NZ717864B2 - Substituted quinolizine derivatives useful as hiv integrase inhibitors - Google Patents
Substituted quinolizine derivatives useful as hiv integrase inhibitors Download PDFInfo
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- NZ717864B2 NZ717864B2 NZ717864A NZ71786414A NZ717864B2 NZ 717864 B2 NZ717864 B2 NZ 717864B2 NZ 717864 A NZ717864 A NZ 717864A NZ 71786414 A NZ71786414 A NZ 71786414A NZ 717864 B2 NZ717864 B2 NZ 717864B2
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- New Zealand
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- alkyl
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- 125000002471 4H-quinolizinyl group Chemical class C=1(C=CCN2C=CC=CC12)* 0.000 title abstract 5
- 239000003084 hiv integrase inhibitor Substances 0.000 title description 17
- 239000000203 mixture Substances 0.000 claims abstract description 247
- 239000011780 sodium chloride Substances 0.000 claims abstract description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 150000001875 compounds Chemical class 0.000 claims description 1041
- 125000000217 alkyl group Chemical group 0.000 claims description 131
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000002950 monocyclic group Chemical group 0.000 claims description 34
- 125000002947 alkylene group Chemical group 0.000 claims description 33
- 125000004429 atoms Chemical group 0.000 claims description 33
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 31
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 28
- 230000002401 inhibitory effect Effects 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 20
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 16
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- JTEGQNOMFQHVDC-NKWVEPMBSA-N 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 14
- 229960001627 Lamivudine Drugs 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- MCGSCOLBFJQGHM-SCZZXKLOSA-N Abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 230000000069 prophylaxis Effects 0.000 claims description 12
- 229960004748 abacavir Drugs 0.000 claims description 11
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 11
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 10
- NCDNCNXCDXHOMX-XGKFQTDJSA-N Ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 10
- 229960000311 ritonavir Drugs 0.000 claims description 10
- 229960004525 lopinavir Drugs 0.000 claims description 9
- 102000000642 HIV Integrase Human genes 0.000 claims description 8
- 108010002459 HIV Integrase Proteins 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- XQSPYNMVSIKCOC-NTSWFWBYSA-N (2R-cis)-4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2(1H)-Pyrimidinone Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229960003277 atazanavir Drugs 0.000 claims description 6
- 229960005107 darunavir Drugs 0.000 claims description 6
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 claims description 6
- 229960000366 emtricitabine Drugs 0.000 claims description 6
- AXRYRYVKAWYZBR-GASGPIRDSA-N Atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 5
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 claims description 5
- 229960002814 rilpivirine Drugs 0.000 claims description 4
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 229960004556 Tenofovir Drugs 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N Tenofovir Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 208000005721 HIV Infections Diseases 0.000 abstract description 31
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 abstract description 30
- 239000000651 prodrug Substances 0.000 abstract description 22
- 229940002612 prodrugs Drugs 0.000 abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 279
- 239000000243 solution Substances 0.000 description 203
- 238000003786 synthesis reaction Methods 0.000 description 192
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 191
- 230000015572 biosynthetic process Effects 0.000 description 186
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 184
- 230000002194 synthesizing Effects 0.000 description 184
- 238000003756 stirring Methods 0.000 description 177
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 174
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 173
- 238000006243 chemical reaction Methods 0.000 description 157
- 235000019439 ethyl acetate Nutrition 0.000 description 138
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 134
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- 239000007787 solid Substances 0.000 description 92
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 87
- 239000008079 hexane Substances 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- 150000003250 quinolizines Chemical class 0.000 description 71
- 235000002639 sodium chloride Nutrition 0.000 description 70
- 238000002360 preparation method Methods 0.000 description 67
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 63
- -1 bicyclic pyrimidinones Chemical class 0.000 description 61
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 58
- 239000012074 organic phase Substances 0.000 description 55
- 239000012071 phase Substances 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- 229960001866 silicon dioxide Drugs 0.000 description 51
- 239000012230 colorless oil Substances 0.000 description 50
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 241000725303 Human immunodeficiency virus Species 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 29
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- VUVGYHUDAICLFK-UHFFFAOYSA-N Perosmic oxide Chemical compound O=[Os](=O)(=O)=O VUVGYHUDAICLFK-UHFFFAOYSA-N 0.000 description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 239000012453 solvate Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 16
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 15
- 125000003342 alkenyl group Chemical group 0.000 description 15
- 125000000732 arylene group Chemical group 0.000 description 15
- 230000000875 corresponding Effects 0.000 description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 15
- 230000002829 reduced Effects 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 239000003443 antiviral agent Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 101700028444 USO1 Proteins 0.000 description 11
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 11
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 11
- 230000017613 viral reproduction Effects 0.000 description 11
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 10
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 8
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- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N Tributyltin hydride Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N Zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 6
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- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- MIMJFNVDBPUTPB-UHFFFAOYSA-N potassium hexacyanoferrate(3-) Chemical compound [K+].[K+].[K+].N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N MIMJFNVDBPUTPB-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (NE)-N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- ZMUQQQPLBINFTP-UHFFFAOYSA-N pyrazolo[1,5-a]pyridin-2-ylmethanamine Chemical compound C1=CC=CN2N=C(CN)C=C21 ZMUQQQPLBINFTP-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical class NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005857 pyrrolidino(C2-C3)alkyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000001850 reproductive Effects 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007086 side reaction Methods 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
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 229940013123 stannous chloride Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- PINIEAOMWQJGBW-FYZOBXCZSA-N tenofovir hydrate Chemical compound O.N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N PINIEAOMWQJGBW-FYZOBXCZSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- UPUJGSUSGASQJV-UHFFFAOYSA-J tetrasodium;disulfite Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])=O.[O-]S([O-])=O UPUJGSUSGASQJV-UHFFFAOYSA-J 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical class [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- 229960005486 vaccines Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 150000003954 δ-lactams Chemical class 0.000 description 1
Abstract
The present invention relates to Substituted Quinolizine Derivatives of Formula (I): and pharmaceutically acceptable salts or prodrug thereof, wherein X, Y, R1, R2, R3, R4, R5, R9 and R10 are as defined herein. The present invention also relates to compositions comprising at least one Substituted Quinolizine Derivative, and methods of using the Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject. inolizine Derivative, and methods of using the Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject.
Description
SUBSTITUTED QUINOLIZINE DERIVATIVES USEFUL AS HIV INTEGRASE
INHIBITORS
FIELD OF THE INVENTION
The present invention relates to Substituted Quinolizine Derivatives, and
compositions comprising at least one Substituted Quinolizine Derivative. Methods of using the
Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject are
described herein.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV), particularly the
strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus, is the etiological agent of
the complex disease that includes progressive destruction of the immune system (acquired
immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous
system. A common feature of retrovirus replication is the insertion by virally-encoded integrase
of +proviral DNA into the host cell genome, a required step in HIV replication in human T-
lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three
steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two
nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3'
OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step
in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open
reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology
provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986);
Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential
for the replication of HIV.
The following references may be of interest as background:
International Publication Nos. WO 11/045330 and WO 11/121105 disclose
macrocyclic compounds having HIV integrase inhibitory activity.
Kinzel et al., Tet. Letters 2007, 48(37): pp. 6552-6555 discloses the synthesis of
tetrahydropyridopyrimidones as a scaffold for HIV-1 integrase inhibitors.
Ferrara et al., Tet. Letters 2007, 48(37), pp. 8379-8382 discloses the synthesis of a
hexahydropyrimido[1,2-a]azepinecarboxamide derivative useful as an HIV integrase
inhibitor.
Muraglia et al., J. Med. Chem. 2008, 51: 861-874 discloses the design and
synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.
US2004/229909 discloses certain compounds having integrase inhibitory
activity.
US 7232819 and US 2007/0083045 disclose certain 5,6-dihydroxypyrimidine
carboxamides as HIV integrase inhibitors.
US 7169780, US 7217713, and US 2007/0123524 disclose certain N-substituted
-hydroxyoxo-1,6-dihydropyrimidinecarboxamides as HIV integrase inhibitors.
US 7279487 discloses certain hydroxynaphthyridinone carboxamides that are
useful as HIV integrase inhibitors.
US 7135467 and US 7037908 disclose certain pyrimidine carboxamides that are
useful as HIV integrase inhibitors.
US 7211572 discloses certain nitrogenous condensed ring compounds that are
HIV integrase inhibitors.
US 7414045 discloses certain tetrahydro-4H-pyrido[1,2-a]pyrimidine
carboxamides, hexahydropyrimido[1,2-a]azepine carboxamides, and related compounds that are
useful as HIV integrase inhibitors.
US 8129385 discloses certain hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-
b][1,3]oxazinecarboxamides, and related compounds that are useful as HIV integrase
inhibitors.
discloses certain tetrahydro-4H-pyrimidooxazepine
carboaxmides, tetrahydropyrazinopyrimidine carboxamides, hexahydropyrimidodiazepine
carboxamides, and related compounds that are useful as HIV integrase inhibitors.
US 2007/0142635 discloses processes for preparing hexahydropyrimido[1,2-
a]azepinecarboxylates and related compounds.
US 2007/0149556 discloses certain hydroxypyrimidinone derivatives having HIV
integrase inhibitory activity.
Various pyrimidinone compounds useful as HIV integrase inhibitors are also
disclosed in US 7115601, US 7157447, US 7173022, US 7176196, US 7192948, US 7273859,
and US 7419969.
US 2007/0111984 discloses a series of bicyclic pyrimidinone compounds useful
as HIV integrase inhibitors.
US 2006/0276466, US 2007/0049606, US 2007/0111985, US 2007/0112190,
US 2007/0281917, US 2008/0004265 each disclose a series of bicyclic pyrimidinone compounds
useful as HIV integrase inhibitors.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
X is -NHC(O)-;
Y is CH ;
R is selected from C -C aryl, 5 or 6-membered monocyclic heteroaryl and 9 or
6 10
-membered bicyclic heteroaryl, wherein said C -C aryl group, said 5 or 6-membered
6 10
monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be
optionally substituted with up to three R groups;
2 11 7 2 4
R is H, C -C alkyl, -N(R ) , or -OR or R and R , together with the carbon
1 6 2
atoms to which they are attached, can join to form a 5 to 8-membered monocyclic cycloalkyl
group, 5 to 8-membered monocyclic heterocycloalkyl group, 5 to 8-membered monocyclic
heterocycloalkenyl group or a 8 to 11-membered bicyclic heterocycloalkyl, wherein said 5 to 8-
membered monocyclic cycloalkyl group, said 5 to 8-membered monocyclic heterocycloalkyl
group, said 5 to 8-membered monocyclic heterocycloalkenyl group and said 8 to 11-membered
bicyclic heterocycloalkyl group can be optionally substituted with up to three R groups, which
can be the same or different;
3 11 7
R is H, C -C alkyl, -N(R ) or -OR ;
1 6 2
4 11
R is selected from H, C -C alkyl, -(C -C alkylene)-O-(C -C alkyl), -N(R )
1 6 1 6 1 6 2
7 2 3 11 4
and -OR , such that when R and/or R are -N(R ) , then R is other than H;
R is C -C alkyl;
each occurrence of R is independently H or C -C alkyl;
each occurrence of R is independently selected from H, C -C alkyl, –(C -C
1 6 1 6
alkylene)-O-(C -C alkyl) and C -C cycloalkyl;
1 6 3 7
each occurrence of R is independently selected from C -C alkyl, halo, -OR , -
6 6 7
SR , C -C haloalkyl, C -C hydroxyalkyl, -O-(C -C haloalkyl), -CN, -NO , -N(R ) , -C(O)OR ,
1 6 1 6 1 6 2 2
-C(O)N(R ) and -NHC(O)R ;
R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR -
1 6 1 6 1 6 1 6
C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl;
1 6 1 6 1 6
6
R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR -
1 6 1 6 1 6 1 6
C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl;
1 6 1 6 1 6
11 12
each occurrence of R is independently selected from H, C -C alkyl, -S(O) R
1 6 2
and –C(O)R ; and
each occurrence of R is independently selected from C -C alkyl, C -C
1 6 3 7
cycloalkyl, C -C aryl, 4 to 7-membered monocyclic heterocycloalkyl, 8 to 11-membered
6 10
bicyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered
bicyclic heteroaryl, wherein said C -C cycloalkyl group, said C -C aryl group, 4 to 7-
3 7 6 10
membered monocyclic heterocycloalkyl, said 8 to 11-membered bicyclic heterocycloalkyl group,
said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic
heteroaryl group can each be optionally substituted with up to three R groups.
In another aspect, the present invention provides a compound selected from
OH O
OH O
, ,
OH O
, ,
OH O
, , ,
, ,
MeOMe
OH O
, ,
, ,
OH O
OH O
, ,
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound of the formula
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical composition
comprising an effective amount of a compound according to the invention, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to use of the compound according
to the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the inhibition of HIV integrase.
In another aspect, the present invention relates to use of the compound according
to the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment of infection by HIV or for the treatment, prophylaxis, or delay in
the onset or progression of AIDS.
Described herein are Compounds of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from a single bond, 5 or 6-membered monocyclic heteroaryl and-
N(R )C(O)-;
Y is a single bond or C -C alkylene;
R is selected from C -C aryl, 5 or 6-membered monocyclic heteroaryl and 9 or
6 10
-membered bicyclic heteroaryl, wherein said C -C aryl group, said 5 or 6-membered
6 10
monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be
optionally substituted with up to three R groups;
2 11 7 2 4
R is H, C -C alkyl, -N(R ) , or -OR or R and R , together with the carbon
1 6 2
atoms to which they are attached, can join to form a 5 to 8-membered monocyclic cycloalkyl
group, 5 to 8-membered monocyclic heterocycloalkyl group, 5 to 8-membered monocyclic
heterocycloalkenyl group or a 8 to 11-membered bicyclic heterocycloalkyl, wherein said 5 to 8-
membered monocyclic cycloalkyl group, said 5 to 8-membered monocyclic heterocycloalkyl
group, said 5 to 8-membered monocyclic heterocycloalkenyl group and said 8 to 11-membered
bicyclic heterocycloalkyl group can be optionally substituted with up to three R groups, which
can be the same or different;
3 11 7
R is H, C -C alkyl, -N(R ) or -OR ;
1 6 2
4 11
R is selected from H, C -C alkyl, -(C -C alkylene)-O-(C -C alkyl), -N(R )
1 6 1 6 1 6 2
7 2 3 11 4
and -OR , such that when R and/or R are -N(R ) , then R is other than H;
11
R is selected from H, C -C alkyl, -(C -C alkylene)-O-(C -C alkyl), -N(R )
1 6 1 6 1 6 2
7 2 3 11 5
and -OR , such that when R and/or R are -N(R ) , then R is other than H;
each occurrence of R is independently H or C -C alkyl;
each occurrence of R is independently selected from H, C -C alkyl, –(C -C
1 6 1 6
alkylene)-O-(C -C alkyl) and C -C cycloalkyl;
1 6 3 7
each occurrence of R is independently selected from C -C alkyl, halo, -OR , -
6 6 7
SR , C -C haloalkyl, C -C hydroxyalkyl, -O-(C -C haloalkyl), -CN, -NO , -N(R ) , -C(O)OR ,
1 6 1 6 1 6 2 2
-C(O)N(R ) and -NHC(O)R ;
R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR -
1 6 1 6 1 6 1 6
C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl;
1 6 1 6 1 6
6
R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR -
1 6 1 6 1 6 1 6
C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl;
1 6 1 6 1 6
each occurrence of R is independently selected from H, C -C alkyl, -S(O) R
1 6 2 12
and –C(O)R ; and
each occurrence of R is independently selected from C -C alkyl, C -C
1 6 3 7
cycloalkyl, C -C aryl, 4 to 7-membered monocyclic heterocycloalkyl, 8 to 11-membered
6 10
bicyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered
bicyclic heteroaryl, wherein said C -C cycloalkyl group, said C -C aryl group, 4 to 7-
3 7 6 10
membered monocyclic heterocycloalkyl, said 8 to 11-membered bicyclic heterocycloalkyl group,
said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic
heteroaryl group can each be optionally substituted with up to three R groups.
The Compounds of Formula (I) (also referred to herein as the “Substituted
Quinolizine Derivatives”) and pharmaceutically acceptable salts or prodrugs thereof can be
useful, for example, for inhibiting HIV viral replication or replicon activity, or for treating or
preventing HIV infection in a subject. Without being bound by any specific theory, it is believed
that the Substituted Quinolizine Derivatives inhibit HIV viral replication by inhibiting HIV
Integrase.
Described herein are methods for treating or preventing HIV infection in a subject,
comprising administering to the subject an effective amount of at least one Substituted
Quinolizine Derivative.
The details of the invention are set forth in the accompanying detailed description
below.
Although any methods and materials similar to those described herein can be used
in the practice or testing of the present invention, illustrative methods and materials are now
described. Other embodiments, aspects and features of the present invention are either further
described in or will be apparent from the ensuing description, examples and appended claims.
In the description in this specification reference may be made to subject matter
which is not within the scope of the appended claims. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention as
defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes Substituted Quinolizine Derivatives, and
compositions comprising at least one Substituted Quinolizine Derivative. Methods of using the
Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject are
described herein.
Definitions and Abbreviations
The terms used herein have their ordinary meaning and the meaning of such terms
is independent at each occurrence thereof. That notwithstanding and except where stated
otherwise, the following definitions apply throughout the specification and claims. Chemical
names, common names, and chemical structures may be used interchangeably to describe the
same structure. These definitions apply regardless of whether a term is used by itself or in
combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl"
applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc...
As used herein, and throughout this disclosure, the following terms, unless
otherwise indicated, shall be understood to have the following meanings:
A “subject” is a human or non-human mammal. In one embodiment, a subject is
a human. In another embodiment, a subject is a primate. In another embodiment, a subject is a
monkey. In another embodiment, a subject is a chimpanzee. In still another embodiment, a
subject is a rhesus monkey.
The term "effective amount" as used herein, refers to an amount of Substituted
Quinolizine Derivative and/or an additional therapeutic agent, or a composition thereof that is
effective in inhibiting HIV replication and in producing the desired therapeutic, ameliorative,
inhibitory or preventative effect when administered to a subject suffering from HIV infection or
AIDS. In the combination therapies of the present invention, an effective amount can refer to
each individual agent or to the combination as a whole, wherein the amounts of all agents
administered are together effective, but wherein the component agent of the combination may
not be present individually in an effective amount.
The term “preventing,” as used herein with respect to an HIV viral infection or
AIDS, refers to reducing the likelihood or severity of HIV infection or AIDS.
The term "alkyl,” as used herein, refers to an aliphatic hydrocarbon group having
one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and
contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains
from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from
1 to 6 carbon atoms (C -C alkyl) or from about 1 to about 4 carbon atoms (C -C alkyl). Non-
1 6 1 4
limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl
group may be unsubstituted or substituted by one or more substituents which may be the same or
different, each substituent being independently selected from the group consisting of halo,
alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl,
alkylthio, -NH , -NH(alkyl), -N(alkyl) , -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-
C(O)-cycloalkyl, -C(O)OH and –C(O)O-alkyl. In one embodiment, an alkyl group is linear. In
another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is
unsubstituted.
The term "alkenyl,” as used herein, refers to an aliphatic hydrocarbon group
containing at least one carbon-carbon double bond and having one of its hydrogen atoms
replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to
about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12
carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon
atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-
methylbutenyl, n-pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or
substituted by one or more substituents which may be the same or different, each substituent
being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl,
cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH , -NH(alkyl), -
N(alkyl) , -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and –
C(O)O-alkyl. The term “C -C alkenyl” refers to an alkenyl group having from 2 to 6 carbon
atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
The term "alkynyl,” as used herein, refers to an aliphatic hydrocarbon group
containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced
with a bond. An alkynyl group may be straight or branched and contain from about 2 to about
carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12
carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon
atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-
methylbutynyl. An alkynyl group may be unsubstituted or substituted by one or more
substituents which may be the same or different, each substituent being independently selected
from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -
O-aryl, -alkylene-O-alkyl, alkylthio, -NH , -NH(alkyl), -N(alkyl) , -NH(cycloalkyl), -O-C(O)-
alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and –C(O)O-alkyl. The term “C -C
alkynyl” refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise
indicated, an alkynyl group is unsubstituted.
The term "alkylene,” as used herein, refers to an alkyl group, as defined above,
wherein one of the alkyl group’s hydrogen atoms has been replaced with a bond. Non-limiting
examples of alkylene groups include –CH -, -CH CH -, -CH CH CH -, -CH CH CH CH -, -
2 2 2 2 2 2 2 2 2 2
CH(CH )CH CH -, -CH(CH )- and -CH CH(CH )CH -. In one embodiment, an alkylene group
3 2 2 3 2 3 2
has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group has from about 3
to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another
embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH -. The
term “C -C alkylene” refers to an alkylene group having from 1 to 6 carbon atoms. The term
“C -C alkylene” refers to an alkylene group having from 2 to 4 carbon atoms.
The term "alkenylene,” as used herein, refers to an alkenyl group, as defined
above, wherein one of the alkenyl group’s hydrogen atoms has been replaced with a bond. Non-
limiting examples of alkenylene groups include –CH=CH-, -CH=CHCH -, -CH CH=CH-, -
CH CH=CHCH -, -CH=CHCH CH -, -CH CH CH=CH- and -CH(CH )CH=CH-. In one
2 2 2 2 2 2 3
embodiment, an alkenylene group has from 2 to about 6 carbon atoms. In another embodiment,
an alkenylene group has from about 3 to about 5 carbon atoms. In another embodiment, an
alkenylene group is branched. In another embodiment, an alkenylene group is linear. The term
“C2-C6 alkylene” refers to an alkenylene group having from 2 to 6 carbon atoms. The term “C3-
C alkenylene” refers to an alkenylene group having from 3 to 5 carbon atoms.
The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic
ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl
group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally
substituted with one or more "ring system substituents" which may be the same or different, and
are as defined herein below. In one embodiment, an aryl group can be optionally fused to a
cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and
naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl
group is unsubstituted.
The term "arylene," as used herein, refers to a bivalent group derived from an aryl
group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group.
An arylene group can be derived from a monocyclic or multicyclic ring system comprising from
about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6
to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In
another embodiment, an arylene group is a phenylene group. An arylene group can be optionally
substituted with one or more "ring system substituents" which may be the same or different, and
are as defined herein below. An arylene group is divalent and either available bond on an
arylene group can connect to either group flanking the arylene group. For example, the group
“A-arylene-B,” wherein the arylene group is:
is understood to represent both:
In one embodiment, an arylene group can be optionally fused to a cycloalkyl or
cycloalkanoyl group. Non-limiting examples of arylene groups include phenylene and
naphthalene. In one embodiment, an arylene group is unsubstituted. In another embodiment, an
arylene group is:
Unless otherwise indicated, an arylene group is unsubstituted.
The term "cycloalkyl," as used herein, refers to a non-aromatic mono- or
multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one
embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another
embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment,
a cycloalkyl contains from about 5 to about 6 ring atoms. The term “cycloalkyl” also
encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or
heteroaryl ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of
multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. A cycloalkyl group can
be optionally substituted with one or more "ring system substituents" which may be the same or
different, and are as defined herein below. In one embodiment, a cycloalkyl group is
unsubstituted. The term “3 to 7-membered cycloalkyl” refers to a cycloalkyl group having from
3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring
carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative
example of such a cycloalkyl group (also referred to herein as a “cycloalkanoyl” group) includes,
but is not limited to, cyclobutanoyl:
The term “halo,” as used herein, means –F, -Cl, -Br or -I.
The term "haloalkyl," as used herein, refers to an alkyl group as defined above,
wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In
one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a
haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl
groups include –CH F, -CHF , -CF , -CH Cl and -CCl . The term “C -C haloalkyl” refers to a
2 2 3 2 3 1 6
haloalkyl group having from 1 to 6 carbon atoms.
The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined
above, wherein one or more of the alkyl group’s hydrogen atoms have been replaced with an –
OH group. In one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-
limiting examples of hydroxyalkyl groups include –CH OH, -CH CH OH, -CH CH CH OH and
2 2 2 2 2 2
-CH CH(OH)CH . The term “C -C hydroxyalkyl” refers to a hydroxyalkyl group having from
2 3 1 6
1 to 6 carbon atoms.
The term "heteroaryl,” as used herein, refers to an aromatic monocyclic or
multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the
ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one
embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl
group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is
bicyclic. In another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms. A
heteroaryl group can be optionally substituted by one or more "ring system substituents" which
may be the same or different, and are as defined herein below. A heteroaryl group is joined via a
ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the
corresponding N-oxide. The term “heteroaryl” also encompasses a heteroaryl group, as defined
above, which is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl,
pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-
a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl,
benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl,
benzothiazolyl and the like, and all isomeric forms thereof. The term “heteroaryl” also refers to
partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl,
tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered
heteroaryl. In another embodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl.
In another embodiment, a heteroaryl group comprises a 5- to 6-membered monocyclic heteroaryl
group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated
monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4
of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon
atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring
nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about
3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has
from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic
and has from about 8 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl
group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is
monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent
oxygen and/or sulfur atoms present in the ring system. Any –NH group in a heterocycloalkyl
ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the
like; such protected heterocycloalkyl groups are considered part of this invention. The term
“heterocycloalkyl” also encompasses a heterocycloalkyl group, as defined above, which is fused
to an aryl (e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally
substituted by one or more "ring system substituents" which may be the same or different, and
are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be
optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and all isomers thereof.
A ring carbon atom of a heterocycloalkyl group may be functionalized as a
carbonyl group. An illustrative example of such a heterocycloalkyl group is:
In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic
heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered
monocyclic heterocycloalkyl. The term “4 to 7-membered monocyclic heterocycloalkyl” refers
to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms. The term “5 to 8-
membered monocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkyl group having
from 5 to 8 ring atoms. The term “8 to 11-membered bicyclic heterocycloalkyl” refers to a
bicyclic heterocycloalkyl group having from 8 to 11 ring atoms. Unless otherwise indicated, a
heterocycloalkyl group is unsubstituted.
The term "heterocycloalkenyl," as used herein, refers to an heterocycloalkyl
group, as defined above, which is non-aromatic and contains at least one endocyclic double bond
between two adjacent ring atoms. A heterocycloalkenyl group can be joined via a ring carbon,
ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group is
monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a
heterocycloalkenyl group is monocyclic has from about 5 to about 8 ring atoms. In another
embodiment, a heterocycloalkenyl group is bicyclic and has from about 8 to about 11 ring atoms.
In still another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
In one embodiment, a heterocycloalkenyl group is monocyclic. In another embodiment, a
heterocycloalkenyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present
in the ring system. Any –NH group in a heterocycloalkenyl ring may be substituted or may exist
protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such
protected heterocycloalkenyl groups are considered part of this invention. The term
“heterocycloalkenyl” also encompasses a heterocycloalkenyl group, as defined above, which is
fused to an aryl (e.g., benzene) or heteroaryl ring. A heterocycloalkenyl group can be optionally
substituted by one or more "ring system substituents" which may be the same or different, and
are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkenyl can be
optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
A ring carbon atom of a heterocycloalkenyl group may be functionalized as a
carbonyl group. An illustrative example of such a heterocycloalkenyl group is:
In one embodiment, a heterocycloalkenyl group is a 5-membered monocyclic
heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered
monocyclic heterocycloalkenyl. The term “4 to 7-membered monocyclic heterocycloalkenyl”
refers to a monocyclic heterocycloalkenyl group having from 4 to 7 ring atoms. The term “5 to
8-membered monocyclic heterocycloalkenyl” refers to a monocyclic heterocycloalkenyl group
having from 5 to 8 ring atoms. The term “8 to 11-membered bicyclic heterocycloalkenyl” refers
to a bicyclic heterocycloalkenyl group having from 8 to 11 ring atoms. Unless otherwise
indicated, a heterocycloalkenyl group is unsubstituted.
The term "ring system substituent," as used herein, refers to a substituent group
attached to an aromatic or non-aromatic ring system which, for example, replaces an available
hydrogen on the ring system. Ring system substituents may be the same or different, each being
independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -
alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-
heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-
alkylene-aryl, acyl, -C(O)-aryl, halo, -NO , -CN, -SF , -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -
C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O) -alkyl, -S(O)-aryl, -S(O) -aryl, -S(O)-heteroaryl, -
S(O) -heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -
S(O) -alkylene-aryl, -S(O) -alkylene-heteroaryl, -Si(alkyl) , -Si(aryl) , -Si(heteroaryl) , -
2 2 2 2 2
Si(alkyl)(aryl), -Si(alkyl)(cycloalkyl), - Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -O-
C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH , -C(=NH)-NH , -C(=NH)-
NH(alkyl), -N(Y )(Y ), -alkylene-N(Y )(Y ), -C(O)N(Y )(Y ) and -S(O) N(Y )(Y ), wherein Y
1 2 1 2 1 2 2 1 2 1
and Y can be the same or different and are independently selected from the group consisting of
hydrogen, alkyl, aryl, cycloalkyl, and –alkylene-aryl. “Ring system substituent” may also mean a
single moiety which simultaneously replaces two available hydrogens on two adjacent carbon
atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy,
ethylenedioxy, -C(CH ) - and the like which form moieties such as, for example:
The term “substituted” means that one or more hydrogens on the designated atom
is replaced with a selection from the indicated group, provided that the designated atom’s normal
valency under the existing circumstances is not exceeded, and that the substitution results in a
stable compound. Combinations of substituents and/or variables are permissible only if such
combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a
compound that is sufficiently robust to survive isolation to a useful degree of purity from a
reaction mixture, and formulation into an efficacious therapeutic agent.
The term "in substantially purified form,” as used herein, refers to the physical
state of a compound after the compound is isolated from a synthetic process (e.g., from a
reaction mixture), a natural source, or a combination thereof. The term "in substantially purified
form,” also refers to the physical state of a compound after the compound is obtained from a
purification process or processes described herein or well-known to the skilled artisan (e.g.,
chromatography, recrystallization and the like), in sufficient purity to be characterizable by
standard analytical techniques described herein or well-known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied
valences in the text, schemes, examples and tables herein is assumed to have the sufficient
number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed “protected”, this means that the
group is in modified form to preclude undesired side reactions at the protected site when the
compound is subjected to a reaction. Suitable protecting groups will be recognized by those with
ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W.
Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
When any substituent or variable (e.g., alkyl, R , R , etc.) occurs more than one
time in any constituent or in Formula (I), its definition on each occurrence is independent of its
definition at every other occurrence, unless otherwise indicated.
As used herein, the term “composition” is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any product which
results from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated
herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel
Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in
Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and
Pergamon Press. The term “prodrug” means a compound (e.g., a drug precursor) that is
transformed in vivo to provide a Substituted Quinolizine Derivative or a pharmaceutically
acceptable salt of the compound. The transformation may occur by various mechanisms (e.g., by
metabolic or chemical processes), such as, for example, through hydrolysis in blood. For
example, if a Substituted Quinolizine Derivative or a pharmaceutically acceptable salt, hydrate
or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise
an ester formed by the replacement of the hydrogen atom of the acid group with a group such as,
for example, (C –C )alkyl, (C -C )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9
1 8 2 12
carbon atoms, 1-methyl(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having
from 4 to 7 carbon atoms, 1-methyl(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolactonyl, di-N,N-(C -C )alkylamino(C -C )alkyl (such as β-
1 2 2 3
dimethylaminoethyl), carbamoyl-(C -C )alkyl, N,N-di (C -C )alkylcarbamoyl-(C -C )alkyl and
1 2 1 2 1 2
piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a Substituted Quinolizine Derivative contains an alcohol functional
group, a prodrug can be formed by the replacement of one or more of the hydrogen atoms of the
alcohol groups with a group such as, for example, (C -C )alkanoyloxymethyl, 1-((C -
1 6 1
C )alkanoyloxy)ethyl, 1-methyl((C -C )alkanoyloxy)ethyl, (C -C )alkoxycarbonyloxymethyl,
6 1 6 1 6
N-(C -C )alkoxycarbonylaminomethyl, succinoyl, (C -C )alkanoyl, α-amino(C -C )alkyl, α-
1 6 1 6 1 4
amino(C -C )alkylene-aryl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each
α-aminoacyl group is independently selected from the naturally occurring L-amino acids, or
glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate).
If a Substituted Quinolizine Derivative incorporates an amine functional group, a
prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group
such as, for example, R-carbonyl-, RO-carbonyl-, NRR’-carbonyl- wherein R and R’ are each
independently (C -C )alkyl, (C -C ) cycloalkyl, benzyl, a natural α-aminoacyl, -
1 10 3 7
1 1 2 3 2
C(OH)C(O)OY wherein Y is H, (C -C )alkyl or benzyl, -C(OY )Y wherein Y is (C -C ) alkyl
1 6 1 4
and Y is (C -C )alkyl; carboxy (C -C )alkyl; amino(C -C )alkyl or mono-N- or di-N,N-(C -
1 6 1 6 1 4 1
4 5 4 5
C )alkylaminoalkyl; -C(Y )Y wherein Y is H or methyl and Y is mono-N- or di-N,N-(C -
C )alkylamino morpholino; piperidinyl or pyrrolidinyl, and the like.
Pharmaceutically acceptable esters of the present compounds include the
following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a
hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester
grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl,
isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g.,
benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted
with, for example, halogen, C alkyl, -O-(C alkyl) or amino); (2) sulfonate esters, such as
1-4 1-4
alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters, including those
corresponding to both natural and non-natural amino acids (e.g., L-valyl or L-isoleucyl); (4)
phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be
further esterified by, for example, a C alcohol or reactive derivative thereof, or by a 2,3-di
1-20
(C )acyl glycerol.
6-24
One or more compounds of the invention may exist in unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like,
and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate"
means a physical association of a compound of this invention with one or more solvent
molecules. This physical association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will be capable of isolation, for
example when one or more solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-
limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a
solvate wherein the solvent molecule is water.
One or more compounds of the invention may optionally be converted to a
solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J.
Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the
antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates,
hemisolvates, hydrates and the like are described by E. C. van Tonder et al, AAPS
PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604
(2001). A typical, non-limiting, process involves dissolving the inventive compound in desired
amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room
temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated
by standard methods. Analytical techniques such as, for example IR spectroscopy, show the
presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The Substituted Quinolizine Derivatives can form salts which are also within the
scope of this invention. Reference to a Substituted Quinolizine Derivative herein is understood
to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed
herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts
formed with inorganic and/or organic bases. In addition, when a Substituted Quinolizine
Derivative contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and
an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be
formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is
a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another
embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of
Formula (I) may be formed, for example, by reacting a Substituted Quinolizine Derivative with
an amount of acid or base, such as an equivalent amount, in a medium such as one in which the
salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates,
benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates,
fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,
naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates,
sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
Additionally, acids which are generally considered suitable for the formation of
pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example,
by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and
Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)
66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The
Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their website). These disclosures are
incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium,
lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts,
salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine,
choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-
containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl,
ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and
dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and
iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable
salts within the scope of the invention and all acid and base salts are considered equivalent to the
free forms of the corresponding compounds for purposes of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on
the basis of their physical chemical differences by methods well-known to those skilled in the
art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can
be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction
with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers. Sterochemically pure
compounds may also be prepared by using chiral starting materials or by employing salt
resolution techniques. Also, some of the Substituted Quinolizine Derivatives may be
atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers
can also be directly separated using chiral chromatographic techniques.
It is also possible that the Substituted Quinolizine Derivatives may exist in
different tautomeric forms, and all such forms are embraced within the scope of the invention.
For example, all keto-enol and imine-enamine forms of the compounds are included in the
invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like)
of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of
the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may
exist due to asymmetric carbons on various substituents, including enantiomeric forms (which
may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this invention. If a Substituted
Quinolizine Derivative incorporates a double bond or a fused ring, both the cis- and trans-forms,
as well as mixtures, are embraced within the scope of the invention.
Individual stereoisomers of the compounds of the invention may, for example, be
substantially free of other isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the present invention can have the S
or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate", “ester”, "prodrug" and the like, is intended to apply equally to the salt, solvate, ester
and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the
inventive compounds.
In the Compounds of Formula (I), the atoms may exhibit their natural isotopic
abundances, or one or more of the atoms may be artificially enriched in a particular isotope
having the same atomic number, but an atomic mass or mass number different from the atomic
mass or mass number predominantly found in nature. The present invention is meant to include
all suitable isotopic variations of the compounds of generic Formula I. For example, different
isotopic forms of hydrogen (H) include protium ( H) and deuterium ( H). Protium is the
predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain
therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or
may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation
by conventional techniques well known to those skilled in the art or by processes analogous to
those described in the Schemes and Examples herein using appropriate isotopically-enriched
reagents and/or intermediates. In one embodiment, a Compound of Formula (I) has one or more
of its hydrogen atoms replaced with deuterium.
The Substituted Quinolizine Derivatives are useful in human and veterinary
medicine for treating or preventing HIV infection in a subject. In one embodiment, the
Substituted Quinolizine Derivatives can be inhibitors of HIV viral replication. In a specific
embodiment, the Substituted Quinolizine Derivatives are inhibitors of HIV-1. Accordingly, the
Substituted Quinolizine Derivatives are useful for treating HIV infections and AIDS. The
Substituted Quinolizine Derivatives can be administered to a subject in need of treatment or
prevention of HIV infection.
Described herein are methods for treating HIV infection in a subject comprising
administering to the subject an effective amount of at least one Substituted Quinolizine
Derivative or a pharmaceutically acceptable salt thereof. Specifically described herein are
methods for treating AIDS in a subject comprising administering to the subject an effective
amount of at least one Substituted Quinolizine Derivative or a pharmaceutically acceptable salt
thereof.
The term “comprising” as used in this specification and claims means “consisting
at least in part of”. When interpreting statements in this specification and claims which include
the term “comprising”, other features besides the features prefaced by this term in each statement
can also be present. Related terms such as “comprise” and “comprises” are to be interpreted in
similar manner.
List of Abbreviations
Anal. = analytical
ACN = acetonitrile
AcOH = acetic acid
n-BuLi = n-butyl lithium
BnBr = benzyl bromide
br = broad
calc. = calculated
m-CPBA = 3-chloroperoxybenzoic acid
d = doublet
DBU = 1,8-diazabicycloundecene
DCM = dichloromethane
DEA = diethylamine
DIPEA or DIEA = N,N-diisopropylethylamine
DMF = dimethylformamide
DMSO = dimethyl sulfoxide
ESI = electrospray ionization
Et2O = diethylether
Et N = triethylamine
EtOAc = ethyl acetate
EtOH = ethanol
HCl = hydrochloric acid
HPLC = high-pressure liquid chromatography
IPA = iso-propyl alcohol
IPAc = iso-propyl acetate
KF = Karl-Fischer titration (to determine water content)
KOt-Bu = potassium tert-butoxide
LCMS = liquid chromatography-mass spectrometry
LiHMDS = lithum hexamethyl silazane
m = multiplet
MeCN = acetonitrile
MeOH = methyl alcohol
MPa = millipascal
MS = mass spectroscopy
MTBE = methyl tert-butyl ether
NaHCO = sodium bicarbonate
NBS = N-bromosuccinimide
NHS = normal human serum
NMP = N-methylpyrrolidine
NMR = nuclear magnetic resonance spectroscopy
Piv = pivalate, 2,2-dimethylpropanoyl
Pd/C = palladium on carbon
rt = room temperature
s = singlet
SFC = supercritical fluid chromatography
SiO = silical gel
t = triplet
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin-layer chromatography
TMSN = trimethylsilyl azide
p-TsOH = para-toluene sulfonic acid
wt% = percentage by weight
The Compounds of Formula (I)
The present invention provides Substituted Quinolizine Derivatives of Formula
(I):
(I)
1 2 3 4 5 9 10
and pharmaceutically acceptable salts thereof, wherein X, Y, R , R , R , R , R , R and R are
defined above for the Compounds of Formula (I).
In one embodiment, X is a single bond.
In another embodiment, X is –NHC(O)-.
In another embodiment, X is 5 or 6-membered heteroaryl.
In still another embodiment, X is 5-membered heteroaryl.
In another embodiment, X is 1,3,4-thiadiazole.
In one embodiment, Y is a single bond.
In another embodiment, Y is C -C alkylene.
In another embodiment, Y is CH .
In one embodiment, X is –NHC(O)- and Y is CH .
In another embodiment, X is 5-membered heteroaryl and Y is CH .
is optionally substituted C -C aryl or optionally
In one embodiment, R 6 10
substituted 9 or 10-membered bicyclic heteroaryl.
In another embodiment, R is optionally substituted C -C aryl.
6 10
In another embodiment, R is optionally substituted phenyl.
In one embodiment, R is selected from:
In another embodiment, R is phenyl with is substituted with one or more halo
groups.
In another embodiment, R is phenyl with is substituted with 1-3 halo groups.
In still another embodiment, R is phenyl with is substituted with one or two F
groups.
In another embodiment, R is 4-fluorophenyl.
In yet another embodiment, R is 2,4-difluorophenyl.
In another embodiment, R is 3-chlorofluorophenyl.
In one embodiment, the group R -Y- is phenyl-CH -, wherein said phenyl group
is substituted with 1-3 groups, independently selected from F and Cl.
In another embodiment, the group R -Y- is phenyl-CH -, wherein said phenyl
group is substituted with one or two F groups.
In one embodiment, R is H.
In another embodiment, R is –O-(C -C alkylene)-O-(C -C alkyl).
1 6 1 6
In one embodiment, R is H.
In another embodiment, R is -OH.
In one embodiment, R is –O-(C -C alkyl).
In another embodiment, R is methoxy.
In one embodiment, R and R are each independently H, –OH or –O-(C -C
alkyl).
In another embodiment, R is H and R is –OH or –O-(C -C alkyl).
In another embodiment, R is H and R is methoxy.
In one embodiment, R is H.
In another embodiment, R is C -C alkyl.
In another embodiment, R is -(C -C alkylene)-O-(C -C alkyl).
1 6 1 6
In still another embodiment, R is methyl.
In another embodiment, R is –CH CH OCH .
2 2 3
In one embodiment, R is H.
In another embodiment, R is C -C alkyl.
In another embodiment, R is -(C -C alkylene)-O-(C -C alkyl).
1 6 1 6
In another embodiment, R is methyl.
In still another embodiment, R is –CH CH OCH .
2 2 3
In one embodiment, R and R are each independently H, C -C alkyl or -(C -C
1 6 1 6
alkylene)-O-(C -C alkyl).
In another embodiment, R and R are each C -C alkyl.
In still another embodiment, R and R are each methyl.
In one embodiment, R and R , together with the carbon atoms to which they are
attached, join to form a 5 to 8-membered monocyclic heterocycloalkyl group.
In one embodiment, R is –O-(C -C alkyl) and R is -(C -C alkylene)-O-(C -C
1 6 1 6 1 6
alkyl).
In one embodiment, R is H.
In another embodiment, R is H.
9 10
In another embodiment, R and R are each H.
In one embodiment, the compounds of formula (I) have the formula (Ia):
(Ia)
or a pharmaceutically acceptable salt thereof,
wherein:
R and R , together with the carbon atoms to which they are attached, join to form
a 5 to 8-membered monocyclic heterocycloalkyl group;
R is H or C -C alkyl; and
R represents 1 or 2 phenyl group substituents, each independently selected from
halo.
In one embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, can join to form a 5 to 8-membered
monocyclic heterocycloalkyl group, 5 to 8-membered monocyclic heterocycloalkenyl group or a
8 to 11-membered bicyclic heterocycloalkyl, wherein said 5 to 8-membered monocyclic
heterocycloalkyl group, said 5 to 8-membered monocyclic heterocycloalkenyl group and said 8
to 11-membered bicyclic heterocycloalkyl group can be optionally substituted with up to three
R groups, which can be the same or different;
In one embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form a 5 to 8-membered
monocyclic heterocycloalkyl group, R is H and R is H.
In another embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form a 5 to 8-membered
monocyclic heterocycloalkyl group, R is H and R is methyl.
In another embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form a 6-membered
monocyclic heterocycloalkyl group.
In still another embodiment, for the compounds of formulas (I) and (Ia), R and
R , together with the carbon atoms to which they are attached, join to form a 5-membered
monocyclic heterocycloalkyl group.
In another embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form a 1,3-dioxane group or a
1,4-dioxane group.
In one embodiment, for the compounds of formulas (I) and (Ia),R and R ,
together with the carbon atoms to which they are attached, join to form a group selected from:
In another embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form a group selected from:
In another embodiment, for the compounds of formulas (I) and (Ia), R and R ,
together with the carbon atoms to which they are attached, join to form the following group:
In one embodiment, for the compounds of formulas (I) and (Ia), R is H; R is H
or methyl; and R and R , together with the carbon atoms to which they are attached, join to form
a group selected from:
In another mbodiment, for the compounds of formulas (I) and (Ia), R is H; R is
methyl; and R and R , together with the carbon atoms to which they are attached, join to form a
group having the structure:
In one embodiment, the compounds of formula (I) have the formula (Ib):
(Ib)
or a pharmaceutically acceptable salt thereof,
wherein:
R is H or –O-C -C alkyl;
R is H, C -C alkyl or –(C -C alkylene)-O-(C -C alkyl);
1 6 1 6 1 6
R is H or C -C alkyl; and
R represents 1 or 2 phenyl group substituents, each independently selected from
halo.
In one embodiment, for the compounds of formula (Ib), R is H.
In one embodiment, for the compounds of formula (Ib), R is –O-(C -C alkyl).
In another embodiment, for the compounds of formula (Ib), R is methoxy.
In one embodiment, for the compounds of formula (Ib), R is H.
is C -C alkyl.
In another embodiment, for the compounds of formula (Ib), R 1 6
In another embodiment, for the compounds of formula (Ib), R is -(C -C
alkylene)-O-(C -C alkyl).
In another embodiment, for the compounds of formula (Ib), R is methyl.
In another embodiment, for the compounds of formula (Ib), R is –CH CH OCH .
2 2 3
In one embodiment, for the compounds of formula (Ib), R is H.
In another embodiment, for the compounds of formula (Ib), R is C -C alkyl.
In another embodiment, for the compounds of formula (Ib), R is -(C -C
alkylene)-O-(C -C alkyl).
In another embodiment, for the compounds of formula (Ib), R is methyl.
In one embodiment, for the compounds of formula (Ib), R and R are each
independently H, C -C alkyl or -(C -C alkylene)-O-(C -C alkyl).
1 6 1 6 1 6
In another embodiment, for the compounds of formula (Ib), R and R are each
C -C alkyl.
In still another embodiment, for the compounds of formula (Ib), R and R are
each methyl.
In one embodiment, for the compounds of formula (Ib), R is –O-(C -C alkyl)
and R is -(C -C alkylene)-O-(C -C alkyl).
1 6 1 6
In another embodiment, for the compounds of formula (Ib), R is -(C -C
alkylene)-O-(C -C alkyl) and R is C -C alkyl.
1 6 1 6
In another embodiment, for the compounds of formula (Ib), R is –CH CH OCH
2 2 3
and R is methyl.
In one embodiment, for the compounds of formula (Ib), R represents a para
fluoro substituent and an ortho fluoro substituent.
1 2 3 4 5 9 10
In one embodiment, variables X, Y, R , R , R , R , R , R and R for the
Compounds of Formula (I) are selected independently of each other.
In another embodiment, the Compounds of Formula (I) are in substantially
purified form.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising an effective amount of a
Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
(b) The pharmaceutical composition of (a), further comprising a second
therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators,
and anti-infective agents.
(c) The pharmaceutical composition of (b), wherein the HIV antiviral agent is
an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase
inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-
nucleoside reverse-transcriptase inhibitors.
(d) A pharmaceutical combination that is (i) a Compound of Formula (I) and
(ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents,
immunomodulators, and anti-infective agents; wherein the Compound of Formula (I) and the
second therapeutic agent are each employed in an amount that renders the combination effective
for inhibiting HIV replication, or for treating HIV infection and/or reducing the likelihood or
severity of symptoms of HIV infection.
(e) The combination of (d), wherein the HIV antiviral agent is an antiviral
selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors,
nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside
reverse-transcriptase inhibitors.
Described herein are the following:
(f) A method of inhibiting HIV replication in a subject in need thereof which
comprises administering to the subject an effective amount of a Compound of Formula (I).
(g) A method of treating HIV infection and/or reducing the likelihood or
severity of symptoms of HIV infection in a subject in need thereof which comprises
administering to the subject an effective amount of a Compound of Formula (I).
(h) The method of (g), wherein the Compound of Formula (I) is administered
in combination with an effective amount of at least one second therapeutic agent selected from
the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents.
(i) The method of (h), wherein the HIV antiviral agent is an antiviral selected
from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, nucleoside
reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse-
transcriptase inhibitors.
(j) A method of inhibiting HIV replication in a subject in need thereof which
comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the
combination of (d) or (e).
(k) A method of treating HIV infection and/or reducing the likelihood or
severity of symptoms of HIV infection in a subject in need thereof which comprises
administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination
of (d) or (e).
The present invention also includes a compound of the present invention for use
(i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine, (b)
inhibiting HIV replication or (c) treating HIV infection and/or reducing the likelihood or severity
of symptoms of HIV infection. In these uses, the compounds of the present invention can
optionally be employed in combination with one or more second therapeutic agents selected
from HIV antiviral agents, anti-infective agents, and immunomodulators.
Additional embodiments of the invention include the pharmaceutical
compositions and combinations set forth in (a)-(e) above, while the methods set forth in (f)-(k)
above are described herein, and the uses set forth in the preceding paragraph, wherein the
compound of the present invention employed therein is a compound of one of the embodiments,
aspects, classes, sub-classes, or features of the compounds described above. In all of these
embodiments, the compound may optionally be used in the form of a pharmaceutically
acceptable salt or hydrate as appropriate. It is understood that references to compounds would
include the compound in its present form as well as in different forms, such as polymorphs,
solvates and hydrates, as applicable.
It is further to be understood that the embodiments of compositions and methods
provided as (a) through (k) above are understood to include all embodiments of the compounds,
including such embodiments as result from combinations of embodiments.
The Compounds of Formula (I) may be referred to herein by chemical structure
and/or by chemical name. In the instance that both the structure and the name of a Compound of
Formula (I) are provided and a discrepancy is found to exist between the chemical structure and
the corresponding chemical name, it is understood that the chemical structure will predominate.
Non-limiting examples of the Compounds of Formula (I) include compounds 1-
124 as set forth in the Examples below, compounds 125-137 as set forth immediately below, and
pharmaceutically acceptable salts thereof.
125 126
132 133
Methods For Making the Compounds of Formula (I)
The Compounds of Formula (I) may be prepared from known or readily prepared
starting materials, following methods known to one skilled in the art of organic synthesis.
Methods useful for making the Compounds of Formula (I) are set forth in the Examples below
and generalized in Schemes 1 and 2 below. Alternative synthetic pathways and analogous
structures will be apparent to those skilled in the art of organic synthesis.
Scheme 1 describes a method for making the compounds of formula (I), which
corresponds to the bridged tetracyclic 4-pyridinone compounds of Formula (I).
Scheme 1
Wherein M is a metal capable of participating in an S 2’ reaction (i.e., Sn, In and Mg).
A pyridyl aldehyde compound of formula i can be reacted with a compound of
formula ii to provide a compound of formula iii. The hydroxyl group of iii can then be protected
and the olefin oxidized via hydroboration and the corresponging alcohol iv can be subsequently
cyclized to provide the bicyclic compounds of formula v. The hydroxyl group of v can then be
deprotected and oxidized to provide the bicyclic ketones of formula vi which can be converted to
their amide derivatives of formula vii using an amine and carbon monoxide ,then reacted with
lithium chloride to convert the methoxy group of vii to the corresponding hydroxyl group and
provide the compounds of formula viii, which correspond to the compounds of formula (I)
wherein X is –NHC(O)-. Alternatively, a compound of formula vi can be oxidized to the
carboxylic acids of formula ix which can be subsequently cyclicized to provide the 1,3,4-
thiadiazole derviatives of formula x, which correspond to the compounds of formula (I), wherein
X is 5 or 6-membered heteroaryl.
Scheme 2
The hydroxyl group of an olefin of formula iii can be protected and the olefin
oxidized via to provide the corresponding diols of formula xi, which can be subsequently
cyclized to provide the bicyclic compounds of formula xii. A compound of formula xii can then
be reactd with an alkyl halide and base to derivatize the free hyrdroxy group of xii, followed by
deprotection and oxidation of the other hydroxyl group to provide the biyclic ketones of formula
xiii. The compounds of formula xiii can be converted to their amide derivatives of formula xiv
using an amine and carbon monoxide ,then reacted with lithium chloride to convert the methoxy
group of xiv to the corresponding hydroxyl group and provide the compounds of formula xv,
which correspond to the compounds of formula (I) wherein X is –NHC(O)-. hydroxyl group of v
can then be deprotected and oxidized to provide the bicyclic ketones of formula vii which can be
reacted with lithium chloride to convert the methoxy group of vii to hydroxyl group and provide
the compounds of formula viii, which correspond to the compounds of formula (I) wherein X is
–NHC(O)- and R is –OR . Alternatively, a compound of formula xii can be oxidized to the
carboxylic acids of formula xvi which can be subsequently cyclicized to provide the 1,3,4-
thiadiazole derviatives of formula xvii, which correspond to the compounds of formula (I),
wherein X is 5 or 6-membered heteroaryl and R is –OR .
In the methods for preparing compounds of the present invention set forth in the
foregoing schemes, functional groups in various moieties and substituents (in addition to those
already explicitly noted in the foregoing schemes) may be sensitive or reactive under the reaction
conditions employed and/or in the presence of the reagents employed. Such sensitivity/reactivity
can interfere with the progress of the desired reaction to reduce the yield of the desired product,
or possibly even preclude its formation. Accordingly, it may be necessary or desirable to protect
sensitive or reactive groups on any of the molecules concerned. Protection can be achieved by
means of conventional protecting groups, such as those described in Protective Groups in
Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M.
rd nd
Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 edition, 1999, and 2
edition, 1991. The protecting groups may be removed at a convenient subsequent stage using
methods known in the art. Alternatively the interfering group can be introduced into the
molecule subsequent to the reaction Step of concern.
One skilled in the art of organic synthesis will recognize that the synthesis of
compounds with multiple reactive functional groups, such as –OH and NH , may require
protection of certain functional groups (i.e., derivatization for the purpose of chemical
compatibility with a particular reaction condition). Suitable protecting groups for the various
functional groups of these compounds and methods for their installation and removal are well-
known in the art of organic chemistry. A summary of many of these methods can be found in
Greene & Wuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, 3 edition (1999).
One skilled in the art of organic synthesis will also recognize that one route for
the synthesis of the Compounds of Formula (I) may be more desirable depending on the choice
of appendage substituents. Additionally, one skilled in the relevant art will recognize that in
some cases the order of reactions may differ from that presented herein to avoid functional group
incompatibilities and thus adjust the synthetic route accordingly.
Compounds of formula vii, x, xv and xvii may be further elaborated using
methods that would be well-known to those skilled in the art of organic synthesis or, for
example, the methods described in the Examples below, to make the full scope of the
Compounds of Formula (I).
The starting materials used and the intermediates prepared using the methods set
forth in Schemes 1 and2 may be isolated and purified if desired using conventional techniques,
including but not limited to filtration, distillation, crystallization, chromatography and alike.
Such materials can be characterized using conventional means, including physical constants and
spectral data.
EXAMPLES
General Methods
The following examples serve only to illustrate the invention and its practice.
The examples are not to be construed as limitations on the scope or spirit of the invention. In
these examples, all temperatures are degrees Celsius unless otherwise noted, and "room
temperature" refers to a temperature in a range of from about 20 °C to about 25 °C. Reactions
sensitive to moisture or air were performed under nitrogen using anhydrous solvents and
reagents. The progress of reactions was determined by either analytical thin layer
chromatography (TLC) performed with E. Merck precoated TLC plates, silica gel 60F-254, layer
thickness 0.25 mm or liquid chromatography-mass spectrum (LC-MS). For HPLC/MS data, the
two HPLC conditions used were as follows: 1) LC2 (Waters C18 XTerra™ 3.5 µm 2.1x20 mm
column with gradient 10:90-98:2 v/v CH CN/H O + v 0.05 % TFA over 1.25 min then hold at
98:2 v/v CH CN/H O + v 0.05% TFA for 0.75 min; flow rate 1.5 mL/min, UV wavelength 254
nm); and 2) LC4 (Waters C18 XTerra 3.5 µm 2.1x20 mm column with gradient 10:90-98:2 v/v
CH CN/H O + v 0.05 % TFA over 3.25 min then hold at 98:2 v/v CH CN/H O + v 0.05 % TFA
3 2 3 2
for 0.75 min; flow rate 1.5 mL/min, UV wavelength 254 nm).
Mass analysis was performed with electrospray ionization in positive ion
detection mode. H NMR spectra were recorded on Varian or Bruker instruments at 400–500
MHz. Concentration of solutions was carried out on a rotary evaporator under reduced pressure
or by lyophilization. Flash chromatography was performed on pre-packed silica gel columns
using a commercial MPLC system. Compounds described herein were synthesized as racemic
mixtures unless otherwise stated in the experimental procedures.
Example 1
Preparation of Intermediate Compound Int-1
Compound Int-1 was prepared using the method described in U.S. Patent
Publication No. US2006/066414.
Example 2
Preparation of Compound 1
Step A– Synthesis of Compound Int-2a
To a mixed solution of NaI (279 mg, 1.862 mmol), indium powder (891 mg, 7.76 mmol)
and prenylbromide (278 mg, 1.862 mmol) in 3 mL of DMF, was added 4-(benzyloxy)bromo-
3-methoxypicolinaldehyde (500 mg, 1.552 mmol). The mixture was allowed to stir at room
temperature for 1 hour. The reaction was diluted with 100 mL of EtOAc . The organic phase was
washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the
organic solvent was removed in vacuo to provide a residue, which was purified using a
preparative TLC plate eluting with 20% EtOAc / hexane to provide compound Int-2a as a
colorless oil. LCMS anal. calcd. for C H BrNO : 391.08; Found: 392.07 (M+1) .
19 22 3
Step B– Synthesis of Compound Int-2b
A solution of compound Int-2a (380 mg, 0.969 mmol) in 0.1 mL of DMF was added
TBSCl (292 mg, 1.937 mmol) and imidazole (198 mg, 2.91 mmol)). The mixture was allowed to
stir at 60 °C overnight. It was diluted with 20 mL of EtOAc. The organic phase was washed
with H O and brine, dried over Na SO and concnetrated. The resulting residue was purified
2 2 4
using a silica-gel column (40 g) eluting with 15% EtOAc / hexane to provide compound Int-2b
as a colorless oil. LCMS anal. calcd. for C H BrNO Si: 505.16; Found: 506.14 (M+1) .
36 3
Step C– Synthesis of Compound Int-2c
To an ice-cold solution of 4-(benzyloxy)bromo(1-((tert-butyldimethylsilyl)oxy)-
2,2-dimethylbutenyl)methoxypyridine (200 mg, 0.395 mmol) in 4 mL of dry THF was
added borane-tetrahydrofuran complex (1 M in THF) (0.592 ml, 0.592 mmol) under an
atmosphere of nitrogen. The mixture was allowed to stir at room temperature for 1 h. After
successive addition of water (2.0 mL), sodium hydroxide (aq) (1.974 ml, 3.95 mmol) and
hydrogen peroxide in water (35% wt.) (448 mg, 3.95 mmol), the resulting mixture was stirred for
an additional hour. The mixture was extracted with EtOAc (3×20 mL). The combined organic
extracts were washed with 20 mL of brine and dried over anhydrous MgSO . After
concentration, the resulting residue was purified using silica gel column chromatography eluting
with 30% EtOAc / hexane to provide compound Int-2c as a clear oil. LCMS anal. calcd. for
C H BrNO Si: 523.18; Found: 524.10 (M+1) .
38 4
Step D– Synthesis of Compound Int-2d
To a stirred solution of triphenylphosphine (255 mg, 0.972 mmol) in 4 mL of
dichloromethane was added iodine (247 mg, 0.972 mmol). The mixture was allowed to stir at
room temperature for 5 min, followed by adding 4-(4-(benzyloxy)bromomethoxypyridin
yl)((tert-butyldimethylsilyl)oxy)-3,3-dimethylbutanol (170 mg, 0.324 mmol) and imidazole
(66.2 mg, 0.972 mmol). The reaction was allowed to stir at room temperature for 2 h. At
completion, it was concentrated to remove most of dichloromethane. The resulting residue was
added 3 mL of 2:1 ACN / H O and the resulting solution was directly purified using a C18
reverse phase column (40 mg, 12 run lengths, 5% ACN / H O-100% ACN / H O with 0.1%
TFA) to afford compound Int-2d as a colorless oil. LCMS anal. calcd. for C H BrNO Si:
18 30 3
415.12; Found: 416.10 (M+1) .
Step E– Synthesis of Compound Int-2e
A mixture of 7-bromo((tert-butyldimethylsilyl)oxy)methoxy-2,2-dimethyl-3,4-
dihydro-1H-quinolizin-8(2H)-one (50 mg, 0.120 mmol), 2,4-difluorobenzylamine (25.8 mg,
0.180 mmol), diethylpropylethylamine (38.8 mg, 0.300 mmol) and Pd(PPh ) (13.87 mg, 0.012
mmol) in 1 mL of DMSO was degassed and heated at 90 °C under a CO balloon for 16 h. LC-
mass showed partial completion of reaction. The above reaction was directly injected onto C18
reverse phase column (40 mg, 12 run lengths, 5% ACN / H O-100% ACN / H O with 0.1%
TFA) to afford compound Int-2e as a white solid. LCMS anal. calcd. for C H F N O Si:
26 36 2 2 4
506.24; Found: 507.30 (M+1) .
Step F– Synthesis of Compound Int-2f
The solution of 1-((tert-butyldimethylsilyl)oxy)-N-(2,4-difluorobenzyl)methoxy-2,2-
dimethyloxo-2,3,4,8-tetrahydro-1H-quinolizinecarboxamide (14.0 mg, 0.028 mmol) in 1
mL of THF was added a solution of tetrabutylammoniumfluoride (1 N in THF) (0.055 ml, 0.055
mmol). The mixture was allowed to stir at room temperature for 1.5 h. At completion, the
reaction mixture was directly purified using a preparative TLC plate eluting with EtOAc to
afford compound Int-2f as a white solid. LCMS anal. calcd. for C H F N O : 392.15; Found:
22 2 2 4
393.08 (M+1) .
Step G– Synthesis of Compound Int-2g
The solution of N-(2,4-difluorobenzyl)hydroxymethoxy-2,2-dimethyloxo-
2,3,4,8-tetrahydro-1H-quinolizinecarboxamide (8.0 mg, 0.020 mmol) in 1 mL of
dichloromethane was added Dess-Martin periodinane (17.29 mg, 0.041 mmol). The mixture was
allowed to stir at room temperature for 30 min. The reaction was then directly purified using a
preparative TLC plate eluting with EtOAc to afford compound Int-2g as a white solid. LCMS
anal. calcd. for C20H20F2N2O4: 390.14; Found: 391.07 (M+1) .
Step H– Synthesis of Compound 1
A mixture of N-(2,4-difluorobenzyl)methoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-
tetrahydro-1H-quinolizinecarboxamide (5.0 mg, 0.013 mmol) and lithium chloride (5.43 mg,
0.128 mmol) in 1 mL of DMF was heated at 100 °C for 4 h. It was cooled to room temperature.
The mixtue was directly purified using a reverse phase-HPLC (Gilson system with a Waters
Sunfire C18 ODB, 5 uM, 19 mm x 100 mm, Part No. 186002567, Ser. No. 20913930114, 10%
to 75% MeCN/ water+0.10% TFA over 10 min, 25 mL / min, UV 254 nM). The product
containing fractions were lyophilized to afford compound 1 as a white solid. H NMR (400
MHz, CDCl ): δ 10.41 (s, 1 H); 8.47 (s, 1 H); 7.40 (m, 1 H); 6.81-6.86 (m, 2 H); 4.67 (d, J = 4.8
Hz, 2 H); 4.27-4.29 (t, J = 4.8 Hz, 2 H); 2.20-2.22 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS anal.
calcd. for C H F N O : 376.12; Found: 377.12 (M+1) .
19 18 2 3 5
Example 3
Preparation of Compound 2
Step A– Synthesis of Compound Int-3a
To a solution of compound Int-2d (60 mg, 0.144 mmol) in THF (2.0 ml) was added
tetrabutyammoniumfluoride (1 M in THF) (0.288 ml, 0.288 mmol). The mixture was allowed to
stir at room temperature for 1.5 h. The reaction mixture was directly purified using a preparative
TLC plate eluting with 10% MeOH / dichloromethane to afford crude compound Int-3a with
some TBAF impurity. LCMS anal. calcd. for C H BrNO : 301.03; Found: 301.98 (M+1) .
12 16 3
Step B– Synthesis of Compound Int-3b
To a solution of 7-bromohydroxymethoxy-2,2-dimethyl-3,4-dihydro-1H-
quinolizin-8(2H)-one (43.0 mg, 0.142 mmol) in 2 mL of dichloromethane was added Dess-
Martin periodinane (121 mg, 0.285 mmol). The mixture was allowed to stir at room temperature
for 30 min. The reaction was then directly purified using a preparative TLC plate eluting with
EtOAc to afford compound Int-3b as a white solid. LCMS anal. calcd. for C12H14BrNO3:
299.02; Found: 300.00 (M+1) .
Step C– Synthesis of Compound Int-3c
A mixture of 7-bromomethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-1,8(2H)-dione (20
mg, 0.067 mmol), 4-fluorobenzylamine (12.5 mg, 0.101 mmol), diisopropylethylamine (34.4 mg,
0.267 mmol) and Pd(PPh ) (7.70 mg, 6.66 µmol) in 2 mL of DMSO was degassed and heated at
90 °C under a CO balloon for 16 h. After cooled to room temperature, the reaction mixture was
directly purified using a reverse phase C18 column (40 mg, 12 run lengths, 5% ACN / H O-
100% ACN / H O with 0.1% TFA) to afford compound Int-3c. LCMS anal. calcd. for
C H FN O : 372.15; Found: 373.16 (M+1) .
21 2 4
Step D– Synthesis of Compound 2
A mixture of N-(4-fluorobenzyl)methoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-
1H-quinolizinecarboxamide (5.0 mg, 0.013 mmol) and lithium chloride (5.69 mg, 0.134
mmol) in 1 mL of DMF was heated at 100 °C for 2 h. It was cooled to room temperature and
directly purified using a reverse phase-HPLC (Gilson system with a Waters Sunfire C18 ODB, 5
uM, 19 mm x 100 mm, Part No. 186002567, Ser. No. 20913930114, 10% to 75% 0.1% TFA in
MeCN / 0.1% TFA in water over 10 min, 25 mL/min, UV 254 nM). The product containing
fractions were lyophilized to afford compound 2 as a white solid. H NMR (400 MHz, CDCl ): δ
.41 (s, 1 H); 8.46 (s, 1 H); 7.35 (m, 2 H); 7.01 (m, 2 H); 5.3 (s, 2 H); 4.64 (d, J = 4.8 Hz, 2 H);
4.28 (t, J = 4.8 Hz, 2 H); 2.21 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS anal. calcd. for
C H FN O : 358.13; Found: 359.12 (M+1) .
19 19 2 4
Example 4
Preparation of Compound 3
OH O
Compound 3 was prepared from compound Int-3b, using essentially the same method
described in the Step C and Step D in Example 3, replacing 4-fluorobenzylamine with
pyrazolo[1,5-a]pyridinylmethanamine in Step C. H NMR (400 MHz, CDCl ): δ 10.60 (s, 1
H); 8.53 (d, J = 4.9 Hz, 1 H); 8.52 (s, 1 H); 7.48 (d, J = 7.2 Hz, 1 H); 7.15 (dd, J= 7.2, 5.2 Hz, 1
H); 6.78 (dd, J = 5.2, 5.1 Hz, 1 H); 6.54 (s, 1 H); 4.90 (d, J = 4.0 Hz, 1 H); 4.30 (t, J = 4.8 Hz, 2
H); 2.21 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS anal. calcd. for C H N O : 380.15; Found:
20 4 4
381.16 (M+1) .
Example 5
Preparation of Compound 4
Br HO
N Step B
Step A N
OMe OH
OMe O
OMe O
Int-2a
Int-4a
Int-4b
Br OH
Step E
Step C N Step D
OMe O
Int-4c
Int-4d
OH O
Step A– Synthesis of Compound Int-4a
To a solution of 1-(4-(benzyloxy)bromomethoxypyridinyl)-2,2-dimethylbut
enol (230 mg, 0.586 mmol) in 10 mL of dichloromethane was added a drop of water, followed
by adding Dess-Martin periodinane (497 mg, 1.173 mmol). The mixture was allowed to stir at
room temperature for 2 h. It was diluted with 20 mL of dichloromethane. The organic phase was
washed with 20 mL of Na CO (aq), dried over Na SO and then concentrated. The resulting
2 3 2 4
residue was purified using a silica-gel column (40 g) eluting with 20% EtOAc / hexane to afford
compound Int-4a as a colorless oil. LCMS anal. calcd. for C H BrNO : 389.06; Found: 390.09
19 20 3
(M+1) .
Step B– Synthesis of Compound Int-4b
To a solution of 1-(4-(benzyloxy)bromomethoxypyridinyl)-2,2-dimethylbut
enone (190 mg, 0.487 mmol) in 4 mL of THF and 1 mL of water, was added a solution of
osmium tetroxide in t-BuOH (2.5% wt.) (0.122 ml, 9.74 µmol) and 4-methylmorpholine N-
oxide (171 mg, 1.461 mmol). The mixture was allowed to stir at room temperature overnight. It
was diluted with 20 mL of EtOAc. The organic phase was washed with NaS O (aq) and brine,
dried over anhydrous Na SO and then concentrated. The resulting residue was purified using a
silica-gel column eluting with EtOAc to afford compound Int-4b as light green oil. LCMS anal.
calcd. For C H BrNO : 423.07; Found: 423.97 (M+1) .
19 22 5
Step C– Synthesis of Compound Int-4c
To a solution of 1-(4-(benzyloxy)bromomethoxypyridinyl)-3,4-dihydroxy-2,2-
dimethylbutanone (170 mg, 0.401 mmol) in 3 mL of pyridine, was added p-toluenesulfonyl
chloride (153 mg, 0.801 mmol). The reaction was allowed to stir at room temperature for 6 h. It
was diluted with 10 mL of MeOH. The resulting solution was then concentrated in vacuo. The
resulting residue was diluted with 2 mL of DMSO and purified using a reverse phase C18
column (40 g, 12 run lengths, 5% ACN / H O-100% ACN / H O with 0.1% TFA) to provide the
crude product which was further purified using a preparative TLC plate eluting with 10% MeOH
/ dichloromethane to afford compound Int-4c as a yellow oil. LCMS anal. calcd. For
C H BrNO : 315.01; Found: 316.05 (M+1) .
12 14 4
Step D– Synthesis of Compound Int-4d
A mixture of 7-bromohydroxymethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-
1,8(2H)-dione (9 mg, 0.028 mmol), 2,4-difluorobenzylamine (6.11 mg, 0.043 mmol),
diisopropylethylamine (9.20 mg, 0.071 mmol) and Pd(PPh ) (3.29 mg, 2.85 µmol) in 1 mL of
DMSO was degassed by passing through a stream of CO gas for 5 min. It was then heated at 90
°C under a CO bolloon for 16 h. After the reaction was cooled to room temperature, it was
purified using a reverse phase C18 column (40 mg, 12 run lengths, 5% ACN / H O-100% ACN
/ H O with 0.1% TFA) to afford compound Int-4d. LCMS anal. calcd. For C H F N O :
2 20 20 2 2 5
406.13; Found: 407.16 (M+1) .
Step E– Synthesis of Compound 4
A mixture of N-(2,4-difluorobenzyl)hydroxymethoxy-2,2-dimethyl-1,8-dioxo-
2,3,4,8-tetrahydro-1H-quinolizinecarboxamide (5.0 mg, 0.012 mmol) and lithium chloride
(5.22 mg, 0.123 mmol) in 1 mL of DMF was heated at 100 °C for 2 h. It was cooled to room
temperature. The resulting solution was directly purified using a reverse phase HPLC (Gilson
system with a Waters Sunfire C18 ODB, 5 uM, 19 mm x 100 mm, Part No. 186002567, Ser. No.
20913930114, 10% to 75% MeCN / water with 0.10% TFA over 10 min, 25 mL/min, UV
254nM). The product containing fractions were lyophilized to afford compound 4 as a white
solid. H NMR (400 MHz, DMSO-d ): δ 10.40 (s, 1 H); 8.34 (s, 1 H); 7.35 (m, 1 H); 6.84 (m, 2
H); 4.65 (d, J = 3.0 Hz, 2 H); 4.46-4.48 (apparent d, J = 10.0 Hz, 1 H); 4.23-4.27 (dd, J = 11.6,
2.4 Hz, 1 H); 4.11 (apparent brs, 1 H); 1.48 (s, 1 H); 1.35 (s, 1 H). LCMS anal. calcd. for
C H F N O : 392.12; Found: 393.14 (M+1) .
19 18 2 2 5
Example 6
Preparation of Compound Int-5e
HO Br OH
N Br
Step B
Step A N
Step C
OTBS
OMe OTBS
OMe OTBS
Int-2b
Int-5b
Int-5a
Br OMe
N Step D
N Step E
OMe OTBS
OMe OH
Int-5c
Int-5d Int-5e
Step A– Synthesis of Compound Int-5a
To solution of 4-(benzyloxy)bromo(1-((tert-butyldimethylsilyl)oxy)-2,2-
dimethylbutenyl)methoxypyridine (430 mg, 0.849 mmol) in 5 mL of (4:1) THF / water,
was added osmium tetroxide (2.5% wt.) in t-BuOH (0.213 ml, 0.017 mmol) and 4-
methylmorpholine N-oxide (298 mg, 2.55 mmol). The mixture was allowed to stir at room
temperature overnight. At completion, it was added 20 mL of EtOAc. The organic phase was
washed with Na S O aqueous solution and brine. It was dried over anhydrous Na SO and
2 2 3 2 4
concentrated. The resulting residue was purified using a silica-gel column eluting with 50%
EtOAc to afford compound Int-5a as a light green oil. LCMS anal. calcd. for C25H38BrNO5Si:
539.17; Found: 540.22 (M+1) .
Step B– Synthesis of Compound Int-5b
A mixture was 4-(4-(benzyloxy)bromomethoxypyridinyl)((tert-
butyldimethylsilyl)oxy)-3,3-dimethylbutane-1,2-diol (650 mg, 1.202 mmol) and 4-
methylbenzenesulfonyl chloride (344 mg, 1.804 mmol) in 10 mL of pyridine was allowed to
stir at room temperature overnight. At completion, it was concentrated in vacuo to remove most
of pyridine. The resulting residue was then was added 2 mL of DMSO and the resulting solution
was purified using a reverse phase C18 column (120 mg, 12 run lengths, 5% ACN / H2O-100%
ACN /H O with 0.1% TFA) to afford compound Int-5b as a white solid. C H BrNO Si:
2 18 30 4
431.11; Found: 432.15 (M+1) .
Step C– Synthesis of Compound Int-5c
To a solution of 7-bromo((tert-butyldimethylsilyl)oxy)hydroxymethoxy-2,2-
dimethyl-3,4-dihydro-1H-quinolizin-8(2H)-one (160 mg, 0.370 mmol) in 4 mL of THF, was
added iodomethane (158 mg, 1.11 mmol), followed by NaH (60% wt. in mineral oil) (44.4 mg,
1.11 mmol). The mixture was allowed to stir at room temperature for 2 h. It was quenched by
adding 1 mL of water. The resulting mixture was directly purified using a preparative TLC plate
eluting with 50% EtOAc / hexane to afford compound Int-5c as a light yellow oil. LCMS anal.
calcd. for C H BrNO Si: 445.13; Found: 446.01 (M+1) .
19 32 4
Step D– Synthesis of Compound Int-5d
To a solution of 7-bromo((tert-butyldimethylsilyl)oxy)-3,9-dimethoxy-2,2-dimethyl-
3,4-dihydro-1H-quinolizin-8(2H)-one (105 mg, 0.235 mmol) in 2 mL of THF, was added
tetrabutylammoniumfluoride (1 M in THF) (0.470 ml, 0.470 mmol). The mixture was allowed to
stir at room temperature for 1.5 h. The reaction solution was directly purified using a preparative
TLC plate eluting with 10% MeOH / dichloromethane to provide the crude compound Int-5d,
which was used immediately in the following reaction. LCMS anal. calcd. for C H BrNO :
13 18 4
331.94; Found: 333.02 (M+1) .
Step E– Synthesis of Compound Int-5e
To a solution of 7-bromohydroxy-3,9-dimethoxy-2,2-dimethyl-3,4-dihydro-1H-
quinolizin-8(2H)-one (78 mg, 0.235 mmol) in 2 mL of dichloromethane, was added Dess-Martin
periodinane (199 mg, 0.470 mmol). The mixture was allowed to stir at room temperature for 1 h.
The reaction mixture was then directly purified using a preparative TLC plate eluting with
EtOAc to afford compound Int-5e as a light yellow solid. LCMS anal. calcd. for C H BrNO :
13 16 4
329.03; Found: 330.05 (M+1) .
Example 7
Preparation of Compound 5
Compound 5 was prepared using essentially the same method described in the Step D and
Step E in Example 5, and replacing compound Int-4c with compound Int-5e in Step D. H
NMR (400 MHz, CDCl ): 10.41 (s, 1 H), 8.42 (s, 1 H); 7.38 (m, 1 H); 6.83-6.85 (m, 2 H); 4.67
(m, 2 H); 4.38 (dd, J = 11.2, 1.6 Hz, 1 H); 4,35 (dd, J = 11.2, 2.8 Hz, 1 H); 3.57 (dd, J = 2.8, 1.6
Hz, 1 H); 3.46 (s, 3 H); 1.43 (s, 3 H); 1.35 (s, 3 H). LCMS anal. calcd. for C H F N O :
20 2 2 5
406.13; Found: 407.12 (M+1) .
Example 8
Preparation of Compound 6
Step A– Synthesis of Compound Int-6a
A mixture of 7-bromo-3,9-dimethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-1,8(2H)-
dione (120 mg, 0.363 mmol), methanol (58.2 mg, 1.817 mmol), diisopropylethylamine (235 mg,
1.817 mmol) and Pd(PPh ) (84 mg, 0.073 mmol) in 3 mL of DMSO, was degassed by passing
through a stream of CO for 5 min. The reaction mixture was then heated at 90 °C under a CO
bolloon for 16 h. After the reaction was cooled to room temperature, it was directly purified
using a reverse phase C18 column (40 mg, 12 run lengths, 5% ACN /H O-100% ACN / H O
with 0.1% TFA) to afford compound Int-6a as a brown solid. LCMS anal. calcd. for
C H NO : 309.12; Found: 310.12 (M+1) .
19 6
Step B– Synthesis of Compound Int-6b
To a solution of methyl 3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-
quinolizinecarboxylate (20.0 mg, 0.065 mmol) in 1 mL of MeOH, was added 2 N lithium
hydroxide aqueous solution (0.323 ml, 0.647 mmol). The mxiture was allowed to stir at room
temperature for 2 h. It was concentrated to removed most of MeOH. To the resulting residue was
added 2 mL of DMSO, and the resulting solution was directly purified using Gilson (10% ACN
(0.1% TFA) /H O- 90% ACN (0.1% TFA) / H O, 12 min) to afford compound Int-6b as a white
solid. LCMS anal. calcd. for C H NO : 295.11; Found: 296.12 (M+1) .
14 17 6
Step C– Synthesis of Compound Int-6c
To a stirred solution of 3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-
quinolizinecarboxylic acid (14.0 mg, 0.047 mmol) in 1 mL of DMF, was added 2-(2,4-
difluorophenyl)acetohydrazide (10.59 mg, 0.057 mmol), diisopropylethylamine (24.51 mg, 0.190
mmol) and ((1H-benzo[d][1,2,3]triazolyl)oxy)tri(pyrrolidinyl)phosphonium
hexafluorophosphate(V) (29.6 mg, 0.057 mmol) sequentially. The mixture was allowed to stir at
room temperature for 1 h. It was diluted with 1.0 mL of DMF and 0.3 mL of water. The clear
solution was purified using a reverse phase Gilson HPLC (10% ACN (0.1% TFA) / H O- 90%
ACN (0.1% TFA) / H O, 12 min) to afford compound Int-6c as a light yellow solid. LCMS
anal. calcd. for C H F N O : 463.16; Found: 464.25 (M+1) .
22 23 2 3 6
Step D– Synthesis of Compound Int-6d
A mixture of N'-(2-(2,4-difluorophenyl)acetyl)-3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-
2,3,4,8-tetrahydro-1H-quinolizinecarbohydrazide (12 mg, 0.026 mmol) and Lawesson's
reagent (11.52 mg, 0.028 mmol) in 0.5 mL of THF was heated at 60 °C overnight. The solvent
was removed in vacuo. The resulting residue was dissolved in 2 mL of DMSO. The resulting
solution was purified using a reverse phase Gilson HPLC (10% ACN (0.1% TFA) / H2O- 90%
ACN (0.1% TFA) / H O, 12 min) to afford compound Int-6d as a yellow solid. LCMS anal.
calcd. for C H F N O S: 461.12; Found: 462.20 (M+1) .
22 21 2 3 4
Step E– Synthesis of Compound 6
A mixture of 7-(5-(2,4-difluorobenzyl)-1,3,4-thiadiazolyl)-3,9-dimethoxy-2,2-
dimethyl-3,4-dihydro-1H-quinolizine-1,8(2H)-dione (6.0 mg, 0.013 mmol) and lithium chloride
(16.54 mg, 0.390 mmol) in 1 mL of DMF was heated at 100 °C for 1 h. It was cooled to room
temperature, and the mixture was diluted with 1.0 mL of DMF and 0.3 mL of water. The
resulting solution was purifed by a reverse phase Gilson HPLC (10% ACN (0.1% TFA) / H2O-
90% ACN (0.1% TFA) / H O, 12 min) to afford compound 6 as a light yellow solid. H NMR
(399 MHz, CDCl3): 8.76 (s, 1 H); 7.35 (m, 1 H); 6.86-6.91 (m, 2 H); 4.49 (dd, J = 1.6, 11.2 Hz, 1
H); 4.45 (dd, J= 2.8, 11.2, Hz, 1 H); 3.63 (dd, J = 2.8, 1.6 Hz, 1 H); 3.50 (s, 3 H); 1.44 (s, 3 H);
1.39 (s, 3 H). LCMS anal. calcd. for C H F N O S: 447.11; Found: 448.01 (M+1) .
21 19 2 3 4
Example 9
Preparation of Compound Int-7b
Step A– Synthesis of Compound Int-7a
To a solution of 6-((tert-butyldiphenylsilyl)oxy)methylhexenol ( 3 g, 8.14 mmol)
in 60 mL of dichloromethane, was added diisopropylethylamine (3.54 ml, 20.35 mmol) followed
by methanesulfonyl chloride (1.029 ml, 13.02 mmol). The reaction was allowed to stir at room
temperature for 2 h. It was diluted with 200 mL of dichloromethane and washed with 100 mL of
0.2 N HCl (aq.) solution, then with 100 mL of brine. The organic phase was concentrated, and
the resulting residue was purified using a silica gel column (80 g) eluting with 5% EtOAc /
hexanes to provide compound Int-7a as a mixture (2.5:1) of (E) and (Z) stereoisomers. H NMR
(400 MHz, CDCl ): δ 7.71-7.74 (m, 4 H); 7.41-7.50 (m, 6 H); 5.42-5.56 (m, 1 H); 4.12 & 4.13
(d, J = 8.0 Hz, 2 H); 3.71 & 3.72 (t, J = 6.4 Hz, 2 H); 2.19 & 2.26 (dd, J = 8.0, 7.7 Hz, 2 H); 1.74
& 1.79 (s, 3 H), 1.66-1.76 (m, 2 H), 1.11 & 1.12 (s, 9 H).
Step B– Synthesis of Compound Int-7b
To a solution of lithium diisopropylamide (7.17 ml, 14.34 mmol) in 20 mL of THF
cooled at 0 °C, was added tributyltinhydride (3.48 ml, 13.04 mmol). The reaction was allowed
to stir at 0 °C for 15 min. It was then cooled to -78 °C, and a solution of compound Int-7a (2523
mg, 6.52 mmol) in 10 mL of THF was added via syringe. The reaction was allowed to stir at -78
°C for 30 min. It was diluted with 150 mL of 20% EtOAc / hexanes, and washed 150 mL of
water. The organic phase was concentrated in vacuo. The resulting residue was purified using a
silica gel column (80 g) eluting initially with hexanes to removed tributyltinhydride, and then
with 3% EtOAc/hexanes to provide compound Int-7b as a colorless oil. H NMR (400 MHz,
CDCl ): δ 7.69-7.73 (m, 4 H); 7.38-7.47 (m, 6 H); 5.28-5.37 (m, 1 H); 3.64-3.75 (m, 2 H); 2.01-
2.13 (m, 2 H); 1.63-1.70 (m, 5 H); 1.46-1.59 (m, 8 H); 1.28-1.36 (m, 6 H), 1.08 (s, 9 H), 0.84-
0.94 (m, 15 H).
Example 10
Preparation of Compounds 7 and 8
Step A Step B
+ Int-7b
Int-1
OMe OMe OAc
OTBDPS OTBDPS
Int-8a Int-8b
Br Br OH
Step E
Step D
Step C N N
BnO O
OMe OMe
OAc OAc
OTBDPS OTBDPS
Int-8d
Int-8c
Br O
Br O
Step G N
Step F
OMe OAc
OAc OMe OAc
OTBDPS OH
Int-8g
Int-8e
Int-8f
Br O
O Br O
Step I N
Step H N
OMe OH OMe
Int-8h
Int-8i
Int-8j
Step J O
Step K
OH O
Int-8k
7(Enantiomer A)
8(Enantiomer B)
Step A– Synthesis of Compound Int-8a
To a solution of 4-(benzyloxy)bromomethoxypicolinaldehyde (390 mg, 1.21 mmol)
and tert-butyl((4-methyl(tributylstannyl)hexenyl)oxy)diphenylsilane (932 mg, 1.45
mmol) in 11 mL of ACN stirred at 0 °C, was added Tin (II) Cl (344 mg, 1.50 mmol). The
reaction was then warmed to room temperature and stirred for 15 min. This was diluted with
100 mL of 30% EtOAc / hexanes, and 100 mL of (15% wt.) NH4F aqueous solution. The
resulting mixture was allowed to stir at room temperature for 15 min. Solid was filtered off.
The organic from the mother liquor was concentrated in vacuo and the resulting residue was
purified using a silica gel column (80 g) eluting initially with dichloromethane to removed Tin
reagent, and then with 3% EtOAc / dichloromethane to provide Compound Int-8a as a mixture
of stereoisomers. LCMS anal. calcd. for C H BrNO Si: 675.22; Found: 676.18 (M+1) .
37 44 4
Step B– Synthesis of Compound Int-8b
To a solution of compound Int-8a (1200 mg, 1.78 mmol) in 8 mL of acetic anhydride
was added triethylamine (2200 mg, 21.7 mmol) and DMAP (65.2 mg, 0.534 mmol). The
reaction was allowed to stir at room temperature for 1 h. It was diluted with 50 mL of
dichloromethane. The solution was cooled to 0 °C and added 10 mL of MeOH. It was stirred
for 1 h at room temperature. The solvent was removed in vacuo. The resulting residue was
purified using a silica gel column (120 g) eluting with 25% EtOAc / hexanes to provide
compound Int-8b as a colorless film. LCMS anal. calcd. for C H BrNO Si: 717.23; Found:
39 46 5
718.35 (M+1) .
Step C– Synthesis of Compound Int-8c
To a solution of compound Int-8b (410 mg, 0.572 mmol) in 3.6 mL of THF/t-
BuOH/water (5:5:1), was added 4-methylmorpholine 4-oxide (67 mg, 0.572 mmol) followed by
osmium(VIII) oxide (2.5% wt. in t-BuOH) (1.06 ml, 0.086 mmol). The reaction was allowed to
stir at room temperature for 16 h. To this was added 10 g of solid Na S O . The mixture was
2 2 5
allowed to stir at room temperature for 1 h. The content was diluted with 70 mL of 50%
EtOAc/hexanes. The brown solid was filtered off. The filtrated was washed with water and then
concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with
55% EtOAc / hexanes to provide compound Int-8c as a colorless oil. LCMS anal. calcd. for
C H BrNO Si: 751.24; Found: 752.29 (M+1) .
39 48 7
Step D– Synthesis of Compound Int-8d
To a mixture of compound Int-8c (300 mg, 0.400 mmol) and 4-methylbenzene
sulfonyl chloride (137 mg, 0.719 mmol), was added 3 mL of pyridine. The reaction solution was
allowed to stir at room temperature overnight. To this was added 10 mL of MeOH. It was
allowed to stir at room temperature for 1 h. It was diluted with 80 mL of EtOAc, and washed
with 100 mL of 0.4 N HCl (aq.). The organic phase was concentrated. The resulting residue
was purified using a silica gel column (40 g) eluting with 5% MeOH / dichloromethane to
provide Compound Int-8d as a colorless film. LCMS anal. calcd. for C H BrNO Si: 643.18;
32 40 6
Found: 644.05 (M+1) .
Step E– Synthesis of Compound Int-8e
To a solution of compound Int-8d (125 mg, 0.195 mmol) in 4 mL of dichloromethane
was added Dess-Martin periodinane (165 mg, 0.389 mmol). The reaction was allowed to stir at
room temperature for 30 min. It was diluted with 15 mL of EtOAc. The solid was filtered off.
The liquid portion was washed with 15 mL of sat. Na CO (aq.) solution and then 15 mL of
brine. It was concentrated in vacuo and purified using a silica gel column (40 g) eluting with 4%
MeOH / dichloromethane to provide compound Int-8e as a white solid. LCMS anal. calcd. for
C H BrNO Si: 641.16; Found: 642.13 (M+1) .
32 38 6
Step F– Synthesis of Compound Int-8f
A solution of compound Int-8e (115 mg, 0.180 mmol) in 4 mL of 1.25 M HCl in MeOH
(50 ml, 63.4 mmol) was allowed to stir at room temperature for 16 h. The solvent was removed
in vacuo. To the resulting residue was added 5 mL of dichloromethane and 0.5 mL of
diisopropylethylamine. The resulting solution was purified using a silica gel column (25 g)
eluting with 6% MeOH / dichloromethane to provide compound Int-8f as a white solid. LCMS
anal. calcd. for C H BrNO : 401.05; Found: 402.09 (M+1) .
16 20 6
Step G– Synthesis of Compound Int-8g
To a solution of compound Int-8f (66 mg, 0.164 mmol) in 2 mL of dichloromethane was
added triethylsilane (382 mg, 3.28 mmol) followed by methanesulfonic acid (200 mg, 2.08
mmol). The reaction was allowed to stir at room temperature for 10 h. This was diluted with 15
mL of dichloromethane. Solid NaHCO3 (2 g) was added. The resulting mixture was allowed to
stir at room temperature until the color of the mixture turned light yellowish. It was filtered.
The filtrate was purified using a preparative TLC plate eluting with 5% MeOH /
dichloromethane to provide compound Int-8g as a colorless film. LCMS anal. calcd. for
C H BrNO : 387.05; Found: 388.06 (M+1) .
16 20 5
Step H– Synthesis of Compound Int-8h
To a solution of compound Int-8g (57 mg, 0.148 mmol) in 5 mL of MeOH, was added
K CO (82 mg, 0.59 mmol). The reaction was then stirred at 60 °C for 1 h. Most of the solvent
was removed in vacuo. To the resulting residue was added 50 mL of dichloromethane. The
solvent was removed in vacuo. The resulting residue was purified using a silica gel column (25
g) eluting with 7% MeOH / dichloromethane to provide compound Int-8h as a white solid.
LCMS anal. calcd. for C H BrNO : 343.04; Found: 344.05 (M+1) .
14 18 4
Step I– Synthesis of Compound Int-8i and Compound Int-8j
To a solution of compound Int-8h (46 mg, 0.134 mmol) in 4 mL of dichloromethane,
was added Dess-Martin reagent (85 mg, 0.20 mmol). The reaction was allowed to stir at room
temperature for 45 min. It was diluted with 15 mL of EtOAc. The solid was filtered off. The
liquid portion was concentrated. The resulting residue was purifed by a reverse phase C18
column (120 g) eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 0-90%) over 15
column length to provide the cis-fused isomer compound Int-8i and the trans-fused isomer
compound Int-8j separately as white solids. LCMS anal. calcd. for C H BrNO : 341.03;
14 16 4
Found: 342.04 (M+1) .
Step J– Synthesis of Compound Int-8k
To a solution of compound Int-8i (18 mg, 0.053 mmol) in 1 mL of DMSO, was added
(2,4-difluorophenyl)methanamine (11.3 mg, 0.079 mmol), diisopropylethylamine (17.0 mg,
0.132 mmol) and Pd(PPh ) (12.2 mg, 10.5 µmol) sequentially. The reaction vessel was filled
with CO gas. It was stirred under a baloon of CO at 90 °C for 8 h. It was cooled to room
temperature. The content was purified using a reverse phase C18 column (40 mg) eluting with
0.05% TFA in water / 0.05% TFA in ACN (from 5-100%) over 12 column length to provide a
mixture of the crude compound Int-8k along with triphenylphosphine oxide. This material was
further purified using a chiral preparative SFC (ChiralPak IA, 30 X 250 mm, 70 mL/min, 120
bar, 40% (2:1 MeOH:ACN) / CO , 35 °C) to provide enantiomer A of compound Int-8k (earlier
eluting component) and enantiomer B of compound Int-8k (later eluting component). LCMS
anal. calcd. for C H F N O : 432.15; Found: 433.18 (M+1) .
22 22 2 2 5
Step K– Synthesis of Compound 7 and Compound 8
To a solution of the earlier eluting Enantiomer A of compound Int-8k (5 mg, 0.012
mmol) in 1 mL of DMF, was added lithium chloride (4.90 mg, 0.116 mmol). The reaction was
allowed to stir at 100 °C for 2 h. It was cooled to room temperature, and the content was
purified using Gilson reverse phase HPLC eluting with 0.05% TFA in water / 0.05% TFA in
ACN (from 10% to 90%) to provide compound 7 as a white solid. ¹H NMR (400 MHz, CDCl ):
δ 10.44 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.40 (m, 1 H); 6.80-6.86 (m, 2 H); 4.67 (m, 2 H); 4.50
(dd, J = 11.2, 1.6 Hz, 1 H); 4.24 (dd, J = 11.2, 2.4 Hz, 1 H); 4.00 (dd, J = 9.2, 1.6 Hz, 1 H); 3.82
(dd, J = 2.4, 1.6 Hz, 1 H), 3.51-3.56 (m, 1 H); 2.69 (dd, J = 9.2, 1.2 Hz, 1 H); 1.56-1.58 (m, 2 H);
1.43-1.50 (m, 1 H); 1.30 (s, 3H). LCMS anal. calcd. for C H F N O : 418.13; Found: 419.18
21 20 2 2 5
(M+1) .
To a solution of the later eluting Enantiomer B of compound Int-8k (5 mg, 0.012 mmol)
in 1 mL of DMF, was added lithium chloride (4.90 mg, 0.116 mmol). The reaction was allowed
to stir at 100 °C for 2 h. It was cooled to room temperature, and the content was purified using
Gilson reverse phase HPLC eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 10%
to 90%) to provide compound 8 as a white solid. ¹H NMR (400 MHz, CDCl ): δ 10.46 (brs, 1
H); 8.48 (s, 1 H); 7.35-7.40 (m, 1 H); 6.80-6.86 (m, 2 H); 4.67 (m, 2 H); 4.50 (dd, J = 11.2, 1.6
Hz, 1 H); 4.25 (dd, J = 11.2, 2.4 Hz, 1 H); 3.99 (dd, J = 9.2, 1.6 Hz, 1 H); 3.82 (dd, J = 2.4, 1.6
Hz, 1 H), 3.51-3.56 (m, 1 H); 2.69 (dd, J = 9.2, 1.2 Hz, 1 H); 1.56-1.58 (m, 2 H); 1.42-1.50 (m, 1
H); 1.29 (s, 3 H). LCMS anal. calcd. for C H F N O : 418.13; Found: 419.18 (M+1) .
21 20 2 2 5
Example 11
Preparation of Compound 14
O O Step B O
Step A
N HO N N N
O F F
O OMe O OMe O
Int-8k Int-15a Int-15b
Step C
OH O
Step A– Synthesis of Compound Int-15a
To a solution of enantiomer A of compound Int-8k (61 mg, 0.141 mmol) in 1 mL of
toluene, was added di-tert-butyl dicarbonate (123 mg, 0.564 mmol) followed by DMAP (51.7
mg, 0.423 mmol). The reaction was allowed to stir at 110 °C for 1 h. The solvent was removed
in vacuo. The resulting residue was dissolved in 2 mL of MeOH. To the resulting solution was
added potassium carbonate (78 mg, 0.564 mmol). The reaction was allowed to stir at room
temperature for 2.5 h. To the resulting mixture was added 1.4 mL of 0.5 N LiOH aqueous
solution. The reaction was allowed to stir at room temperature for 1 h. The solvent was removed
in vacuo. The resulting residue was purified using a reverse phase Gilson (5-100% 0.05% TFA
in ACN / 0.05% TFA in water) to provide compound Int-15a as a white solid. C15H17NO6:
307.11; Found: 308.02 (M+1) .
Step B– Synthesis of Compound Int-15b
To a solution of compound Int-15a (12 mg, 0.039 mmol) in 0.5 mL of DMF, was added
(2,4,6-trifluorophenyl)methanamine (9.44 mg, 0.059 mmol), 4-methylmorpholine (15.80 mg,
0.156 mmol), and HATU (22.27 mg, 0.059 mmol) sequentially. The reaction was allowed to stir
at room temperature for 16 h. The reaction solution was purified using Gilson reverse phase
HPLC (0-100% 0.05% TFA in ACN / 0.05% TFA in water) to provide compound Int-15b as a
light yellow film. C H F N O : 450.14; Found: 451.01 (M+1) .
22 21 3 2 5
Step C– Synthesis of Compound 14
Using the method described in Step K in example 10, compound 14 was prepared
from compound Int-15b. 1H NMR (500 MHz, CDCl ): δ 10.40 (brs, 1 H); 8.48 (s, 1 H); 6.69
(t, J = 8.2 Hz, 2 H); 4.65-4.74 (m, 2 H); 4.46-4.55 (m, 1 H); 4.20-4.28 (m, 1 H); 3.99 (dd, J =
11.5, 2.0 Hz, 1 H); 3.82 (m, 1 H); 3.48-3.57 (m, 1 H); 2.64-2.78 (m, 1 H); 1.53-1.61 (m, 2 H);
1.42-1.52 (m, 1 H); 1.29 (s, 3 H). LCMS anal. calcd. for C H F N O : 436.12; Found: 437.01
21 19 3 2 5
(M+1) .
Example 12
Preparation of Compound 15-18
Starting from compound Int 15a, following essentially the same method described in
Step B and Step C of Example 11, only replacing (2,4,6-trifluorophenyl)methanamine with
appropriate amine in Step B, compounds 15 - 18 were prepared.
Compound 15: H NMR (500 MHz, CDCl3): δ 10.50 (brs, 1 H); 8.50 (s, 1 H); 7.27-
7.35 (m, 2 H); 7.06 (t, J = 7.9 Hz, 1 H); 4.70-4.78 (m, 2 H); 4.52 (dd, J = 13.7, 1.4 Hz, 1 H);
4.27 (dd, J = 13.8, 2.4 Hz, 1 H); 3.99 (dd, J = 11.5, 2.4 Hz, 1 H); 3.82 (m, 1 H); 3.51-3.56 (m,
1 H); 2.65-2.78 (m, 1 H); 1.53-1.61 (m, 2 H); 1.42-1.52 (m, 1 H); 1.30 (s, 3 H). LCMS anal.
calcd. for C H ClFN O : 434.10; Found: 434.97 (M+1) .
21 20 2 5
Compound 16: H NMR (500 MHz, CDCl ): δ 10.53 (brs, 1 H); 8.51 (s, 1 H); 7.40 (d,
J = 7.0 Hz, 1 H); 7.19-7.27 (m, 1 H); 7.11 (t, J = 8.6 Hz, 1 H); 4.57-4.66 (m, 2 H); 4.48-4.55
(m, 1 H); 4.28 (dd, J = 13.6, 1.6 Hz, 1 H); 4.00 (dd, J = 11.5, 2.0 Hz, 1 H); 3.83 (m, 1 H);
3.50-3.58 (m, 1 H); 2.66-2.79 (m, 1 H); 1.53-1.61 (m, 2 H); 1.22-1.52 (m, 1 H); 1.30 (s, 3 H).
LCMS anal. calcd. for C H ClFN O : 434.10; Found: 434.97 (M+1) .
21 20 2 5
Compound 17: H NMR (400 MHz, CDCl ): 10.46 (broad, 1 H); 8.45 (s, 1 H); 7.10-7.14
(m, 1 H); 6.91-6.96 (m, 1 H); 4.65-4.70 (m, 2 H); 4.51 (dd, J = 10.8 Hz, 1 H); 4.24 (dd, J = 1.6,
11.2 Hz, 1 H); 3.99 (dd, J = 8.8 Hz, 1 H); 3.83 (m, 1 H); 3.52-3.56 (m, 1 H); 2.68-2.73 (m, 1 H);
1.55-1.60 (m, 2 H); 1.43-1.50 (m, 1 H); 1.30 (s, 3 H). LCMS anal. calcd. for C H F N O :
21 19 3 2 5
436.12; Found: 437.17 (M+1) .
Compound 18: H NMR (400 MHz, CDCl ): 10.47 (broad, 1 H); 8.48 (s, 1 H); 7.33-7.36
(m, 2 H); 7.01-7.05 (m, 2 H); 4.60-4.68 (m, 2 H); 4.51 (dd, J = 10.8 Hz, 1 H); 4.26 (dd, J = 1.6,
11.2 Hz, 1 H); 3.98 (dd, J = 1.2, 8.8 Hz, 1 H); 3.83 (m, 1 H); 3.51-3.57 (m, 1 H); 2.68-2.73 (m, 1
H); 1.56-1.61 (m, 2 H); 1.44-1.50 (m, 1 H); 1.30 (s, 3 H). LCMS anal. calcd. for C H FN O :
21 21 2 5
400.14; Found: 401.18 (M+1) .
Example 13
Preparation of Compounds 19-30
Starting from enantiomer B of compound Int 8k, using essentially the same method
described in Step A to Step C in example 11 and only substituted with the appropriate amines in
Step B, the following compounds were prepared:
Compound # Structure Rt (min)
(M + H)
19 2.93 (LC5) 401.1
3.12 (LC5) 437.1
21 1.78 (LC3) 401.1
22 1.79 (LC3) 419.1
23 0.97 (LC2) 437.1
24 1.02 (LC2) 415.1
1.05 (LC2) 480.9
OH O
26 1.04 (LC2) 435.1
27 1.05 (LC2) 433.2
28 1.02 (LC2) 437.1
29 0.90 (LC2) 427.0
1.04 (LC2) 435.1
31 0.81 (LC2) 419.1
32 0.94 (LC2) 448.2
Example 14
Preparation of Compound 9
The trans-fused compound Int-8j (prepared in the Step I of Example 10) was converted
into compound 9 using the method described in Step J and Step K of Example 10. H NMR
(400 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41 (m, 1 H); 6.82-6.88 (m, 2 H);
4.68 (d, J = 5.9 Hz, 2 H); 4.12-4.24 (m, 3 H); 3.92 (dd, J = 11.3, 5.4 Hz, 1 H); 3.52-3.59 (m, 1
H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H); 1.37 (s, 3 H). LCMS anal. calcd.
for C H F N O : 418.13; Found: 419.18 (M+1) .
21 20 2 2 5
Example 15
Preparation of Compound 33 and Compound 34
Using the methods described above for making compounds 7 and 8, and starting from
compound Int-8j, compound 33 and 34 were prepared by chiral separation separation (IC
column, 20x250mm, 50% MeOH (0.2%NH OH)/CO , 50 ml/min, 100bar) of the intermediate
prior to the last step in the synthesis of compound 9. The earlier eluting compound was
deprotected using the conditions described in Step K of Example 10 to provide compound 33,
the later eluting compound was deprotected to provide compound 34.
Compound 33: H NMR (400 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41
(m, 1 H); 6.82-6.88 (m, 2 H); 4.68 (d, J = 5.9 Hz, 2 H); 4.12-4.24 (m, 3 H); 3.92 (dd, J = 11.3,
.4 Hz, 1 H); 3.52-3.59 (m, 1 H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H);
1.37 (s, 3 H). LCMS anal. calcd. for C H F N O : 418.13; Found: 419.18 (M+1) .
21 20 2 2 5
Compound 34: H NMR (400 MHz, CDCl ): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41
(m, 1 H); 6.82-6.88 (m, 2 H); 4.68 (d, J = 5.9 Hz, 2 H); 4.12-4.24 (m, 3 H); 3.92 (dd, J = 11.3,
.4 Hz, 1 H); 3.52-3.59 (m, 1 H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H);
1.37 (s, 3 H). LCMS anal. calcd. for C H F N O : 418.13; Found: 419.18 (M+1) .
21 20 2 2 5
Example 16
Preparation of Compound 35 and Compound 36
Starting from compound Int 8j, compound 35 and 36 were prepared by essentially the
same method described in step J and K of Example 10, only replacing 2,4-difluorobenzylamine
with 2-fluorochlorobenzylamine. The earlier eluting compound in the chiral separation
process (IC column, 20x250mm, 40% MeOH (0.2%NH OH)/CO , 55 ml/min, 100bar) of step J
was deprotected to provide compound 35, the later eluting compound was deprotected to provide
compound 36.
Compound 35: H NMR (500 MHz, CDCl ): δ 10.36 (brs, 1 H), 8.49 (s, 1 H), 7.34-7.27
(m, 2H), 7.05 (t, J = 7.8 Hz, 1 H), 4.73 (m, 2 H), 4.20-4.28 (m, 1 H), 4.09-4.19 (m, 2 H), 3.88-
3.96 (m, 1 H), 3.48-3.59 (m, 1 H), 2.21-2.32 (m, 1 H), 1.96-2.06 (m, 1 H), 1.68-1.78 (m, 2 H),
1.36 (s, 3 H). LCMS anal. calcd. for C H ClFN O : 434.10; Found: 435.04 (M+1) .
21 20 2 5
Compound 36: H NMR (500 MHz, CDCl ): δ 10.36 (brs, 1 H), 8.49 (s, 1 H), 7.35-7.27
(m, 2H), 7.05 (t, J = 7.8 Hz, 1 H), 4.73 (m, 2 H), 4.20-4.28 (m, 1H), 4.09-4.19 (m, 2 H), 3.88-
3.98 (m, 1 H), 3.51-3.57 (m, 1 H), 2.21-2.32 (m, 1 H), 1.96-2.06 (m, 1 H), 1.68-1.78 (m, 2 H),
1.36 (s, 3 H). LCMS anal. calcd. for C H ClFN O : 434.10; Found: 435.06 (M+1) .
21 20 2 5
Example 17
Preparation of Compound Int-9b
Step A– Synthesis of Compound Int-9a
To a solution of 5-((tert-butyldimethylsilyl)oxy)pentenol (2070 mg, 9.57 mmol) in
mL of dichloromethane, was added diisopropylethylamine (1545 mg, 11.96 mmol). The
reaction solution was cooled to 0 °C, and methanesulfonyl chloride (1205 mg, 10.52 mmol) was
then added. The reaction was allowed to stir at room temperature overnight. It was diluted with
60 mL of dichloromethane, and washed with 50 mL of 0.5 N HCl (aq.), and then 60 mL of sat.
NaHCO (aq.) solution. The organic phase was concentrated. The resulting residue was purified
using a silica gel column (40 g) eluting with 10% EtOAc / hexanes to provide compound Int-9a
as a colorless oil. H NMR (400 MHz, CDCl ): δ 5.62-5.84 (m, 2 H), 4.06 (d, J = 7.0 Hz, 2 H),
3.68 (t, J = 6.5 Hz, 2 H), 2.31 (apparent q, J = 6.6 Hz, 2 H), 0.92 (s, 9 H), 0.08 (s, 6 H).
Step B– Synthesis of Compound Int-9b
To a solution of lithium diisopropylamide (3.85 ml, 7.69 mmol) in 10 mL THF cooled at
0 °C, was added tributyltinhydride (1.953 ml, 7.31 mmol). The reaction was allowed to stir at 0
°C for 15 min. The resulting lithium tributyltin solution was then cooled at -78 °C, and a
solution of compound Int-9a (903 mg, 3.85 mmol) in 10 mL of THF was then added. The
reaction was allowed to stir at -78 °C for 30 min. It was diluted with 80 mL of 20% EtOAc /
hexanes, and washed 100 mL of water. The organic phase was concentrated in vacuo. The
resulting residue was purified using a silica gel column (80 g) eluting with hexanes to provide
compound Int-9b as a colorless oil. H NMR (400 MHz, CDCl ): δ 5.62 (dt, J = 15.3, 8.4 Hz, 1
H), 5.62 (dt, J = 15.1, 7.0 Hz, 1 H), 3.87 (t, J = 7.3 Hz, 2 H), 2.22 (apparent q, J = 7.3 Hz, 2 H),
1.72 (d, J = 8.5 Hz, 2 H), 1.42-1.58 (m, 6 H), 1.28-1.36 (m, 6 H), 0.79-1.06 (m, 24 H), 0.08 (s, 6
Example 18
Preparation of Compound Int-10f
Step A– Synthesis of Compound Int-10a
To a solution of compound Int-1 (500 mg, 1.552 mmol) and compound Int-9b (912 mg,
1.862 mmol) in 15 mL of ACN stirred at 0 °C, was added Tin (II) Cl (441 mg, 2.328 mmol).
The reaction was stirred for 30 min. The content was diluted with 100 mL of 30% EtOAc /
hexanes, and washed with 100 mL of 15% wt. NH F in water. The organic phase was separated
and filtered. The mother liquor was concentrated in vacuo and the resulting residue was purified
using a silica gel column (80 g) eluting initially with dichloromethane to removed Tin reagent,
and then with 5% EtOAc / dichloromethane to provide compound Int-10a as a mixture of
stereoisomers. LCMS anal. calcd. for C H BrNO Si: 523.16; Found: 524.07 (M+1) .
36 4
Step B– Synthesis of Compound Int-10b
To a solution of compound Int-10a (610 mg, 1.167 mmol) in 8 mL of dichloromethane,
was added acetic anhydride (2000 mg, 19.59 mmol), triethylamine (800 mg, 7.91 mmol), and
DMAP (143 mg, 1.167 mmol) sequentially. The reaction was allowed to stir at room
temperature for 1 h. It was further diluted with 20 mL of dichloromethane, and then added 3 mL
of MeOH. It was allowed to stir at room temperature for 2 h to quench excess acetic anhydride.
The solvent was removed in vacuo and the resulting residue was purified using a silica gel
column (120 g) eluting with 15% EtOAc / hexanes to provide compound Int-10b as a colorless
film. LCMS anal. calcd. for C H BrNO Si: 565.17; Found: 566.11 (M+1) .
27 38 5
Step C– Synthesis of Compound Int-10c
To a solution of compound Int-10b (293 mg, 0.519 mmol) in 4.5 mL of THF / t-BuOH /
water (5:5:1), was added 4-methylmorpholine 4-oxide (66.9 mg, 0.571 mmol) followed by 4-
methylmorpholine N-oxide (66.9 mg, 0.571 mmol). The reaction was allowed to stir at room
temperature for 16 h. To this was added 5 g of solid Na S O . The mixture was allowed to stir
2 2 5
at room temperature for 1 h. The content was diluted with 70 mL of 50% EtOAc/hexanes. The
brown solid was filtered off. The filtrate was washed with water and then concentrated. The
resulting residue was purified using a silica gel column (40 g) eluting with 5% MeOH /
dichloromethane to provide compound Int-10c as a colorless oil. LCMS anal. calcd. for
C H BrNO Si: 599.17; Found: 600.12 (M+1) .
27 40 7
Step D– Synthesis of Compound Int-10d
To a solution of compound Int-10c (272 mg, 0.454 mmol) in 3 mL of pyridine, was
added 4-methylbenzenesulfonyl chloride (130 mg, 0.682 mmol). The reaction was allowed to
stir at room temperature for 36 h. To the reaction was added 1 mL of MeOH. It was allowed to
stir at room temperature for 1 h. The content was diluted with 30 mL of dichloromethane, and
washed with 20 mL fo 0.5 N HCl (aq.) solution. The organic phase was concentrated. The
resulting residue was purified using a silica gel column (80 g) eluting with EtOAc to provide
compound Int-10d as a colorless film. LCMS anal. calcd. for C H BrNO Si: 491.12; Found:
32 6
492.02 (M+1) .
Step E– Synthesis of Compound Int-10e
To a solution of compound Int-10d (80 mg, 0.163 mmol) in 2 mL of MeOH, was added
1.25 N HCl in MeOH (0.5 ml, 0.625 mmol). The reaction was allowed to stir at room
temperature for 2 h. The solvent was removed in vacuo. The resulting residue was purified
using a silica gel column (40 g) eluting with 20% MeOH / dichloromethane to provide
compound Int-10e as a colorless film. LCMS anal. calcd. for C H BrNO : 377.03; Found:
14 18 6
378.00 (M+1) .
Step F– Synthesis of Compound Int-10f
To a solution of compound Int-10e (18.64 mg, 0.090 mmol) in 1 mL of ACN, was added
methanesulfonic anhydride (14.82 mg, 0.085 mmol). The reaction was allowed to stir at room
temperature for 30 min. This solution was then added via syringe into a vial containing 7-
bromohydroxy(2-hydroxyethyl)methoxyoxo-2,3,4,8-tetrahydro-1H-quinolizinyl
acetate (20 mg, 0.053 mmol). The reaction was allowed to stir at 50 °C overnight. The solvent
was removed in vacuo. The resulting residue was purified using Gilson reverse phase column
eluting with 0.05% TFA in ACN / 0.05% TFA in water (0 to 90%) to provide compound Int-10f
as a colorless film. LCMS anal. calcd. for C H BrNO : 359.02; Found: 359.96 (M+1) .
14 16 5
Example 19
Preparation of Compound 10
Compound 10 was prepared by following essentially the same reaction sequence from
Step H to Step K in Example 10, and replacing compound Int-8g with compound Int-10f. ¹H
NMR (400 MHz, CDCl ): δ 10.27 (b, 1 H), 8.46 (s, 1 H), 7.35-7.40 (m, 1 H), 6.81-6.86 (m, 2
H), 4.67 (m, 2 H), 4.59 (m, 1 H), 4.24 (dd, J = 2.4, 11.2 Hz, 1 H), 3.98 (dd, J = 1.6, 9.2 Hz, 1
H), 3.76 (m, 1 H), 3.54 (m, 1 H), 3.42 (m, 1 H), 2.77 (m, 1 H), 2.48 (m, 1 H). LCMS anal. calcd.
for C H F2N2O5: 390.10; Found: 391.12 (M+1) .
19 16
Example 20
Preparation of Compound Int-11
Compound Int-11 was prepared as a roughly 1:1 mixture of (E) and (Z) isomers using
the method described in Baldwin et al, Chem. Commun. 22:2786 (2003).
Example 21
Preparation of Compound Int-12
Compound Int-12 was prepared as a roughly 1:1 mixture of (E) and (Z) isomers by
following essentially the same mathod described in Example 17, and replacing 5-((tert-
butyldimethylsilyl)oxy)pentenol with compound Int-11 in Step A. H NMR (400 MHz,
CDCl ): δ 5.60 & 5.40 (dt, J = 9.0, 1.1 Hz, 1 H), 4.16 & 4.03 (s, 2 H), 1.70-1.84 (m, 2 H), 1.61
& 1.59 (s, 3 H), 1.42-1.58 (m, 6 H), 1.28-1.36 (m, 6 H), 0.79-1.02 (m, 24 H), 0.11 & 0.08 (s, 6
Example 22
Preparation of Compound Int-13
Compound Int-13 was prepared using the method described in Steps A to D of Example
18, and replacing compound Int-9b with compound Int-12 in Step A. LCMS anal. calcd. for
C H BrNO Si: 491.12; Found: 492.04 (M+1) .
32 6
Example 23
Preparation of Compounds 11 and 12
Step A– Synthesis of Compound Int-14a
To a solution of praraformaldehyde (93 mg, 3.09 mmol) in 4 mL of AcOH was added
sulfuric acid (120 mg, 1.224 mmol). The reaction was allowed to stir at room temperature for 20
min before compound Int-13 (160 mg, 0.309 mmol) was added. The reaction was allowed to stir
at room temperature for 1 h and then at 70 °C for 1 h. It was cooled to room temperature. To the
content was added 1 g of NaHCO solid portionwise. The mixture was diluted with 20 mL of
EtOAc and then filtered. The filtrate was concentrated in vacuo and purified using a reverse
phase column (120 g) eluting with 0.05% TFA in water and 0.05% TFA in ACN (from 0% to
90% over 10 column length) to provide compound Int-14a. LCMS anal. calcd. for
C H BrNO : 389.03; Found: 390.02 (M+1) .
18 6
Step B– Synthesis of Compound Int-14b
To a solution of compound Int-14a, TFA salt (150 mg, 0.299 mmol) in 5 mL of MeOH,
was added potassium carbonate (165 mg, 1.195 mmol). The reaction was allowed to stir at room
temperature for 2 h. The solvent was removed in vacuo. The resulting residue was purified
using a silica gel column (40 g) eluting with 8% MeOH / dichloromethane to provide compound
Int-14b as a colorless film. LCMS anal. calcd. for C H BrNO : 347.02; Found: 348.11 (M+1) .
13 16 5
Step C– Synthesis of Compound Int-14c and Compound Int-14d
To a solution of compound Int-14b (88 mg, 0.254 mmol) in 5 mL of dichloromethane,
was added Dess-Martin periodinane (162 mg, 0.381 mmol). The reaction was allowed to stir at
room temperature for 45 min. It was diluted with 60 mL of EtOAc. The solid was filtered off.
The liquid portion was concentrated. The resulting residue was purifed by a silica gel column
(40 g) eluting with EtOAc to provide cis-fused compound Int-14c and trans-fused compound
Int-14d individually as a white solid. LCMS anal. calcd. for C H BrNO : 345.00; Found:
13 14 5
346.02 (M+1) .
Step D– Synthesis of Compound Int-14e
To a solution of compound Int-14d (42 mg, 0.122 mmol) in 2 mL of DMSO, was added
(2,4-difluorophenyl)methanamine (34.9 mg, 0.244 mmol), diisopropylethylamine (39.4 mg,
0.305 mmol) and Pd(PPh ) (35.3 mg, 0.031 mmol) sequentially. The reaction vessel was filled
with CO gas by boubling CO into the solution through a needle over 20 min. It was stirred under
a baloon of CO at 90 °C for 6 h. It was cooled to room temperature. The content was purified
using reverse phase Gilson eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 10-
90%) to provide the crude compound Int-14e. This material was further purified using a chiral
preparative SFC (Chiral AD 30X250 mm column, 40% 2:1 MeOH:ACN / CO2, 70 mL / min, 100
bar, 4 mg/mL in MeOH / dichloromethane, 35 °C, 254 nM) to provide enantiomer A of
compound Int-14e (earlier eluting component) and enantiomer B of compound Int-14e (later
eluting component). LCMS anal. calcd. for C H F N O : 434.13; Found: 435.04 (M+1) .
21 20 2 2 6
Step E– Synthesis of Compound 11 and 12
To a solution of the enantiomer A of compound Int-14e (4.0 mg, 9.21 µmol) in 4 mL of
DMF, was added lithium chloride (7.81 mg, 0.184 mmol). The mixture was allowed to stir at
100 °C for 1 h. It was cooled to room temperature. The mixture was separated by reverse phase
Gilson (10% ACN(0.05% TFA) / H O- 90% ACN (0.05% TFA) / H O, 12 min) to afford
compound 11 as a white solid. ¹H NMR (400 MHz, CDCl ): δ 10.25 (b, 1 H), 8.51 (s, 1 H),
7.35-7.40 (m, 1 H), 6.81-6.87 (m, 2 H), 5.19 (d, J = 5.2 Hz, 1 H), 4.80 (d, J = 5.2 Hz, 1 H), 4.67
(d, J = 4.8 Hz, 2 H), 4.28-4.34 (4 H), 3.87 (d, J = 9.2 Hz, 1 H), 1.6 (brs, 1 H), 1.57 (s, 3 H).
LCMS anal. calcd. for C H F N O : 420.11; Found: 421.04 (M+1) .
18 2 2 6
To a solution of the enantiomer B of compound Int-14e (4.0 mg, 9.21 µmol) in 4 mL of
DMF, was added lithium chloride (7.81 mg, 0.184 mmol). The mixture was allowed to stir at
100 °C for 1 h. It was cooled to room temperature. The mixture was separated by reverse phase
Gilson (10% ACN (0.05% TFA) / H O- 90% ACN (0.05% TFA) / H O, 12 min) to afford
compound 12 as a white solid. H NMR (400 MHz, CDCl ) δ 10.29 (b, 1 H); 8.53 (s, 1 H), 7.35-
7.40 (m, 1 H), 6.81-6.87 (m, 2 H), 5.19 (d, J = 5.2 Hz, 1 H), 4.80 (d, J = 5.2 Hz, 1 H), 4.67 (d, J
= 4.8 Hz, 2 H), 4.27-4.34 (4 H), 3.87 (d, J = 9.2 Hz, 1 H), 1.6 (brs, 1 H); 1.61 (s, 3 H). LCMS
anal. calcd. for C H F N O : 420.11; Found: 421.04 (M+1) .
18 2 2 6
Example 24
Preparation of Compound 13
The cis-fused compound Int-14c prepared in the Step C of Example 23 was converted
into compound 13 using the method described in Step D and Step E of Example 23. H NMR
(400 MHz, CDCl ) δ 10.38 (b, 1 H); 8.47 (s, 1 H); 7.35-7.42 (m, 1 H); 6.81-6.88 (m, 2 H), 5.07
(d, J = 6.3 Hz, 1 H), 4.82 (d, J = 6.3 Hz, 1 H), 4.78 (d, J = 11.5 Hz, 1 H), 4.62-4.73 (m, 2 H),
4.51 (d, J = 13.8 Hz, 1 H), 4.31 (d, J = 13.9 Hz, 1 H), 4.16 (s, 1 H), 3.45 (d, J = 11.4 Hz, 1 H),
1.21 (s, 3 H). LCMS anal. calcd. for C H F N O : 420.11; Found: 421.06 (M+1) .
18 2 2 6
Example 25
Preparation of Compound 37 and 38
Step A– Synthesis of Compound Int-16a
To a solution of butynol (10 g, 143 mmol) in 110 mL of dichloromethane was
added tert-butylchlorodiphenylsilane (37.3 g, 136 mmol) followed by 1H-imidazole (14.6 g, 214
mmol) and N,N-dimethylpyridinamine (17.4 g, 143 mmol). The reaction was allowed to stir
at 20 °C for 2 hours. The progress of the reaction was monitored by TLC. It was diluted with
150 mL of water, extracted by 50% EtOAc/hexanes (2 x 150 mL). The organic phase was
concentrated in vacuo and the resulting residue was purified using a silica gel column
chromatography (PET: EtOAc = 200: 1) to provide compound Int-16a as a colorless oil. H
NMR (400 MHz, CDCl3): δ 7.68 (d, J = 6.4 Hz, 4 H), 7.34-7.48 (m, 6 H), 3.79 (t, J = 7.0 Hz, 2
H), 2.45 (dt, J = 7.0, 2.4 Hz, 2 H), 1.95 (brs, 1H), 1.06 (s, 9 H).
Step B– Synthesis of Compound Int-16b
To a stirred solution of compound Int-16a (13.4 g, 43.4 mmol) in 200 mL of THF at -78
°C was added butyllithium (18.24 ml, 45.6 mmol). It was allowed to stir at this temperature for
min. To this was added a solution of methyl carbonochloridate (5.336 g, 56.5 mmol) in 20
mL of THF via canula, and the reaction was stirred for 2 hours while warming up to 0 °C. The
reaction was quenched by addition of saturated NH Cl solution (100 mL) and extracted with
EtOAc (2 x 200 mL). The organic layer was dried over anhydrous Na SO . The solvent was
filtered and the filtrate was concentrated to provide compound Int-16b as a clear oil. H NMR
(400 MHz, CDCl ): δ 7.67 (d, J = 6.4 Hz, 4 H), 7.33-7.50 (m, 6 H), 3.81 (t, J = 6.8 Hz, 2 H),
3.76 (s, 3 H), 2.58 (t, J = 6.8 Hz, 2 H), 1.05 (s, 9 H).
Step C– Synthesis of Compound Int-16c
To a stirred solution of copper(I) iodide (13.8 g, 72.6 mmol) in THF (10 mL) at 0 °C was
added methyllithium (29.7 ml, 47.5 mmol) and stirred for 15 min at 0 °C. The resulting solution
was cooled to -78 °C and a solution of compound Int-16b (17.4 mg, 47.5 mmol) in THF (5 mL)
was added via canula and stirred for 2 hours at that temperature. The reaction mixture was then
quenched by the addition of saturated NH Cl (10 mL) followed by water (200 mL). The mixture
was extracted with EtOAc (3 x 20 mL), the combined organic layer was dried over anhydrous
Na SO , then filtered. The filtrate was concentrated to provide compound Int-16c as a clear oil.
H NMR (400 MHz, CDCl ): δ 7.66 (d, J = 6.4 Hz, 4 H), 7.35-7.42 (m, 6 H), 5.72 (s, 1 H), 3.83
(t, J = 6.4 Hz, 2 H), 3.62-3.70 (m, 3 H), 2.91 (t, J = 6.4 Hz, 2 H), 1.92 (s, 3 H), 1.03 (s, 9 H).
Step D– Synthesis of Compound Int-16d
To a solution of compound Int-16c (19 g, 49.7 mmol) in dichloromethane (200 mL)
cooled at -78 °C was added diisopropylaluminum hydride (109 ml, 109 mmol). The reaction
was allowed to stir at -78 °C for 1 h. and warm up to 0 °C. At this time, it was quenched by
adding 500 mL of saturated Rochelle salt solution. The mixture was allowed to stir at 0 °C for 1
hour and the organic phase was isolated. The organic layer was washed with 50 mL of brine and
dried over Na SO , then it was filtered and the filtrate was concentrated. The resulting residue
was purified using silica gel column chromatography (PET: EtOAc = 10: 1) to provide
compound Int-16d as a colorless oil.
H NMR (400 MHz, CDCl ): δ 7.67 (d, J = 6.4 Hz, 4 H), 7.36-7.44 (m, 6 H), 5.64 (t, J = 6.8 Hz,
1 H), 4.04 (d, J = 6.8 Hz, 2 H), 3.67 (t, J = 6.4 Hz, 2 H), 2.36 (t, J = 6.4 Hz, 2 H), 1.69 (s, 3 H),
1.04 (s, 9 H).
Step E– Synthesis of Compound Int-16e
To a solution of compound Int-16d (7 g, 19.74 mmol) and lithium chloride (1.7 g, 39.5
mmol) in dichloromethane (70 mL) was added N-ethyl-N-isopropylpropanamine (6.4 g, 49.4
mmol) followed by methanesulfonyl chloride (3619 mg, 31.6 mmol). The reaction mixture was
allowed to stir at 20 °C for 2 hours. Then it was diluted with 200 mL of dichloromethane and
washed with 200 mL of 0.2 N HCl (aq.) solution and 100 mL of brine. The organic phase was
concentrated to provide compound Int-16e as a colorless oil. H NMR (400 MHz, CDCl ): δ
7.66 (d, J = 6.4 Hz, 4 H), 7.36-7.46 (m, 6 H), 5.50 (t, J = 7.6 Hz, 1 H), 3.96-4.14 (m, 2 H), 3.64-
3.80 (m, 2 H), 2.35 (t, J = 6.8 Hz, 2 H), 1.63-1.77 (m, 3 H), 1.04 (s, 9 H).
Step F– Synthesis of Compound Int-16f
To a solution of lithium diethylamide (19.17 mL, 38.3 mmol) in THF (70 mL) cooled at 0
°C, was added tributylstannane (10 g, 34.9 mmol). The reaction was allowed to stir at 0 °C for
minutes. It was then cooled to -78 °C, and a solution of compound Int-16e (6.5 g, 17.43
mmol) in 30 mL of THF was added via syringe. The reaction was allowed to stir at -78 °C for
30 minutes. It was diluted with 100 mL of 20% EtOAc/hexanes and washed with 100 mL of
water. The organic phase was isolated and the aqueous phase was extracted with 100 mL of
% EtOAc/hexanes. The combined organic were washed with water, brine and concentrated
under reduce pressure. The resulting residue was purified using a silica gel column
chromatography (PET: EtOAc = 100: 1) to provide compound Int-16f as a colorless oil. H
NMR (400 MHz, CDCl ): δ 7.63-7.75 (m, 4 H), 7.32-7.45 (m, 6 H), 5.30 (t, J = 8.8 Hz, 1 H),
3.66 (t, J = 7.6 Hz, 2 H), 2.18-2.33 (m, 2 H), 1.54-1.63 (m, 5 H), 1.39-1.50 (m, 6 H), 1.21-1.33
(m, 6 H), 1.03-1.08 (m, 9 H), 0.74-0.92 (m, 15 H). MS (M+H) : 628.
Step G– Synthesis of Compound Int-16g
To a solution of compound Int-16f (7.6 g, 12.11 mmol) and compound Int-1 (3.3 g,
.09 mmol) in acetonitrile (100 mL) stirred at 0 °C was added Tin (II) chloride (5.8 g, 30.3
mmol). The reaction was then warmed to 20 °C and stirred for 15 minutes. This color was
gradually disappeared over 5 minutes. The progress of the reaction was monitored by TLC. It
was found that the reaction completed when the color almost all gone. This was diluted with 100
mL of 30% EtOAc/hexane, and 100 mL of 15% (wt) NH F aqueous solution. The resulting
mixture was allowed to stir at 20 °C for 20 min. Solid was filtered off. The organic from the
mother liquor was concentrated in vacuo and the resulting residue was purified using silica gel
column chromatography (PET: EtOAc = 10: 1) to compound Int-16g as colorless oil. H NMR
(400 MHz, CDCl ): δ 8.35 (brs, 1 H), 7.66 (brs, 4 H), 7.48 (d, J = 5.4 Hz, 2 H), 7.36 (brs, 9 H),
.61-5.81 (m, 1 H), 5.15~5.27 (m, 1 H), 4.90-5.14 (m, 2 H), 4.77 (d, J = 18.0 Hz, 2 H), 3.84 (brs,
3 H), 3.59-3.78 (m, 3 H), 1.87 (d, J = 5.4 Hz, 1 H), 1.68-1.80 (m, 1 H), 1.03 (brs, 9 H), 0.88-0.96
(m, 3 H). MS (M+H) : 662.
Step H– Synthesis of Compound Int-16h
To a solution of compound Int-16g (11 g, 16.65 mmol), N,N-dimethylpyridinamine
(407 mg, 3.33 mmol) and N-ethyl-N-isopropylpropanamine (10 g, 83 mmol) in
dichloromethane (100 mL) was added chloro (methoxy)methane (6.7 g, 83 mmol). The reaction
mixture was allowed to stir at 30 °C for 16 hours, LCMS showed the starting material was
consumed completely. The solvent was removed in vacuo. The resulting residue was purified
using silica gel column chromatography (PET: EtOAc = 10: 1) to provide compound Int-16h as
a colorless oil. H NMR (400 MHz, CDCl ): δ 8.43 (s, 1 H), 7.64 (d, J = 6.8 Hz, 4 H), 7.47 (d, J
= 5.8 Hz, 2 H), 7.30-7.43 (m, 9 H), 5.75-5.85 (m, 1 H), 5.18-5.25 (m, 1 H), 5.11 (d, J = 11.6 Hz,
1 H), 4.98 (d, J = 11.0 Hz, 1 H), 4.84-4.90 (m, 1 H), 4.71-4.79 (m, 1 H), 4.54-4.60 (m, 1 H),
4.37-4.44 (m, 1 H), 3.85 (s, 3 H), 3.62-3.72 (m, 2 H), 3.12-3.31 (m, 3 H), 1.94-2.03 (m, 1 H),
1.59-1.68 (m, 1 H), 1.02 (s, 9 H), 0.82-0.96 (m, 3 H). MS (M+H) : 706.
Step I– Synthesis of Compound Int-16i
To a solution of compound Int-16h (10 g, 14.19 mmol) in 100 mL of THF / water (3: 2),
was added 4-methylmorpholine 4-oxide (3.3 g, 28.4 mmol) followed by osmium (VIII) oxide
(541 mg, 2.128 mmol). The reaction was allowed to stir at 35 °C for 48 hours. To this mixture
was added 10 g of solid Na2S2O5. The mixture was allowed to stir at 35 °C for 1 hour. The
mixture was diluted with 100 mL of 50% EtOAc/hexanes. The brown solid was filtered off and
the filtrate was washed with water, brine and dried over anhydrous Na SO . The solid was
filtered and the filtrate was concentrated. The resulting residue was purified using silica gel
column chromatography (PET: EtOAc = 1: 1) to provide compound Int-16i as a white solid. H
NMR (400 MHz, CDCl ): δ 8.27-8.48 (m, 1 H), 7.62-7.74 (m, 4 H), 7.27-7.46 (m, 11 H), 5.18-
.26 (m, 1 H), 5.10-5.16 (m, 1 H), 5.07 (d, J = 3.6 Hz, 1 H), 4.49 (t, J = 7.0 Hz, 1 H), 4.34 (d, J =
6.8 Hz, 1 H), 3.77-3.89 (m, 5 H), 3.45-3.76 (m, 3 H), 3.08-3.26 (m, 3 H), 2.40-2.58 (m, 1 H),
1.67-2.07 (m, 1 H), 1.40-1.58 (m, 1 H), 1.01-1.10 (m, 9 H), 0.78 (s, 3 H). MS (M+H) : 740.
Step J– Synthesis of Compound Int-16j
A solution of 4-methylbenzenesulfonyl chloride (2.8 g, 14.62 mmol) in Pyridine (10
mL) was added to a solution of compound Int-16i (6 g, 8.12 mmol) in Pyridine (50 mL). The
reaction mixture was allowed to stir at 35 °C for 16 hours. LCMS showed the starting material
was consumed completely. The reaction was concentrated in vacuo and the resulting residue
was purified using silica gel column chromatography (PET: EtOAc = 1: 1 then dichloromethane:
MeOH = 100: 1) to provide compound Int-16i as a white solid. H NMR (400 MHz, CDCl ): δ
7.52-7.82 (m, 5 H), 7.34-7.51 (m, 6 H), 4.62-4.96 (m, 3 H), 4.33-4.57 (m, 2 H), 3.91-4.00 (m, 3
H), 3.64-3.90 (m, 3 H), 3.24-3.41 (m, 3 H), 1.21-1.31 (m, 2 H), 0.60-1.17 (m, 12 H). MS
(M+H) : 632.
Step K– Synthesis of Compound Int-16k
To a solution of compound Int-16j (246 mg, 0.390 mmol) in 5 mL of DMF, was added
allyl iodide (262 mg, 1.560 mmol), followed by sodium hydride (31.2 mg, 0.780 mmol). The
reaction was allowed to stir at room temperature for 40 min. It was cooled to 0 °C, and
quenched by adding 1 mL of water. The mixture was diluted with 70% EtOAc/hexanes (80 mL)
and washed with 80 mL of water. The organic phase was concentrated. The resulting residue
was purified using a silica gel column eluting with 3% MeOH / dichloromethane to provide
compound Int-16k as a colorless film. LCMS anal. calcd. for C H BrNO Si: 670.7; Found:
34 44 6
671.9 (M+1) .
Step L– Synthesis of Compound Int-16l
To a solution of compound Int-16k (248 mg, 0.370 mmol) in 4 mL of THF, was added 1
M TBAF in THF (387 mg, 1.479 mmol). The reaction was allowed to stir at room temperature
for 1 h. The solvent was removed in vacuo. The resulting residue was purified using a silica gel
column (40 g) eluting with 8% MeOH / dichloromethane to provide compound Int-16l as a
colorless film. LCMS anal. calcd. for C H BrNO : 433.1; Found: 433.8 (M+1) .
18 26 6
Step M– Synthesis of Compound Int-16m
To a solution of compound Int-16l (152 mg, 0.352 mmol) in 4 mL of dichloromethane,
was added Dess-Martin periodinate (373 mg, 0.879 mmol). The reaction was allowed to stir at
room temperature for 1 h. To this was added 2 drops of water, and the resulting mixture was
diluted with 20 mL of EtOAc. The solid was filtered off. The mother liqor was concentrated in
vacuo. The resulting residue was purified using a silica gel column eluting with 6% MeOH /
dichloromethane to provide compound Int-16m as a colorless film. LCMS anal. calcd. for
C H BrNO : 429.1; Found: 429.9 (M+1) .
18 24 6
Step N– Synthesis of Compound Int-16n
To a mixture of bromo(methyl)triphenylphosphorane (7472 mg, 20.92 mmol) (pre-dried
under house vacuum at 120 °C in a flask overnight) in 60 mL of THF cooled at 0 °C, was added
lithium bis(trimethylsilyl)amide (13.94 ml, 20.92 mmol). It was allowed to stir at 0 °C for 0.5 h.
A solution of compound Int-16m (3000 mg, 6.97 mmol) in 20 mL of THF was then added. The
reaction was warmed to room temperature and stirred for 1 h. This was diluted with 200 mL of
70% EtOAc/hexanes. The solid was filtered off. The filtrate was concentrated in vacuo. The
resulting residue was purified using a silica gel column (220 g)) eluting with 70%
EtOAc/hexanes to provide compound Int-16n as a colorless film. LCMS anal. calcd. for
C H BrNO : 427.1; Found: 428.0 (M+1) .
19 26 5
Step O– Synthesis of Compound Int-16o
To a solution of compound Int-16n (28 mg, 0.065 mmol) in 5 mL of dichloromethane,
was added Zhang's (1B) olefin metathesis cataylyst (8 mg, 10.89 µmol). The reaction was
allowed to stir at room temperature for 2 h. It was concentrated in vacuo. The resulting residue
was purified using a silica gel column (25 g) eluting with 5% MeOH/ dichloromethane to
provide compound Int-16o as a colorless film. LCMS anal. calcd. for C H BrNO : 401.1;
17 22 5
Found: 401.8 (M+1) .
Step P– Synthesis of Compound Int-16p
To a solution of compound Int-16o (24 mg, 0.060 mmol) in MeOH (1 mL), was added
12 N aqueous HCl (200 µl, 2.435 mmol). The reaction was allowed to stir at 60 °C for 1h. The
reaction mixture was concentrated in vacuo. The resulting residue was neutralized by adding
Et N. It was purified using ISCO, normal phase HP Gold silica gel (12g), eluting with
dichloromethane / MeOH (100% DCM for 5 min; gradient to 10% MeOH in dichloromethane
over 12 min, isocratic for 5 min) to provide compound Int-16p as a white solid. LCMS anal.
calcd. for C H BrNO : 355.04; Found: 355.84 (M+1) .
18 4
Step Q– Synthesis of Compound Int-16q and Compound Int-16r
To a solution of compound Int-16p (190 mg, 0.533 mmol) in 8 mL of dry
dichloromethane, was added Dess-Martin periodinate (339 mg, 0.800 mmol). The reaction was
allowed to stir at room temperature for 1 h. To the resulting solution, was added two drops of
water. White solid was formed. The mixture was diluted with 20 mL of dichloromethane and
filtered. The filtrate was washed with 10 mL of sat. Na CO aqueous solution. The organic
phase was isolated. The aqueous was extracted with 20 mL of 10% MeOH / dichloromethane
solution. The combined organics were concentrated. The resulting residue was purified using a
silica gel column (80 g) eluting with EtOAc to provide the cis-fused compound Int-16q and
trans-fused compound Int-16r separately as white solids. LCMS anal. calcd. for C H BrNO :
16 4
353.03; Found: 353.82 (M+1) .
Step R– Synthesis of Compound Int-16s
A mixture of compound Int-16q (25.6 mg, 0.072 mmol), N-ethyl-N-isopropylpropan
amine (38.6 µl, 0.217 mmol)), (3-chlorofluorophenyl)methanamine (14.99 mg, 0.094 mmol)
and (oxybis(2,1-phenylene))bis(diphenylphosphine) (11.68 mg, 0.022 mmol) in DMSO (1.8 mL)
was degassed for 5 min before adding diacetoxypalladium (4.87 mg, 0.022 mmol). The resulting
mixture was flushed with a stream of CO under a balloon of CO for 30 min. The mixture was
heated at 90 °C under CO baloon for 1 h. At completion, the reaction was diluted with DMSO
and was filtered. The crude was purified using preparative HPLC (reverse phase, YMC-Pack
ODS C-18 100x20mm) eluting with acetonitrile/water/0.05% TFA (20% to 90% organic in 10
min, then to 100% in 2 min, 20 mL/min). Related fractions were pooled and evaporated under
reduced pressure to afford compound Int-16s as its racemic mixture. This material was resolved
by chiral preparative SFC (ChiralPak OJ, 20 X 250 mm, 50 ml/min, 100bar, 25% MeOH
(0.2%NH OH)/CO , 35 °C) to provide enantiomer A of compound Int-16s (the first eluting
compound)) and enantiomer B of compound Int-16s (the second eluting compound). LCMS
anal. calcd. for C H ClFN O racemate: 460.12; Found: 461.01 (M+1) .
23 22 2 5
Step S– Synthesis of Compound Int-16t
Two enantiomers of compound Int-16s were converted into enantiomers of compound
Int-16t separately by following the same method described in Step K of Example 10. LCMS
anal. calcd. for C H ClFN O : 446.10; Found: enantiomer A-446.97 (M+1) ; enantiomer B-
22 20 2 5
446.99 (M+1) .
Step T– Synthesis of Compound 37 and Compound 38
To a solution of enantiomer B of compound Int-16t (6 mg, 10.70 µmol) in 2 mL of
MeOH, was added Pd-C (0.569 mg, 5.35 µmol). The mixture was allowed to stir at room
temperature under a baloon of H for 1 h. At the completion, the catalyst was filtered off. The
filtrate was concentrated in vacuo. The resulting residue was purified using preparative HPLC
(reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile/water/0.1% TFA
(20% to 90% organic in 10 min, then to 100% in 2 min, 20 mL/min). Related fractions were
pooled and evaporated under reduced pressure to afford compound 38. Under essentially the
same conditions, enantiomer B of compound Int-16t was converted into compound 37.
Compound 37 and compound 38 show identical NMR and LCMS spectrum. H NMR (500
MHz, CDCl ): δ 10.48 (brs, 1 H); 8.48 (s, 1 H); 7.29-7.33 (m, 2 H); 7.05 (t, J = 7.7 Hz, 1 H);
4.74 (m, 2 H); 4.42-4.45 (m, 1 H); 4.23-4.31 (m, 1 H); 3.94-3.98 (m, 1 H); 3.85 (m, 1 H);
3.67-3.69 (m, 1 H); 2.33-2.46 (m, 1 H); 1.77-1.80 (m, 1 H); 1.62-1.75 (m, 4 H); 1.30 (s, 3 H).
LCMS anal. calcd. for C H ClFN2O : 448.12; Found: 448.97 (M+1) .
22 22 5
Example 26
Preparation of Compound 39-42
Starting from compound Int-16q, compound 39- 42 were prepared by essentially the
same method described from Step R to Step T of Example 25, only replacing 2,4-
difluorobenzylamine with appropriate benzylamines in Step R. Compound 39 and 41 were
prepared from the earlier eluting enantiomer in the chiral separation process of the corresponding
intermediate in step R. Compound 40 and 42 were prepared from the later eluting enantiomer in
the chiral separation process of the coresponding intermediate in step R.
Compound # Rt(min) M+1 (found)
Structure Enantiomer
39 A 1.91 (LC3) 433.0
40 B 1.89 (LC3) 433.0
41 H A 1.92 (LC3) 451.0
F F O
OH O
42 B 1.92 (LC3) 451.0
F F O
OH O
Example 27
Preparation of Compound 43-46
Starting from compound Int-16r, compound 43- 46 were prepared by essentially the
same method described from Step R to Step T of Example 25, employing appropriate
benzylamines in Step R. Compound 43 and 45 were prepared from the earlier eluting
enantiomer in the chiral separation process of the coresponding intermediate in step R.
Compound 44 and 46 were prepared from the later eluting enantiomer in the chiral separation
process of the coresponding intermediate in step R.
Compound 43: H NMR (500 MHz, CDCl ): δ 10.44 (s, 2 H); 8.51 (s, 1 H); 7.38 (q, J =
7.7 Hz, 2 H); 7.29 (s, 1 H); 6.81-6.86 (m, 2 H); 4.68 (m, 2 H); 4.05-4.20 (m, 3 H); 3.88-3.92
(m, 2 H); 2.26-2.29 (m, 1 H); 1.92-2.01 (m, 1 H); 1.85-1.91 (m, 1 H); 1.72-1.83 (m, 3 H);
1.32 (s, 3H). LCMS anal. calcd. for C22H22F2N2O5: 432.15; Found: 433.06 (M+1) .
Compound Structure Enantiomer Rt(min) M+1 (found)
43 H A 1.93 (LC3) 433.1
OH O
44 B 1.96 (LC3) 433.0
OH O
45 A 2.06 (LC3) 449.0
46 B 2.04 (LC3) 449.0
Example 28
Preparation of Compound 47-50
Starting from compound Int 16q, compound 47 and compound 48 were prepared by
essentially the same method described from step R to step S of example 25. Compound 47 was
prepared from the earlier eluting enantiomer in the chiral separation process of the coresponding
intermediate in Step R. Compound 48 was prepared from the later eluting enantiomer in the
chiral separation process of the coresponding intermediate in Step R. Similarly, compound 49
and compound 50 were prepared starting from compound Int 16r.
Compound 47: H NMR (500 MHz, CDCl ) δ 10.42 (brs, 1 H); 8.53 (s, 1H); 7.30-7.39
(m, 1 H); 6.75-6.90 (m, 2 H); 5.81-5.96 (m, 1 H); 5.62-5.77 (m, 1 H); 4.63-4.73 (m, 2 H); 4.12-
4.53 (m, 4 H); 3.90-4.12 (m, 1 H); 2.90 (dd, J = 14.2, 6.6 Hz, 1 H); 2.38 (dd, J = 14.4, 6.7 Hz, 1
H); 1.39 (s, 3 H). LCMS anal. calcd. for C H F N O : 430.13; Found: 431.00 (M+1) .
22 20 2 2 5
Compound 48: H NMR (500 MHz, CDCl ) δ 10.42 (brs, 1 H); 8.53 (s, 1H); 7.30-7.39
(m, 1 H); 6.75-6.90 (m, 2 H); 5.81-5.96 (m, 1 H); 5.62-5.77 (m, 1 H); 4.63-4.73 (m, 2 H); 4.12-
4.53 (m, 4 H); 3.90-4.12 (m, 1 H); 2.90 (dd, J = 14.2, 6.6 Hz, 1 H); 2.38 (dd, J = 14.4, 6.7 Hz, 1
H); 1.39 (s, 3 H). LCMS anal. calcd. for C H F N O : 430.13; Found: 431.00 (M+1) .
22 20 2 2 5
Compound 49: H NMR (500 MHz, CDCl ): δ 10.36 (brs, 1 H); 8.52 (s, 1 H); 7.32-7.45
(m, 1 H); 6.81-6.85 (m, 2 H); 5.94 (m, 2 H); 4.60-4.72 (m, 2 H); 4.35-4.50 (m, 1 H); 4.06-4.32
(m, 4 H); 3.02-3.15 (m, 1 H); 2.35-2.50 (m, 1 H); 1.33 (s, 3 H). LCMS anal. calcd. for
C H F N O : 430.13; Found: 430.98 (M+1) .
22 20 2 2 5
Compound 50: H NMR (500 MHz, CDCl ): δ 10.36 (brs, 1 H); 8.52 (s, 1 H); 7.32-7.45
(m, 1 H); 6.81-6.85 (m, 2 H); 5.94 (m, 2 H); 4.60-4.72 (m, 2 H); 4.35-4.50 (m, 1 H); 4.06-4.32
(m, 4 H); 3.02-3.15 (m, 1 H); 2.35-2.50 (m, 1 H); 1.33 (s, 3 H). LCMS anal. calcd. for
C H F N O : 430.13; Found: 430.98 (M+1) .
22 20 2 2 5
Example 29
Preparation of Compound 51-52
Step A– Synthesis of Compound Int-17a
To a solution of butane-1,3-diol (3.8 g, 42.2 mmol) in 30 mL of DMF, was added 1H-imidazole
(5.74 g, 84 mmol). The solution was cooled to 0 °C and tert-butylchlorodimethylsilane (6.67 g,
44.3 mmol) was added. The reaction was allowed to stir at room temperature overnight. The
solution was poured into 200 mL of water. The resulting mixture was extracted by 40% EtOAc /
hexanes (120 mL x 2). The combined organic phase was washed with 100 mL of 0.2 N HCl
aqueous solution, and then 100 mL of brine. The solvent was removed in vacuo to provide
compound Int-17a as a colorless oil. H NMR (400 MHz, CDCl ): δ 4.00-4.08 (m, 1 H), 3.80-
3.94 (m, 2 H), 1.55-1.72 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H), 0.92 (s, 9H), 0.10 (s, 6 H).
Step B– Synthesis of Compound Int-17b
To a solution of compound Int-17a (1500 mg, 7.34 mmol) in 23 mL of THF, was added
triphenylphosphine (4812 mg, 18.35 mmol) and 1-phenyl-1H-tetrazolethiol (1962 mg, 11.01
mmol). The solution was cooled to 0 °C, and diisopropyl diazene-1,2-dicarboxylate (3.61 ml,
18.35 mmol) was then added dropwise. The reaction was then warmed to room temperature and
stirred for 20 h. The mixture was diluted with 100 mL of 20% EtOAc/hexanes. It was then
filtered. The filtrate was concentrated. The resulting residue was purified using a silica gel
column (120 g) eluting with 10% EtOAC/hexanes to provide compound Int-17b as a colorless
oil. LCMS anal. calcd. for C H N OSSi: 364.2; Found: 365.1 (M+1) .
17 28 4
Step C– Synthesis of Compound Int-17c
To a solution of compound Int-17b (1.840 g, 5.05 mmol) in 20 mL of EtOH cooled at 0
°C, was added a pre-mixed solution of NH molybdate tetrahydrate (2.495 g, 2.019 mmol) in 10
mL of 30% H O in water. The resulting mixture was warmed to room temperature and stirred
for 3 h. To this was added 100 mL of saturated NaHCO aq. solution. It was extracted by 50%
EtOAc/hexanes (60 mL x 2). The organic phase was concentrated. The resulting residue was
purified using a silica gel column eluting with 20% EtOAc/hexanes to provide compound Int-
17c as a colorless oil. LCMS anal. calcd. for C H N OSSi: 396.2; Found: 397.2 (M+1) .
17 28 4
Step D– Synthesis of Compound Int-17d
To a solution of compound Int-17c (98 mg, 0.248 mmol) in 4 mL of THF cooled at -78
°C, was added sodium bis(trimethylsilyl)amide (1 M in THF) (0.497 ml, 0.497 mmol). The
yellowish solution was allowed to stir at -78 °C for 30 min. A solution of compound Int-1 (80
mg, 0.248 mmol) in 1 mL of THF was then added. The reaction was allowed to stir at -78 °C for
1 h. It was warmed to 0 °C by allowing the ice bath expire. During the time, the color of the
reaction changed from blue/green to yellowish. It was quenched by 10 mL of saturated aqueous
NH Cl solution. The resulting mixture was extracted by 20 mL of 50% EtOAc/hexanes. The
organic phase was concentrated in vacuo. The resulting residue was purified using a silica gel
column (40 g) eluting with 12% EtOAc/hexanes to provide a compound Int-17d as a colorless
film. LCMS anal. calcd. for C H BrNO Si: 491.2; Found: 492.0 (M+1) .
24 34 3
Step E– Synthesis of Compound Int-17e
To a solution of compound Int-17d (40 mg, 0.081 mmol) in 1 mL of t-BuOH / water /
pyridine (5:5:1), was added methanesulfonamide (15.45 mg, 0.162 mmol), potassium
ferricyanide (80 mg, 0.244 mmol), and potassium carbonate (67.3 mg, 0.487 mmol) , followed
by osmium(VIII) oxide (0.050 ml, 4.06 µmol). The reaction was allowed to stir at room
temperature for 1 day. LCMS indicates it was less than half completed. To this was added a
solution of 1 M sodium hydroxide (0.162 ml, 0.162 mmol). The reaction was stirred for
additional 1 day. It was diluted with 1 mL of THF, and quenched by adding 700 mg of sodium
bissulfite. The mixture was diluted with 20 mL of EtOAc, and washed with water (20 mL). The
organic phase was concentrated in vacuo and the resulting residue was purified using a silica gel
prep-TLC plate (1000 mm) eluting with 50% EtOAc/hexanes to provide compound Int-17e as a
white film. LCMS anal. calcd. for C H BrNO Si: 527.2; Found: 528.0 (M+1) .
24 36 5
Step F– Synthesis of Compound Int-17f
2-Iodoxybenzoic acid (42.5 mg, 0.152 mmol) was stirred in 1 mL of DMSO for 5 min
until it dissolved. The resulting solution was added into a flask containing compound Int-17e
(40 mg, 0.076 mmol). The reaction was allowed to stir at room temperature for 4 h. This was
diluted with 20 mL of 50% EtOAc / hexanes, and washed with water. The organic phase was
concentrated in vacuo and purified using a silica gel prep-TLC plate (1000 mm) eluting with
% EtOAc/hexanes to provide compound Int-17f as a colorless film. LCMS anal. calcd. for
C H BrNO Si: 525.1; Found: 526.0 (M+1) .
24 34 5
Step G– Synthesis of Compound Int-17g
To a solution of compound Int-17f (28 mg, 0.053 mmol) in 1 mL of DMF, was added
iodomethane (30.3 mg, 0.214 mmol) . This was cooled to 0 °C and sodium hydride (6.41 mg,
0.160 mmol) was then added. The reaction was allowed to stir at 0 °C for 15 min. It was then
quenched by adding 10 mL of water. This was extracted by 20 mL of 40% EtOAc/hexanes. The
organic phase was concentrated. The resulting residue was purified using a silica gel prep-TLC
plate (1000 mm) eluting with 10% EtOAc / hexanes to provide compound Int-17g as a colorless
film. LCMS anal. calcd. for C H BrNO Si: 539.2; Found: 540.1 (M+1) .
36 5
Step H– Synthesis of Compound Int-17h
To a solution of compound Int-17g (20 mg, 0.037 mmol) in 1 mL of MeOH, was added
0.5 mL of 1.25 M HCl in MeOH. The reaction was allowed to stir at room temperature for 15
min. The solvent was removed in vacuo. The resulting residue was diluted in 2 mL of
dichloromethane. To this was added 0.2 mL of NEt . The resulting solution was purified using
a silica gel column (25 g), eluting with 80% EtOAc/hexanes to provide compound Int-17h as a
colorless film. LCMS anal. calcd. for C19H22BrNO5: 425.1; Found: 425.9 (M+1) .
Step I– Synthesis of Compound Int-17i
To a solution of compound Int-17h (10 mg, 0.024 mmol) in 0.5 mL of pyridine, was
added 4-methylbenzenesulfonyl chloride (17.97 mg, 0.094 mmol). The reaction was allowed
to stir at room temperature overnight. At this time, 0.5 mL of MeOH was added. It was allowed
to stir at room temperature for 1 h. The reaction was diluted with 2 mL of toluene and
thenconcentrated in vacuo. The resulting residue was purified using a silica gel prep-TLC plate
eluting with EtOAc to provide compound Int-17i as a colorless film. LCMS anal. calcd. for
C H BrNO : 317.0; Found: 318.1 (M+1) .
12 14 4
Step J– Synthesis of Compound Int-17j
A mixture of compound Int-17i (18 mg, 0.057 mmol), N-ethyl-N-isopropylpropan
amine (30.4 µl, 0.171 mmol)), (2,4-difluorophenyl)methanamine (10.19 µl, 0.085 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (6.13 mg, 0.011 mmol) in DMSO (569 µl) was
added diacetoxypalladium (2.56 mg, 0.011 mmol). CO balloon was attached to the reaction
vessel and CO gas was bubbled through a long needle to the mixture at room temperature for 20
min. The mixture was then heated under CO ballon at 80 °C for 2 h. At completion, the reaction
was diluted with 1.5 mL of DMSO and was then filtered. The filtrate was purified using
preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with
acetonitrile/water/0.1% TFA (10% to 90% organic in 10 min, then to 100% in 2 min, 20
mL/min). Related fractions were pooled and evaporated under reduced pressure to afford
compound Int-17j as a racemate. This material was further resolved by a chiral preparative SFC
(ChiralPak AD, 30 X 250 mm, 70 mL/min, 100 bar, 40% MeOH (0.2% NH OH) / CO , 35 °C)
to provide enantiomer A of compound Int-17j (first to elute) and enantiomer B of compound
Int-17j (second to elute) as pure enantiomers. LCMS anal. calcd. for C H F N O : 406.13;
20 2 2 5
Found: 407.05 (M+1) .
Step K– Synthesis of Compound 51 and Compound 52
Using the method described in Step K in example 10, compound 51 was prepared from
enantiomer A of compound Int-17j. Similarly, compound 52 was prepared from enantiomer B of
compound Int-17j.
Compound 51: H NMR (500 MHz, CDCl ): δ 10.32 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.42
(m, 1 H); 6.78-6.88 (m, 2 H); 4.56-4.71 (m, 3 H); 4.01-4.15 (m, 1 H); 3.30 (s, 3 H); 2.26-2.47
(m, 2 H); 1.51 (s, 3 H). LCMS anal. calcd. for C H F N O : 392.12; Found: 392.94 (M+1) .
19 18 2 2 5
Compound 52: H NMR (500 MHz, CDCl ): δ 10.32 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.42
(m, 1 H); 6.78-6.88 (m, 2 H); 4.56-4.71 (m, 3 H); 4.01-4.15 (m, 1 H); 3.30 (s, 3 H); 2.26-2.47
(m, 2 H); 1.51 (s, 3 H). LCMS anal. calcd. for C H F N O : 392.12; Found: 392.94 (M+1) .
19 18 2 2 5
Example 30
Preparation of Compound 53
Starting from compound Int-17f, compound 53 was prepared as its racemic mixture
following essentially the same procedure from Step H to Step K of example 29. H NMR (500
MHz, DMSO): δ 10.29 (brs, 1 H); 8.42 (s, 1 H); 7.37-7.42 (m, 1 H); 7.21-7.25 (m, 1 H); 7.05
(m, 1 H); 6.02 (s, 1 H); 4.50-4.58 (m, 2 H); 4.27-4.45 (m, 2 H); 2.11-2.30 (m, 2 H); 1.36 (s, 3
H). LCMS anal. calcd. for C H F N O : 378.10; Found: 378.94 (M+1) .
18 16 2 2 5
Example 31
Preparation of Compound 54-57
Step A– Synthesis of Compound Int-18a
To a mixture of NaH (60%wt. in mineral oil) (8.5 g, 212 mmol) in 800 mL of THF
cooled at 0 °C, was added methyl 2- (dimethoxyphosphoryl)acetate (33.7 g, 185 mmol) dropwise
(caution!). It was allowed to stir at 0 °C for 10 min. A solution of 1-methoxypropanone (12.5
g, 143 mmol) in 100 mL of THF was then added. The reaction was allowed to stir at 18 °C for
16 hours. The mixture was quenched by adding 200 mL of saturated NH Cl (aq.). It was further
diluted with 800 mL of water and 600 mL of 50% EtOAc / hexanes. The organic phase was
dried over Na SO and concentrated in vacuo. The resulting residue was purified using column
chromatography (SiO , EtOAc: PET = 1: 50) to provide compound Int-18a as a colorless oil. H
NMR (400 MHz, CDCl ): δ 5.92 (s, 1 H), 3.89 (s, 2 H), 3.69 (s, 3 H), 3.34 (s, 3 H), 2.08 (s, 3 H).
Step B– Synthesis of Compound Int-18b
To a solution of compound Int-18a (15 g, 104 mmol) in 600 mL of dichloromethane
cooled at -78 °C was added DIBAL-H (228 mL, 228 mmol). The reaction was allowed to stir at
-78 °C for 1 hour and warm up to 0 °C. At this time, it was quenched by adding 600 mL of (sat.)
Rochelle salt solution. The mixture was allowed to stir at 20 C for 2 hours. The organic phase
was isolated. It was washed with 200 mL of brine. The organic phase was then concentrated in
vacuo at 30 C and the resulting residue was purified using column chromatography (SiO , PET
to EtOAc: PET = 1: 2) to provide compound Int-18b as a colorless oil. H NMR (400 MHz,
CDCl ): δ 5.62 (s, 1 H), 4.17 (t, J = 6.0 Hz, 2 H), 3.79 (s, 2 H), 3.29 (s, 3 H), 1.66 (s, 3 H).
StepC– Synthesis of Compound Int-18c
To a solution of compound Int-18b (7.5 g, 65 mmol) in dichloromethane (100 mL), was
added diisopropylethylamine (34 mL, 194 mmol) followed by methanesulfomyl chloride (7.5
mL, 97 mmol). The reaction was allowed to stir at 17 °C for 2 hours. It was diluted with 200
mL of dichloromethane and washed with 200 mL of water. The organic phase was concentrated
in vacuo at 30 C, and the resulting residue was purified quickly by a silica gel column (SiO
PET: EtOAc = 30: 1) to provide compound Int-18c as a yellow oil. H NMR (400 MHz,
CDCl ): δ 5.69 (t, J = 8.0 Hz, 1 H), 4.11~4.14 (m, 2 H), 3.83 (s, 2 H), 3.31 (s, 3 H), 1.73 (s, 3 H).
Step D– Synthesis of Compound Int-18d
To a solution of lithium diisopropylamide (31.2 mL, 2 M in THF, 63 mmol) in 100 mL
THF cooled at 0 °C, was added tributylstannane (15.1 g, 52 mmol)). The reaction was allowed
to stir at 0 °C for 15 min. It was then cooled to -78 °C, and a solution of compound Int-18c (7 g,
52 mmol) in 5 mL of THF was added via syringe. The reaction was allowed to stir at -78 °C for
30 min. It was diluted with 400 mL of 50% EtOAc: PET, and washed with 500 mL of water.
The organic phase was concentrated in vacuo. The resulting residue was purified using a silica
gel column eluting initially with PET to remove Bu SnH, and then EtOAc: PET = 1: 50 to afford
compound Int-18d as a yellow oil. H NMR (400 MHz, CDCl3) δ 5.60~5.72 (m, 1 H), 4.11~4.15
(m, 2 H), 3.31 (s, 3 H), 1.62~1.82 (m, 5 H), 1.43~1.53 (m, 6 H), 1.24~1.34 (m, 6 H), 0.76~0.96
(m, 15 H).
Step E– Synthesis of Compound Int-18e
To a solution of compound Int-1 (4.1 g, 12.7 mmol) and compound Int-18d (6 g, 15.27
mmol) in acetonitrile (100 mL) stirred at 0 °C, was added Tin (II) chloride (3.62 g, 19.1 mmol).
The reaction was then warmed to 16 °C and stirred for 2 hours. The progress of the reaction was
monitored by TLC and LCMS. The mixture was diluted with 50 mL EtOAc, and 100 mL of
% (wt) NH F aqueous solution. The resulting mixture was allowed to stir at 16 °C for 15 min.
Solid was filtered off. The organic from the mother liquor was extracted EtOAc (50 mL x 3) and
the organic phase was dried over anhydrous Na SO , concentrated in vacuo and the resulting
residue was purified using column chromatography (SiO PET: EtOAc = 3: 1) to provide
compound Int-18e as a colorless oil. H NMR (400 MHz, CDCl ): δ 8.37 (s, 1 H), 7.47 (d, J =
6.0 Hz, 2 H), 7.35-7.39 (m, 3 H), 6.04-6.12 (m, 1 H), 4.88-5.22 (m, 4 H), 3.87-3.98 (m, 1 H),
3.86 (s, 3 H), 3.48-3.55 (m, 2 H), 3.37 (s, 3 H), 3.24-3.27 (m, 1 H), 0.93 (s, 3 H). MS (M+H)
422.
Step F– Synthesis of Compound Int-18f
Under a nitrogen atmosphere, MOMCl (4.3 mL, 56.8 mmol) was added to a solution of
compound Int-18e (4.8 g, 11.4 mmol), diisopropylethylamine (20 mL, 114 mmol) and DMAP
(0.72 g, 5.76 mmol) in anhydrous dichloromethane (80 mL) at 0 C. The reaction mixture was
allowed to stir at 35 C for 16 hours and washed with saturated aqueous NaHCO solution,
extracted with dichloromethane (40 mL x 3). The organic phase was dried over anhydrous
Na SO , concentrated in vacuo and purified using column chromatography (SiO
2 4 2,
dichloromethane: EtOAc = 1: 1) to provide compound Int-18f as a yellow oil. H NMR (400
MHz, CDCl ): δ 8.42 (s, 1 H), 7.47 (d, J = 6.0 Hz, 2 H), 7.35-7.39 (m, 3 H), 6.08-6.14 (m, 1 H),
.16-5.29 (m, 4 H), 4.87-5.11 (m, 2 H), 4.46-4.65 (m, 2 H), 3.88 (s, 3 H), 3.58-3.60 (m, 1 H),
3.35 (s, 3 H), 3.20 (s, 3 H), 1.12 (s, 3 H). MS (M+H) 466.
Step G– Synthesis of Compound Int-18g
To a solution of compound Int-18f (4.8 g, 10.3 mmol)) in 110 mL of THF/t-BuOH/water
(5: 5: 1), was added NMO (2.4 g, 20.6 mmol), followed by osmium tetroxide (262 mg, 1 mmol)
in H O. The reaction was allowed to stir at 16 °C for 16 hours. To this was added Na SO
2 2 3
aqueous solution. The mixture was allowed to stir at 16 °C for 1 hour and extracted with EtOAc
(50 mL x 3), the organic phase was dried over anhydrous Na SO and concentrated, the resulting
residue was purified using column chromatography (SiO dichloromethane: MeOH = 20: 1) to
afford compound Int-18g as yellow oil. H NMR (400 MHz, CDCl3): δ 8.44 (s, 1 H), 7.47 (d, J
= 6.0 Hz, 2 H), 7.35-7.39 (m, 3 H), 5.17-5.35 (m, 4 H), 4.44-4.60 (m, 2 H), 3.91 (s, 3 H), 3.63-
3.66 (m, 4 H), 3.19-3.34 (m, 8 H), 1.04 (s, 3 H). MS (M+H) 500.
Step H– Synthesis of Compound Int-18h
To a mixture of compound Int-18g (4.0 g, 8.00 mmol) in pyridine (30 mL) was added p-TsCl
(2.0 g, 10.4 mmol). The reaction solution was allowed to stir at 30 °C for 16 hours. The reaction
was concentrated. The resulting residue was purified using column chromatography (SiO
DCM: EtOAc = 1: 1) to provide compound Int-18h as a yellow oil. H NMR (400 MHz,
CDCl ): δ 7.68 (s, 1 H), 4.38~5.00 (m, 4 H), 3.75~4.25 (m, 4 H), 3.18~3.47 (m, 8 H), 2.96~3.03
(m, 1 H), 0.85~0.88 (m, 3 H). MS (M+H) 392.
Step I– Synthesis of Compound Int-18i
To a solution of compound Int-18h (2.0 g, 5.1 mmol) in DMF (20 mL) was added NaH
(60% wt. in mineral oil) (0.6 g, 15.3 mmol). The reaction mixture was allowed to stir at 15 °C
for 10 min, iodomethane (3.2 mL, 51 mmol) was then added, and the reaction mixture was
allowed to stir at 15 °C for 1 hour. It was quenched by water, extracted with dichloromethane (20
mL x 5), the organic phase was concentrated. The resulting residue was purified using column
chromatography (SiO DCM: MeOH = 30: 1) to afford compound Int-18i as a yellow oil. H
NMR (400 MHz, CDCl ): δ 7.63 (s, 1 H), 4.61-5.04 (m, 4 H), 3.94-3.98 (m, 4 H), 3.20-3.45 (m,
12 H), 0.83-0.87 (m, 3 H). MS (M+H) 406.
Step J– Synthesis of Compound Int-18j
To a stirred solution of compound Int-18i (1.0 g, 2.46 mmol) in MeOH (20 mL) was
added p-TsOH (1.873 g, 9.85 mmol). The reaction mixture was allowed to stir at 35 °C for 48
hours. The solvent was removed in vacuo. The resulting residue was washed with saturated
aqueous NaHCO solution, extracted with dichloromethane (30 mL x 5), the organic phase was
concentrated in vacuo and purified using column chromatography (SiO dichloromethane:
MeOH = 30: 1) to provide compound Int-18j as a yellow oil. H NMR (400 MHz, CDCl ): δ
7.63 (s, 1 H), 4.70-5.08 (m, 2 H), 3.79-4.79 (m, 4 H), 3.30-3.51 (m, 10 H), 1.19-1.26 (m, 3 H).
MS (M+H) 362.
Step K– Synthesis of Compound Int-18k
To a stirred solution of compound Int-18j (500 mg, 1.38 mmol) in 1,2-dichloroethane
(15 mL) was added Dess-Martin periodinane (585 mg, 1.38 mmol). The reaction mixture was
allowed to stir at 15 °C for 2 hours. The solvent was concentrated in vacuo and the resulting
residue was purified using column chromatography (SiO dichloromethane: MeOH = 10: 1) to
provide compound Int-18k as a yellow solid. H NMR (400 MHz, CDCl ): δ 7.69 (s, 1 H), 3.26-
4.35 (m, 14 H), 1.17 (m, 3 H). MS (M+H) 360.
Step L– Synthesis of Compound Int-18l and Compound Int-18m
To a mixture of compound Int-18k (60 mg, 0.167 mmol), disopropylethylamine (0.116
mL, 0.666 mmol) and (2,4-difluorophenyl)methanamine (47.7 mg, 0.333 mmol) in DMSO (5
mL) was added Pd (Ph P) (96 mg, 0.083 mmol) under N . The mixture was allowed to stir at 80
3 4 2
°C for 4 hours under a CO balloon. The reaction mixture was diluted with EtOAc, and washed
with diluted HCl. The organic phase was dried over anhydrous Na SO . It was then concentrated
in vacuo and purified via prep-TLC (SiO EtOAc: PET = 1: 1) to afford compound Int-18l and
compound Int-18m as yellow oil.
Compound Int-18l: H NMR (400 MHz, CDCl ): δ 10.39 (s, 1 H), 8.37 (s, 1 H), 7.26-
7.32 (m, 1 H), 6.70-6.78 (m, 2 H), 4.56 (d, J = 5.6 Hz, 2 H), 4.22~4.34 (m, 2 H), 3.93 (s, 3H),
3.75 (s, 1 H), 3.67 (d, J = 8.8 Hz, 1 H), 3.54 (d, J = 8.8 Hz, 1 H), 3.36 (s, 3 H), 3.30 (s, 3 H), 1.21
(m, 3 H). MS (M+H) : 451.
Compound Int-18m: H NMR (400 MHz, CDCl ): δ 10.39 (s, 1 H), 8.39 (s, 1 H), 7.26-
7.32 (m, 1 H), 6.75-6.81 (m, 2 H), 4.62 (d, J = 5.6 Hz, 2 H), 4.46-4.49 (m, 1 H), 4.10-4.19 (m, 1
H), 4.00 (s, 3 H), 3.84 (d, J = 3.2 Hz, 1 H), 3.71 (d, J = 8.8 Hz, 1 H), 3.38-3.42 (m, 4 H), 3.25 (s,
3 H), 1.17 (m, 3 H). MS (M+H) : 451.
Compound Int-18l was further purified using a chiral preparative SFC (Column:
Chiralpak AS-H 250×4.6mm I.D., 5um Mobile phase: isopropanol (0.05% DEA) in CO from
5% to 40% Flow rate: 2.5mL/min Wavelength: 220 nm) to provide an earlier eluting component
which is corresponding to the enantiomer A of compound Int-18l (MS (M+H) : 451), and a later
eluting component corresponding to the enantiomer B of compound Int-18l (MS (M+H) : 451).
Compound Int-18m was further purified using a chiral preparative SFC (Column:
Chiralpak AS-H 250×4.6mm I.D., 5um Mobile phase: isopropanol (0.05% DEA) in CO from
% to 40% Flow rate: 2.5mL/min Wavelength: 220 nm) to provide an earlier eluting component
which is corresponding to the enantiomer A of compound Int-18m (MS (M+H) : 451), and a
later eluting component corresponding to the enantiomer B of compound Int-18m (MS (M+H) :
451).
Step M– Synthesis of Compound 54-57
Following essentially the same method described in Step K of Example 10, starting from
enantiomer A of compound Int-18l, compound 54 was prepared. Similarly, compound 55 was
prepared from enantiomer B of compound Int-18l.
Compound 54: H NMR (400 MHz, CDCl ): δ 10.40 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36 (m, 1 H),
6.77-6.83 (m, 2 H), 4.63-4.66 (m, 2 H), 4.41 (d, J = 4.0 Hz, 1 H), 4.28-4.32 (m, 1 H), 3.83 (s, 1
H), 3.67-3.74 (m, 2 H), 3.44 (s, 3 H), 3.37 (s, 3 H), 1.35 (m, 3 H). MS (M+H) : 437.
Compound 55: H NMR (400 MHz, CDCl ): δ 10.40 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36
(m, 1 H), 6.77-6.83 (m, 2 H), 4.63-4.66 (m, 2 H), 4.41 (d, J = 4.0 Hz, 1 H), 4.28-4.32 (m, 1 H),
3.82 (s, 1 H), 3.67-3.74 (m, 2 H), 3.44 (s, 3 H), 3.37 (s, 3 H), 1.35 (m, 3 H). MS (M+H) : 437.
Following essentially the same method described in Step K of Example 10, starting from
enantiomer A of compound Int-18m, compound 56 was prepared. Similarly, compound 57 was
prepared from enantiomer B of compound Int-18m.
Compound 56: H NMR (400 MHz, CDCl ): δ 10.45 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36 (m,
1 H), 6.77-6.83 (m, 2 H), 4.58-4.66 (m, 3 H), 4.26-4.29 (m, 1 H), 3.81 (d, J = 2.4 Hz, 1 H), 3.65
(d, J = 9.6 Hz, 1 H), 3.43-3.47 (m, 4 H), 3.24 (s, 3 H), 1.27 (m, 3 H). MS (M+H) : 437.
Compound 57: H NMR (400 MHz, CDCl ): δ 10.45 (s, 1 H), 8.43 (s, 1 H), 7.32~7.36
(m, 1 H), 6.77~6.83 (m, 2 H), 4.58~4.66 (m, 3 H), 4.26~4.29 (m, 1 H), 3.81 (d, J = 2.4 Hz, 1 H),
3.65 (d, J = 9.6 Hz, 1 H), 3.43~3.47 (m, 4 H), 3.25 (s, 3 H), 1.27 (m, 3 H). MS (M+H) : 437.
Example 32
Preparation of Compound 58-61
Br O
Br OH
Br O
Br OH N
N Step A
Step C
Step B
O OMe
O OH
O OMe
O OTBDPS
OMe OH
OMe OMOM OMe OMOM
OMe OMOM
Int-19b
Int-19a Int-19c
Int-16j
Br O OMe
Step E
Step D N N N
F F O OMe
O OMe F F O OMe
OMe O
OMe O OMe O
Int-19f
Int-19d Int-19e
Enantiomer A
Enantiomer A
Enantiomer B
Enantiomer B
Step F N N
F F O OMe
F F O OMe
OH O
OH O
58 (Enantiomer A)
60 (Enantiomer A)
59 (Enantiomer B) 61 (Enantiomer B)
Step A– Synthesis of Compound Int-19a
To a stirring solution of compound Int-16j (6.65 g, 10.54 mmol) in THF (60 mL) was
added 1 M solution of tetrabutylammonium fluoride in THF (10.54 mL, 10.54 mmol). The
reaction mixture was allowed to stir at 10 °C for 18 hours and the solvent was then removed in
vacuo. The resulting residue was purified using silica gel column chromatography
(dichloromethane: MeOH = 20: 1) to provide compound Int-19a as a colorless oil. H NMR
(400 MHz, CDCl ): δ 7.70 (s, 1 H), 4.80-4.98 (m, 1 H), 4.65-4.72 (m, 1 H), 4.34-4.58 (m, 2 H),
4.09-4.33 (m, 2 H), 3.96 (d, J = 7.2 Hz, 3 H), 3.70-3.90 (m, 2 H), 3.34-3.50 (m, 3 H), 1.64 (brs, 1
H), 1.45 (m, 1 H), 0.80 (d, J = 13.8 Hz, 3 H). MS (M+H) 392.
Step B– Synthesis of Compound Int-19b
To a stirred mixture of compound Int-19a (3.5 g, 8.92 mmol) in THF (50 mL) cooled at
0 °C, was added NaH (60%wt in mineral oil) (2.141 g, 53.5 mmol). The reaction mixture was
allowed to stir at 10 °C for 20 minutes, and iodomethane (19 g, 134 mmol) was added. The
reaction mixture was allowed to stir at 10 °C for 16 hours. It was quenched by water (2 mL) and
the solvent was removed in vacuo. The resulting residue was purified using silica gel column
chromatography (dichloromethane: MeOH = 25: 1) to provide compound Int-19b as a colorless
oil. H NMR (400 MHz, CDCl ): δ 7.60-7.69 (m, 1 H), 4.89-5.05 (m, 1 H), 4.36-4.76 (m, 3 H),
4.07-4.23 (m, 1 H), 3.93-4.05 (m, 3 H), 3.69-3.85 (m, 1 H), 3.55 (t, J = 7.0 Hz, 1 H), 3.22-3.48
(m, 10 H), 1.66-1.73 (m, 1 H), 1.42-1.52 (m, 1 H), 0.71-1.03 (m, 3 H). MS (M+H) 420.
Step C– Synthesis of Compound Int-19c
To a stirred solution of compound Int-19b (3.4 g, 8.09 mmol) in MeOH (30 mL) was
added TsOH (4616 mg, 24.27 mmol). The reaction mixture was allowed to stir at 35 °C for 20
hours. The solvent was removed in vacuo. The resulting residue was purified using silica gel
column chromatography (dichloromethane: MeOH = 10: 1) to provide compound Int-19c as a
colorless oil. H NMR (400 MHz, CDCl ): δ 7.59 (s, 1 H), 4.94 (brs, 1 H), 4.10-4.17 (m, 2 H),
4.01 (s, 3 H), 3.78-3.88 (m, 1 H), 3.47-3.55 (m, 2 H), 3.42 (s, 3 H), 3.31 (s, 3 H), 1.24-1.27 (m, 2
H), 1.17 (s, 3 H). MS (M+H) : 376.
Step D– Synthesis of Compound Int-19d
To a stirred solution of compound Int-19c (2.5 g, 6.64 mmol) in 1,2-dichloroethane (30
mL) was added Dess-Martin periodinane (3.4 g, 7.97 mmol). The reaction mixture was allowed
to stir at 15 °C for 1 hour. The solvent was removed in vacuo, the resulting residue was purified
using silica gel column chromatography (dichloromethane: MeOH = 10: 1) to provide compound
Int-19d as a colorless oil. H NMR (400 MHz, CDCl ): δ 7.68 (s, 1 H), 4.08-4.43 (m, 3 H), 4.00
(s, 3 H), 3.77-3.85 (m, 1 H), 3.53 (t, J = 5.6 Hz, 1 H), 3.42 (d, J = 8.8 Hz, 3 H), 3.19-3.32 (m, 3
H), 2.10~2.24 (m, 1 H), 1.94-2.03 (m, 1 H), 1.28 (d, J = 7.8 Hz, 3 H). MS (M+H) : 374.
Step E– Synthesis of Compound Int-19e and 19f
To a solution of compound Int-19d (300 mg, 0.802 mmol) in DMSO (5 mL) was added
(2,4-difluorophenyl)methanamine (215 mg, 1.499 mmol), N-ethyl-N-isopropylpropanamine
(259 mg, 2.004 mmol) and Pd (Ph P) (232 mg, 0.200 mmol). The reaction was stirred under a
balloon of CO at 96 °C for 2 hours. It was cooled to 25 °C. The reaction mixture was filtered
and the filtrate was concentrated, the resulting residue was purified using prep-TLC
(dichloromethane: EtOAc = 1: 1) to provide a crude mixture of all four stereoisomers of
compound Int-19e and 19f as a colorless oil. This was further purified using SFC (M7
"Column: Chiralpak AD-H 250×4.6mm I.D., 5 um Mobile phase: ethanol (0.05% DEA) in CO
from 5% to 40% Flow rate: 2.35mL/min Wavelength: 220 nm" ) to provide each individual
stereoisomer: enantiomer A of compound Int-19e (the first eluting compound), enantiomer B of
compound Int-19e (the second eluting compound), enantiomer A of compound Int-19f (the third
eluting compound), and enantiomer B of compound Int-19f (the fourth eluting compound). MS
(M+H) : 465.
Enantiomer A of compound Int-19e: H NMR (400 MHz, CDCl ): δ 10.48 (brs, 1H),
8.40 (s, 1H), 7.32-7.42 (m, 1H), 6.74-6.87 (m, 2H), 4.57-4.70 (m, 2H), 4.44 (dd, J = 1.60, 13.60
Hz, 1H), 4.22 (dd, J = 4.40, 13.60 Hz, 1H), 4.00 (s, 3H), 3.79 (d, J = 1.20 Hz, 1H), 3.46-3.51 (m,
1H), 3.35-3.44 (m, 4H), 3.20 (s, 3H), 1.94-2.02 (m, 1H), 1.78 (m, 1H), 1.30 (s, 3H).
Enantiomer B of compound Int-19e: H NMR (400 MHz, CDCl ): δ 10.49 (brs, 1 H),
8.40 (s, 1 H), 7.31-7.41 (m, 1 H), 6.80 (d, J = 8.40 Hz, 2 H), 4.63 (dd, J = 6.40, 8.80 Hz, 2 H),
4.44 (d, J = 13.60 Hz, 1 H), 4.23 (dd, J = 4.00, 13.60 Hz, 1 H), 3.99 (s, 3 H), 3.78 (brs, 1 H),
3.46-3.50 (m, 1 H), 3.36-3.44 (m, 4 H), 3.20 (s, 3 H), 1.92-2.04 (m, 1 H), 1.78 (m, 1 H), 1.30 (s,
3 H).
Enantiomer A of compound Int-19f: H NMR (400 MHz, CDCl ): δ 10.35-10.56 (m, 1
H), 8.40 (s, 1 H), 7.30-7.42 (m, 1 H), 6.73-6.88 (m, 2 H), 4.63 (d, J = 5.60 Hz, 2 H), 4.24-4.35
(m, 2 H), 4.00 (s, 3 H), 3.85 (brs, 1 H), 3.49-3.59 (m, 2 H), 3.39 (s, 3 H), 3.30 (s, 3 H), 2.14-2.23
(m, 1 H), 1.95-2.03 (m, 1 H), 1.27 (s, 3 H).
Enantiomer B of compound Int-19f: H NMR (400 MHz, CDCl ): δ 10.35-10.56 (m, 1
H), 8.40 (s, 1 H), 7.30-7.42 (m, 1 H), 6.73-6.88 (m, 2 H), 4.63 (d, J = 5.60 Hz, 2 H), 4.24-4.35
(m, 2 H), 4.00 (s, 3 H), 3.85 (brs, 1 H), 3.49-3.59 (m, 2 H), 3.39 (s, 3 H), 3.30 (s, 3 H), 2.14-2.23
(m, 1 H), 1.95-2.03 (m, 1 H), 1.27 (s, 3 H).
Step F– Synthesis of Compound 58-61
Following essentially the same method described in Step K of Example 10, compound 58
was prepared starting from enantiomer A of compound Int-19e. Similarly, compound 59 was
prepared from enantiomer B of compound Int-19e.
Compound 58: H NMR (400 MHz, CDCl ): δ 10.44 (brs, 1 H), 8.41 (s, 1 H), 7.32-7.39
(m, 1 H), 6.76-6.85 (m, 2 H), 4.65 (d, J = 3.60 Hz, 2 H), 4.52 (d, J = 13.60 Hz, 1 H), 4.28 (dd, J
= 3.60, 13.60 Hz, 1 H), 3.82 (d, J = 1.60 Hz, 1 H), 3.52-3.59 (m, 1 H), 3.41 (s, 4 H), 3.22 (s, 3
H), 1.98-2.06 (m, 1 H), 1.73-1.80 (m, 1 H), 1.38 (s, 3 H). MS (M+H) 451.
Compound 59: H NMR (400 MHz, CDCl ) δ 10.44 (brs, 1 H), 8.41 (s, 1 H), 7.31-7.40
(m, 1 H), 6.75-6.87 (m, 2 H), 4.65 (brs, 2 H), 4.52 (d, J = 13.60 Hz, 1 H), 4.24-4.31 (m, 1 H),
3.82 (brs, 1 H), 3.56 (t, J = 7.20 Hz, 1 H), 3.42 (s, 4 H), 3.22 (s, 3 H), 2.02 (m, 1 H), 1.76 (d, J =
.20 Hz, 1 H), 1.38 (s, 3 H). MS (M+H) 451.
Following essentially the same method described in Step K of Example 10, compound 60
was prepared starting from enantiomer A of compound Int-19f. Similarly, compound 61 was
prepared from enantiomer B of compound Int-19e.
Compound 60: H NMR (400 MHz, CDCl ) δ 10.43 (br. s., 1 H), 8.42 (s, 1 H), 7.31-7.40
(m, 1 H), 6.74-6.89 (m, 2 H), 4.65 (t, J = 5.60 Hz, 2 H), 4.28-4.39 (m, 2 H), 3.91 (br. s., 1 H),
3.52-3.63 (m, 2 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.20 (dd, J = 5.60, 7.60 Hz, 1 H), 2.09-2.16 (m, 1
H), 1.33 (s, 3 H). MS (M+H) 451.
Compound 61: H NMR (400 MHz, CDCl ) δ 10.45 (brs, 1 H), 8.44 (s, 1 H), 7.30-7.40
(m, 1 H), 6.72-6.89 (m, 2 H), 4.64 (t, J = 5.60 Hz, 2 H), 4.28-4.40 (m, 2 H), 3.91 (brs, 1 H), 3.58
(m, 2 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.08-2.26 (m, 2 H), 1.33 (s, 3 H). MS (M+H) 451.
Example 33
Preparation of Compound 62-73
Compound 62-71 were prepared by essentially the same method described in Example
32, only substituting (2,4-difluorophenyl)methanamine in Step E with appropriate benzylamines.
Compound 62: H NMR (400 MHz, CDCl ) δ 10.45 (brs, 1 H), 8.38 (s, 1H), 7.27-7.31
(m, 2 H), 7.02 (t, J = 7.83 Hz, 1 H), 4.72 (brs, 2 H), 4.52 (d, J = 12.72 Hz, 1 H), 4.26 (dd, J =
4.01, 13.99 Hz, 1 H), 3.82 (brs, 1 H), 3.55 (dd, J = 2.93, 9.00 Hz, 1 H), 3.42 (s, 4 H), 3.23 (s, 3
H), 1.99-2.05 (m, 1 H), 1.75-1.79 (m, 1 H), 1.38 (s, 3 H). MS (M+H) 467.
Compound 63: H NMR (400 MHz, CDCl ) δ 10.45 (brs, 1 H), 8.38 (s, 1 H), 7.26-7.32
(m, 2 H), 7.02 (t, J = 7.83 Hz, 1 H), 4.68-4.75 (m, 2 H), 4.52 (d, J = 13.11 Hz, 1 H), 4.26 (dd, J
= 4.11, 13.89 Hz, 1 H), 3.82 (d, J = 1.76 Hz, 1 H), 3.53-3.59 (m, 1 H), 3.38-3.47 (m, 4 H), 3.22
(s, 3 H), 2.00-2.06 (m, 1 H), 1.78 (brs, 1 H), 1.38 (s, 3 H). MS (M+H) 467.
Compound 64: H NMR (400 MHz, CDCl ) δ 10.44 (brs, 1 H), 8.40 (s, 1 H), 7.28 (brs, 2
H), 7.02 (t, J = 7.73 Hz, 1 H), 4.71 (brs, 2 H), 4.33 (brs, 2 H), 3.91 (brs, 1 H), 3.53-3.62 (m, 2
H), 3.40 (s, 3 H), 3.32 (s, 3 H), 2.18-2.23 (m, 1 H), 2.11-2.17 (m, 1 H), 1.34 (s, 3 H). MS
(M+H) 467.
Compound 65: H NMR (400 MHz, CDCl ) δ 10.44 (brs, 1 H), 8.40 (s, 1 H), 7.28 (brs, 2
H), 7.02 (t, J = 7.63 Hz, 1 H), 4.71 (brs, 2 H), 4.32 (brs, 2 H), 3.91 (brs, 1 H), 3.53-3.62 (m, 2
H), 3.40 (s, 3 H), 3.32 (s, 3 H), 2.18-2.24 (m, 1 H), 2.14 (t, J = 4.99 Hz, 1 H), 1.34 (s, 3 H). MS
(M+H) 467.
Compound 66: H NMR (400 MHz, CDCl ) δ 10.41 (brs, 1 H), 8.40 (s, 1 H), 7.36-7.40
(m, 1 H), 7.17~7.25 (m, 1 H), 6.98-7.12 (m, 2 H), 4.70 (d, J = 4.50 Hz, 2 H), 4.51 (d, J = 13.89
Hz, 1 H), 4.26 (dd, J = 3.72, 13.89 Hz, 1 H), 3.81 (brs, 1 H), 3.38-3.60 (m, 5 H), 3.22 (s, 3 H),
2.00-2.05 (m, 1 H), 1.74-1.78 (m, 1 H), 1.37 (s, 3 H). MS (M+H) 433.
Compound 67: H NMR (400 MHz, CDCl ) δ 10.41 (brs, 1 H), 8.40 (s, 1 H), 7.38 (t, J =
6.85 Hz, 1 H), 7.17-7.25 (m, 1 H), 6.95-7.14 (m, 2 H), 4.70 (d, J = 3.91 Hz, 2 H), 4.50 (d, J =
13.69 Hz, 1 H), 4.26 (dd, J = 3.72, 13.89 Hz, 1 H), 3.81 (brs, 1H), 3.52-3.58 (m, 1 H), 3.41 (s, 4
H), 3.22 (s, 3 H), 1.99-2.05 (m, 1 H), 1.73-1.79 (m, 1 H), 1.37 (s, 3 H). MS (M+H) 433.
Compound 68: H NMR (400 MHz, CDCl ) δ 10.39 (brs, 1 H), 8.41 (s, 1 H), 7.38 (t, J =
7.14 Hz, 1 H), 7.17-7.25 (m, 1 H), 6.98-7.12 (m, 2 H), 4.70 (brs, 2 H), 4.25-4.39 (m, 2 H), 3.89
(brs, 1 H), 3.50-3.64 (m, 2 H), 3.39 (s, 3 H), 3.32 (s, 3 H), 2.19 (dd, J = 5.58, 7.73 Hz, 1 H),
2.09-2.16 (m, 1 H), 1.33 (s, 3 H). MS (M+H) 433.
Compound 69: H NMR (400 MHz, CDCl ) δ 10.41 (brs, 1 H), 8.44 (brs, 1 H), 7.37 (t, J
= 6.75 Hz, 1 H), 7.17-7.25 (m, 1 H), 6.97-7.14 (m, 2 H), 4.70 (brs, 2 H), 4.24-4.41 (m, 2 H),
3.88 (brs, 1 H), 3.50~3.64 (m, 2 H), 3.39 (s, 3 H), 3.31 (s, 3 H), 2.08-2.25 (m, 2 H), 1.33 (s, 3 H).
MS (M+H) 433.
Compound 70: H NMR (400 MHz, CDCl ) δ 10.32 (brs, 1 H), 8.37 (s, 1H), 7.16-7.25
(m, 1 H), 6.87 (t, J = 7.63 Hz, 2 H), 4.65-4.81 (m, 2 H), 4.49 (d, J = 13.50 Hz, 1 H), 4.23 (dd, J
= 3.91, 13.89 Hz, 1 H), 3.81 (brs, 1 H), 3.51-3.59 (m, 1 H), 3.36-3.47 (m, 4 H), 3.21 (s, 3 H),
1.97-2.06 (m, 1 H), 1.73-1.78 (m, 1 H), 1.36 (s, 3 H). MS (M+H) 451.
Compound 71: H NMR (400 MHz, CDCl ) δ 10.31 (brs, 1 H), 8.36 (s, 1 H), 7.14-7.23
(m, 1 H), 6.86 (t, J = 7.53 Hz, 2 H), 4.64-4.79 (m, 2 H), 4.47 (d, J = 13.50 Hz, 1 H), 4.22 (dd, J
= 3.72, 13.69 Hz, 1 H), 3.79 (brs, 1 H), 3.49-3.56 (m, 1 H), 3.39 (s, 4 H), 3.20 (s, 3 H), 1.97-2.04
(m, 1 H), 1.75 (d, J = 4.30 Hz, 1 H), 1.34 (s, 3 H). MS (M+H) 451.
Compound 72: H NMR (400 MHz, CDCl3) δ 10.33 (brs, 1 H), 8.36-8.44 (m, 1 H), 7.16-
7.25 (m, 1 H), 6.88 (t, J = 7.53 Hz, 2 H), 4.73 (dq, J = 5.38, 14.51 Hz, 2 H), 4.26-4.36 (m, 2 H),
3.89 (brs, 1 H), 3.51-3.62 (m, 2 H), 3.39 (s, 3 H), 3.31 (s, 3 H), 2.10-2.21 (m, 2 H), 1.32 (s, 3 H).
MS (M+H) 451.
Compound 73: H NMR (400 MHz, CDCl ) δ 10.32 (brs, 1 H), 8.40 (s, 1 H), 7.14-7.25
(m, 1 H), 6.87 (t, J = 7.63 Hz, 2 H), 4.66-4.80 (m, 2 H), 4.31 (brs, 2 H), 3.89 (brs, 1 H), 3.51-
3.63 (m, 2 H), 3.38 (s, 3 H), 3.31 (s, 3 H), 2.10-2.22 (m, 2 H), 1.32 (s, 3 H). MS (M+H) 451.
Example 34
Preparation of Compound 74-93
Compound 74-93 were prepared by essentially the same method described in Example
32, only replacing compound Int-16j in Step A with compound Int-20a, and substituting
appropriate benzylamine in Step E.
Compound 74: H NMR (400 MHz, CDCl ) δ 10.38 (br. s, 1 H), 8.39 (s, 1 H), 7.29-7.38
(m, 1 H), 6.72-6.85 (m, 2 H), 4.55-4.71 (m, 2 H), 4.23-4.41 (m, 2 H), 3.64 (s., 1 H), 3.26-3.48
(m, 8 H), 1.86-1.92 (m, 2 H), 1.59-1.68 (m, 1 H), 1.47-1.57 (m, 1 H), 1.27 (s, 3 H). MS (M+H) :
465.
Compound 75: H NMR (400 MHz, CDCl ) δ 10.42 (br. s, 1 H), 8.44 (s, 1 H), 7.31-7.38
(m, 1 H), 6.75-6.86 (m, 2 H), 4.56-4.70 (m, 2 H), 4.26-4.46 (m, 2 H), 3.65 (s., 1 H), 3.33-3.47
(m, 8 H), 1.85-1.95 (m, 2 H), 1.60-1.71 (m, 1 H), 1.48-1.58 (m, 1 H), 1.29 (s, 3 H). MS (M+H) :
465.
Compound 76: H NMR (400 MHz, CDCl ) δ 10.38 (br. s., 1 H), 8.38 (s, 1 H), 7.29-7.39
(m, 1 H), 6.73-6.84 (m, 2 H), 4.56-4.69 (m, 2 H), 4.24-4.44 (m, 2 H), 3.65 (s, 1 H), 3.32-3.43 (m,
4 H), 3.18-3.30 (m, 4 H), 1.69-1.80 (m, 1 H), 1.53-1.66 (m, 3 H), 1.33 (s, 3 H). MS (M+H) :
465.
Compound 77: H NMR (400 MHz, CDCl ) δ 10.42 (br. s, 1 H), 8.42 (s, 1 H), 7.31-7.40
(m, 1 H), 6.74-6.86 (m, 2 H), 4.56-4.71 (m, 2 H), 4.25-4.47 (m, 2 H), 3.66 (s, 1 H), 3.35-3.44 (m,
4 H), 3.21-3.31 (m, 4 H), 1.72-1.83 (m, 1 H), 1.54-1.69 (m, 3 H), 1.35 (s, 3 H). MS (M+H) :
465.
Compound 78: H NMR (400 MHz, CDCl ) δ 10.48 (br. s, 1 H), 8.47 (s, 1 H), 7.24-7.31
(m, 2 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.64-4.78 (m, 2 H), 4.26-4.45 (m, 2 H), 3.65 (s, 1 H), 3.32-
3.47 (m, 8 H), 1.87-1.94 (m, 2 H), 1.60-1.70 (m, 1 H), 1.47-1.58 (m, 1 H), 1.29 (s, 3 H). MS
(M+H) : 481.
Compound 79: H NMR (400 MHz, CDCl ) δ 10.48 (br. s, 1 H), 8.46 (s, 1 H), 7.23-7.32
(m, 2 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.64-4.77 (m, 2 H), 4.26-4.45 (m, 2 H), 3.65 (s, 1 H), 3.30-
3.49 (m, 8 H), 1.84-1.96 (m, 2 H), 1.60-1.71 (m, 1 H), 1.48-1.59 (m, 1 H), 1.28 (s, 3 H). MS
(M+H) : 481.
Compound 80: H NMR (400 MHz, CDCl ) δ 10.47 (br. s, 1 H), 8.44 (s, 1 H), 7.24-7.31
(m, 2 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.65-4.77 (m, 2 H), 4.29-4.44 (m, 2 H), 3.66 (s, 1 H), 3.35-
3.43 (m, 4 H), 3.22-3.31 (m, 4 H), 1.72-1.82 (m, 1 H), 1.54-1.67 (m, 3 H), 1.35 (s, 3 H). MS
(M+H) : 481.
Compound 81: H NMR (400 MHz, CDCl3) δ 10.48 (br. s, 1 H), 8.44 (s, 1 H), 7.23-7.31
(m, 2 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.65-4.77 (m, 2 H), 4.29-4.45 (m, 2 H), 3.66 (s, 1 H), 3.34-
3.45 (m, 4 H), 3.21-3.31 (m, 4 H), 1.72-1.82 (m, 1 H), 1.54-1.68 (m, 3 H), 1.35 (s, 3 H). MS
(M+H) : 481.
Compound 82: H NMR (400 MHz, CDCl ) δ 10.31 (br. s, 1 H), 8.40 (s, 1 H), 7.14-7.23
(m, 1 H), 6.86 (t, J = 7.6 Hz, 2 H), 4.64-4.77 (m, 2 H), 4.25-4.40 (m, 2 H), 3.63 (s, 1 H), 3.28-
3.46 (m, 8 H), 1.81-1.93 (m, 2 H), 1.58-1.67 (m, 1 H), 1.46-1.55 (m, 1 H), 1.26 (s, 3 H). MS
(M+H) : 465.
Compound 83: H NMR (400 MHz, CDCl ) δ 10.32 (br. s, 1 H), 8.41 (s, 1 H), 7.16-7.23
(m, 1 H), 6.86 (t, J = 7.6 Hz, 2 H), 4.63-4.77 (m, 2 H), 4.34-4.41 (m, 1 H), 4.24-4.31 (m, 1 H),
3.63 (s, 1 H), 3.31-3.44 (m, 8 H), 1.84-1.92 (m, 2 H), 1.58-1.67 (m, 1 H), 1.46-1.56 (m, 1 H),
1.26 (s, 3 H). MS (M+H) : 465.
Compound 84: H NMR (400 MHz, CDCl ) δ 10.32 (br. s, 1 H), 8.40 (s, 1 H), 7.17-7.24
(m, 1 H), 6.87 (t, J = 7.6 Hz, 2 H), 4.65-4.79 (m, 2 H), 4.36-4.42 (m, 1 H), 4.25-4.33 (m, 1 H),
3.65 (s, 1 H), 3.33-3.43 (m, 4 H), 3.19-3.30 (m, 4 H), 1.71-1.81 (m, 1 H), 1.53-1.67 (m, 3 H),
1.34 (s, 3 H). MS (M+H) : 465.
Compound 85: H NMR (400 MHz, CDCl ) δ 10.35 (br. s, 1 H), 8.42 (s, 1 H), 7.16-7.25
(m, 1 H), 6.87 (t, J = 7.6 Hz, 2 H), 4.65-4.79 (m, 2 H), 4.36-4.43 (m, 1 H), 4.25-4.34 (m, 1 H),
3.65 (s, 1 H), 3.34-3.43 (m, 4 H), 3.20-3.30 (m, 4 H), 1.70-1.81 (m, 1 H), 1.54-1.66 (m, 3 H),
1.34 (s, 3 H). MS (M+H) : 465.
Compound 86: H NMR (400 MHz, CDCl ) (400 MHz, CDCl ) δ 10.38 (s, 1 H), 8.43 (s,
1 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.18-7.24 (m, 1 H), 6.99-7.12 (m, 2 H), 4.64-4.76 (m, 2 H), 4.36-
4.44 (m, 1 H), 4.24-4.31 (m, 1 H), 3.63 (s, 1 H), 3.30-3.47 (m, 8 H), 1.87-1.93 (m, 2 H), 1.60-
1.68 (m, 1 H), 1.47-1.57 (m, 1 H), 1.28 (s, 3 H). MS (M+H) : 447.
Compound 87: H NMR (400 MHz, CDCl ) δ 10.40 (s, 1 H), 8.45 (s, 1 H), 7.37 (t, J =
7.2 Hz, 1 H), 7.19-7.24 (m, 1 H), 7.00-7.11 (m, 2 H), 4.64-4.76 (m, 2 H), 4.36-4.44 (m, 1 H),
4.24-4.31 (m, 1 H), 3.63 (s, 1 H), 3.32-3.47 (m, 8 H), 1.85-1.95 (m, 2 H), 1.60-1.70 (m, 1 H),
1.47-1.57 (m, 1 H), 1.27 (s, 3 H). MS (M+H) : 447.
Compound 88: H NMR (400 MHz, CDCl3) δ 10.37 (s., 1 H), 8.40 (s, 1 H), 7.36 (t, J =
7.2 Hz, 1 H), 7.16-7.23 (m, 1 H), 6.98-7.10 (m, 2 H), 4.63-4.74 (m, 2 H), 4.26-4.42 (m, 2 H),
3.64 (s, 1 H), 3.33-3.43 (m, 4 H), 3.19-3.30 (m, 4 H), 1.72-1.79 (m, 1 H), 1.54-1.66 (m, 3 H),
1.33 (s, 3 H). MS (M+H) : 447.
Compound 89: H NMR (400 MHz, CDCl ) δ 10.36 (s, 1 H), 8.40 (s, 1 H), 7.36 (t, J =
7.2 Hz, 1 H), 7.16-7.23 (m, 1 H), 6.98-7.09 (m, 2 H), 4.63-4.74 (m, 2 H), 4.26-4.40 (m, 2 H),
3.63 (s, 1 H), 3.32-3.42 (m, 4 H), 3.20-3.29 (m, 4 H), 1.72-1.78 (m, 1 H), 1.54-1.64 (m, 3 H),
1.33 (s, 3 H). MS (M+H) : 447.
Compound 90: H NMR (400 MHz, CDCl ) δ 10.29 (br. s, 1 H), 8.37 (s, 1 H), 6.63 (t, J
= 8.0 Hz, 2 H), 4.56-4.72 (m, 2 H), 4.23-4.39 (m, 2 H), 3.63 (s, 1 H), 3.27-3.46 (m, 8 H), 1.83-
1.93 (m, 2 H), 1.57-1.67 (m, 1 H), 1.44-1.55 (m, 1 H), 1.26 (s, 3 H). MS (M+H) : 483.
Compound 91: H NMR (400 MHz, CDCl ) δ 10.29 (br. s, 1 H), 8.37 (s, 1 H), 6.63 (t, J
= 8.0 Hz, 2 H), 4.57-4.72 (m, 2 H), 4.24-4.38 (m, 2 H), 3.63 (s, 1 H), 3.25-3.47 (m, 8 H), 1.84-
1.93 (m, 2 H), 1.58-1.67 (m, 1 H), 1.45-1.55 (m, 1 H), 1.26 (s, 3 H). MS (M+H) : 483.
Compound 92: H NMR (400 MHz, CDCl ) δ 10.27 (br. s, 1 H), 8.33 (s, 1 H), 6.59 (t, J
= 8.0 Hz, 2 H), 4.54-4.67 (m, 2 H), 4.30-4.36 (m, 1 H), 4.18-4.25 (m, 1 H), 3.59 (s, 1 H), 3.28-
3.36 (m, 4 H), 3.15-3.23 (m, 4 H), 1.66-1.74 (m, 1 H), 1.49-1.59 (m, 3 H), 1.28 (s, 3 H). MS
(M+H) : 483.
Compound 93: H NMR (400 MHz, CDCl ) δ 10.20 (br. s, 1 H), 8.34 (s, 1 H), 6.64 (t, J
= 8.0 Hz, 2 H), 4.59-4.73 (m, 2 H), 4.23-4.46 (m, 2 H), 3.64 (s, 1 H), 3.33-3.41 (m, 4 H), 3.19-
3.28 (m, 4 H), 1.66-1.74 (m, 1 H), 1.49-1.59 (m, 3 H), 1.32 (s, 3 H). MS (M+H) : 483.
Example 35
Preparation of Compound Int-20d
Step A– Synthesis of Compound Int-20a
To a mixture of sodium hydride (60% wt. in mineral oil) (2.56 g, 64.00 mmol) in 90 mL
of THF at 0 °C was added methyl 2-oxocyclohexanecarboxylate (5.00 g, 32.00 mmol) in 50 mL
of THF dropwise. The resulting mixture was allowed to stir at 0 °C for 30 min. Diethyl
phosphorocyanidate (4.91 ml, 32.3 mmol) was then added to above mixture. The reaction was
allowed to stir at 0 °C for another 1 h. It was slowly quenched with 200 mL of NH Cl saturated
aqueous solution. The aqueous was extracted with 2×150 mL EtOAc. The combined organic
phase was dried over anhydrous Na SO and concentrated to provide the virtually pure
phosphono ester derivative compound Int-20a as a colorless oil. H NMR (400 MHz, CDCl ): δ
4.17-4.23 (m, 4 H); 3.72 (s, 3 H); 2.45-2.48 (m, 2 H); 2.35-2.37 (m, 2 H); 1.70-1.74 (m, 2 H);
1.62-1.64 (m, 2 H); 1.35-1.37 (m, 6 H).
Step B– Synthesis of Compound Int-20b
In a 500 mL round bottle flask, methyllithium (40.6 ml, 65.0 mmol) was added dropwise
to a suspension of copper (I) iodide (4.95 g, 26.0 mmol) in 180 mL of ether at 0 °C. The
resulting solution was immediately cooled to -40 °C, and a solution of compound Int-20a (7.6 g,
26.0 mmol) in 10 mL Et O was added. The reaction was slowly warmed up to room temperature
for overnight. Saturated NH Cl (20 mL) was added slowly to quench the reaction. Filtration
followed by concentration of the filtrate gave a residue which was purified using silica gel
column chromatography eluting with 10% EtOAc / hexanes to provide compound Int-20b as a
colorless oil. H NMR (400 MHz, CDCl ): δ 3.73 (s, 3 H); 2.25-2.28 (m, 2 H); 2.11-2.14 (m, 2
H); 2.00 (s, 3 H); 1.61-1.62 (m, 4 H).
Step C– Synthesis of Compound Int-20c
1 M Diisobutylaluminium hydride in dichloromethane (20.75 ml, 20.75 mmol) was
added to a solution of compound Int-20b (1.6 g, 10.38 mmol) in 100 mL of CH Cl cooled to -
78 °C. The reaction was allowed to stir at this temperature for 1.5 h. It was added 10 mL MeOH
and followed by 10 mL saturated Na CO solution. The mixture was allowed to stir at room
temperature for 1 h. To above mixture was added Na SO . It was filtered through celite and the
cake was washed with 50 mL of CH Cl . The combined organic phase was concentrated to
provide virtually pure compound Int-20c as a colorless oil. H NMR (400 MHz, CDCl ): δ 4.13
(s, 2 H); 2.11-2.13 (m, 2 H); 1.98-2.00 (m, 2 H); 1.72 (s, 3 H); 1.62-1.67 (m, 4 H).
Step D– Synthesis of Compound Int-20d
To a solution of compound Int-20c in 50 mL Et O was added tribromophosphine (0.452
ml, 4.75 mmol) at 0 °C. The reaction was then slowly warm up to room temperature for
overnight. It was quenched with 100 mL saturated NaHCO aqueous solution at 0 °C. The
aqueous was extracted with 2×100 mL Et O. The combined organic phase was washed with
brine, dried over Na SO and concentrated to compound Int-20d as a colorless oil. H NMR (400
MHz, CDCl ): δ 4.05 (s, 2 H); 2.14-2.15 (m, 2 H); 2.01-2.03 (m, 2 H); 1.74 (s, 3 H); 1.60-1.67
(m, 4 H).
Example 36
Preparation of Compound 94 and 95
Step A– Synthesis of Compound Int-21a
The mixture of sodium iodide (1.331 g, 8.88 mmol) and compound Int-20d (1.550 g,
8.19 mmol) in 15 mL of DMF was added indium powder (3.92 g, 34.1 mmol). It was allowed to
stir at room temperature for 10 min. Compound Int-1 (2.2 g, 6.83 mmol) was then added to
above mixture. The reaction was allowed to stir at room temperature for 1 hour, and then 50 °C
for 30 min. It was diluted with 100 mL of EtOAc and filtered. The organic phase was washed
with water and brine, dried over anhydrous sodium sulfate. After filtration, the organic solvent
was removed in vacuum to provide a residue which was purified using silica gel column
chromatography eluting with 20% EtOAc/hexane to provide compound Int-21a as colorless oil.
LCMS anal. calcd. for C H BrNO : 431.11; Found: 432.00 (M+1) .
22 26 3
Step B– Synthesis of Compound Int-21b
To a solution of compound Int-21a (2.10 g, 4.86 mmol) in acetic anhydride (10 ml, 106
mmol) was added triethylamine (2.45 g, 24.29 mmol) and 4-dimethylaminopyridine (0.30 g,
2.429 mmol). The reaction was allowed to stir at room temperature for 1 h. The solvent was
removed in vacuo. The resulting residue was purified using silica gel column chromatography
eluting with 20% EtOAc/hexanes to compound Int-21b as a colorless foam. LCMS anal. calcd.
for C H BrNO : 473.12; Found: 474.03 (M+1) .
24 28 4
Step C– Synthesis of Compound Int-21c
The solution of compound Int-21b (2.10 g, 4.43 mmol) in 35 mL of THF / 9 mL H O
was added osmium tetroxide in t-BuOH (4.50 mL, 0.443 mmol) and 4-methylmorpholine 4-
oxide (1.56 g, 13.28 mmol). The mixture was allowed to stir at room temperature for overnight.
It was diluted with 100 mL of EtOAc and then added 3 g sodium metathiosulfite solid. The
mixture was then stirred for 30 min. It was filtered and the filtrate was concentrated. The
resulting residue was purified using silica gel column chromatography eluting with 60% EtOAc /
hexanes to compound Int-21c as a white solid. LCMS anal. calcd. for C H BrNO : 507.13;
24 30 6
Found: 508.02 (M+1) .
Step D– Synthesis of Compound Int-21d
To a stirred solution of compound Int-21c (1.9 g, 3.74 mmol) in 12 mL pyridine was
added 4-methylbenzenesulfonyl chloride (1.07 g, 5.61 mmol). The reaction was allowed to
stir at room temperature for overnight, followed by heated at 60 °C for 2 h. The reaction was
then added 5 mL MeOH and concentrated to remove most of pyridine. The resulting residue was
purified using silica gel column chromatography eluting with 10% MeOH/DCM to afford
compound Int-21d as a white solid. LCMS anal. calcd. for C H BrNO : 399.07; Found: 400.03
17 22 5
(M+1) .
Step E– Synthesis of Compound Int-21e
To a solution of compound Int-21d (0.22 g, 0.550 mmol) in 6 mL of MeOH was added
potassium carbonate (380 mg, 2.75 mmol). The reaction was allowed to stir at 60 °C for 30 min.
Most of the solvent was removed in vacuo. To the resulting residue was added 10 mL of 10%
mL MeOH / dichloromethane. The resulting mixture was filtered. The mother liquor was
concentrated in vacuo and the resulting residue was purified using silica gel column
chromatography eluting with 10% MeOH / dichloromethane to afford compound Int-21e as a
white solid. LCMS anal. calcd. for C H BrNO : 357.06; Found: 357.98 (M+1) .
20 4
Step F– Synthesis of Compound Int-21f
To a stirred solution of compound Int-21e (0.70 g, 1.95 mmol) in 20 mL of
dichloromethane was added Dess-Martin periodinate (1.32 g, 3.13 mmol). The mixture was
allowed to stir at room temperature for 2 h. It was added 1 mL of H O and the precipitate was
filtered off. The filtrate was concentrated in vacuo and the resulting residue was added 2 mL of
DMSO. The mixture was purified using C18 reverse-phase column (150 g) eluting with 5%
ACN/H O to 100% ACN/H O with 0.1% TFA to afford compound Int-21f as a white solid.
LCMS anal. calcd. for C H BrNO : 355.04; Found: 356.02 (M+1) .
18 4
Step G– Synthesis of Compound Int-21g and Int-21h
To a mixture of compound Int-21f (0.50 g, 1.404 mmol), N-ethyl-N-isopropylpropan
amine (0.54 g, 4.21 mmol), (2,4-difluorophenyl)methanamine (0.30 g, 2.105 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (0.15 mg, 0.281 mmol) in 12 mL of DMSO was
added diacetoxypalladium (63.0 mg, 0.281 mmol). The above mixture was then flushed through
CO for 20 min with CO balloon at room temperature, then heated at 80 °C under CO balloon for
2 h. The reaction was cooled down and directly purified using C18 reverse-phase column (150 g)
eluting with 5% ACN/H2O-100% ACN/H2O with 0.1% TFA to afford the desired product as its
racemic mixture. The enantiomers were then separated by chiral AD column (30×250 mm)
eluting with 50% MeOH/CO at 70 mL/min to afford compound Int-21g and compound Int-21h
as white solids. LCMS anal. calcd. for C H F N O : 446.17; Found: 446.99 (M+1) .
23 24 2 2 5
Step H– Synthesis of Compound 94 and 95
To a stirred solution of compound Int-21g (0.13 g, 0.291 mmol) in 3 mL of DMF was
added lithium chloride (0.25 g, 5.82 mmol). The mixture was allowed to stir at 100 °C for 30
min. It was cooled down and added 0.2 mL H O. The mixture was purified directly by C18
reverse-phase column (40 g) eluting with 5% ACN/H2O to 100% ACN/H2O with 0.1% TFA.
The fraction was collected and dried by lypholizer to afford compound 94 (0.11g, 0.250 mmol)
as white solid. H NMR (400 MHz, CDCl3): δ 10.46 (s, 1 H); 8.40 (s, 1 H); 7.33-7.37 (m, 1 H);
6.81-6.86 (m, 2 H); 4.63 (d, 2 H); 4.21-4.33 (2 H); 1.52-2.01 (8 H); 1.39 (s, 3 H). LCMS anal.
calcd. for C H F N O : 432.15; Found: 433.06 (M+1) .
22 22 2 2 5
Compound 95 was prepared using the method described in Step H of Example 36, and
replacing compound Int-21g with compound Int-21h. H NMR (400 MHz, CDCl ): δ 10.47 (s, 1
H); 8.43 (s, 1 H); 7.35-7.38 (m, 1 H); 6.81-6.86 (m, 2 H); 4.65 (d, 2 H); 4.21-4.33 (2 H); 1.52-
2.03 (8 H); 1.39 (s, 3 H). LCMS anal. calcd. for C H F N O : 432.15; Found: 433.06 (M+1) .
22 22 2 2 5
Example 37
Preparation of Compound 96, and 97
Compound 96 was prepared using the method described in Step G to Step H of Example
36, and replacing compound (2,4-difluorophenyl)methanamine with (3-chloro
fluorophenyl)methanamine in Step G. The stereoisomer mixture was separated by chiral OD
column instead of chiral AD column in Step G. H NMR (400 MHz, CDCl ): δ 10.52 (s, 1 H);
8.42 (s, 1 H); 7.38 (d, J = 5.2 Hz, 1 H); 7.22 (d, J = 1.6 Hz, 1 H); 7.10 (dd, J = 6.8, 1.6 Hz, 1 H);
4.55-4.62 (m, 2 H); 4.18-4.32 (2 H); 2.02-2.03 (m, 2 H); 1.51-1.84 (6 H); 1.40 (s, 3 H). LCMS
anal. calcd. for C H ClFN O : 448.87; Found: 449.05 (M+1) .
22 22 2 5
Compound 97 was prepared by following essentially the same method described for
compound 96. H NMR (400 MHz, CDCl ): δ 10.52 (s, 1 H); 8.44 (s, 1 H); 7.39 (d, J = 5.2 Hz, 1
H); 7.22 (d, J = 1.6 Hz, 1 H); 7.10 (dd, J = 6.8, 1.6 Hz, 1 H); 4.54-4.60 (m, 2 H); 4.18-4.32 (2
H); 2.02-2.03 (m, 2 H); 1.51-1.84 (6 H); 1.40 (s, 3 H). LCMS anal. calcd. for C H ClFN O :
22 22 2 5
448.87; Found: 449.05 (M+1) .
Example 38
Preparation of Compound Int-22
Compound Int-22 was prepared using the method described in Step A to Step D of
Example 35, and replacing methyl 2-oxocyclohexanecarboxylate with methyl 2-
oxocycloheptanecarboxylate in Step A. H NMR (400 MHz, CDCl ): δ 4.10 (s, 2 H); 2.28-2.29
(m, 2 H); 2.19-2.21 (m, 2 H); 1.82 (s, 3 H); 1.72-1.77 (m, 2 H); 1.54-1.58 (m, 2 H); 1.46-1.50
(m, 2 H).
Example 39
Preparation of Compound Int-23
Compound Int-23 was prepared using the method described in Step A to Step F of
Example 36, and replacing compound Int-20d with compound Int-22 in Step A. LCMS anal.
calcd. for C H BrNO : 369.06; Found: 370.95 (M+1) .
16 2 4
Example 40
Preparation of Compound 98-101
OMe O
OMe O
Step A
Int-24a Int-24b
Int-23
OMe O
OMe O
Int-24d
Int-24c
F O F O
OH O
OH O
98 99
Step B
OH O
OH O
Step A– Synthesis of Compound Int-24a, Int-24b, Int-24c and Int-24d
To a mixture of compound Int-23 (0.12 g, 0.32 mmol), N-ethyl-N-isopropylpropan
amine (0.13 g, 0.97mmol), (2,4-difluorophenyl)methanamine (0.07 g, 0.48 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (0.03 mg, 0.05 mmol) in 3 mL of DMSO was
added diacetoxypalladium (11.0 mg, 0.049 mmol). The resulting mixture was then flushed
through CO for 20 min with CO balloon at room temperature, then heated at 80 °C under CO
balloon for 2 h. The reaction was cooled down and directly purified using a C18 reverse-phase
column (40 g) eluting with 5% ACN/H O to 100% ACN/H O with 0.1% TFA to afford
stereoisomer mixture (104 mg, 0.226 mmol) as yellow solid. The stereoisomer mixture was then
separated by chiral IC column (30×250 mm) eluting with 30% MeOH/CO at 70 mL/min to
afford compound Int-24a, compound Int-24b, compound Int-24c, compound Int-24d
individually as awhite solid. LCMS anal. calcd. for C H F N O : 460.18; Found: 461.15
24 26 2 2 5
(M+1) .
Step B– Synthesis of Compound 98-101
To a stirred solution of compound Int-24a (15.0 mg, 0.032 mmol) in 3 mL of DMF was
added lithium chloride (0.27 g, 6.52 mmol). The mixture was allowed to stir at 100 °C for 30
min. It was cooled down and added 0.2 mL H O. The mixture was purified directly by a C18
reverse-phase column (40 g) eluting with 5% ACN / H O to 100% ACN / H O with 0.1% TFA.
The fraction was collected and dried by lypholizer to afford compound 98 as a white solid. H
NMR (400 MHz, CDCl ): δ 10.49 (s, 1 H); 8.69 (s, 1 H); 7.35-7.38 (m, 1 H); 6.83-6.87 (m, 2 H);
4.54-4.59 (m, 2 H); 3.86 (d, J = 9.6 Hz, 1 H); 3.77 (d, J = 9.6 Hz, 1 H); 2.34-2.37 (m, 2 H);
2.13-2.19 (m, 2 H); 1.53-1.90 (6 H); 1.46 (s, 3 H). LCMS anal. calcd. for C H F N O : 446.44;
23 24 2 2 5
Found: 446.99 (M+1) .
Compound 99 was prepared using the method described in Step B of Example 40, and
replacing compound Int-24a with compound Int-24b. LCMS anal. calcd. for C H F N O :
23 24 2 2 5
446.44; Found: 446.99 (M+1) . H NMR (400 MHz, CDCl ): δ 10.39 (s, 1 H); 8.79 (s, 1 H);
7.39-7.42 (m, 1 H); 6.81-6.86 (m, 2 H); 4.54-4.62 (m, 2 H); 3.88 (d, J = 9.2 Hz, 1 H); 3.87 (d, J
= 9.2 Hz, 1 H); 2.34-2.39 (m, 2 H); 2.15-2.19 (m, 2 H); 1.53-1.90 (6 H); 1.45 (s, 3 H).
Compound 100 was prepared using the method described in Step B of Example 40, and
replacing compound Int-24a with compound Int-24c. H NMR (400 MHz, CDCl ): δ 10.51 (s, 1
H); 8.32 (s, 1 H); 7.33-7.37 (m, 1 H); 6.81-6.84 (m, 2 H); 4.63-4.65 (m, 2 H); 4.48 (d, J = 9.6 Hz,
1 H); 4.16 (d, J = 9.6 Hz, 1 H); 2.24-2.27 (m, 1 H); 2.03-2.11 (m, 2 H); 1.49-1.82 (7 H); 1.44 (s,
3 H). LCMS anal. calcd. for C H F N O : 446.44; Found: 446.99 (M+1) .
23 24 2 2 5
Compound 101 was prepared using the method described in Step B of Example 40, and
replacing compound Int-24a with compound Int-24d. H NMR (400 MHz, CDCl ): δ 10.45 (s, 1
H); 8.32 (s, 1 H); 7.30-7.33 (m, 1 H); 6.82-6.84 (m, 2 H); 4.61-4.63 (m, 2 H); 4.48 (d, J = 9.6 Hz,
1 H); 4.16 (d, J = 9.6 Hz, 1 H); 2.24-2.27 (m, 1 H); 2.03-2.11 (m, 2 H); 1.49-1.82 (7 H); 1.44 (s,
3 H). LCMS anal. calcd. for C H F N O : 446.44; Found: 446.99 (M+1) .
23 24 2 2 5
Example 41
Preparation of Compound 102, 103
Compound 102 was prepared using the method described in Step A to Step B of Example
40, and replacing compound (2,4-difluorophenyl)methanamine with compound (3-chloro
fluorophenyl)methanamine in Step A. H NMR (400 MHz, CDCl ): δ 10.55 (s, 1 H); 8.38 (s, 1
H); 7.32 (m, 1 H); 7.22 (m, 1 H); 7.05 (m, 1H); 4.65 (m, 2 H); 4.51 (d, J = 9.2 Hz, 1 H); 4.37
(d, J = 9.2 Hz, 1 H); 3.05 (m, 1 H); 1.28-2.18 (9 H); 1.43 (s, 3 H). LCMS anal. calcd. for
C H ClFN O : 462.14; Found: 462.79 (M+1) .
23 24 2 5
Compound 103 was prepared using the method described in Step A to Step B of Example
40, and replacing (2,4-difluorophenyl)methanamine with (3-chloro
fluorophenyl)methanamine in Step A. H NMR (400 MHz, CD OD): δ 8.45(s, 1 H); 7.38 (m, 1
H); 7.34 (m, 1 H); 7.12 (m, 1H); 4.68 (m, 2 H); 4.51 (d, J = 9.2 Hz, 1 H); 4.18 (d, J = 9.2 Hz, 1
H); 1.59-2.20 (10 H); 1.40 (s, 3 H). LCMS anal. calcd. for C23H24ClFN2O5: 462.14; Found:
462.79 (M+1) .
Example 42
Preparation of Compound Int-25
Compound Int-25 was prepared using the method described in Step A to Step D of
Example 35, and replacing methyl 2-oxocyclohexanecarboxylate with methyl 2-
oxocyclopentanecarboxylate in Step A. H NMR (400 MHz, CDCl ): δ 4.12 (s, 2 H); 2.48-2.51
(m, 2 H); 2.35-2.38 (m, 2 H); 1.83-1.88 (m, 2 H); 1.73 (s, 3 H).
Example 43
Preparation of Compound 104
Br Br Br
N N N
Step B Step C
Step A
Int-1 Int-25
BnO BnO BnO
OMe OH OMe OTBS OMe OTBS
Int-26b
Int-26a Int-26c
OH OH OH
Br Br
N N N
Step D
Step E Step F
OMe OH
OMe OTBS OMe O
Int-26e
Int-26d Int-26f
Step H
Step G N N
OH O
Int-26g
Step A– Synthesis of Compound Int-26a
The mixture of sodium iodide (0.907 g, 6.05 mmol) and compound Int-25 (1.06 g, 6.05
mmol) in 10 mL of DMF was added indium (2.67 g, 23.28 mmol). It was allowed to stir at room
temperature for 10 min. Compound Int-1 (1.5 g, 4.66 mmol) was then added to the above
mixture. The reaction was allowed to stir at room temperature for 1 hour, and then 50 °C for 30
min. It was diluted with 100 mL EtOAc and filtered. The organic phase was washed with water
and brine, dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed
in vacuo to provide a residue which was purified using silica gel column chromatography eluting
with 20% EtOAc/hexane to provide compound Int-26a as a colorless oil. LCMS anal. calcd. for
C H BrNO : 417.09; Found: 417.93 (M+1) .
21 24 3
Step B– Synthesis of Compound Int-26b
The solution of compound Int-26a (1.30 g, 3.11 mmol) in 6 mL of DMF was added tert-
butylchlorodimethylsilane (0.94 g, 6.22 mmol) and imidazole (0.64 g, 9.32 mmol). The mixture
was allowed to stir at 60 °C for overnight. It was added 50 mL of EtOAc. The organic phase
was washed with H O and brine, dried over Na SO and concentrated. The resulting residue was
2 2 4
purified using silica gel column chromatography eluting with 5% EtOAc/hexane to provide
compound Int-26b as colorless oil. LCMS anal. calcd. for C H BrNO Si: 531.18; Found:
27 38 3
532.03 (M+1) .
Step C– Synthesis of Compound Int-26c
A solution of compound Int-26b (1.40 g, 2.63 mmol) in 21 mL of THF and 5 mL of
water was added osmium tetroxide (1.67 mL, 0.263 mmol) and 4-methylmorpholine 4-oxide
(0.92 g, 7.89 mmol). The mixture was allowed to stir at room temperature for overnight. It was
added 20 mL EtOAc. The organic phase was added 2 g of sodium metathiosulfite solid and
stirred for 30 min. It was filtered and the filtrate was concentrated. The resulting residue was
purified using silica gel column chromatography eluting with 30% EtOAc/hexane to afford
compound Int-26c as light green oil. LCMS anal. calcd. for C H BrNO : 565.19; Found:
27 40 5
566.04 (M+1) .
Step D– Synthesis of Compound Int-26d
To a stirred solution of compound Int-26c (0.50 g, 0.88 mmol) in 4 mL of pyridine was
added 4-methylbenzenesulfonyl chloride (022 g, 1.15 mmol). The reaction was allowed to stir
at room temperature for overnight, followed by heated at 60 °C for 2 h. The reaction was then
added 5 mL MeOH and concentrated to remove most of pyridine. The resulting residue was
purified using silica gel column chromatography eluting with 5% MeOH / dichloromethane to
afford compound Int-26d as a white solid. LCMS anal. calcd. for C H BrNO : 457.13; Found:
32 4
457.98 (M+1) .
Step E– Synthesis of Compound Int-26e
A solution of compound Int-26d (0.12 g, 0.26 mmol) in 2 mL of THF at room
temperature was added a solution of 1 N tetrabutylammonium fluoride in THF (0.52 mL, 0.524
mmol). The mixture was allowed to stir at room temperature for 3 h. The reaction was then
directly purified using silica gel column chromatography eluting with 10% MeOH /
dichloromethane to afford compound Int-26e as a white solid. LCMS anal. calcd. for
C H BrNO : 343.03; Found: 344.01 (M+1) .
14 18 4
Step F– Synthesis of Compound Int-26f
To a stirred solution of compound Int-26e (86 mg, 0.25 mmol) in 3 mL of
dichloromethane was added Dess-Martin periodinate (0.15 g, 0.38 mmol). The mixture was
allowed to stir at room temperature for 1 h. It was added 1 mL H2O and the precipitate was
filtered off. The filtrate was concentrated in vacuo and the resulting residue was added 2 mL
DMSO. The mixture was purified using C18 reverse-phase column (40 g) eluting with 5%
ACN/H O to 100% ACN/H O with 0.1% TFA to afford compound Int-26f as white solid.
LCMS anal. calcd. for C H BrNO : 341.03; Found: 341.97 (M+1) .
14 16 4
Step G– Synthesis of Compound Int-26g
A mixture of compound Int-26f (12 mg, 0.035 mmol), N-ethyl-N-isopropylpropan
amine (14 mg, 0.105 mmol), (2,4-difluorophenyl)methanamine (7.5 mg, 0.053 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (4.7 mg, 0.008 mmol) in 2 mL of DMSO was
added diacetoxypalladium (2.0 mg, 0.008 mmol). The above mixture was then flushed through
CO for 20 min with CO balloon at room temperature, then heated at 80 °C with CO balloon for 2
h. The reaction was cooled down and directly purified using C18 reverse-phase column (25 g)
eluting with 5% ACN/H O to100% ACN/H O with 0.1% TFA to afford stereoisomer mixture of
compound Int-26g as yellow solid. LCMS anal. calcd. for C H F N O : 432.15; Found: 433.10
22 22 2 2 5
(M+1) .
Step H– Synthesis of Compound 104
To a stirred solution of compound Int-26g (8.0 mg, 0.019 mmol) in 1 mL of DMF was
added lithium chloride (16 mg, 0.37 mmol). The mixture was allowed to stir at 100 °C for 30
min. It was cooled down and added 0.2 mL H O. The mixture was purified directly by a C18
reverse-phase column (40 g) eluting with 5% ACN/H O to 100% ACN/H2O with 0.1% TFA.
The fraction was collected and dried by lypholizer to afford compound 104 as white solid. H
NMR (400 MHz, CD OD): δ 10.52(m, 1 H); 8.45 (s, 1 H); 7.39-7.44 (m, 1 H); 6.91-6.98 (m, 2
H); 4.59-4.77 (m, 2 H); 4.36 (d, J = 10.8, 1 H); 4.20 (d, J = 10.8, 1 H); 3.30 (s, 3 H); 2.26-2.31
(m, 1 H); 1.83-2.04 (m, 4 H); 1.64-1.69 (m, 1 H); 1.34 (s, 3 H). LCMS anal. calcd. for
C H F N O : 418.13; Found: 418.98 (M+1) .
21 20 2 2 5
Example 44
Preparation of Compound 105
Br Br
Step B Step C
Step A
Int-26d
OMe OH OMe O
OMe OTBS
Int-27c
Int-27b
Int-27a
Step D Step E
F O F O
OMe O
OH O
Int-27d
Step A– Synthesis of Compound Int-27a
A solution of compound Int-26d (145 mg, 0.316 mmol) in 2 mL of THF at room
temperature was added iodomethane (135 mg, 0.949 mmol) and followed by adding sodium
hydride (22.77 mg, 0.949 mmol)). The mixture was allowed to stir at room temperature for 5 h.
The reaction was then quenched by 1 mL H O. The reaction was then directly purified using
silica gel column chromatography eluting with 30%EtOAc/hexane to afford compound Int-27a
as light yellow solid. LCMS anal. calcd. for C H BrNO Si: 471.14; Found: 472.28 (M+1) .
21 34 4
Step B– Synthesis of Compound Int-27b
To a solution of compound Int-27a (90 mg, 0.19 mmol) in 2 mL of THF at room
temperature was added a solution of 1 N tetrabutylammonium fluoride in THF (0.40 mL, 0.40
mmol). The mixture was allowed to stir at room temperature for 3 h. The reaction was then
directly purified using silica gel column chromatography eluting with 10%
MeOH/dichloromethane to afford compound Int-27b as white solid. LCMS anal. calcd. for
C15H20BrNO4: 357.06; Found: 358.01 (M+1) .
Step C– Synthesis of Compound Int-27c
To a stirred solution of compound Int-27b (60 mg, 0.17 mmol) in 2 mL of
dichloromethane was added Dess-Martin periodinate (71 mg, 0.17 mmol). The mixture was
allowed to stir at room temperature for 1 h. It was added 1 mL of H O and the precipitate was
filtered off. The filtrate was concentrated in vacuo and the resulting residue was added 2 mL of
DMSO. The mixture was purified using C18 reverse-phase column (40 g) eluting with 5%
ACN/H O to 100% ACN/H O with 0.1% TFA to afford compound Int-27c as a white solid.
LCMS anal. calcd. for C H BrNO : 355.04; Found: 356.04 (M+1) .
18 4
Step D– Synthesis of Compound Int-27d
To a mixture of compound Int-27c (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan
amine (21 mg, 0.168 mmol), (2,4-difluorophenyl)methanamine (12 mg, 0.084 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (7.6 mg, 0.014 mmol) in 2 mL of DMSO was
added diacetoxypalladium (3.0 mg, 0.014 mmol). The above mixture was then flushed through
CO for 20 min with CO balloon at room temperature, then heated at 80 °C under a CO balloon
for 2 h. The reaction was cooled down and directly purified using C18 reverse-phase column (25
g) eluting with 5% ACN/H O to100% ACN/H O with 0.1% TFA to afford stereoisomer mixture
of compound Int-27d as a yellow solid. LCMS anal. calcd. for C H F N O : 446.17; Found:
23 24 2 2 5
447.18 (M+1) .
Step E– Synthesis of Compound 105
To a stirred solution of compound Int-27d (12.0 mg, 0.027 mmol) in 1 mL of DMF was
added lithium chloride (23 mg, 0.54 mmol). The mixture was allowed to stir at 100 °C for 30
min. It was cooled down and added 0.2 mL of H O. The mixture was purified directly by a C18
reverse-phase column (40 g) eluting with 5% ACN/H O to 100% ACN/H O with 0.1% TFA.
The fraction was collected and dried by lypholizer to afford compound 105 as a white solid. H
NMR (400 MHz, CD OD): δ 8.54 (s, 1 H); 7.43-7.45 (m, 1 H); 6.90-6.97 (m, 2 H); 4.61-4.64 (2
H); 4.34-4.36 (2 H); 3.31 (s, 3 H); 2.26-2.32 (m, 1 H); 2.13-2.19 (m, 1 H); 1.97-2.00 (m, 1 H);
1.84-1.91 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H). LCMS anal. calcd. for C H F N O :
22 22 2 2 5
432.15; Found: 433.17 (M+1) .
Example 45
Preparation of Compound 106 and 107
Compound 106 was prepared by following essentially the same method as described in
Example 44 for compound 105, and replacing (2,4-difluorophenyl)methanamine with (4-
fluorophenyl)methanamine in Step D. H NMR (400 MHz, CD OD): δ 8.56 (s, 1 H); 7.36-7.39
(m, 2 H); 7.05-7.08 (m, 2 H); 4.60-4.65 (2 H); 4.31-4.37 (2 H); 3.31 (s, 3 H); 2.26-2.32 (m, 1 H);
2.14-2.20 (m, 1 H); 1.97-2.01 (m, 1 H); 1.84-1.91 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H).
LCMS anal. calcd. for C H FN O : 414.16; Found: 415.16 (M+1) .
22 23 2 5
Compound 107 was prepared by following essentially the same method as described in
Example 44 for compound 105, and replacing (2,4-difluorophenyl)methanamine with (2,3,4-
trifluorophenyl)methanamine in Step D. H NMR (400 MHz, CD OD): δ 8.53 (s, 1 H); 7.04-
7.21 (m, 2 H); 4.60-4.67 (2 H); 4.33-4.36 (2 H); 3.31 (s, 3 H); 2.26-2.31 (m, 1 H); 2.14-2.20 (m,
1 H); 1.97-2.01 (m, 1 H); 1.84-1.90 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H). LCMS anal.
calcd. for C H F N O : 450.14; Found: 450.97 (M+1) .
22 21 3 2 5
Example 46
Preparation of Compound Int-28b
Step A– Synthesis of Compound Int-28a
Diisobutylaluminium hydride (35.50 ml, 35.50 mmol) was added to a solution of 2,6,6-
trimethylcyclohexenecarbaldehyde (4.50 g, 29.60 mmol) in 200 mL of CH Cl cooled to -40
°C. The resulting mixture was allowed to stir at this temperature for 1.5 h. It was added 10 mL
MeOH and followed by 200 mL of saturated Rochelle solution. The mixture was allowed to stir
at room temperature for 1 h. The organic phase was separated and the aqueous was extracted
with 2 × 50 mL of EtOAc. The combined organic phase was dried over anhydrous Na SO ,
filtered and concentrated to provide compound Int-28a as a colorless oil. H NMR (400 MHz,
CDCl ): δ 4.15 (s, 2 H); 1.99 (t, J = 4.8 Hz, 2 H); 1.77 (s, 3 H); 1.59-1.64 (m, 2 H); 1.45-1.48 (m,
2 H); 1.06 (s, 6 H).
Step B– Synthesis of Compound Int-28b
To a solution of compound Int-28a (3.70 g, 23.99 mmol) in 200 mL of Et O was added
tribromophosphine (1.14 ml, 11.99 mmol) at 0 °C. The reaction was then slowly warmed up to
room temperature overnight. It was quenched with 200 mL of saturated NaHCO aqueous
solution at 0 °C. The aqueous was extracted with 2×200 mL Et O. The combined organic phase
was washed with brine, dried over anhydrous Na SO and concentrated to compound Int-28b as
a colorless oil. H NMR (400 MHz, CDCl ): δ 4.11 (s, 2 H); 2.05 (t, J = 4.8 Hz, 2 H); 1.77 (s, 3
H); 1.57-1.64 (m, 2 H); 1.45-1.49 (m, 2 H); 1.13 (s, 6 H).
Example 47
Preparation of Compound 108 and 109
OH O
OH O
Compound 108 was prepared by following essentially the same method as described in
Example 36 for compound 94, and replacing compound Int-20d with compound Int-28b in Step
A. H NMR (400 MHz, CDCl ): δ 10.51 (s, 1 H); 8.52 (s, 1 H); 7.36-7.41 (m, 1 H); 6.81-6.87
(m, 2 H); 4.64-4.73 (m, 2 H); 4.37 (d, J = 10.4, 1 H); 4.23 (d, J = 10.4, 1 H); 2.32-2.34 (m, 1
H); 1.57-1.72 (m, 3 H); 1.37 (s, 3 H); 1.29-1.34 (m, 2 H); 1.24 (s, 3 H); 0.73 (s, 3 H). LCMS
anal. calcd. for C H F N O : 460.18; Found: 461.18 (M+1) .
24 26 2 2 5
Compound 109 was prepared by following essentially the same method as described in
Example 36 for compound 95, and replacing compound Int-20d with compound Int-28b in
Step A. H NMR (400 MHz, CDCl ): δ 10.46 (s, 1 H); 8.49 (s, 1 H); 7.37-7.40 (m, 1 H); 6.84-
6.89 (m, 2 H); 4.66-4.69 (m, 2 H); 4.34 (d, J = 10.4, 1 H); 4.22 (d, J = 10.4, 1 H); 2.33-2.35 (m,
1 H); 1.61-1.72 (m, 3 H); 1.37 (s, 3 H); 1.29-1.34 (m, 2 H); 1.14 (s, 3 H); 0.73 (s, 3 H). LCMS
anal. calcd. for C24H26F2N2O5: 460.18; Found: 461.18 (M+1) .
Example 48
Preparation of Compound 110 and 111
Step A– Synthesis of Compound Int-29a
To a stirred solution of compound Int-21f (70 mg, 0.197 mmol) in 2 mL of CH Cl was
added chloro(methoxy)methane (15.82 mg, 0.197 mmol), N-ethyl-N-isopropylpropanamine
(25.4 mg, 0.197 mmol) and N,N-dimethylpyridinamine (24.01 mg, 0.197 mmol). The mixture
was allowed to stir at 60 °C for 4 h. The reaction was concentrated in vacuo and the resulting
residue was added 2 mL of DMSO. It was purified using Gilson eluting with 10% ACN(0.1%
TFA)/H O to 90% ACN (0.1% TFA)/H O for 12 min to afford compound Int-29a as light
yellow solid.. LCMS anal. calcd. for C H BrNO : 399.07; Found: 400.07 (M+1) .
17 22 5
Step B– Synthesis of Compound Int-29b and Int-29c
To a mixture of compound Int-29a (50 mg, 0.125 mmol)), N-ethyl-N-isopropylpropan
amine (48.4 mg, 0.375 mmol)), (2,4-difluorophenyl)methanamine (26.8 mg, 0.187 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (10.09 mg, 0.019 mmol) in 2 mL of DMSO was
added diacetoxypalladium (4.21 mg, 0.019 mmol). The above mixture was flushed through CO
for 20 min with CO balloon at room temperature, then heated at 80 °C under a CO balloon for 2
h. The reaction was cooled down and directly purified using a C18 reverse-phase column (40 g)
eluting with 5% ACN/H O to 100% ACN/H O with 0.1% TFA to afford stereoisomer mixture of
the desired product which was then separated by chiral AD column (30×250 mm) eluting with
45% MeOH/CO at 70 mL/min to afford compound Int-29b and compound Int-29c individually
as a white solid. LCMS anal. calcd. for C H F N O : 490.19; Found: 491.15 (M+1) .
228 2 2 6
Step C– Synthesis of Compound 110 and 111
Compound 110 was prepared by following essentially the same method as described in
Example 36 for compound 94, and replacing compound Int-21g with compound Int-29b in Step
H. H NMR (400 MHz, CDCl ): δ 10.48 (s, 1 H); 8.47 (s, 1 H); 7.36-7.40 (m, 1 H); 6.81-6.87
(m, 2 H); 4.98 (d, J = 6.4 Hz, 1 H);4.64-4.67 (m, 2 H); 4.58 (d, J = 6.4 Hz, 1 H); 4.54 (1 H); 4.35
(d, J = 11.2, 1 H); 3.20 (s, 3 H); 1.66-1.96 (6 H); 1.49-1.51 (2 H); 1.42 (s, 3 H). LCMS anal.
calcd. for C H F N O : 476.18; Found: 477.16 (M+1) .
24 26 2 2 5
Compound 111 was prepared by following essentially the same method as described in
Example 36 for compound 95, and replacing compound Int-21h with compound Int-29c in Step
H. H NMR (400 MHz, CDCl ): δ 10.46 (s, 1 H); 8.45 (s, 1 H); 7.36-7.40 (m, 1 H); 6.80-6.86
(m, 2 H); 4.97 (d, J = 6.4 Hz, 1 H);4.64-4.67 (m, 2 H); 4.57 (d, J = 6.4 Hz, 1 H); 4.53 (1 H); 4.35
(d, J = 11.2, 1 H); 3.20 (s, 3 H); 1.66-1.95 (6 H); 1.48-1.49 (2 H); 1.41 (s, 3 H). LCMS anal.
calcd. for C H F N O : 476.18; Found: 477.16 (M+1) .
24 26 2 2 5
Example 49
Preparation of Compound 112 and 113
Step A– Synthesis of Compound Int-30a
To a solution of compound Int-21e (0.25 g, 0.698 mmol) in 7 mL of CH Cl was added
N-ethyl-N-isopropylpropanamine (0.45 g, 3.49 mmol), N,N-dimethylpyridinamine (17.05
mg, 0.140 mmol) and chloro(methoxy)methane (281 mg, 3.49 mmol). The mixture was allowed
to stir at 50 °C for 1 h. It was cooled down and concentrated. The resulting residue was dissolved
in 5 mL of DMSO and purified using Gilson (10% ACN(0.1% TFA)/H O- 90% ACN (0.1%
TFA)/H O, 12 min) to afford compound Int-30a as a light yellow solid. LCMS anal. calcd. for
C H BrNO : 401.08; Found: 402.07 (M+1) .
17 24 5
Step B– Synthesis of Compound Int-30b
To a solution of compound Int-30a (85 mg, 0.211 mmol) in 2 mL of DMF was added
iodomethane (90 mg, 0.634 mmol) and followed by sodium hydride (15.21 mg, 0.634 mmol).
The mixture was allowed to stir at 0 °C for 30 min. It was quenched with 0.5 mL of saturated
NH Cl aqueous solution. The mixture was diluted by 3 mL of DMF and purified using Gilson
(10% ACN(0.1% TFA)/H O- 90% ACN (0.1% TFA)/H O, 12 min) to provide compound Int-
30b as a light yellow solid. LCMS anal. calcd. for C H BrNO : 415.10; Found: 415.98 (M+1) .
18 26 5
Step C– Synthesis of Compound Int-30c
To a stirred solution of compound Int-30b (50 mg, 0.120 mmol) in 2 mL of MeOH was
added hydrogen chloride (1201 µl, 1.201 mmol). The mixture was allowed to stir at 50 °C for 30
min. It was concentrated. To the crude product was added 2 mL of CH Cl , followed by Dess-
Martin periodinane (102 mg, 0.240 mmol). The reaction was allowed to stir at room temperature
for 30 min. It was concentrated in vacuo and the resulting residue was dissolved in 3 mL of
DMSO. The mixture was purified using Gilson (10% ACN(0.1% TFA)/H O- 90% ACN (0.1%
TFA)/H2O, 12 min) to provide compound Int-30c as a white solid. LCMS anal. calcd. for
C H BrNO : 369.06; Found: 370.05 (M+1) .
16 20 4
Step D– Synthesis of Compound Int-30d and Int-30e
Compound Int-30d and compound Int-30e were prepared by following essentially the
same method as compound Int-29b and compound Int-29c described in Example 48, and
replacing compound Int-29a with compound Int-30c in Step B. LCMS anal. calcd. for
C H F N O : 460.18; Found: 461.08 (M+1) .
24 26 2 2 5
Step F– Synthesis of Compound 112 and 113
Compound 112 was prepared by following essentially the same method as described in
Example 36 for compound 94, and replacing compound Int-21g with compound Int-30d in
Step H. H NMR (400 MHz, CDCl ): δ 10.56 (s, 1 H); 8.52 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-
6.87 (m, 2 H); 4.64-4.67 (m, 2 H); 4.40 (1 H); 4.25 (d, J = 10.8, 1 H); 3.26 (s, 3 H); 1.47-1.97 (8
H); 1.37 (s, 3 H). LCMS anal. calcd. for C H F N O : 446.16; Found: 447.07 (M+1) .
24 26 2 2 5
Compound 113 was prepared by following essentially the same method as described in
Example 36 for compound 95, and replacing compound Int-21h with compound Int-30e in Step
H. H NMR (400 MHz, CDCl ): δ 10.56 (s, 1 H); 8.47 (s, 1 H); 7.32-7.40 (m, 1 H); 6.81-6.86
(m, 2 H); 4.67-4.69 (m, 2 H); 4.37 (1 H); 4.22 (d, J = 10.8, 1 H); 3.27 (s, 3 H); 1.47-1.97 (8 H);
1.37 (s, 3 H). LCMS anal. calcd. for C H F N O : 446.16; Found: 447.07 (M+1) .
24 26 2 2 5
Example 50
Preparation of Compound 114-117
Compound 114 was prepared by following essentially the same method as described in
Example 49 for compound 112, and replacing iodomethane with 1-bromomethoxyethane in
Step B. H NMR (400 MHz, CDCl ): δ 10.42 (s, 1 H); 8.37(s, 1 H); 7.36-7.40 (m, 1 H); 6.82-
6.87 (m, 2 H); 4.67 (d, , J = 4.8,2 H); 4.35 (1 H); 4.22 (d, J = 11.2, 1 H); 3.63-3.65 (m, 2 H);
3.49-3.53 (m, 2 H); 3.42 (s, 3 H); 3.28 (s, 3 H); 1.43-1.97 (8 H); 1.39 (s, 3 H). LCMS anal. calcd.
for C H F N O : 490.19; Found: 491.06 (M+1) .
28 2 2 6
Compound 115 was prepared by following essentially the same method as described in
Example 49 for compound 113, and replacing iodomethane with 1-bromomethoxyethane in
Step B. H NMR (400 MHz, CDCl ): δ 10.42 (s, 1 H); 8.39(s, 1 H); 7.34-7.40 (m, 1 H); 6.79-
6.86 (m, 2 H); 4.67 (d, , J = 4.4,2 H); 4.40 (1 H); 4.23 (d, J = 10.8, 1 H); 3.62-3.66 (m, 2 H);
3.49-3.53 (m, 2 H); 3.42 (s, 3 H); 3.27 (s, 3 H); 1.43-1.97 (8 H); 1.39 (s, 3 H). LCMS anal. calcd.
for C H F N O : 490.19; Found: 491.06 (M+1) .
28 2 2 6
Compound 116 was prepared by following essentially the same method as described in
Example 49 for compound 112, and replacing iodomethane with 1-bromomethoxypropane in
Step B. H NMR (400 MHz, CDCl ): δ 10.46 (s, 1 H); 8.44 (s, 1 H); 7.36-7.39 (m, 1 H); 6.81-
6.86 (m, 2 H); 4.67 (d, , J = 4.4, 2 H); 4.38 (1 H); 4.22 (d, J = 10.8, 1 H); 3.58-3.62 (m, 2 H);
3.29-3.41 (4 H); 3.25 (6 H); 1.43-1.97 (8 H); 1.38 (s, 3 H). LCMS anal. calcd. for C H F N O :
28 2 2 6
504.21; Found: 505.11 (M+1) .
Compound 117 was prepared by following essentially the same method as described in
Example 49 for compound 113, and replacing iodomethane with 1-bromomethoxypropane in
Step B. H NMR (400 MHz, CDCl ): δ 10.46 (s, 1 H); 8.44 (s, 1 H); 7.36-7.41 (m, 1 H); 6.81-
6.86 (m, 2 H); 4.67 (d, , J = 4.4, 2 H); 4.38 (1 H); 4.22 (d, J = 10.8, 1 H); 3.58-3.62 (m, 2 H);
3.29-3.41 (4 H); 3.25 (6 H); 1.43-1.97 (8 H); 1.38 (s, 3 H). LCMS anal. calcd. for
C H F N O : 504.21; Found: 505.11 (M+1) .
28 2 2 6
Example 51
Preparation of Compound Int-31
Compound Int-31 was prepared using the method described in Step A to Step E of
Example 36, and replacing compound Int-20d with compound Int-22 in Step A. LCMS anal.
calcd. for C H BrNO : 371.06; Found: 372.95 (M+1) .
16 22 4
Example 52
Preparation of Compound 118 and compound 119
Compound 118 was prepared by following essentially the same method as described in
Example 49 for compound 112, and replacing compound Int-21e with compound Int-31 in Step
A. H NMR (400 MHz, CDCl ): δ 10.60 (s, 1 H); 8.54 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87
(m, 2 H); 4.65-4.73 (m, 2 H); 4.52 (d, J = 11.2, 1 H); 4.30 (d, J = 10.8, 1 H); 3.17 (s, 3 H); 1.48-
2.02 (10 H); 1.43 (s, 3 H). LCMS anal. calcd. for C H F N O : 460.18; Found: 461.16 (M+1) .
24 26 2 2 5
Compound 119 was prepared by following essentially the same method as described in
Example 49 for compound 113, and replacing compound Int-21e with compound Int-31 in Step
A. H NMR (400 MHz, CDCl ): δ 10.60 (s, 1 H); 8.55 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87
(m, 2 H); 4.64-4.73 (m, 2 H); 4.52 (d, J = 11.2, 1 H); 4.30 (d, J = 10.8, 1 H); 3.16 (s, 3 H); 1.48-
2.02 (10 H); 1.43 (s, 3 H). LCMS anal. calcd. for C H F N O : 460.18; Found: 461.16 (M+1) .
24 26 2 2 5
Example 53
Preparation of Compound Int-32h
Step A– Synthesis of Compound Int-32a
To a stirred solution of tri-O-acetyl-D-glucal (10.0 g, 36.7 mmol) in 100 mL of CH Cl
was added triethylsilane (5.13 g, 44.1 mmol) and boron trifluoride etharate (5.21 g, 36.7 mmol)
at 0 °C. The mixture was allowed to stir at this temperature for 2 h. It was quenched by adding
100 mL of 0.2 N HCl aqueous solution and 200 mL of CH Cl . The organic phase was separated
and dried over anhydrous Na SO . It was concentrated in vacuo and the resulting residue was
purified using silica gel column chromatography eluting with 40% EtOAc/hexane to provide
compound Int-32a as a colorless oil. LCMS anal. calcd. for C H O : 214.08; Found: 237.07
14 5
(M+Na) .
Step B– Synthesis of Compound Int-32b
To a solution of compound Int-32a (6.8 g, 31.7 mmol) in 100 mL of MeOH was added
sodium methanolate (0.686 g, 3.17 mmol). The reaction was allowed to stir at room temperature
overnight. It was concentrated. The resulting residue was purified using silica gel column
chromatography eluting with 80% EtOAc/hexane to provide compound Int-32b as a colorless
oil. H NMR (400 MHz, CDCl ): δ 5.81-5.89 (2 H); 4.16-4.24 (3 H); 3.89 (dd, J = 3.2, 5.6 Hz, 1
H); 3.83 (dd, J = 3.2, 5.6 Hz, 1 H); 3.34-3.38 (m, 1 H), 2.67 (2 H).
Step C– Synthesis of Compound Int-32c
The solution of compound Int-32b (3.5 g, 26.9 mmol )in 120 mL of MeOH was added
10% wt. palladium on carbon (2.86 g, 2.69 mmol). The mixture was stirred under H balloon
overnight. It was filtered through celite. The filtrate was concentrated to provide compound Int-
32c as a colorless oil. H NMR (400 MHz, CDCl ): δ 3.93 (dd, J = 0.8, 9.6 Hz, 1 H); 3.84 (dd, J
= 2.4, 9.2 Hz, 1 H ); 3.78 (dd, J = 4.0, 5.6 Hz, 1 H ); 3.54-3.59 (m, 1 H); 3.36-3.43 (m, 1 H);
3.13-3.16 (m, 1 H); 2.84 (broad, 1 H); 2.12-2.15 (m, 1 H); 1.67-1.74 (m, 2 H); 1.41-1.49 (m, 1
H).
Step D– Synthesis of Compound Int-32d
The solution of compound Int-32c (3.0 g, 22.70 mmol) in 40 mL of DMF was added
imidazole (4.64 g, 68.10 mmol) and tert-butyldimethychlorosilane(4.45 g, 29.50 mmol). The
mixture was allowed to stir at room temperature for 3 h. It was added 200 mL of H O. The
aqueous was extracted with 2×200 mL of EtOAc. The combined organic phase was dried over
Na2SO4 and concentrated. The resulting residue was purified using silica gel column
chromatography eluting with 15% EtOAc/hexane to provide compound Int-32d as a colorless
oil. LCMS anal. calcd. for C H O Si: 246.17; Found: 247.17 (M+H) .
12 26 3
Step E– Synthesis of Compound Int-32e
To a solution of compound Int-32d (5.0 g, 20.29 mmol) in 150 mL of CH Cl and 30 mL
of DMSO was added triethylamine (6.16 g, 60.9 mmol)) and PySO complex (6.46 g, 40.6
mmol) at 0 °C. After 10 min, the ice bath was removed and the mixture was allowed to stir at
room temperature for 2 h. The resulting mixture was added 100 mL of H O and 100 mL of
CH2Cl2. The organic phase was separated and the aqueous was extracted with 2×50 mL of
CH Cl . The combined organic phase was dried over Na SO and concentrated. The resulting
2 2 2 4
residue was purified using silica gel column chromatography eluting with 10% EtOAc/hexane to
provide compound Int-32e as a colorless oil. LCMS anal. calcd. for C H O Si: 244.40; Found:
12 26 3
245.33 (M+H) .
Step F– Synthesis of Compound Int-32f
To a solution of ethyl 2-(trimethylsilyl)acetate (4.98 g, 31.1 mmol) in 150 mL of THF at -
78 °C was added a solution of 2 N lithium diisopropylamide in THF (17.10 ml, 34.2 mmol)
dropwise. The reaction mixture was stirred for 15 minutes, then compound Int-32e (3.8 g, 15.55
mmol) was added. The reaction mixture was allowed to warm up to 40 °C over 3 h, and was
quenched by adding 100 mL of saturated aqueous NH Cl solution. The mixture was extracted
with 2×150 mL of ethyl acetate and the combined organic extracts were washed with 150 mL of
brine . After drying over MgSO and filtration, the solvent was removed under reduced pressure.
The resulting residue was purified using silica gel column chromatography eluting with 15%
EtOAc/hexane to afford compound Int-32f as a colorless oil. LCMS anal. calcd. for C H O Si:
16 30 4
314.19; Found: 315.12 (M+H) .
Step G– Synthesis of Compound Int-32g
To a solution of compound Int-32f (4.0 g, 12.72 mmol) in 120 mL of CH Cl cooled at -
78 °C was added 1 N diisobutylaluminum hydride in toluene (28.0 ml, 28.0 mmol). The reaction
was allowed to stir at -78 °C for 1 h and then warmed up to 0 °C. At this time, it was quenched
by adding 100 mL of saturated Rochelle salt solution. The mixture was allowed to stir at room
temperature for 1 h. The organic phase was separated. It was washed with 50 mL of brine and
concentrated to provide compound Int-32g as a colorless oil. LCMS anal. calcd. for C14H28O3Si:
272.18; Found: 255.05 (M-H O) .
Step H– Synthesis of Compound Int-32h
To a solution of compound Int-32g (1.0 g, 3.67 mmol) in 36 mL of THF was added
triethylamine (1.11 g, 11.01 mmol), followed by methanesulfonyl chloride (0.84 g, 7.34 mmol)
at 0 °C. The reaction was allowed to stir at 0 °C for 1 h. It was diluted with 100 mL of EtOAc
and washed with 100 mL of 0.2 N aqueous HCl solution 3 times, then with 100 mL of brine.
The organic phase was concentrated in vacuo. The resulting crude mesylate was dissolved in 10
mL of THF and used in the next reaction without further purification.
In a separate reaction vessel, a solution of 2 N lithium diisobutylamide in THF (3.77 ml,
7.53 mmol) solution was cooled at 0 °C. To this was added tributylstannane (1.993 g, 6.85
mmol). The reaction was allowed to stir at 0 °C for 15 min. It was then cooled to -78 °C, and the
above mentioned mesylate solution was added via syringe. The reaction was allowed to stir at -
78 °C for 30 min. It was diluted with 150 mL of 20% EtOAc/hexanes, and washed 150 mL of
water. The organic phase was concentrated in vacuo. The resulting residue was purified using
silica gel column chromatography eluting initially with hexanes to removed Bu SnH, and then
with 10% EtOAc/hexanes to provide compound Int-32h as a colorless oil. H NMR (400 MHz,
CDCl ): δ 5.40-5.43 (m, 1 H); 4.52-4.54 (m, 1 H); 3.91-3.98 (2 H); 3.76-3.90 (m, 2 H); 3.62-3.68
(m, 2 H); 2.31-2.37 (m, 2 H); 2.11-2.18 (m, 2 H); 1.58-1.70 (m, 6 H); 1.44 (m, 6 H); 1.30-1.37
(m, 6 H); 0.86-1.00 (19 H); 0.09-0.11 (6 H).
Example 54
Preparation of Compound 120
Step A– Synthesis of Compound Int-33a
To a solution of compound Int-1 (810 mg, 2.51 mmol)) and compound Int-32h (1.50 g,
2.75 mmol) in 25 mL of ACN at 0 °C was added stannous chloride (763 mg, 4.02 mmol). The
reaction was then warm to room temperature and stirred for 30 min. It was added 20 mL of
saturated NH Cl aqueous solution. The resulting mixture was allowed to stir at room
temperature for 5 min. This was diluted with 100 mL of 30% EtOAc/hexanes, and washed with
100 mL of water. The organic phase was separated and filtered. The mother liquor was
concentrated in vacuo and the resulting residue was purified using silica gel column
chromatography eluting with 10%EtOAc/hexane to compound Int-33a as colorless oil. LCMS
anal. calcd. for C28H40BrNO5Si: 577.19; Found: 578.12 (M+H) .
Step B– Synthesis of Compound Int-33b
A solution of compound Int-33a (755 mg, 1.305 mmol) in acetic anhydride (6 ml, 63.5
mmol) was added triethylamine (660 mg, 6.52 mmol) and N,N-dimethylpyridinamine (80 mg,
0.652 mmol). The reaction was allowed to stir at room temperature for 1 h. The solvent was
removed in vacuo. The resulting residue was purified using silica gel column chromatography
eluting with 20% EtOAc/hexanes to provide compound Int-33b as a colorless film. LCMS anal.
calcd. for C H BrNO Si: 619.20; Found: 620.16 (M+H) .
42 6
Step C– Synthesis of Compound Int-33c
To a stirred solution compound Int-33b (800 mg, 1.289 mmol) in 12 mL of THF was
added 1 N tetrabutylammonium fluoride in THF (2578 µl, 2.58 mmol). The mixture was allowed
to stir at room temperature for 3 h. It was concentrated to remove most of THF. The resulting
residue was purified using silica gel column chromatography eluting with 50% EtOAc/hexane to
compound Int-33c as a colorless foam. LCMS anal. calcd. for C H BrNO : 505.11; Found:
42 6
505.96 (M+H) .
Step D– Synthesis of Compound Int-33d
To a solution of compound Int-33c (70 mg, 0.138 mmol) in 10 mL of THF at 0 °C was
added triethylamine (42.0 mg, 0.415 mmol) and methanesulfonyl chloride (31.7 mg, 0.276
mmol). The mixture was allowed to stir at this temperature for 15 min. It was diluted with 20 mL
of EtOAc. The organic phase was washed with 20 mL of 0.5 N HCl, dried over Na2SO4. After
filtration, it was concentrated. The resulting residue was dissolved in 2 mL of DMF and then
added sodium iodide (207 mg, 1.382 mmol). The reaction was allowed to stir at 70 °C for 30
min. After cooled to room temperature, it was then purified using Gilson (10% ACN(0.1%
TFA)/H O- 90% ACN (0.1% TFA)/H O, 12 min) to afford the desired iodo intermediate. This
intermediate was then dissolved in 2 mL of DMF, followed by adding cesium carbonate (225
mg, 0.691 mmol). The reaction mixture was allowed to stir at 70 °C for 30 min. It was cooled to
room temperature and purified using Gilson (10% ACN(0.1% TFA)/H O- 90% ACN (0.1%
TFA)/H O, 12 min) to afford compound Int-33d as a white solid. LCMS anal. calcd. for
C17H20NO5: 397.05; Found: 398.02 (M+H) .
Step D– Synthesis of Compound Int-33e
To a stirred mixture of compound Int-33d (40 mg, 0.101 mmol) in 2 mL of MeOH was
added potassium carbonate (45 mg,0.303 mmol). The mixture was allowed to stir at room
temperature for 1 h. It was concentrated in vacuo and the resulting residue was dissolved in 3
mL of DMSO. This was purified using Gilson (10% ACN(0.1% TFA)/H O- 90% ACN (0.1%
TFA)/H O, 12 min) to provide the desired alcohol intermediate, which was then dissolved in 3
mL of CH Cl . Dess-Martin periodinane (79 mg, 0.187 mmol) was then added. The reaction was
allowed to stir at room temperature for 30 min. It was added 1 drop of water and the resulting
reaction mixture was filtered. The filtrate was concentrated in vacuo and the resulting residue
was dissolved in 3 mL of DMSO. It was purified using Gilson (10% ACN(0.1% TFA)/H O-
90% ACN (0.1% TFA)/H O, 12 min) to afford compound Int-33e as a white solid. LCMS anal.
calcd. for C H BrNO : 353.03; Found: 353.97 (M+H) .
16 4
Step E– Synthesis of Compound Int-33f
To a mixture of compound Int-33e (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan
amine (21.89 mg, 0.169 mmol), (2,4-difluorophenyl)methanamine (12.12 mg, 0.085 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (6.08 mg, 0.011 mmol) in 1 mL of DMSO was
added diacetoxypalladium (2.54 mg, 0.011 mmol). The above mixture was then flushed through
CO for 20 min with CO balloon at room temperature, then heated at 80 °C under CO balloon for
2 h. The reaction was cooled down to room temperature and directly purified using Gilson (10%
ACN(0.1% TFA)/H O - 90% ACN (0.1% TFA)/H O, 12 min) to afford the carbonylation
product, which was then dissolved in 2 mL of MeOH. To this was added 10 mg 10% Pd on
carbon. The reaction was allowed to stir at room temperature under a H2 balloon for 3 h. It was
filtered. The filtrate was concentrated in vacuo and the resulting residue was purified using silica
gel column chromatography eluting with 20% EtOAc/CH Cl to provide compound Int-33f as a
white solid. LCMS anal. calcd. for C H F N O : 446.17; Found: 447.12 (M+H) .
23 24 2 2 5
Step F– Synthesis of Compound 120
Compound 120 was prepared by following essentially the same method as compound 94
described in Example 36, and replacing compound Int-21g with compound Int-33f in Step H.
H NMR (400 MHz, CDCl ): δ 10.36 (s, 1 H); 8.47 (s, 1 H); 7.36-7.40 (m, 1 H); 6.81-6.87 (m, 2
H); 4.68 (d, J = 8.4 Hz, 2 H); 4.20 (m, 2 H); 4.13 (dd, J = 4.8, 9.2 Hz, 1 H); 3.99 (dd, , J = 4.8,
9.2 Hz, 1 H); 3.56 (m, 1 H); 2.45-2.48 (m, 1 H); 2.27 (m, 1 H); 1.85 (m, 1 H); 1.65 (m, 1 H);
1.54 (m, 1 H); 0,91 (t, J = 5.6, 3 H). LCMS anal. calcd. for C22H22F2N2O5: 432.15; Found:
433.07(M+1) .
Example 55
Preparation of Compound 121 and Compound 122
Br Br
N Step B N Step C
N Step A
BnO BnO
OMe OMOM OMe OMOM
OMe OH
OTBDPS OH OMe OMOM
OTBDPS
Int-34a
Int-8a Int-34b
Int-34c
Br OH
HO N
Br N Step G
Step F
N Step E
Step D
OMe OMOM
OMOM N
OMe OMOM
Int-34f
Int-34e
Int-34d
H Cbz
Br N
Br O Br Br N
Step I N
Step J
Step H
OMe OH
OMe OMe OMe OMOM
OMOM OMOM
Int-34j
Int-34i
Int-34g Int-34h
Cbz F O F O
Br N H
Step L
Step K
N N N
Step M
F O F O
OMe O
OMe OMe
Int-34k
Int-34l
Int-34m
(Enantiomer A)
(Enantiomer A)
(Enantiomer B)
(Enantiomer B)
Step N
121 (Enantiomer A)
122 (Enantiomer B)
OH O
Step A– Synthesis of Compound Int-34a
To a solution of compound Int-8a (4.85 g, 7.19 mmol) in CH Cl (71.9 ml) was added
Hunig's Base (6.28 ml, 35.9 mmol) followed by chloromethyl methyl ether (2.457 ml, 32.3
mmol) and DMAP (0.044 g, 0.359 mmol). The reaction was allowed to stir at room temperature
for 72 h. At the completion, the volatiles were removed under vacuo. The resulting residue was
purified using ISCO, normal phase HP Gold silica gel (120g), eluting with hexanes/EtOAc
(100% hexanes for 5 min; gradient to 30% EtOAc in hexanes over 30 min, isocratic for 5 min) to
afford compound Int-34a as a colorless oil. LCMS anal. calcd. for C39H48BrNO5Si: 717.25;
Found: 717.81 (M+1) .
Step B– Synthesis of Compound Int-34b
To a solution of compound Int-34a (4.35 g, 6.05 mmol) in THF (30.3 ml) was added
TBAF (1M in THF) (18.16 ml, 18.16 mmol). The reaction was allowed to stir at room
temperature for 2 h. At the completion, the volatiles were removed under vacuo. The resulting
residue was purified using ISCO, normal phase HP Gold silica gel (80g), eluting with
hexanes/EtOAc (100% hexanes for 5 min; gradient to 100% EtOAc in hexanes over 25 min,
isocratic for 10 min) to afford compound Int-34b as a colorless oil. LCMS anal. calcd. for
C H BrNO : 479.13; Found: 480.01 (M+1) .
23 30 5
Step C– Synthesis of Compound Int-34c
To a solution of compound Int-34b (3 g, 6.24 mmol) in THF (62.4 ml), was added
Hunig's Base (3.27 ml, 18.73 mmol). It was cooled to 0 °C, and methanesulfonyl chloride (0.888
ml, 11.24 mmol) was then added. The reaction was allowed to stir at 0 °C for 30 min. It was
diluted with 60 mL of hexanes and then filtered. The filtrate was concentrated in vacuo. The
resulting residue was mixed with sodium azide (4.06 g, 62.4 mmol) and then added DMF (62.4
ml). The resulting mixture was heated at 60 °C for 1 h. The reaction was allowed to cool to room
temperature. It was diluted with 500 mL of 50% EtOAc/hexanes and washed with 300 mL of
water. The organic layer was dried over anhydrous Na SO , filtered and concentrated in vacuo.
The resulting residue was purified using a silica gel column (120 g) eluting with EtOAc/hexanes
0-35% in 35 min to provide compound Int-34c. LCMS anal. calcd. for C H BrN O : 504.14;
23 29 4 4
Found: 505.08 (M+1) .
Step D– Synthesis of Compound Int-34d
To a solution of compound Int-34c (2.4 g, 4.75 mmol) in 47.3 mL of THF/t-BuOH/water
(5:5:1), was added 4-methylmorpholine n-oxide (0.612 g, 5.22 mmol) followed by 4% wt.
osmium tetroxide in water (8.93 ml, 0.712 mmol). The reaction was allowed to stir at room
temperature for 24 h. To this was added 30 g of solid Na S O . The mixture was allowed to stir
2 2 5
at room temperature for 1 h. The content was diluted with 300 mL of 50% EtOAc/hexanes. The
brown solid was filtered off. The filtrated was washed with water and concentrated. The
resulting residue was purified using a silica gel column (120 g) eluting with 0-100%
EtOAc/hexanes over 30 min, 100% for 5 min to provide compound Int-34d as a colorless oil.
LCMS anal. calcd. for C H BrN O : 538.14; Found: 539.09 (M+1) .
23 31 4 6
Step E– Synthesis of Compound Int-34e
To a mixture of compound Int-34d (2.2 g, 4.08 mmol) and 4-methylbenzenesulfonyl
chloride (1.555 g, 8.16 mmol), was added pyridine (20.39 ml). The reaction solution was
allowed to stir at room temperature for 7 h. To this was added 20 mL of MeOH. It was allowed
to stir at room temperature for 20 min. The volatile was removed in vacuo. The resulting residue
was diluted with 200 mL of CH Cl , and washed with 100 mL of 0.5 N HCl (aq.) twice. The
organic layer was dried over anhydrous Na SO and then concentrated. The resulting residue
was purified using ISCO, normal phase HP Gold silica gel (120g), eluting with hexanes/EtOAc
(100% hexanes for 5 min; gradient to 100% EtOAc in hexanes over 25 min, isocratic for 5 min)
to provide compound Int-34e. LCMS anal. calcd. for C H BrN O : 430.09; Found: 431.00
16 23 4 5
(M+1) .
Step F– Synthesis of Compound Int-34f
To a solution of compound Int-34e (1.55 g, 3.59 mmol) in CH Cl (71.9 ml) at room
temperature under N , was added Dess-Martin Periodinane (3.05 g, 7.19 mmol) portionwise. The
reaction was allowed to stir at room temperature for 1 h. To the reaction mixture was added 1 ml
of water and stirred for a while. Then reaction was diluted with 50 mL of EtOAc. The solid was
filtered off. The filtrate was concentrated in vacuo. The resulting residue was purified using
ISCO, normal phase HP Gold silica gel (120g), eluting with hexanes/EtOAc (100% hexanes for
min; gradient to 100% EtOAc over 15 min, isocratic for 10 min) to provide compound Int-34f.
LCMS anal. calcd. for C H BrN O : 428.07; Found: 429.00 (M+1) .
16 21 4 5
Step G– Synthesis of Compound Int-34g
To a solution of compound Int-34f (1.4 g, 3.26 mmol) and Et N (2.273 ml, 16.31 mmol)
in THF (26.1 ml) and Water (6.52 ml) was added Ph P (1.711 g, 6.52 mmol). The reaction was
allowed to stir at room temperature overnight. The volatile was removed under vacuo. The
resulting residue was purified using ISCO, reverse phase HP Gold C18 (100g), eluting with
acetonitrile (with 0.1% TFA)/water (0% water for 2 min; gradient to 100% ACN in water over
min, isocratic for 5 min). Related fractions were pooled and evaporated under reduced
pressure to afford compound Int-34g. LCMS anal. calcd. for C H BrN O : 402.08; Found:
16 23 2 5
402.98 (M+1) .
Step H– Synthesis of Compound Int-34h
To a mixture of compound Int-34g TFA salt form (1.641 g, 3.29 mmol) in CH2Cl2 (49.8
ml) and MeOH (9.96 ml) was added sodium cyanoborohydride (0.413 g, 6.57 mmol). The
mixture was allowed to stir at room temperature for 2 h. The mixture was quenched by adding
dropwise 1 mL of HOAc, and then concentrated in vacuo. The resulting residue was purified
using ISCO, reverse phase HP Gold C18 (275 g), eluting with acetonitrile (with 0.1%
TFA)/water (0% water for 4 min; gradient to 40% ACN in water over 30 min, isocratic for 5
min). Related fractions were pooled and evaporated under reduced pressure to provide
compound Int-34h as a colorless oil. LCMS anal. calcd. for C H BrN O : 386.08; Found:
16 23 2 4
387.00 (M+1) .
Step I– Synthesis of Compound Int-34i
To a mixture of compound Int-34h TFA salt form (600 mg, 1.197 mmol) in 12 mL of
CH Cl was added triethylamine (1001 µl, 7.18 mmol) followed by benzyl chloroformate (342
µl, 2.394 mmol) dropwise. The mixture was allowed to stir at room temperature for 2 h. The
mixture was diluted with water and extracted with ethyl acetate twice. The combined organic
fractions were washed with brine, dried (Na ₂SO ₄), filtered and the solvent was evaporated under
reduced pressure. The resulting residue was purified using ISCO, normal phase HP Gold silica
gel (40 g), eluting with hexanes /EtOAc (100% hexanes for 5 min; gradient to 100% EtOAc over
min, isocratic for 10 min) to provide compound Int-34i. LCMS anal. calcd. for
C H BrN O : 520.12; Found: 521.03 (M+1) .
24 29 2 6
Step J– Synthesis of Compound Int-34j
To a solution of compound Int-34i (527 mg, 1.011 mmol) in 10 mL of MeOH, was added
2 ml of 12 N aqueous HCl. The reaction was allowed to stir at 60 °C for 5 h. The volatile was
removed under vacuo. The resulting residue was dissolved in EtOAc and neutralized by adding
Et N dropwise. The resulting mixture was washed with water followed by brine. The organic
phase was dried over anhydrousNa ₂SO ₄, filtered and concentrated in vacuo. The resulting
residue was purified using ISCO, normal phase HP Gold silica gel (80 g), eluting with
Cl /MeOH (100% CH Cl for 5 min; gradient to 10% MeOH in CH Cl over 24 min,
CH2 2 2 2 2 2
isocratic for 5 min) to provide compound Int-34j. LCMS anal. calcd. for C H BrN O : 476.09;
22 25 2 5
Found: 477.05 (M+1) .
Step K– Synthesis of Compound Int-34k
To a solution of compound Int-34j (482 mg, 1.010 mmol) in 20 mL of CH Cl at room
temperature under N , was added Dess-MartinPeriodinane (557 mg, 1.313 mmol). The reaction
was allowed to stir at room temperature for 2 h. The reaction was diluted with EtOAc and
washed with saturated Na CO aqueous solution. The organic suspension was concentrated in
vacuo. To the resulting residue was added 10 mL of CH Cl . The solid was collected by filtration
to provide compound Int-34k. The filtrate was purified using by ISCO, normal phase HP Gold
silica gel (80 g) column and eluting with hexanes/EtOAc (100% hexanes for 5 min; gradient to
100% EtOAc over 35 min, isocratic for 6 min) to provide additional compound Int-34k as a
white solid. LCMS anal. calcd. for C H BrN O : 474.08; Found: 475.03 (M+1) .
22 23 2 5
Step L– Synthesis of Compound Int-34l
To a mixture of compound Int-34k (93.7 mg, 0.197 mmol), N-ethyl-N-isopropylpropan-
2-amine (105 µl, 0.591 mmol)), (2,4-difluorophenyl)methanamine (42.3 µl, 0.355 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (42.5 mg, 0.079 mmol) in 5 mL of DMSO was
added diacetoxypalladium (17.70 mg, 0.079 mmol). The mixture was flushed with CO balloon
for 30 min. Then the mixture was heated at 90 °C for 1 h under CO balloon. The reaction
mixture was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20
mm) eluting with acetonitrile/water/0.05% TFA (20% to 90% organic in 10 min, then to 100% in
2 min, 20 mL/min). Related fractions were pooled and evaporated under reduced pressure to
afford compound Int-34l as its racemic mixture. This material was resolved by a chiral
preparative SFC (ChiralPak AS, 30 X 250 mm, 70 mL/min, 100 bar, 50% MeOH (0.2% NH OH)
/ CO2, 35 °C) to provide enantiomer A of compound Int-34l (first to elute) and enantiomer B of
compound Int-34l (second to elute). LCMS anal. calcd. for C H F N O : 565.20; Found:
29 2 3 6
566.16 (M+1) .
Step M– Synthesis of Compound Int-34m
To a solution of enantiomer A of compound Int-34l (8.8 mg, 0.016 mmol) in MeOH (2
ml), was added 10% wt. Pd-C (2.484 mg, 2.334 µmol). The mixture was stirred under H balloon
for 1 h. At the completion, the catalyst was filtered off. The filtrate was concentrated in vacuo to
afford enantiomer A of compound Int-34m as a pale yellow solid. LCMS anal. calcd. for
C H F N O : 431.17; Found: 432.11 (M+1) .
22 23 2 3 4
Step N– Synthesis of Compound 121 and 122
A mixture of enantiomer A of compound Int-34m (7.5 mg, 0.017 mmol) and lithium
chloride (7.37 mg, 0.174 mmol) in DMF (435 µl) was heated at 100 °C for 2 h. At completion, it
was cooled down and diluted with 1 mL of DMSO. The crude was purified using preparative
HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile/water/0.1%
TFA (0% to 70% organic in 10 min, then to 100% in 2 min, 20 mL/min). Related fractions were
pooled and evaporated under reduced pressure to afford compund 121 as a pale yellow solid. H
NMR (500 MHz, CD OD): δ 10.3 (brs, 1 H); 8.50 (s, 1 H); 7.41-7.45 (m, 1 H); 6.93-6.99 (m, 2
H); 4.93-5.02 (m, 1 H); 4.51-4.67 (m, 3 H); 4.02-4.07 (m, 1 H); 3.36-3.45 (m, 1 H); 3.13-3.24
(m, 1 H); 2.60-2.75 (m, 1 H); 1.83-1.93 (m, 1 H); 1.52-1.68 (m, 2 H); 1.48 (s, 3 H). LCMS
anal. calcd. for C H F N O : 417.15; Found: 418.11 (M+1) .
21 21 2 3 4
Compound 122 was prepared from enantiomer B of compound Int-34l, using essentially
the same method described in Step M and Step N of example 55 for making compound 121. H
NMR (500 MHz, CD OD): δ 10.3 (brs, 1 H); 8.50 (s, 1 H); 7.41-7.45 (m, 1 H); 6.93-6.99 (m, 2
H); 4.93-5.02 (m, 1 H); 4.51-4.67 (m, 3 H); 4.02-4.07 (m, 1 H); 3.36-3.45 (m, 1 H); 3.13-3.24
(m, 1 H); 2.60-2.75 (m, 1 H); 1.83-1.93 (m, 1 H); 1.52-1.68 (m, 2 H); 1.48 (s, 3 H). LCMS
anal. calcd. for C H F N O : 417.15; Found: 418.11 (M+1) .
21 21 2 3 4
Example 56
Preparation of Compound 123 and Compound 124
Step A– Synthesis of Compound Int- 35a
To a mixture of compound Int-34h (724 mg, 1.870 mmol) in 15 mL of CH Cl and 3
mL of MeOH was added formaldehyde (696 µl, 9.35 mmol) followed by sodium
cyanoborohydride (235 mg, 3.74 mmol). The mixture was allowed to stir at room temperature
for 1 h. At the competion, acetic acid (642 µl, 11.22 mmol) was added to the mixture slowly to
quench the reaction. The mixture was concentrated in vacuo. The resulting residue was purified
using ISCO, reverse phase HP Gold C18 (150 g), eluting with acetonitrile (0.05% TFA)/water
(0.05% TFA) (0% water for 4 min; gradient to 60% ACN in water over 10 min, isocratic for 5
min). Related fractions were pooled and evaporated under reduced pressure to provide
compound Int-35a as a colorless oil. LCMS anal. calcd. for C H BrN O : 400.10; Found:
17 25 2 4
401.01 (M+1) .
Step B– Synthesis of Compound Int- 35b
To a solution of compound Int-35a TFA salt form (680 mg, 1.320 mmol) in MeOH (10
ml), was added HCl (concentrated) (2 ml, 24.35 mmol). The reaction was allowed to stir at 60
°C for 5 h. The volatile was removed under vacuo. The resulting residue was redissolved in
CH Cl and neutralized by adding Et N dropwise. The resulting residue was purified using
2 2 3
ISCO, reverse phase HP Gold C18 (150 g), eluting with acetonitrile (0.05% TFA)/water (0.05%
TFA) (0% water for 4 min; gradient to 50% ACN in water over 10 min, isocratic for 5 min).
Related fractions were pooled and evaporated under reduced pressure to provide compound Int-
35b as a colorless oil. LCMS anal. calcd. for C H F N O : 356.07; Found: 357.01 (M+1)+.
21 21 2 3 4
Step C– Synthesis of Compound Int- 35c
To a solution of compound Int-35b TFA salt form (520 mg, 1.103 mmol) in 22 mL of
CH Cl stirred at room temperature under N , was added Dess-Martin Periodinane (608 mg,
2 2 2
1.434 mmol). The reaction was allowed to stir at room temperature for 2 h. The mixture was
added 1 drop of water and stir for 5 min. The solid was filtered off. The filtrate was concentrated
in vacuo. The resulting residue was purified using ISCO, normal phase HP Gold silica gel (80 g),
eluting with CH Cl /MeOH (gradient from 5% to 10% MeOH in CH Cl over 25 min, isocratic
2 2 2 2
for 5 min) to provide compound Int-35c as a white solid. LCMS anal. calcd. for C H BrN O :
19 2 3
354.06; Found: 355.01 (M+1) .
Step D– Synthesis of Compound Int- 35d
To a mixture of compound Int-35c (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan
amine (30.1 µl, 0.169 mmol)), (2,4-difluorophenyl)methanamine (8.06 µl, 0.068 mmol) and
(oxybis(2,1-phenylene))bis(diphenylphosphine) (18.19 mg, 0.034 mmol) in DMSO (1408 µl)
was added diacetoxypalladium (7.58 mg, 0.034 mmol). The above reaction was flushed with CO
balloon through a long needle to the solution for 30 min. Then the mixture was heated at 90 °C
under a balloon of CO for 1 h. The reaction was diluted with 2 mL of DMSO and filtered
through a filter disc. The filtrate was purified using preparative HPLC (reverse phase, YMC-
Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05% TFA)/water (0.05% TFA) (0% to
70% organic in 10 min, then to 100% in 2 min, 20 mL/min). Related fractions were pooled and
evaporated under reduced pressure to afford compound Int-35d as its racemic mixture. This
material was resolved by a chiral preparative SFC (ChiralPak OJ, 20 X 250 mm, 50 mL/min, 100
bar, 40% MeOH (0.2% NH4OH) / CO2, 35 °C) to provide enantiomer A of compound Int-35d
(first to elute) and enantiomer B of compound Int-35d (second to elute). LCMS anal. calcd. for
C H F N O : 445.18; Found: 446.14 (M+1) .
21 21 2 3 4
Step D– Synthesis of Compound 123 and 124
A mixture of enantiomer A of compound Int-35d (3.9 mg, 8.76 µmol) and lithium
chloride (7.42 mg, 0.175 mmol) in DMF (292 µl) was heated at 100 °C for 2 h. At completion, it
was cooled down and diluted with 1 mL of DMSO. The crude was purified using preparative
HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05%
TFA)/water (0.05% TFA) (0% to 70% organic in 10 min, then to 100% in 2 min, 20 mL/min).
Related fractions were pooled and evaporated under reduced pressure to afford compound 123 as
a pale yellow solid. H NMR (500 MHz, CD OD): δ 8.63 (s, 1 H); 7.43 (m, 1 H); 6.92-6.99
(m, 2 H); 4.81-5.16 (m, 2 H); 4.57-4.69 (m, 2 H); 3.93-4.04 (m, 1 H); 3.47-3.57 (m, 1 H);
3.15-3.26 (m, 1 H); 3.07 (s, 3 H); 2.64-2.75 (m, 1 H); 1.80-1.92 (m, 1 H); 1.60-1.73 (m, 2 H);
1.52 (s, 3 H). LCMS anal. calcd. for C21H21F2N3O4: 431.17; Found: 432.12 (M+1) .
A mixture of enantiomer B of compound Int-35d and lithium chloride (7.42 mg, 0.175
mmol) in DMF (88 µl) was heated at 100 °C for 2 h. At completion, it was cooled down and
diluted with 1 mL of DMSO. The crude was purified using preparative HPLC (reverse phase,
YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05% TFA)/water (0.05% TFA)
(0% to 70% organic in 10 min, then to 100% in 2 min, 20 mL/min). Related fractions were
pooled and evaporated under reduced pressure to afford compound 124 as a pale yellow solid.
H NMR (500 MHz, CD OD): δ 8.63 (s, 1 H); 7.43 (m, 1 H); 6.92-6.99 (m, 2 H); 4.81-5.16
(m, 2 H); 4.57-4.69 (m, 2 H); 3.93-4.04 (m, 1 H); 3.47-3.57 (m, 1 H); 3.15-3.26 (m, 1 H); 3.07
(s, 3 H); 2.64-2.75 (m, 1 H); 1.80-1.92 (m, 1 H); 1.60-1.73 (m, 2 H); 1.52 (s, 3 H). LCMS anal.
calcd. for C21H21F2N3O4: 431.17; Found: 432.12 (M+1) .
Example 57
Assay for inhibition of HIV replication
This assay is a kinetic assay that employs a reporter cell line (MT4-gag-GFP) to
quantify the number of new cells infected in each round of replication.
MT4-GFP cells (250,000 cells/ml) were bulk-infected with HIV-1 (NL4-3 strain)
at low multiplicity of infection (MOI) in RPMI + 10% FBS for 24 hours. Cells were then washed
once in RPMI + 10% FBS and resuspended in RPMI + 0% or 10% or 100% normal human
serum (NHS). Test compounds were serial-diluted in DMSO on ECHO. The infected MT4-GFP
cells were added to a 384-well poly-D-lysine coated black plate with clear bottom in which the
diluted test compounds were placed. The cells were seeded at 8,000 cells per well and the final
DMSO concentration was 0.4%. The infected cells (Green GFP cells) were quantified at both 24
and 48 hours post incubation using Acumen eX3. Viral reproductive ratio (R ) was determined
using the number of infected cells at 48 hours divided by the number of infected cells at 24
hours. Percent viral growth inhibition was calculated by [1-(R-R )/(R -R )]*100.
tripledrug DMSO tripledrug
Compound potency IP or IC was determined by a 4-parameter dose response curve analysis.
Illustrative compounds of the present invention were tested using this assay
protocol and results are presented in the Table below.
WILD TYPE WILD TYPE
CELL ASSAY CELL ASSAY
Compound
Viking IP Viking IP
(0% NHS) (100% NHS)
(nM) (nM)
1 5.5 NA
2 27 NA
3 6.5 NA
4 74 1852
2.6 102
6 10 NA
7 2.2 154
8 1.8 500
9 2.6 235
66 NA
11 3.2 484
12 2.6 595
13 3.8 124
14 0.7 26
0.5 73
16 4.1 257
17 2.9 117
18 8.7 315
19 4.6 709
3.5 839
21 2.4 385
22 2.7 251
23 1.5 1260
24 4.3 >8400
4.2 >8400
26 1.1 2554
27 2.0 >8400
28 4.4 >8400
29 17 >8400
2.8 >8400
31 48 >8400
32 8.2 >8400
33 0.5 281
34 1.7 1500
0.4 337
36 0.6 1400
37 1.5 80
38 1.8 1600
39 0.8 33
40 1.5 442
41 2.0 34
42 2.1 517
43 3.2 1999
44 1.9 316
45 2.3 4748
46 1.3 459
47 1.3 70
48 1.7 913
49 3.2 4066
50 1.6 293
51 3.6 2200
52 3.4 >8400
53 64 >8400
54 1.8 55
55 8.1 >8400
56 3.4 342
57 4.7 3501
58 2.6 99
59 2.0 110
60 2.9 2228
61 1.3 32
62 0.9 481
63 0.9 249
64 0.9 2957
65 0.8 34
66 2.5 126
67 1.7 154
68 1.8 604
69 1.2 24
70 1.9 80
71 2.2 89
72 2.2 467
73 1.0 22
74 4.0 262
75 0.5 13
76 0.9 35
77 1.2 60
78 0.8 15
79 1.0 662
80 1.1 101
81 1.0 296
82 4.1 160
83 0.9 19
84 1.8 31
85 2.2 53
86 1.3 18
87 8.0 269
88 2.3 63
89 2.1 73
90 0.8 13
91 3.8 273
92 1.3 59
93 1.2 52
94 1.8 282
95 2.2 41
96 6.2 >8400
97 2.4 151
98 28 1114
99 3.7 616
100 1.9 60
101 2.1 105
102 0.5 365
103 0.8 46
104 3.6 343
105 3.5 2292
106 3.3 3336
107 5.7 4933
108 2.0 105
109 3.2 714
110 2.1 140
111 3.0 858
112 0.65 4114
113 1.3 >8000
114 1.9 137
115 1.4 225
116 2.3 256
117 2.5 1443
118 1.4 873
119 2.1 2059
120 0.8 116
121 2.6 62
122 3.3 35
123 NA NA
124 3.2 53
Treatment or Prevention of HIV Infection
The Substituted Quinolizine Derivatives are useful in the inhibition of HIV, the
inhibition of HIV integrase, the treatment of HIV infection and/or reduction of the likelihood or
severity of symptoms of HIV infection and the inhibition of HIV viral replication and/or HIV
viral production in a cell-based system. For example, the Substituted Quinolizine Derivatives
are useful in treating infection by HIV after suspected past exposure to HIV by such means as
blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to subject
blood during surgery or other medical procedures.
Described herein are methods for treating HIV infection in a subject, the methods
comprising administering to the subject an effective amount of at least one Substituted
Quinolizine Derivative or a pharmaceutically acceptable salt or prodrug thereof. In a specific
embodiment, the amount administered is effective to treat or prevent infection by HIV in the
subject. In another specific embodiment, the amount administered is effective to inhibit HIV
viral replication and/or viral production in the subject. In one embodiment, the HIV infection
has progressed to AIDS.
The Substituted Quinolizine Derivatives are also useful in the preparation and
execution of screening assays for antiviral compounds. For example the Substituted Quinolizine
Derivatives are useful for identifying resistant HIV cell lines harboring mutations, which are
excellent screening tools for more powerful antiviral compounds. Furthermore, the Substituted
Quinolizine Derivatives are useful in establishing or determining the binding site of other
antivirals to the HIV Integrase.
The compositions and combinations of the present invention can be useful for
treating a subject suffering from infection related to any HIV genotype.
Combination Therapy
In another embodiment, the present methods for treating or preventing HIV
infection can further comprise the administration of one or more additional therapeutic agents
which are not Substituted Quinolizine Derivatives.
In one embodiment, the additional therapeutic agent is an antiviral agent.
In another embodiment, the additional therapeutic agent is an immunomodulatory
agent, such as an immunosuppressive agent.
Described herein are methods for treating a viral infection in a subject, the
method comprising administering to the subject: (i) at least one Substituted Quinolizine
Derivative (which may include two or more different Substituted Quinolizine Derivatives), or a
pharmaceutically acceptable salt or prodrug thereof, and (ii) at least one additional therapeutic
agent that is other than a Substituted Quinolizine Derivative, wherein the amounts administered
are together effective to treat or prevent a viral infection.
When administering a combination therapy descibed herein to a subject,
therapeutic agents in the combination, or a pharmaceutical composition or compositions
comprising therapeutic agents, may be administered in any order such as, for example,
sequentially, concurrently, together, simultaneously and the like. The amounts of the various
actives in such combination therapy may be different amounts (different dosage amounts) or
same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a
Substituted Quinolizine Derivative and an additional therapeutic agent may be present in fixed
amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
In one embodiment, at least one Substituted Quinolizine Derivative is
administered during a time when the additional therapeutic agent(s) exert their prophylactic or
therapeutic effect, or vice versa.
In another embodiment, at least one Substituted Quinolizine Derivative and the
additional therapeutic agent(s) are administered in doses commonly employed when such agents
are used as monotherapy for treating a viral infection.
In another embodiment, at least one Substituted Quinolizine Derivative and the
additional therapeutic agent(s) are administered in doses lower than the doses commonly
employed when such agents are used as monotherapy for treating a viral infection.
In still another embodiment, at least one Substituted Quinolizine Derivative and
the additional therapeutic agent(s) act synergistically and are administered in doses lower than
the doses commonly employed when such agents are used as monotherapy for treating a viral
infection.
In one embodiment, at least one Substituted Quinolizine Derivative and the
additional therapeutic agent(s) are present in the same composition. In one embodiment, this
composition is suitable for oral administration. In another embodiment, this composition is
suitable for intravenous administration. In another embodiment, this composition is suitable for
subcutaneous administration. In still another embodiment, this composition is suitable for
parenteral administration.
Viral infections and virus-related disorders that can be treated or prevented using
the combination therapy methods described herein include, but are not limited to, those listed
above.
In one embodiment, the viral infection is HIV infection.
In another embodiment, the viral infection is AIDS.
The at least one Substituted Quinolizine Derivative and the additional therapeutic
agent(s) can act additively or synergistically. A synergistic combination may allow the use of
lower dosages of one or more agents and/or less frequent administration of one or more agents of
a combination therapy. A lower dosage or less frequent administration of one or more agents
may lower toxicity of therapy without reducing the efficacy of therapy.
In one embodiment, the administration of at least one Substituted Quinolizine
Derivative and the additional therapeutic agent(s) may inhibit the resistance of a viral infection
to these agents.
As noted above, the present invention is also directed to use of a compound of
Formula I with one or more anti-HIV agents. An "anti-HIV agent" is any agent which is directly
or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required
for HIV replication or infection, the treatment or prophylaxis of HIV infection, and/or the
treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an
anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV
infection or AIDS and/or diseases or conditions arising therefrom or associated therewith. For
example, the compounds of this invention may be effectively administered, whether at periods of
pre-exposure and/or post-exposure, in combination with effective amounts of one or more anti-
HIV agents selected from HIV antiviral agents, immunomodulators, antiinfectives, or vaccines
useful for treating HIV infection or AIDS. Suitable HIV antivirals for use in combination with
the compounds of the present invention include, for example, those listed in Table A as follows:
Table A
Name Type
abacavir, ABC, Ziagen® nRTI
abacavir +lamivudine, Epzicom® nRTI
abacavir + lamivudine + zidovudine, Trizivir® nRTI
amprenavir, Agenerase® PI
atazanavir, Reyataz® PI
AZT, zidovudine, azidothymidine, Retrovir® nRTI
darunavir, Prezista® PI
ddC, zalcitabine, dideoxycytidine, Hivid® nRTI
ddI, didanosine, dideoxyinosine, Videx® nRTI
ddI (enteric coated), Videx EC® nRTI
delavirdine, DLV, Rescriptor® nnRTI
dolutegravir, Tivicay® II
efavirenz, EFV, Sustiva®, Stocrin® nnRTI
efavirenz + emtricitabine + tenofovir DF, Atripla® nnRTI +
nRTI
emtricitabine, FTC, Emtriva® nRTI
emtricitabine + tenofovir DF, Truvada® nRTI
emvirine, Coactinon® nnRTI
enfuvirtide, Fuzeon® FI
enteric coated didanosine, Videx EC® nRTI
etravirine, TMC-125 nnRTI
fosamprenavir calcium, Lexiva® PI
indinavir, Crixivan® PI
lamivudine, 3TC, Epivir® nRTI
lamivudine + zidovudine, Combivir® nRTI
lopinavir PI
lopinavir + ritonavir, Kaletra® PI
maraviroc, Selzentry® EI
nelfinavir, Viracept® PI
nevirapine, NVP, Viramune® nnRTI
rilpivirine, TMC-278 nnRTI
ritonavir, Norvir® PI
saquinavir, Invirase®, Fortovase® PI
stavudine, d4T,didehydrodeoxythymidine, Zerit® nRTI
tenofovir DF (DF = disoproxil fumarate), TDF, nRTI
Viread®
tipranavir, Aptivus® PI
EI = entry inhibitor; FI = fusion inhibitor; PI = protease inhibitor; nRTI
= nucleoside reverse transcriptase inhibitor; II =integrase inhibitor;
nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the
drugs listed in the table are used in a salt form; e.g., abacavir sulfate,
indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.
In one embodiment, one or more anti-HIV drugs are selected from, lamivudine,
abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
In another embodiment, the compound of formula (I) is used in combination with
lamivudine.
In still another embodiment, the compound of formula (I) is used in combination
atazanavir.
In another embodiment, the compound of formula (I) is used in combination with
darunavir.
In another embodiment, the compound of formula (I) is used in combination with
rilpivirine.
In one embodiment, the compound of formula (I) is used in combination with
lamivudine and abacavir.
In another embodiment, the compound of formula (I) is used in combination with
darunavir.
In another embodiment, the compound of formula (I) is used in combination with
emtricitabine and tenofovir.
In still another embodiment, the compound of formula (I) is used in combination
atazanavir.
In another embodiment, the compound of formula (I) is used in combination with
ritonavir and lopinavir.
In another embodiment, the compound of formula (I) is used in combination with
lamivudine.
In one embodiment, the compound of formula (I) is used in combination with
abacavir and lamivudine.
In another embodiment, the compound of formula (I) is used in combination with
lopinavir and ritonavir.
In one embodiment, the present invention provides pharmaceutical compositions
comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug
thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti-HIV
agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the amounts present of components (i) and (iii) are
together effective for the treatment or prophylaxis of infection by HIV or for the treatment,
prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.
In another embodiment the present invention provides use of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for the inhibition of HIV integrase.
In another embodiment the present invention provides use of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for the treatment of infection by HIV or for the treatment, prophylaxis, or delay in the onset or
progression of AIDS.
Described herein is a method for the treatment or prophylaxis of infection by HIV
or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in
need thereof, which comprises administering to the subject (i) a compound of formula (I) or a
pharmaceutically acceptable salt or prodrug thereof and (ii) one or more additional anti-HIV
agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the amounts administered of components (i) and (ii)
are together effective for the treatment or prophylaxis of infection by HIV or for the treatment,
prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.
It is understood that the scope of combinations of the compounds of this invention
with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in
principle any combination with any pharmaceutical composition useful for the treatment or
prophylaxis of AIDS. The HIV antiviral agents and other agents will typically be employed in
these combinations in their conventional dosage ranges and regimens as reported in the art,
including, for example, the dosages described in the Physicians' Desk Reference, Thomson PDR,
th th th
Thomson PDR, 57 edition (2003), the 58 edition (2004), the 59 edition (2005), and the like.
The dosage ranges for a compound of the invention in these combinations are the same as those
set forth above.
The doses and dosage regimen of the other agents used in the combination
therapies described herein for the treatment or prevention of HIV infection can be determined by
the attending clinician, taking into consideration the approved doses and dosage regimen in the
package insert; the age, sex and general health of the subject; and the type and severity of the
viral infection or related disease or disorder. When administered in combination, the Substituted
Quinolizine Derivative(s) and the other agent(s) can be administered simultaneously (i.e., in the
same composition or in separate compositions one right after the other) or sequentially. This is
particularly useful when the components of the combination are given on different dosing
schedules, e.g., one component is administered once daily and another component is
administered every six hours, or when the pharmaceutical compositions are different, e.g., one is
a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore
advantageous.
Compositions and Administration
When administered to a subject, the Substituted Quinolizine Derivatives can be
administered as a component of a composition that comprises a pharmaceutically acceptable
carrier or vehicle. The present invention provides pharmaceutical compositions comprising an
effective amount of at least one Substituted Quinolizine Derivative and a pharmaceutically
acceptable carrier. In the pharmaceutical compositions of the present invention and methods
described herein, the active ingredients will typically be administered in admixture with suitable
carrier materials suitably selected with respect to the intended form of administration, i.e., oral
tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution,
oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with
conventional pharmaceutical practices. For example, for oral administration in the form of
tablets or capsules, the active drug component may be combined with any oral non-toxic
pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and
the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets
and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent
inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage
forms suitable for oral administration.
Moreover, when desired or needed, suitable binders, lubricants, disintegrating
agents and coloring agents may also be incorporated in the mixture. Suitable binders include
starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia,
sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants
there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium
acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum,
and the like. Sweetening and flavoring agents and preservatives may also be included where
appropriate.
Liquid form preparations include solutions, suspensions and emulsions and may
include water or water-propylene glycol solutions for parenteral injection.
Liquid form preparations may also include solutions for intranasal administration.
Also included are solid form preparations which are intended to be converted,
shortly before use, to liquid form preparations for either oral or parenteral administration. Such
liquid forms include solutions, suspensions and emulsions.
For preparing suppositories, a low melting wax such as a mixture of fatty acid
glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously
therein as by stirring. The molten homogeneous mixture is then poured into convenient sized
molds, allowed to cool and thereby solidify.
Additionally, the compositions of the present invention may be formulated in
sustained release form to provide the rate controlled release of any one or more of the
components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the
like. Suitable dosage forms for sustained release include layered tablets containing layers of
varying disintegration rates or controlled release polymeric matrices impregnated with the active
components and shaped in tablet form or capsules containing such impregnated or encapsulated
porous polymeric matrices.
In one embodiment, the one or more Substituted Quinolizine Derivatives are
administered orally.
In another embodiment, the one or more Substituted Quinolizine Derivatives are
administered intravenously.
In one embodiment, a pharmaceutical preparation comprising at least one
Substituted Quinolizine Derivative is in unit dosage form. In such form, the preparation is
subdivided into unit doses containing effective amounts of the active components.
Compositions can be prepared according to conventional mixing, granulating or
coating methods, respectively, and the present compositions can contain, in one embodiment,
from about 0.1% to about 99% of the Substituted Quinolizine Derivative(s) by weight or volume.
In various embodiments, the present compositions can contain, in one embodiment, from about
1% to about 70% or from about 5% to about 60% of the Substituted Quinolizine Derivative(s) by
weight or volume.
The compounds of Formula I can be administered orally in a dosage range of
0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in
divided doses. One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single
dose or in divided doses. Another dosage range is 0.1 to 100 mg/kg body weight per day orally
in single or divided doses. For oral administration, the compositions can be provided in the form
of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5,
10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient
for the symptomatic adjustment of the dosage to the subject to be treated. The specific dose
level and frequency of dosage for any particular subject may be varied and will depend upon a
variety of factors including the activity of the specific compound employed, the metabolic
stability and length of action of that compound, the age, body weight, general health, sex, diet,
mode and time of administration, rate of excretion, drug combination, the severity of the
particular condition, and the host undergoing therapy.
For convenience, the total daily dosage may be divided and administered in
portions during the day if desired. In one embodiment, the daily dosage is administered in one
portion. In another embodiment, the total daily dosage is administered in two divided doses over
a 24 hour period. In another embodiment, the total daily dosage is administered in three divided
doses over a 24 hour period. In still another embodiment, the total daily dosage is administered
in four divided doses over a 24 hour period.
The unit dosages of the Substituted Quinolizine Derivatives may be administered
at varying frequencies. In one embodiment, a unit dosage of a Substituted Quinolizine
Derivative can be administered once daily. In another embodiment, a unit dosage of a
Substituted Quinolizine Derivative can be administered twice weekly. In another embodiment, a
unit dosage of a Substituted Quinolizine Derivative can be administered once weekly. In still
another embodiment, a unit dosage of a Substituted Quinolizine Derivative can be administered
once biweekly. In another embodiment, a unit dosage of a Substituted Quinolizine Derivative
can be administered once monthly. In yet another embodiment, a unit dosage of a Substituted
Quinolizine Derivative can be administered once bimonthly. In another embodiment, a unit
dosage of a Substituted Quinolizine Derivative can be administered once every 3 months. In a
further embodiment, a unit dosage of a Substituted Quinolizine Derivative can be administered
once every 6 months. In another embodiment, a unit dosage of a Substituted Quinolizine
Derivative can be administered once yearly.
The amount and frequency of administration of the Substituted Quinolizine
Derivatives will be regulated according to the judgment of the attending clinician considering
such factors as age, condition and size of the subject as well as severity of the symptoms being
treated. The compositions of the invention can further comprise one or more additional
therapeutic agents, selected from those listed above herein.
Kits
Also described herein is a kit comprising a therapeutically effective amount of at
least one Substituted Quinolizine Derivative, or a pharmaceutically acceptable salt or prodrug of
said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Also described herein is a kit comprising an amount of at least one Substituted
Quinolizine Derivative, or a pharmaceutically acceptable salt or prodrug of said compound and
an amount of at least one additional therapeutic agent listed above, wherein the amounts of the
two or more active ingredients result in a desired therapeutic effect. In one embodiment, the one
or more Substituted Quinolizine Derivatives and the one or more additional therapeutic agents
are provided in the same container. In one embodiment, the one or more Substituted
Quinolizine Derivatives and the one or more additional therapeutic agents are provided in
separate containers.
The present invention is not to be limited by the specific embodiments disclosed
in the examples that are intended as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope of this invention. Indeed,
various modifications of the invention in addition to those shown and described herein will
become apparent to those skilled in the art and are intended to fall within the scope of the
appended claims.
A number of references have been cited herein, the entire disclosures of which are
incorporated herein by reference.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
Claims (37)
1. A compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X is -NHC(O)-; 10 Y is CH ; R is selected from C -C aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 6 10 10-membered bicyclic heteroaryl, wherein said C -C aryl group, said 5 or 6-membered 6 10 monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally substituted with up to three R groups; 2 11 7 2 4 15 R is H, C -C alkyl, -N(R ) , or -OR or R and R , together with the carbon 1 6 2 atoms to which they are attached, can join to form a 5 to 8-membered monocyclic cycloalkyl group, 5 to 8-membered monocyclic heterocycloalkyl group, 5 to 8-membered monocyclic heterocycloalkenyl group or a 8 to 11-membered bicyclic heterocycloalkyl, wherein said 5 to 8- membered monocyclic cycloalkyl group, said 5 to 8-membered monocyclic heterocycloalkyl 20 group, said 5 to 8-membered monocyclic heterocycloalkenyl group and said 8 to 11-membered bicyclic heterocycloalkyl group can be optionally substituted with up to three R groups, which can be the same or different; 3 11 7 R is H, C -C alkyl, -N(R ) or -OR ; 1 6 2 4 11 R is selected from H, C -C alkyl, -(C -C alkylene)-O-(C -C alkyl), -N(R ) 1 6 1 6 1 6 2 7 2 3 11 4 25 and -OR , such that when R and/or R are -N(R )2, then R is other than H; R is C -C alkyl; each occurrence of R is independently H or C1-C6 alkyl; each occurrence of R is independently selected from H, C -C alkyl, –(C -C 1 6 1 6 alkylene)-O-(C -C alkyl) and C -C cycloalkyl; 1 6 3 7 each occurrence of R is independently selected from C -C alkyl, halo, -OR , - 6 6 7 SR , C -C haloalkyl, C -C hydroxyalkyl, -O-(C -C haloalkyl), -CN, -NO , -N(R ) , -C(O)OR , 1 6 1 6 1 6 2 2 -C(O)N(R ) and -NHC(O)R ; R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR - 1 6 1 6 1 6 1 6 5 C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl; 1 6 1 6 1 6 10 6 R is selected from H, C -C alkyl, -C -C alkyl-O-C -C alkyl,-C -C alkyl-NR - 1 6 1 6 1 6 1 6 C -C alkyl, -C -C haloalkyl, -C -C hydroxyalkyl; 1 6 1 6 1 6 11 12 each occurrence of R is independently selected from H, C -C alkyl, -S(O) R 1 6 2 and –C(O)R ; and 10 each occurrence of R is independently selected from C -C alkyl, C -C 1 6 3 7 cycloalkyl, C -C aryl, 4 to 7-membered monocyclic heterocycloalkyl, 8 to 11-membered 6 10 bicyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C -C cycloalkyl group, said C -C aryl group, 4 to 7- 3 7 6 10 membered monocyclic heterocycloalkyl, said 8 to 11-membered bicyclic heterocycloalkyl group, 15 said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally substituted with up to three R groups.
2. The compound of claim 1, wherein R is optionally substituted C -C aryl or 6 10 optionally substituted 9 or 10-membered bicyclic heteroaryl.
3. The compound of claim 2, wherein R is phenyl, which is substituted by 1 to 3 halo groups, which can be the same or different.
4. The compound of claim 2, wherein R is 2,4-difluorophenyl or 3-chloro 25 fluorophenyl.
5. The compound of any one of claims 1-4, wherein R and R are each independently selected from H, –OH and –O-(C -C alkyl). 30
6. The compound of any one of claims 1-5, wherein one of R is H and R is –OH or –O-(C1-C6 alkyl).
7. The compound of any one of claims 1-6, wherein R is selected from C1-C6 alkyl and –(C -C alkylene)-O-(C -C alkyl). 1 6 1 6
8. The compound of claim 7, wherein R is selected from methyl and – CH CH OCH . 2 2 3 5
9. The compound of any one of claims 1-4, wherein R and R , together with the carbon atoms to which they are attached, join to form a 5 to 8-membered monocyclic heterocycloalkyl group.
10. The compound of any one of claims 1-9, wherein R is methyl. 3 5 2 4
11. The compound of claim 2 wherein R is H; R is methyl; and R and R , together with the carbon atoms to which they are attached, join to form a group selected from: 15
12. The compound of any one of claims 1-4 and 9-11, wherein R and R , together with the carbon atoms to which they are attached, join to form:
13. A compound selected from OH O OH O 5 , , OH O OH O OH O 10 , , OH O OH O OH O , , , 5 , , MeOMe OH O 5 , , 5 , , OH O 5 , , OH O or a pharmaceutically acceptable salt thereof.
14. A compound of the formula or a pharmaceutically acceptable salt thereof. 5
15. A compound of the formula or a pharmaceutically acceptable salt thereof.
16. A compound of the formula or a pharmaceutically acceptable salt thereof.
17. A compound of the formula 15 or a pharmaceutically acceptable salt thereof.
18. The compound of the formula or a pharmaceutically acceptable salt thereof.
19. A compound of the formula or a pharmaceutically acceptable salt thereof. 5
20. A compound of the formula or a pharmaceutically acceptable salt thereof.
21. A compound of the formula or a pharmaceutically acceptable salt thereof.
22. A compound of the formula or a pharmaceutically acceptable salt thereof.
23. A compound of the formula 20 or a pharmaceutically acceptable salt thereof.
24. A compound of the formula or a pharmaceutically acceptable salt thereof. 5
25. A compound of the formula or a pharmaceutically acceptable salt thereof.
26. A compound of the formula or a pharmaceutically acceptable salt thereof.
27. A compound of the formula 15 or a pharmaceutically acceptable salt thereof.
28. A compound of the formula or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5
30. The pharmaceutical composition of claim 29, further comprising one or more additional therapeutic agents selected from, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
31. Use of the compound according to any one of claims 1 to 28, or a 10 pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of HIV integrase.
32. Use of the compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment 15 of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS.
33. The use of claim 32, wherein the medicament further comprises one or more additional therapeutic agents selected from, abacavir, lamivudine, ritonavir and lopinavir.
34. The use of claim 33, wherein the medicament is formulated for administration in combination with one or more additional therapeutic agents selected from, abacavir, lamivudine, ritonavir and lopinavir. 25
35. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, substantially as herein described with reference to any example thereof.
36. A pharmaceutical composition according to claim 29 or 30 substantially as herein described with reference to any example thereof.
37. Use according to any one of claims 31 to 34 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361883463P | 2013-09-27 | 2013-09-27 | |
US61/883,463 | 2013-09-27 | ||
PCT/US2014/057572 WO2015048363A1 (en) | 2013-09-27 | 2014-09-26 | Substituted quinolizine derivatives useful as hiv integrase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ717864A NZ717864A (en) | 2021-09-24 |
NZ717864B2 true NZ717864B2 (en) | 2022-01-06 |
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