL of ethanolic solution of
HCl (3 mL concentrated aqueous HCl in 97 mL of ethanol) was stirred at room
temperature for 2 h. Ethanol was removed in vacuo, the residue was dissolved in ethyl
acetate, and washed with saturated aqueous sodium bicarbonate solution and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (4.5 g, 66%) as a pale yellow solid, which was carried
on to the next step without further purification.
4-Chloro(4-methoxybenzyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
(100D):
A slurry of product of Example 100C (4.5 g, 12.63 mmol) and TEA (8.8 mL, 63.2 mmol)
in acetonitrile (60 mL) was stirred at 80 C for 16 h. The reaction was cooled,
concentrated in vacuo, diluted with ethyl acetate, and washed with water and saturated
aqueous brine. The organic layer was dried over sodium sulfate, filtered and concentrated
in vacuo to afford title compound (3 g, 74.3%) as a white solid. H NMR (400MHz,
DMSO-d ): 8.77 (s, 1H), 7.3 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H),
4.41 (t, J = 4.8 Hz, 2H), 3.74 (s, 3H), 3.71 (t, J = 3.6 Hz, 2H).
4-Amino(4-methoxybenzyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
(100E):
A solution of product of Example 100D (3 g, 9.38 mmol) in 0.5M ammonia in p-dioxane
(30 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated in
vacuo, diluted with ethyl acetate, and washed with water and saturated aqueous brine. The
organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford
title compound (2.5 g, 77%) as a white solid. H NMR (300MHz, DMSO-d ):
1H), 7.63 (bs, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.65 (s, 2H), 4.31 (t,
J = 4.2 Hz, 2H), 3.74 (s, 3H), 3.56 (t, J = 4.8 Hz, 2H).
4-Amino-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (100F):
TFA (15 mL, 195 mmol) was added to a solution of 100E (2.5 g, 8.32 mmol) in anisole (1
mL, 9.15 mmol) at 0 C, and the mixture was stirred for 2 h at 90 C for 16 h in sealed-
tube. The reaction mixture was concentrated to get the residue and it was triturated with 25
mL (50%) ethyl acetate in hexane to afford to afford title compound (1.0 g, 66.7%) as an
PU64642PCT
off-white-solid. H NMR (400MHz, DMSO-d -D O): 8.26 (s, 1H), 4.57 (t, J = 3.9 Hz,
2H), 3.47 (t, J = 4.2 Hz, 2H).
Reagents and conditions: a) di(cyclopenta-2,4-dienyl)zirconium(IV) chloride, CH Cl ,
RT, 16h, b) K PO dibasic, Pd(OAc) , dicyclohexyl(2‟,6‟-dimethoxy-[1,1‟-biphenyl]
3 4 2 ,
yl)phosphine, ACN, water, 80 C, 16h, c), AcOH, 140 C, 4h; d) n-propyl bromide,
Cs CO , DMF, 25 C, 4h, e) K PO dibasic, CuI, (1S,2S)-cyclohexane-1,2-diamine, 1,4-
2 3 3 4
dioxane, 110 C, 24h.
Procedures:
4-Amino(5-propyl-5H-pyrrolo[3,2-d]pyrimidinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
(E)(2-Ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100G):
Di(cyclopenta-2,4-dienyl)zirconium(IV) chloride (0.685 g, 2.344 mmol) was added to a
solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.0 g, 39.1 mmol) in dichloromethane
(15 mL) followed by ethoxyethyne (3.01 g, 43.0 mmol) at 0 C, and the mixture was
stirred for 16 h at 25 C. Insoluble solids were filtered off, and filtrate was concentrated.
Residue was partitioned between ethyl acetate and water. Organic layer was separated,
washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to
afford title compound (6.04 g, 78.13%) as oil. H NMR (400 MHz, CDCl ): 7.04 (d, J =
14.0 Hz, 1H), 4.43 (d, J = 14.8 Hz, 1H), 3.84 (q, J = 7.2 Hz, 2H), 1.32-1.2 (m, 15H).
(E)Chloro(2-ethoxyvinyl)pyrimidinamine (100H):
A mixture of 2,4-dichloropyrimidinamine (2.0 g, 12.2 mmol), product of Example
100G (6.04 g, 30.5 mmol), potassium phosphate dibasic (5.31 g, 30.5 mmol),
palladium(II) acetate (0.027 g, 0.122 mmol) and dicyclohexyl-(2‟,6‟-dimethoxy-[1,1‟-
biphenyl]yl)phosphine (0.050 g, 0.122 mmol) in acetonitrile (30 mL) and water (20
PU64642PCT
mL) under argon was refluxed at 80 C for 16 h. The reaction mixture was cooled, diluted
with ethyl acetate, and washed with water (2x30 mL) and saturated aqueous brine. The
organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and
purified by flash chromatography using 30% ethyl acetate in hexane to afford title
compound (0.3 g, 12.32%) as an oil. H NMR (300MHz, CDCl ): 7.89 (s, 1H), 7.85 (d, J
= 11.7 Hz, 1H), 5.69 (d, J = 11.7 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.49 (bs, 2H), 1.37 (t,
J = 7.5 Hz, 3H).
2-Chloro-5H-pyrrolo[3,2-d]pyrimidine (100I):
A solution of product of Example 100H (0.3 g, 1.503 mmol) in acetic acid (20 mL) was
stirred at 140 C for 4 h. Acetic acid was removed in high vacuo, the residue was co-
distilled with toluene to afford title compound (0.22 g, 88%) as a yellow solid, which was
carried on to the next step without further purification. H NMR (400MHz, DMSO-d ):
J = 3.2 Hz, 1H), 6.72 (s, 1H).
2-Chloropropyl-5H-pyrrolo[3,2-d]pyrimidine (100J):
1-Bromopropane (132 mg, 1.074 mmol) was added to a solution of product of Example
100I (150 mg, 0.977 mmol) in DMF (10 mL) followed by cesium carbonate (0.477 g,
1.074 mmol), and the mixture was stirred at 25 C for 4 h. Insoluble solids were filtered
off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and
water. Organic layer was separated, washed with brine, dried over sodium sulphate,
filtered and concentrated in vacuo. The crude product was purified by flash
chromatography using 5% ethyl acetate in hexane to afford title compound (0.15 g,
74.6%) as a brown color syrup. H NMR (300MHz, CDCl ): 8.68 (s, 1H), 7.51 (d, J =
3.0 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 4.16 (t, J = 6.9 Hz, 2H), 1.91 (m, 2H), 0.94 (t, J =
7.5 Hz, 3H).
4-Amino(5-propyl-5H-pyrrolo[3,2-d]pyrimidinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (100):
A mixture of product of Example 100J (0.195 g, 1.0 mmol), Example 100F (0.15 g, 0.833
mmol), potassium phosphate dibasic (0.29 g, 1.665 mmol), CuI (15.86 mg, 0.083 mmol)
and trans (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.023 g, 0.167 mmol) in 1,4-
dioxane (5 mL) under Argon was refluxed at 110 C for 24 h in sealed-tube. The reaction
PU64642PCT
mixture was diluted with methanol, insoluble solids were filtered off and filtrate was
concentrated to get the residue. The residue was purified by flash chromatography using
3% methanol in ethyl acetate to afford title compound (0.02 g) as a H
NMR (400MHz, DMSO-d ): 9.12 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.69
(bs, 2H), 6.62 (d, J = 2.8 Hz, 1H), 4.61 (t, J = 4.4 Hz, 2H), 4.29 (t, J = 7.2 Hz, 2H), 4.15 (t,
J = 4.8 Hz, 2H), 1.83 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); ESI-MS m/z = 340.1 (M+H) ;
LCMS Purity: 96.2%.
Example-101: 4-Amino(1-propyl-1H-pyrrolo[3,2-b]pyridinyl)-7,8-
dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one:
Reagents and conditions: a) n-propyl bromide, Cs CO , DMF, 70 C, 0.5h; b) CuI,
(1S,2S)-N,N‟-Dimethyl cyclohexyl-1,2-diamine, K PO , Toluene, 120 C, 2.5h;
Procedures:
4-Amino(1-propyl-1H-pyrrolo[3,2-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one:
-Chloropropyl-1H-pyrrolo[3,2-b]pyridine (101A):
1-Bromopropane (192 mg, 1.57 mmol) was added to a solution of 2-chloro-5H-
pyrrolo[3,2-d]pyrimidine (200 mg, 1.31 mmol) in DMF (15 mL) followed by cesium
carbonate (0.855 g, 2.63 mmol), and the mixture was stirred at 70 C for 0.5 h. Insoluble
solids were filtered off, filtrate was concentrated and partitioned between ethyl acetate and
water. Organic layer was separated, washed with brine, dried over sodium sulphate and
filtered. The filtrate was concentrated in vacuo to afford title compound (0.22 g, 86%) as
an oil. H NMR (300MHz, CDCl ): 7.59 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H),
7.10 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 4.07 (t , J = 6.9 Hz, 2H), 1.86 (m, 2H),
0.91 (t, J = 7.5 Hz, 3H).
4-Amino(1-propyl-1H-pyrrolo[3,2-b]pyridinyl)-7,8-dihydropyrimido[5,4-
f][1,4]oxazepin-5(6H)-one (101):
PU64642PCT
A mixture of product of Example 101A (0.064 g, 0.33 mmol), Example 100F (0.05 g, 0.27
mmol), potassium phosphate dibasic (0.117 g, 0.555 mmol), CuI (0.005 g, 0.027 mmol)
and trans (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.0076 g, 0.055 mmol) in
1,4-dioxane (5 mL) under argon was refluxed at 110 C for 24 h in sealed-tube. The
reaction mixture was diluted with methanol, insoluble solids were filtered off and filtrate
was concentrated to get the residue. The residue was purified by flash chromatography
using 3% methanol in ethyl acetate to afford title compound (0.005 g) as a yellow solid.
H NMR (400MHz, DMSO-d ): J = 8.4 Hz, 1H), 7.71 (d, J = 3.0
Hz, 1H), 7.60 (bs, 2H), 7.49 (d, J = 8.7 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 4.63 (m, 2H),
4.26 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 1.78 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); ESI-MS m/z
= 339.1 (M+H) ;
Examples 102 – 105 were prepared by the procedures analogous to those described in
Examples 65, 66, 82 or 83 using appropriately substituted starting materials.
Ex Structure Analytical Data Mass/Purity
102 H NMR (400 MHz, DMSO- ESI-MS m/z
= 387
d ): 8.71 (d, J = 2.4 Hz, 1H),
(M+H) ;
8.18 (s, 1H), 7.96 (dd, J = 2.4
HPLC purity:
Hz, J = 8.0 Hz, 1H), 7.74 (d, J
97%.
= 2.8 Hz, 1H), 7.7-7.6 (m, 3H),
7.54 (d, J = 8.8 Hz, 1H), 7.48
(d, J = 8.4 Hz, 1H), 7.18 (dd,
J = 1.6 Hz, J = 8.8 Hz, 1H),
6.77 (d, J = 2.8 Hz, 1H), 4.65
(t, J = 4.0 Hz, 2H), 4.01 (t, J =
4.4 Hz, 2H), 2.57 (s, 3H).
103 H NMR (400MHz, DMSO- ESI-MS m/z
= 422
d ): 8.18 (s, 1H), 7.82-7.76
(M+H) ;
(m, 5H), 7.68-7.60 (m, 4H),
LCMS
7.21 (dd, J = 2.0 Hz, J = 8.8
purity: 95%.
Hz, 1H), 7.15 (t, J = 56 Hz,
1H), 6.78 (d, J = 2.8 Hz, 1H),
4.65 (t, J = 4.0 Hz, 2H), 4.02
(t, J = 4.4 Hz, 2H).
104 H NMR (300MHz, DMSO- ESI-MS m/z
= 423
d ): 8.34 (d, J = 2.4 Hz, 1H),
(M+H) ;
8.17 (s, 1H), 8.15-8.06 (m,
LCMS
4H), 7.75 (d, J = 8.7 Hz, 2H),
purity: 97%.
7.65 (bs, 2H), 7.10 (t, J = 55.8
Hz, 1H), 6.80 (d, J = 3.9 Hz,
1H), 4.68 (t, J = 3.9 Hz, 2H),
4.05 (t, J = 3.9 Hz, 2H).
PU64642PCT
105 H NMR (400MHz, DMSO- ESI-MS m/z
= 442
d ): 9.37 (s, 1H), 8.82 (d, J =
(M+H) ;
4.8 Hz, 1H), 8.54-8.50 (m,
2H), 8.21 (d, J = 2.4 Hz, 1H), LCMS
purity: 99%.
8.19 (s, 1H), 7.72 (d, J = 5.2
Hz, 1H), 7.68 (bs, 2H), 6.88 (d,
J = 4.0 Hz, 1H), 4.71 (t, J = 3.6
Hz, 2H), 4.09 (t, J = 4.4 Hz,
2H).
Biological Assay
Human DGAT1 was expressed in Sf9 insect cells using a baculovirus expression system.
Microsomes were prepared and used as enzyme for in vitro inhibition testing in either of
two formats measuring production of coenzyme A or tridecanoylglycerol product,
respectively. All steps were performed at 21- C. All data for DGAT1 inhibition by
test compounds were collected under conditions where product formation was linear with
reaction time.
For inhibition of CoA product formation, test compounds were prepared in 100% DMSO,
diluted 100-fold into assay buffer, and 10 uL added to 96-well half-area plates (Greiner
675076). An equal volume (10 uL) of 3X enzyme in buffer was added and the
components incubated for 30 minutes pre-reaction incubation to allow enzyme and test
compounds to attain binding equilibrium. The 3X enzyme mixture contained 30 uM {4-
[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazinyl)phenyl]cyclohexyl}acetic
acid for fully inhibited control wells. Some assays were performed with inclusion of
didecanoylglycerol in the pre-reaction incubation of test compound and enzyme. DGAT
reactions (30 uL) were initiated upon addition of 10 uL of 3X substrate solution. Final
reaction conditions consisted of 20 mM HEPES pH 7.5, 2 mM MgCl , 1 mM CHAPS, 50
uM didecanoylglycerol, 3 uM decanoyl-CoA, 1 ug/mL microsomal protein, and 1%
DMSO. Following a 60 minute reaction incubation, reactions were stopped and CoA
product derivatized with 30 uL of buffer containing 10 uM {4-[4-(4-amino-7,7-dimethyl-
7H-pyrimido[4,5-b][1,4]oxazinyl)phenyl]cyclohexyl}acetic acid and 50 uM 7-
diethylamino(4‟-maleimidylphenyl)methylcoumarin (CPM). Fluorescence was read
using Envision reader at Ex 405 nm/Em 480 nm about 30 minutes after addition of final
solution. Inhibition was normalized to controls containing DMSO or 10 uM {4-[4-(4-
PU64642PCT
amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazinyl)phenyl]cyclohexyl}acetic acid.
IC s were fitted using GraphPad Prism to a sigmoidal dose response.
For inhibition of triacylglycerol product formation, 11 uL reactions were run in white
Polyplate-384 (PerkinElmer6007300) starting with a 30 minute pre-reaction incubation of
uL of 2.2X enzyme and 1 uL of 100% DMSO containing test compound or control
compound, {4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin
yl)phenyl]cyclohexyl}acetic acid. Some assays were performed with inclusion of
didecanoylglycerol in the pre-reaction incubation of test compounds and enzyme.
Reactions were initiated after 30 minute pre-reaction incubation via addition of 5 uL of
2.2X substrate. Final reaction conditions consisted of 50 mM HEPES pH 7.5, 2 mM
MgCl , 1 mM CHAPS, 25 uM didecanoylglycerol, 0.5 uM decanoyl-CoA, 0.3 nCi/uL
14 3
[ C]-decanoyl-CoA or 0.5 nCi/uL [ H]-decanoyl-CoA, 0.05-4 ug/mL microsomal protein,
and 1% DMSO. Following 60 minute reaction incubation, reactions were stopped with 40
uL of 45% isopropanol and 50 mM sodium carbonate in water and mixed. Extraction of
tridecanoylglycerol product was accomplished via addition of 30 uL Microscint-E (Perkin
Elmer) and 2 hours of incubation (sealed). Plates were read on a Microbeta Microplate
reader. Inhibition was normalized to controls containing DMSO or 10 uM {4-[4-(4-
amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazinyl)phenyl]cyclohexyl}acetic acid.
IC s were fitted using GraphPad Prism to a sigmoidal dose response.
Biological Data
Exemplified compounds of the present invention are inhibitors of DGAT1. All of
of the compounds except Example 101 were tested at one or more DGAT assays described
above and were found to be inhibitors of DGAT1 with IC < 10 uM or inhibition >50% at
uM. Data for some specific examples tested at the human DGAT1 fluorescene (CPM)
or lipid extraction (LE) assays are listed below.
hDGAT1 CPM Assay hDGAT1 LE Assay
IC (nM) IC (nM)
50 50
3 371.6
6 85.8
42.0
11 6.3
12 16.3
33 23.3
PU64642PCT
34 25.7
59 49.5
60 14.8
63 2.3
64 8.8
65 3.9
66 42.5
68 2.8
72 9.3
74 4.5
76 2.5
78 7.3
80 3.6
81 2.1
82 20.5
83 40.0
87 55.1
94 872.5
95 10.1
96 7.3
97 200.8
98 623.0
PU64642PCT
Claims (12)
1. A compound of Formula (I): wherein R is a bicyclic ring system which contains 9 to 11 ring members including 1 to 4 hetero atoms, in which said bicyclic ring system may be substituted by 1 to 3 groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C - 1 6 1 6 3 C cycloalkyl, halo, hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, 7 a 2 a -(C -C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy, 1 3 1 4 in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo, 2 3 1 6 1 6 hydroxyl, amide, carboxylic acid or C -C alkoxy; and m is 0-2; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, which is represented by Formula (I)(A) (I)(A) wherein A is a 5- or 6-membered heterocyclic ring, which may contain 0 to 3 double bonds and may be substituted by 1 to 3 groups selected from the group consisting of PU64642PCT C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, hydroxyl, oxo, amide, 1 6 1 6 3 7 carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C -C alkyl)aryloxy, aryl, heteroaryl and a 2 a 1 3 C -C alkoxy, in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo, 2 3 1 6 1 6 hydroxyl, amide, carboxylic acid or C -C alkoxy; R is halo or alkoxy; X is N or CH; and m is 0-2; n is 0-2; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2, wherein A is a 5-membered heterocyclic ring, which may contain 0-2 double bonds and may be substituted by 1 to 3 groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, 1 6 1 6 3 7 hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C - a 2 a 1 C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy, 3 1 4 in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo, 2 3 1 6 1 6 hydroxyl, amide, carboxylic acid or C -C alkoxy; R is halo or alkoxy; X is N or CH; and m is 0-2; n is 0-2; or a pharmaceutically acceptable salt thereof.
4. A compound of claim 2, wherein A is a 6-membered heterocyclic ring, which may contain 0-3 double bonds and may be substituted by 1 to 3 groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, halo, 1 6 1 6 3 7 hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C - a 2 a 1 C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy, 3 1 4 PU64642PCT in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; each R and R is independently hydrogen, C -C alkyl, substituted C -C alkyl, halo, 2 3 1 6 1 6 hydroxyl, amide, carboxylic acid or C -C alkoxy; R is halo or alkoxy; X is N or CH; and m is 0-2; n is 0-2; or a pharmaceutically acceptable salt thereof.
5. A compound of any one of claims 2-4, wherein m is 0; n is 0; R is hydrogen; and X is N; or a pharmaceutically acceptable salt thereof.
6. A compound of any one of claims 2-4, wherein m is 0; n is 0; R is hydrogen; and X is CH; or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1, wherein m is 0; R is hydrogen; R is a bicyclic ring system selected from the group consisting of tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolyl, dihydroindolyl, indazolyl, dihydroindazolyl, benzothiophenyl, benzodiazolyl, dihydrobenzodiazolyl, benzimidazolyl, indolinyl, benzotriazolyl, pyrrolopyridinyl, benzothiazolyl, benzofuranyl, dihydroquinazolinyl, and pyrrolopyrimidinyl; wherein said bicyclic ring system may be substituted by 1 to 3 groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, 1 6 1 6 3 7 PU64642PCT halo, hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C - a 2 a 1 C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy, 3 1 4 in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; or a pharmaceutically acceptable salt thereof.
8. A compound of claim 7, wherein m is 0; R is hydrogen; R is a bicyclic ring system selected from the group consisting of tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolyl, dihydroindolyl, indazolyl, dihydroindazolyl, and pyrrolopyridinyl; wherein said bicyclic ring system may be substituted by 1 to 3 groups selected from the group consisting of C -C alkyl, substituted C -C alkyl, C -C cycloalkyl, 1 6 1 6 3 7 halo, hydroxyl, oxo, amide, carboxylic acid, -C(O)R , -SO R , arylalkyl, -(C - a 2 a 1 C alkyl)aryloxy, aryl, heteroaryl and C -C alkoxy, 3 1 4 in which each R is independently C -C alkyl, substituted C -C alkyl or a 1 6 1 6 unsubstituted C -C cycloalkyl; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 which is: 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo- 1,2,3,4-tetrahydroisoquinolinyl)acetic acid; ethyl 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl} oxo-1,2,3,4-tetrahydroquinolinyl)acetate; 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}oxo- 1,2,3,4-tetrahydroquinolinyl)acetic acid; ethyl 2-(6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl} oxo-1,2,3,4-tetrahydroisoquinolinyl)acetate; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}methyl- 1,2,3,4-tetrahydroquinolinone; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}methyl- 1,2,3,4-tetrahydroisoquinolinone; PU64642PCT 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl- 1,2,3,4-tetrahydroisoquinolinone; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl- 1,2,3,4-tetrahydroisoquinolinone; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl- 1,2,3,4-tetrahydroquinolinone; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl (propenyl)-2,3-dihydro-1H-indazolone; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl- 2,3-dihydro-1H-indazolone; 4-amino(1-propyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin- 5-one; 4-amino(1-propyl-1H-indazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1-benzothiophenyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin one; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-1,3-dipropyl- 2,3-dihydro-1H-1,3-benzodiazolone; 4-amino(2-propyl-2H-indazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1,3-benzothiazolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin one; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl- 2,3-dihydro-1H-indole-2,3-dione; 4-amino(1-benzofuranyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1-cyclopropyl-1,2,3,4-tetrahydroquinolinyl)-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino(2-propyl-1,2,3,4-tetrahydroisoquinolinyl)-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinolinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 5-{4-aminooxo-5H,6H,7H,8H-oxepino[2,3-d]pyrimidinyl}(propanyl)- 2,3-dihydro-1H-indazolone; PU64642PCT 5-{4-aminooxo-5H,6H,7H,8H-oxepino[2,3-d]pyrimidinyl}(2- methoxyethyl)-2,3-dihydro-1H-indazolone; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}(2,2- difluoroethyl)-2,3-dihydro-1H-indazolone; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl} cyclopropyl-2,3-dihydro-1H-indazolone; 6-amino(1-propyl-1H-1,3-benzodiazolyl)-2,3,4,5-tetrahydro-1,4- benzoxazepinone; 4-amino(1-propyl-1H-1,3-benzodiazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(2-propyl-2H-1,2,3-benzotriazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1-propyl-1H-1,2,3-benzotriazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(2-methyl-1,3-benzothiazolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-cyclopropyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(cyclopropylmethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 3-(5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-1H-indol- 1-yl)propanoic acid; 4-amino[1-(cyclohexylmethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(pentanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{1-[(4-methoxyphenyl)methyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[(4-fluorophenyl)methyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[2-(benzyloxy)ethyl]-1H-indolyl}-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; PU64642PCT 4-amino(1-benzyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin- 5-one; 4-amino[1-(3-methoxypropyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2,2-difluoroethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1-methyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin- 5-one; 4-amino[1-(2-methoxyethyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(propanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1-propyl-2,3-dihydro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(2,3-dihydro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2-methoxyethyl)-2,3-dihydro-1H-indolyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1,2-dimethyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-propyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-cyclohexyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(propanyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; PU64642PCT 4-amino[1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1-methanesulfonyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(1-cyclopropyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 5-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}propyl- 1H-indolecarboxylic acid; 4-amino[1-propyl(trifluoroacetyl)-1H-indolyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-propyl(1,1,1-trifluoromethoxypropanyl)-1H-indolyl]- 5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1-phenyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepin- 5-one; 4-amino{1-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridinyl}- 5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(3-chlorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(2-methoxyphenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{1-phenyl-1H-pyrrolo[2,3-b]pyridinyl}-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(3,4-difluorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; PU64642PCT 4-amino[1-(2-fluorophenyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{1-[4-(trifluoromethyl)phenyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[3-(trifluoromethyl)phenyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridinyl}- 5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(1,3-thiazolyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{1-[6-(trifluoromethyl)pyridinyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(pyridinyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino[1-(pyridinyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(pyrazinyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(pyrazinyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{1-[5-(trifluoromethyl)pyridinyl]-1H-indolyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[5-(trifluoromethyl)pyridinyl]-1H-pyrrolo[2,3-b]pyridinyl}- 5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-(1,3-thiazolyl)-1H-pyrrolo[2,3-b]pyridinyl]-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino{1-[6-(trifluoromethyl)pyridinyl]-1H-pyrrolo[2,3-b]pyridinyl}- 5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinone; 4-amino[1-phenyl(propanyl)-1H-indolyl]-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino(2-phenylpropyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; PU64642PCT 4-amino(6-fluorophenyl-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}benzyl- 3,4-dihydroquinazolinone; 6-{4-aminooxo-5H,6H,7H,8H-pyrimido[5,4-f][1,4]oxazepinyl}-3,4- dihydroquinazolinone; 4-amino(1-benzylfluoro-1H-indolyl)-5H,6H,7H,8H-pyrimido[5,4- f][1,4]oxazepinone; 4-amino{5-propyl-5H-pyrrolo[3,2-d]pyrimidinyl}-5H,6H,7H,8H- pyrimido[5,4-f][1,4]oxazepinone; 4-amino(1-propyl-1H-pyrrolo[3,2-b]pyridinyl)-7,8-dihydropyrimido[5,4- f][1,4]oxazepin-5(6H)-one; 4-amino(1-(6-methylpyridinyl)-1H-indolyl)-7,8-dihydropyrimido[5,4- f][1,4]oxazepin-5(6H)-one; 4-amino(1-(4-(difluoromethyl)phenyl)-1H-indolyl)-7,8-dihydropyrimido[5,4- f][1,4]oxazepin-5(6H)-one; 4-amino(1-(4-(difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8- dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one; or 4-amino(1-(4-(trifluoromethyl)pyridinyl)-1H-pyrrolo[2,3-b]pyridinyl)-7,8- dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one; or a pharmaceutically acceptable salt thereof.
10. The use of a compound according to any one of the preceding claims for the preparation of a medicament for treating obesity.
11. A pharmaceutical composition comprising a compound according to any one of claims 1-7, and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition according to claim 11, substantially as herein described with reference to any example thereof.
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US61/503,728 | 2011-07-01 | ||
PCT/US2012/038523 WO2012162129A1 (en) | 2011-05-20 | 2012-05-18 | Novel compounds as diacylglycerol acyltransferase inhibitors |
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