OA19047A - Novel phosphinane and azaphosphinane derivatives, method for preparing same and pharmaceutical compositions containing same. - Google Patents
Novel phosphinane and azaphosphinane derivatives, method for preparing same and pharmaceutical compositions containing same. Download PDFInfo
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- OA19047A OA19047A OA1201800262 OA19047A OA 19047 A OA19047 A OA 19047A OA 1201800262 OA1201800262 OA 1201800262 OA 19047 A OA19047 A OA 19047A
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- OA
- OAPI
- Prior art keywords
- mhz
- ppm
- oxo
- nmr
- azaphosphinane
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
- 150000008285 azaphosphinanes Chemical class 0.000 title description 3
- VXTFGYMINLXJPW-UHFFFAOYSA-N phosphinane Chemical compound C1CCPCC1 VXTFGYMINLXJPW-UHFFFAOYSA-N 0.000 title 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 134
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000007792 addition Methods 0.000 claims abstract description 35
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 230000003287 optical Effects 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 242
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 113
- -1 4-hydroxy-2-phenylphenyl Chemical group 0.000 claims description 92
- 239000000203 mixture Substances 0.000 claims description 77
- 239000002253 acid Substances 0.000 claims description 75
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 10
- 230000003480 fibrinolytic Effects 0.000 claims description 9
- 240000006225 Blighia sapida Species 0.000 claims description 7
- 206010012289 Dementia Diseases 0.000 claims description 7
- 108090000373 Tissue plasminogen activator Proteins 0.000 claims description 7
- 102000003978 Tissue plasminogen activator Human genes 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 239000003146 anticoagulant agent Substances 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 239000003527 fibrinolytic agent Substances 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 5
- 108010039185 Tenecteplase Proteins 0.000 claims description 5
- 229960000216 Tenecteplase Drugs 0.000 claims description 5
- 229960003318 alteplase Drugs 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 208000010125 Myocardial Infarction Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 206010002383 Angina pectoris Diseases 0.000 claims description 3
- 208000007474 Aortic Aneurysm Diseases 0.000 claims description 3
- 206010003230 Arteritis Diseases 0.000 claims description 3
- 210000003141 Lower Extremity Anatomy 0.000 claims description 3
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 3
- 230000002429 anti-coagulation Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 206010047249 Venous thrombosis Diseases 0.000 claims description 2
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 230000003000 nontoxic Effects 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 230000000702 anti-platelet Effects 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 864
- 238000000034 method Methods 0.000 description 423
- 238000004885 tandem mass spectrometry Methods 0.000 description 237
- 238000000921 elemental analysis Methods 0.000 description 208
- 239000000243 solution Substances 0.000 description 128
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 122
- 229910052799 carbon Inorganic materials 0.000 description 106
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 90
- 238000005160 1H NMR spectroscopy Methods 0.000 description 75
- 239000011541 reaction mixture Substances 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 47
- 229910052786 argon Inorganic materials 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 101700067048 CDC13 Proteins 0.000 description 37
- 229910001868 water Inorganic materials 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- 238000004679 31P NMR spectroscopy Methods 0.000 description 29
- 230000002829 reduced Effects 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000004293 19F NMR spectroscopy Methods 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 150000007942 carboxylates Chemical class 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- VNFALQTYXAPCKJ-UHFFFAOYSA-N N1PC(CCC1)C(=O)O Chemical compound N1PC(CCC1)C(=O)O VNFALQTYXAPCKJ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- CXNIUSPIQKWYAI-UHFFFAOYSA-N Xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- VNFALQTYXAPCKJ-UHFFFAOYSA-M N1PC(CCC1)C(=O)[O-] Chemical compound N1PC(CCC1)C(=O)[O-] VNFALQTYXAPCKJ-UHFFFAOYSA-M 0.000 description 9
- 229940095076 benzaldehyde Drugs 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 7
- 101700046984 CDK20 Proteins 0.000 description 7
- 102100005992 CPB2 Human genes 0.000 description 7
- 230000035492 administration Effects 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000002194 synthesizing Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- LCRCBXLHWTVPEQ-UHFFFAOYSA-N 2-phenylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CC=C1 LCRCBXLHWTVPEQ-UHFFFAOYSA-N 0.000 description 5
- OZAIFHULBGXAKX-VAWYXSNFSA-N Azobisisobutyronitrile Chemical compound N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 5
- YCRYJWJNPWZJSR-UHFFFAOYSA-O butylideneazanium Chemical group [CH2-]CCC=[NH2+] YCRYJWJNPWZJSR-UHFFFAOYSA-O 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-Hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- 101700012665 CPB2 Proteins 0.000 description 4
- 108010088842 Fibrinolysin Proteins 0.000 description 4
- 206010062060 Hyperlipidaemia Diseases 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- YDTIJCIYCSFHBF-UHFFFAOYSA-N O=C1NCCPC1C(=O)O Chemical compound O=C1NCCPC1C(=O)O YDTIJCIYCSFHBF-UHFFFAOYSA-N 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- DTUQWGWMVIHBKE-UHFFFAOYSA-N Phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 4
- 210000002381 Plasma Anatomy 0.000 description 4
- 229940012957 Plasmin Drugs 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 201000001084 cerebrovascular disease Diseases 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 201000005577 familial hyperlipidemia Diseases 0.000 description 4
- 230000020764 fibrinolysis Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 150000004878 phosphinanes Chemical class 0.000 description 4
- 230000000896 plasminic Effects 0.000 description 4
- HEMHJVSKTPXQMS-DYCDLGHISA-M sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 4
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 3
- 206010001897 Alzheimer's disease Diseases 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 3
- 108010057987 Desmodus rotundus salivary plasminogen activator alpha 1 Proteins 0.000 description 3
- 229950001282 Desmoteplase Drugs 0.000 description 3
- 229950003499 FIBRIN Drugs 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- GQZXNSPRSGFJLY-UHFFFAOYSA-N Hypophosphorous acid Chemical compound OP=O GQZXNSPRSGFJLY-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 3
- 229960002917 Reteplase Drugs 0.000 description 3
- SMQUZDBALVYZAC-UHFFFAOYSA-N Salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 3
- 229960005202 Streptokinase Drugs 0.000 description 3
- 108010023197 Streptokinase Proteins 0.000 description 3
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 3
- 229940100445 WHEAT STARCH Drugs 0.000 description 3
- 229960005080 Warfarin Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- 201000001320 atherosclerosis Diseases 0.000 description 3
- FAKKOTXPHDKJRH-UHFFFAOYSA-N azaphosphinane Chemical compound C1CCPNC1 FAKKOTXPHDKJRH-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108010051412 reteplase Proteins 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001732 thrombotic Effects 0.000 description 3
- 201000004810 vascular dementia Diseases 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 2
- SEXZHJJUKFXNDY-UHFFFAOYSA-N 1-(bromomethyl)-2-phenylbenzene Chemical compound BrCC1=CC=CC=C1C1=CC=CC=C1 SEXZHJJUKFXNDY-UHFFFAOYSA-N 0.000 description 2
- RTFPTPXBTIUISM-UHFFFAOYSA-N 1-(bromomethyl)-3-phenylbenzene Chemical compound BrCC1=CC=CC(C=2C=CC=CC=2)=C1 RTFPTPXBTIUISM-UHFFFAOYSA-N 0.000 description 2
- HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical compound C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 description 2
- LLLBDLDNTMMZHL-UHFFFAOYSA-N 1-benzofuran-5-carbaldehyde Chemical compound O=CC1=CC=C2OC=CC2=C1 LLLBDLDNTMMZHL-UHFFFAOYSA-N 0.000 description 2
- ZDVRPKUWYQVVDX-UHFFFAOYSA-N 2-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC=C1C=O ZDVRPKUWYQVVDX-UHFFFAOYSA-N 0.000 description 2
- MWYVQGTVFMAUOH-UHFFFAOYSA-N 2-thiophen-2-ylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CS1 MWYVQGTVFMAUOH-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000002537 thrombolytic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- YHUJJSRZURTOQK-UHFFFAOYSA-M trimethylsilicon;bromide Chemical compound [Br-].C[Si](C)C YHUJJSRZURTOQK-UHFFFAOYSA-M 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
Compounds of formula (I) wherein : Ak1 represents an alkyl chain, X represents -(CH2)m-, CH(R)-, -N(R)-,-CH2-N(R)-, –N(R)-CH2- or -CH2N(R)-CH2-, m and R are as defined in the description, R1 and R2 each represent H when X represents -(CH2)m-, -CH(R)-, -N(R)-, -CH2-N(R)or –N(R)-CH2-, or indeed together form a bond when X represents -CH2-N(R)-CH2-, R3 represents NH2, Cy-NH2, Cy-Ak3-NH2 or piperidin-4-yle, Cy and Ak3 are as defined in the description, R4 and R5, identical or different, each represent H or F, their optical isomers of same, and addition salts thereof with a pharmaceutically acceptable acide. Medicaments
Description
NEW COMPOUNDS OF PHOSPHINANES AND AZ A PHOSPHINANES,
A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The présent invention relates to new compounds of phosphinanes and azaphosphinanes, to a 5 process for their préparation, and to pharmaceutical compositions containing them.
The compounds of the invention are TAFIa (activated thrombin-activatable fibrinolysis inhibitor) inhibitors.
TAFI (also called plasma procarboxypeptidase B, procarboxypeptidase R or procarboxypeptidase U) is a plasma glycoprotein of 60 kDa produced by the lîver, which 10 circulâtes in the form of a zymogen. During blood coagulation and fibrinolysis, thrombin and plasmin cleave the pro-segment of TAFI in the région of the Arg92-Ala93 bond and couvert it into an active enzyme, TAFIa, the half-life of which is from 8 to 15 minutes at 37°C. Cleavage of the pro-segment by thrombin is accelerated by thrombomodulin, a cofactor which îs présent in plasma and at the surface of vascular endothélial cells (Bouma BN and Meijers 15 JC, Thrombin-activatable fibrinolysis inhibitor, 2003, Journal of Thrombosis and
Haemostasis, 1 : 1566-1574). TAFIa régulâtes fibrinolysis negatively by cleaving the Cterminal lysine residues of the fibrin fibres which appear during the partial dégradation of fibrin by the first traces of plasmin. These C-terminal lysine residues on the partially degraded fibrin behave like ligands of the circulating plasma plasminogen and of the tissue 20 plasminogen activator (tPA) generated by the endothélial cells during thrombotic ischaemia.
They thus permit localisation of the conversion of plasminogen to plasmin by the tPA without interférence either with the circulating plasmin inhibitor a2-antiplasmin or with the circulating tissue plasminogen activator inhibitor (PAI-1). Cleavage of the C-terminal lysine sites by TAFIa therefore reduces the rate at which plasmin is generated. Endogenous 25 fibrinolysis is then inhibited and lysis of arterial and venons fibrinous thromboses as well as therapeutic thrombolysis undertaken in patients in the acute post-thrombotic ischaemic phase are likewise diminished. TAFIa inhibitors therefore hâve the potential to increase endogenous and therapeutic fibrinolysis and to behave like antithrombotic and profibrinolytic agents without the risk of major haemorrhage, since they do not interfère either with platelet 30 activation or with coagulation during blood haemostasis.
-2- ,
-s The property of inhibiting TAFIa therefore makes it possible to envisage using the compounds of the invention in the treatment and prévention of thrombotic events in at-nsk patients.
Their use will be valuable in the treatment, prévention and secondary prévention of vascular complications, more especially cardiovascular, pulmonary and cerebrovascular complications associated with atherottaombotic diseases, with atherosclerosis, with diabètes, wit hyperlipidaemia, with hypertension, with chronic venons diseases, with obesity-related metabolic syndrome or with cancer.
The compounds according to the invention are especially useful for the treatment, prévention 10 and secondary prévention of myocardial infarction, angina pectoris, cerebrovascular accidents, aortic aneurysms, arteritis of the lower limbs, fibrotic diseases, venons thromboses and pulmonary embolism.
Vascular risk factors and vascular diseases such as hypertension, obesity, diabètes, cardiac diseases cerebrovascular diseases and hyperlipidaemia, and therefore atherosclerosts, play a 15 rôle in the genesis of dementias such as Alzheimer's disease and vascular detnentia (Qtu C. De Ronchi D. and Fratiglioni L., The epidemiology of the dementias : an update, 2007, Current Opinion in Psychiatry, 20 : 380-385). The compounds of the invention will therefore also be of use for the treatment and/or prévention of dementias such as Alzheimer's dtsease and vascular dementia.
20 TAFIa lowers endogenous fibrinolytic potential. As TAFIa mhibitors, the compounds of the présent invention are therefore of use to accompany acute treatment by tnjectable fibrinolytics, such as recombinant tPA (for example alteplase, tenecteplase, reteplase, desmoteplase), recombinant nPA or streptokinase, which are used in emergenctes (for example myocardial infarction, cerebrovascular accident).
25 The compounds of the présent invention reinforce the activity of these injectable Ebrinolytics and therefore lead to the use thereof with fewer hacmotrhagic and neurotoxte nsks (réduction of the dose thereof and therefore réduction of the side-effects thereof).
-3The présent invention relates more especially to compounds of formula (I):
wherein:
Aki represents a Ci-Câ-alkyl chain, .
X represents -(CH2)m-, -CH(R)-, -N(R)-, -CH2-N(R)-, -N(R)-CH2- or -CH2-N(R)-CH2-, m represents 0 or an integer from 1 to 4,
R represents a hydrogen atom or a group selected from Ci-Cô-alkyl, -Ak2-Ari, -Ak2Ari-Ar2 and -Ak2-Ari-O-Ar2, -Ak2-cycloalkyl or -Ak2-OH,
Ak2 represents a linear or branched Ci-Ce-alkyl chain,
Ari and Ar2, which may be identical or different, each represent an aryl or heteroaryl group,
Ri and R2 each represent a hydrogen atom when X represents -(CH2)m-, -CH(R)-, -N(R), -CH2-N(R)- or-N(R)-CH2-, or together form a bond when X represents -CH2-N(R)-CH2-,
R3 represents NH2, Cy-NH2, Cy-Ak3-NH2 or piperidin-4-yl,
Cy represents a group selected from cycloalkyl, aryl and heteroaryl,
Àk3 represents a Ci-C3-alkyl chain,
R4 and R5, which may be identical or different, each represent a hydrogen atom or a fluorine atom, their optical isomers and addition salts thereof with a pharmaceuticaîly acceptable acid.
Aryl group is understood as meaning phenyl, naphthyl or biphenyl optionally substituted by one or more identical or different groups selected from halogen, hydroxy, amino, linear or branched (Ci-Cû)-alkyl optionally substituted by one or more halogen atoms, methylsulphonyl, methylthio, carboxy, linear or branched (Ci-Q)-alkoxy optionally substituted by one or more halogen atoms,
-4linear or branched (Ci-Côj-aminoalkyl, the amino group of the aminoalkyl group being optionally substituted by one or two linear or branched (Ci-Ce)-alkyl groups.
Heteroaryl group is understood as meaning a monocyclic aromatic group or a bicyclic aromatic or partially aromatic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may be optionally substituted by one or more identical or different groups selected from halogen, hydroxy, amino, oxo, linear or branched (Ci-CôJ-alkyl optionally substituted by one or more halogen atoms, linear or branched (Ci-Cô)-alkoxy optionally substituted by one or more halogen atoms, linear or branched (Ci-Cgj-aminoalkyl, the amino group of the aminoalkyl group being optionally substituted by one or two linear or branched (Ci-Ce)-alkyl groups.
Among the heteroaryl groups there may be mentioned, without implying any limitation, the groups pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, benzimidazolyl, îmidazopyridinyl, isoquinolinyl, dihydrobenzofuryl, dihydrobenzoxazolyl, dihydroindolyl, dihydroindazolyl, benzodioxolyl.
Cycloalkyl group is understood as meaning a monocyclic, saturated hydrocarbon group having from 5 to 7 ring members, it being understood that the ring may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-Cû)-alkyl. Among the cycloalkyl groups there may be mentioned, without implying any limitation, the groups cyclopentyl, cyclohexyl, cycloheptyl.
Opticai isomers are understood as being the diastereoisomers and the enantiomers.
The compounds of formula (I) hâve at least one asymmetric centre:
When the configuration of a compound of formula (I) having a single asymmetric centre is
-5- .
not specified, the compound is obtained in the form of a mixture of the two enantiomers.
When the configuration of a compound of formula (I) having two asymmetric centres is not specified, the compound is obtained in the form of a mixture of diastereoisomers.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, benzenesulphonic, p-toluenesulphonic, camphoric acid.
One aspect of the present invention relates to the compounds of formula (I) wherein Aki represents -(CH2)4-.
Another aspect of the present invention relates to the compounds of formula (I) wherein X represents -N(R)-.
Another aspect of the present invention relates to the compounds of formula (I) wherein X represents -N(R)-, -CH2-N(R)-, -N(R)-CH2- or -CH2-N(R)-CH2-, and R represents a group selected from -Ak2-Ari, -Ak2-Ari-Ar2 and -Ak2-An-O-Ai’2.
Another aspect of the present invention relates to the compounds of formula (I) wherein X represents -N(R)-, -CH2-N(R)-, -N(R)-CH2- or -CH2-N(R)-CH2-, R represents a group selected from -Ak2-Ari, -Ak2-Ari-Ar2 and —Ak2-Ari-O-Ar2, and Ak2 represents -CH2-.
Another aspect of the present invention relates to the compounds of formula (I) wherein Ri and R2 each represent a hydrogen atom.
Another aspect of the present invention relates to the compounds of formula (I) wherein R3 represents NH2.
Another aspect of the present invention relates to the compounds of formula (I) wherein R4 and R5 each represent a hydrogen atom,
Another aspect of the present invention relates to the compounds of formula (I) wherein Ri, R2, R4 and R5 each represent a hydrogen atom, R3 represents NH2, X represents -N(R)-, -CH219047
-6N(R)-, -N(R)-CH2- or -CH2-N(R)-CH2-, and R represents a group selected from -AkaAri, -Ak2-Ari-Ai2 and -Aka-An-O-Ar?.
Another aspect of the present invention relates to the compounds of formula (la), a particular case of the compounds of formula (I):
wherein Ra represents a group selected from -CHa-An and -CH2-Ari-Ar2, wherein An and Ara are as defined for formula (I).
The present invention relates also to a process for the préparation of the compounds of formula (I) starting from the compound of formula (Π):
Ri r2 (Π) wherein X, Ri, R2, R4 and R5 are as defined for formula (I), Y represents a linear or branched Ci-C4-alkoxy group or a dialkylamino group in which the alkyl groups are C1-C4, linear or branched, which is reacted with CO(OG)2, wherein G represents a protecting group of the acid function, such as alkyl or benzyl, preferably tert-butyl or benzyl, in the presence of a base, to yield the compound of formula (III):
-7’ wherein X, Y, Ri, R2 and G are as defined hereinbefore, which is reacted, in the presence of a base, with the compound Br-Aki-R’3, wherein Aki is as defined for formula (I), and R’3 represents N(Boc)2, Cy-N(Boc)2, Cy-Ak3-N(Boc)2 or N-Bocpiperidin-4-yl, to yield the compound of formula (IV):
wherein X, Y, Ri, R2, G, Aki and R’3 are as defined hereinbefore, the amino, carboxy and phosphinic functions of which are deprotected to yield the compound of formula (I) or an addition sait thereof with a pharmaceutically acceptable acid.
The compound of formula (TV) has at least two asymmetric centres:
The diastereoisomers of the compound of formula (IV) can be separated by means of a chiral column, allowing the optically pure compounds of formula (I) to be obtained by the process described above.
The nomenclature (3a/?*, 45*, 6a5*) used for the octahydrophospholo[3,4-c]pyrrole compounds indicates a relative configuration. It means that the compound is in the form of a mixture of the compounds of absolute configurations (3aÆ, 45, 6a5) and (3a5, 4R, 6aÆ).
The présent invention relates also to a process for the préparation of the compounds of formula (la), a particular case of the compounds of formula (I),
-8starting from the compound of formula (IVa), a particular case of the compounds of formula (IV):
wherein Y and G are as defined for formula (Π), and Ga represents a protecting group of the amino function, such as Boc, which is debenzylated to yield the compound of formula (V):
N(Ga)2 wherein Y, G and Ga are as defined hereinbefore, which is subjected to a reductîve amination reaction with the aldéhyde of formula Re-CHO, wherein Re represents -An or -An-An, wherein An and An are as defined for formula (I), to yield the compound of formula (VI):
wherein Y, G, Ga and Ra are as defined hereinbefore, the amino, carboxy and phosphinic functions of which are deprotected to yield the compound
-9of formula (la) or an addition sait thereof with a pharmaceutically acceptable acid.
The compound of formula (IVa) has two asymmetric centres:
The diastereoisomers of the compound of formula (IVa) can easily be separated by means of a chiral column, allowing the optically pure compounds of formula (la) to be obtained by the process described above.
The compounds of the invention are TAFIa inhibitors.
As such, they can be used in the prévention or treatment of thrombotic events in at-risk patients. Their use will be valuable in the treatment and prévention of vascular complications, more especially cardiovascular, pulmonary and cerebrovascular complications, associated with atherothrombotic diseases, with atherosclerosis, with diabètes, with hyperlipidaemia, with hypertension, with chronic venous diseases, with obesity-related metabolic syndrome or with cancer.
The compounds according to the invention are especially useful for the treatment, prévention and secondary prévention of myocardial infarctîon, angina pectoris, cerebrovascular accidents of any origin (especially atherothrombotic, cardioembolic or caused by atrial fibrillation), aortic aneurysms or arteritis of the lower limbs, venous thromboses (especially in catheterised cancer patients) and pulmonary embolism.
Vascular risk factors and vascular diseases such as hypertension, obesity, diabètes, cardiac diseases, cerebrovascular diseases and hyperlipidaemia, and therefore atherosclerosis, play a rôle in the genesis of dementias such as Alzheimer's disease and vascular dementia (Qiu C., De Ronchi D. and Fratiglioni L., The epidemiology of the dementias : an update, 2007, Current Opinion in Psychiatry, 20 : 380-385). The compounds of the invention will therefore
-10Γ also be of use for the treatment and/or prévention of dementias such as Alzheimer's disease and vascular dementia.
TAFIa lowers endogenous fibrinolytic potential. As TAFIa inhibitors, the compounds of the present invention are therefore of use to accompany acute treatment by injectable 5 fibrinolytics, such as recombinant tPA (for example alteplase, tenecteplase, reteplase, desmoteplase), recombinant uPA or streptokinase, which are used in emergencies (for example myocardial infarction, cerebrovascular accident).
The compounds of the present invention reinforce the activity of these injectable fibrinolytics and therefore lead to the use thereof with fewer haemorrhagic and neurotoxic risks (réduction 10 of the dose thereof and therefore réduction of the side-effects thereof).
The present invention relates also to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
The useful dosage varies according to the âge and weight of the patient, the administration 15 route, the nature and severity of the disorder and any associated treatments, and ranges from
0.5 mg to 1000 mg per day in one or more administrations.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral (intravenous, intramuscular or subeutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory 20 administration, and especially tablets or dragées, sublingual tablets, gelatin capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable préparations, aérosols, and eye or nasal drops.
According to one aspect of the present invention, the pharmaceutical composition is an injectable préparation for intravenous administration.
According to another aspect of the present invention, the pharmaceutical composition is a tablet for oral administration.
In addition to the compound of formula (I), the tablets according to the invention comprise one or more excipients or carriers, such as diluents, lubricants, binders, disintegrators,
-11' absorbents, colourants and sweeteners.
There may be mentioned as examples of excipients or carriers:
♦ for the diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, ♦ for the lubricants: silica, talc, stearic acid and its magnésium and calcium salts, 5 polyethylene glycol, ♦ for the binders: aluminium and magnésium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, ♦ for the disintegrators: agar, alginic acid and its sodium sait, effervescent mixtures.
The percentage of active ingrédient of formula (I) in the tablet is preferably between 5% and 10 50% by weight.
According to one aspect of the present invention, the compound of formula (I) according to the present invention is administered in association with a fïbrinolytic, more especially an injectable fibrinolytic, such as recombinant tPA (for example alteplase, tenecteplase, reteplase or desmoteplase), recombinant uPA or streptokinase, or with an anticoagulant, such as, for 15 example, warfarin, dabigatran etexilate, rivaroxaban.
The administration in association may be in the form of a simultaneous or successive co-, administration of two separate pharmaceutical compositions each containing one of the active ingrédients (free association), or in the form of the administration of a fixed association of the two active ingrédients in the same pharmaceutical composition.
According to one aspect of the present invention, the compound of formula (I) is administered in the form of an injectable préparation, in free association with an injectable préparation of alteplase.
According to another aspect of the present invention, the compound of formula (I) is administered in the form of an injectable préparation, in free association with an injectable 25 préparation of tenecteplase.
The examples which follow illustrate the present invention. The structures of the compounds described in the examples hâve been determined by the conventional spectrophotometric techniques (infra-red, nuclear magnetic résonance, mass spectrometry).
-12C ABBREVIATIONS
AcOEt : ethyl acetate
AIBN : azobisisobutyronitrile
DCM : dichloromethane
DEA : diethylamine
DIBA1H : diisobutylaluminium hydride
DMAP : dimethylaminopyridine
DMF : dimethylformamide
DMSO or dmso : dimethyl sulphoxide
OD : optical density
EDTA : ethylenediaminetetraacetic acid eq : molar équivalent
HMPA : hexamethylphosphoramide
HPLC : high performance liquid chromatography
IR : infra-red
LDA : lithium diïsopropylamide
LiHMDS : lithium hexamethyldisilazane or lithium bis(trimethylsilyl)amide
MTBE : methyl tert-butyl ether
RP : rotatory power
NMR : nuclear magnetic résonance
TAFIa : activated thrombin-activatable fibrinolysis inhibitor
TEA : triethylamine
TFA : trifluoroacetic acid
THF : tetrahydrofuran
TMS : trimethylsilyl tPA : tissue plasminogen activator uPa : urokinase plasminogen activator or urokinase
Xantphos : 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
-13f ' Procedure for synthesis of the side chains - Procedures I, J, K (intermediates 204 to 212)
DMF
CS2CO3
Intermediate 204
Procedure I :
Caesium carbonate (60 g, 184 mmol, 2 eq) is added in portions to a solution of di-teri-butyl iminodicarboxylate (20 g, 92 mmol) in IL of DMF under an argon atmosphère and at ambient température. Vigorous stirring is maintained for 1 hour, before 1,4-dibromobutane (99.2 g, 459 mmol, 5 eq) is added. After 24 hours at ambient température, the reaction mixture is filtered over Celite and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/AcOEt gradient (100% to 10 90:10). Intermediate 204 (26.1 g, 74.1 mmol) is obtained in the form of an colourless oil with a yield of 81%.
Intermediate 204
]H NMR: (CDCI3, 400 MHz) δ 3.60 (t, 2 H), 3.42 (t, 2 H), 1.87 (quint., 2 H), 1.73 (quint., 2 H), 1.51 (s, 18 H).
IR: 1790-1744-1693 cm’1 (C=O), 1125 cm1 (C-O).
-14Intermediate 205
Intermediate 205 is obtained starting from 1,3-dibromopropane in accordance with procedure I described hereinbefore.
Product isolated in the form of a colourless oil (24.7 g, 73.0 mmol) with a yield of 79%.
Ή NMR: (CDCh, 400 MHz) δ 3.6 (m, 2 H), 3.5 (t, 2 H), 2.05 (quint., 2 H), 1.51 (s, 18 H).
IR: 1791-1744-1693 cm’1 (C=O), 1125 cm1 (C-O).
Intermediate 206
Intermediate 206 is obtained starting from 1,5-dibromopentane in accordance with procedure I described hereinbefore.
Product obtained in the form of a colourless oil (27.9 g, 76.2 mmol) with a yield of 83%.
H NMR: (CDCh, 400 MHz) δ 3.60 (t, 2 H), 3.40 (t, 2 H), 1.90 (m, 2 H), 1.60 (m, 2 H), 1.45 (m, 2 H), 1.50 (s, 18 H) ppm.
IR: 1740,1693 (C=O), 1787cm1 (C=Oweak).
Intermediate 207
Intermediate 207 is obtained starting from 1,6-dibromohexane in accordance with procedure I described hereinbefore.
-15NMR: (CDCh. 400 MHz) δ 3.58 (t, 2 H), 3.40 (t, 2 H), 1.89 (m, 2 H), 1.65-1.25 (m, 6 H),
1.45 (m, 6H), 1.51 (s, 18 H) ppm.
Procedure J
Intermediate 208
tert-Butyl iminodicarboxylate (2.47 g, 11.37 mmol, 1 eq) is added, in portions, to a 60% NaH suspension (0.682 g, 17 mmol, 1.5 eq) in a mixture of THF (25 mL) and DMF (3 mL) under argon and at ambient température. The reaction mixture is stirred at ambient température for 15 minutes and then warmed at 45 °C for 45 minutes. This suspension is then added to a solution of 1,3-dibromomethylbenzene (3 g, 11.37 mmol, 1 eq) in THF (100 mL). Stirring is continued at ambient température for 16 hours. The mixture is hydrolysed dropwise with a 10% NH4CI solution (100 mL). The organic phase is. extracted with AcOEt (2 x 50 mL), washed with a saturated NaCl solution (50 mL) and dried over MgSCL. The solvent is evaporated off under reduced pressure and the crude product is purified by flash chromatography on silica gel using as eluant a heptane/DCM gradient (50:50 to 100%). Intermediate 208 (2.07 g, 5.17 mmol) is obtained in the form of a colourless oil with a yield of45%.
Ή NMR: (DMSO-de, 400 MHz) δ 7.33 (d, 2 H), 7.3 (si, 1 H), δ 3.15 (t, 1 H), 4.70 /4.68 (2s, 4 H), 1.40 (s, 18 H).
IR: 1790-1747-1699 cm’1 (C=O), 1224-1143-1110 cm1 (C-O-C), 854-781-699 cm1 (CHAr).
MS : m/z 422 [M+Na].
Intermediate 209
Intermediate 209 is obtained starting from 1,4-dibromomethylbenzene in accordance with procedure J described hereinbefore.
A white solid (2.02 g, 5.05 mmol) is obtained with a yield of 44 %.
jH NMR : (DMSO-dô, 400 MHz) δ 7.40 (d, 2 H), 7.20 (d, 2 H), 4.69 (2s, 4 H), 1.39 (s, 18 H). 5 IR : 1767-1693 cm’1 (C=O).
MS : m/z 343 [M-C4H8].
Procedure K
Intermediate 210
Diisopropylethylamine (59.34 g, 462 mmol, 2 eq) is added dropwise to a solution of 2-amino5-methylpyridine (25 g, 230 mmol) in DCM (450 mL) at 0°C under an argon atmosphère. A solution of (Boc)2O (125.5 g, 575 mmol, 2.5 eq) is then added dropwise, followed by N,Ndimethylaminopyridine (28.1 g, 230 mmol, 1 eq). The reaction mixture is stirred for 15 hours at ambient température. The aqueous phase is extracted with AcOEt (2 x 400 mL). The 15 organic phases are combîned and washed with a 10% NH4C1 solution (400 mL), with a saturated NaCl solution (400 mL), with a 10% NaHCCh solution (400 mL) and finally with a saturated NaCl solution (400 mL). The organic phase is dried over MgSO4 and the solvent is evaporated off under reduced pressure. The residue obtained în purified by flash chromatography on silica gel using as eluant a heptane/AcOEt gradient (90:10 to 75:25).
Intermediate 210 (32.78 g, 106.3 mmol) is obtained in the form of a colourless oil with a yield of 46 %.
NMR: (400 MHz, CDC13) δ ppm 8.3 (s, 1 H), 7.75 (dd, 1 H), 7.1 (d, 1 H), 2.3 (s, 3 H),
1.45 (s, 18 H)
1R_: 1742-1707 cm’1(C=0).
-17C Intermediate 211
AIBN (0.164 g, 1 mmol) is added to a solution of intermediate 210 (3.08 g, 10 mmol) and Nbromosuccinimide (1.87 g, 10.5 mmol, 1.05 eq) in CC14 (50 mL). The réaction mixture is 5 heated at reflux for 20 hours. Once at ambient température, the insoluble components are fïltered off and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using as eluant a DCM/AcOEt gradient (from 99:1 to 95.5). Intermediate 211 (2.15 g, 5.56 mmol) is obtained in the form of a white solid with a yield of 56 %.
]H NMR: (400 MHz, CDC13) δ ppm 8.55 (d, 1 H), 7.75 (dd, 1 H), 7.3 (d, 1 H), 4.45 (s, 2 H),
1.45 (s, 18 H)
IRj 1753-1743-1710 cm_1(C=0).
Intermediate 212
Intermediate 212 is obtained starting from 2-amino-4-methylpyridine in accordance with procedure K described hereinbefore.
1H NMR: (400 MHz, CDC13) δ ppm 8.48 (d, 1 H), 7.3 (d, 1 H), 7.22 (d, 1 H), 4.4 (s, 2 H),
1.45 (s, 18 H)
IR: 1788-1755-1724 cm4(C=O).
-18Ç Procedure A - Synthesis of Examples 1 to 19.
Step Al
m 0 to 4
Tetraethyl orthosilicate (25 mL, 112 mmol, 1.0 eq) is added to a solution of 5 hypophosphorous acid (7.42 g, 112 mmol, 1.0 eq) in acetonitrile (160 mL) under argon and at ambient température. The reaction mixture is heated at reflux for 2 hours 30 minutes and then cooled to ambient température. Bromoalkene CH2=CH-(CH2)m+2-Br (0.5 eq), Pd2dba3 (0.769 g, 0.84 mmol) and Xantphos (0.356 g, 0.62 mmol) are then added and the reaction mixture is heated at reflux for 18 hours. The solution is then filtered over filter paper at 10 ambient température and concentrated under reduced pressure. The crude product is purified by flash chromatography on a silica column using a heptane/AcOEt gradient as eluant. The compound of step Al is obtained in the form of an oil.
Step A2
m= 0to4
A solution of 1.06M LiHMDS/THF (220 mL, 1.0 eq) is added dropwise to a solution, degassed with argon for 30 minutes, of the compound of step Al (233 mmol, 1 eq) in THF (870 mL) at -78°C. After the addition, the reaction mixture is stirred at ambient température for 2 hours 30 minutes. The reaction is then quenched at 0°C by addition of a saturated aqueous NaCl solution (870 mL). After extraction with ethyl acetate (3 x 800 mL), the
-19organic phases are combined, washed with a saturated NaCI solution and dried over MgSO4, before being concentrated under reduced pressure. The crude product is then purified by flash chromatography on a silica column using as eluant a DCM/EtOH mixture 95:5. The compound of step A2 is obtained in the form of an oil.
Step A3
m = 0 to 4
LDA (6.4 mL, 12,8 mmol, 1,5 eq) is added to a solution of the compound of step A2 (8.5 mmol, 1 eq) in THF (20 mL) at -70°C and under a stream of argon. Stirring is maintained for 20 minutes. A solution of dibenzyl carbonate (2.88 g, 11.9 mmol, 1.4 eq) in THF (11 mL) 10 is then added dropwise. The mixture is stirred for 45 minutes, and then a second addition of
LDA (6.4 mL, 12.8 mmol, 1.5 eq) is carried out. The solution is stirred for 2 hours at -70°C. A 10% NH4CI solution (60 mL) is then added dropwise, the température of the reaction mixture being maintained at -70°C. AcOEt (20 mL) is then added and the reaction mixture is gradually brought to ambient température. The reaction mixture is then extracted with AcOEt 15 (2 x 80 mL). The organic phases are combined and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on a silica column using as eluant a DCM/EtOH gradient. The compound of step A3 is obtained in the form of an oil.
( Step A4
-20.-
m, Aki as defined for formula (I)
A solution of intermediate 204 to 212 (7.65 mmol, 1.1 eq.) in 8 ml of DMSO and then, dropwise, a solution of the compound of step A3 (6.96 mmol, 1 eq) in 5 mL of DMSO are 5 added in succession to a 60% NaH suspension (0.448 g, 11.14 mmol) in 5 mL of DMSO at
C and under argon. When the addition is complété, the reaction mixture is brought to ambient température and stirred for 3 hours. The treatment is carried out at 0°C by adding 10% NH4CI (100 mL) and then AcOEt (100 mL). After décantation, the aqueous phase is reextracted with AcOEt (2 x 80 mL). The organic phases are combined, washed with a saturated 10 NaCI solution (2 x 80 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on a silica column using as eluant a DCM/EtOH gradient. The compound of step A4, a mixture of diastereoisomers, is obtained in the form of a colourless oil.
Step A5
m, Aki as defined for formula (I)
Bromotrimethylsilane (0.721 mL, 5.47 mmol, 8 eq) is added dropwise to a solution of the compound of step A4 (0.683 mmol, 1.0 eq) in DCM (30 mL) at 0°C and under argon. The mixture is stirred for 20 hours at ambient température. Evaporation under reduced pressure is carried out, and then the mixture is evaporated to dryness using a vane-type pump for ·2μ minutes. The mixture is taken up in MeOH (30 mL), stirred for 30 minutes and then evaporated under pressure and to dryness using a vane-type pump for 30 minutes. The mixture is taken up in MeOH again, stirred and evaporated. This operation is carried out a third time. The compound of step A5 is obtained in the form of the hydrobromide sait and is 5 used directly in the following hydrogénation reaction.
Step A6 - Examples 1 to 19
10% Pd/C (10 mol%) is added to a solution of the compound of step A5 in MeOH (15 mL).
The mixture is stirred for 18 hours under an H2 atmosphère at ambient température. The catalyst is filtered off over a Whatman frit. The filtrate is evaporated to dryness. 12 eq of TFA 10 are added to the crude product. The product is purified by flash chromatography on a reversephase RP 18 column using an HîO/MeCN/TFA gradient as eluant, After lyophilisation, the expected product (Examples 1 to 19), TFA sait, is obtained in the form of a white hygroscopic solid.
EXAMPLE 1: 2-(3-Aminopropyl)-l-hydroxy-l-oxo-l-phosphoIane-2-carboxylic acid, trifluoroacetate
Example 1 is obtained starting from intermediate 205 in accordance with procedure A described hereinbefore.
ΧΗ NMR: (300 MHz, dmso-d6) δ ppm 12-11 (si, IH), 8.3-7.3 (si, 3 H), 2.8 (q, 2 H), 2.25 (m, 1 H), 1.9 (m, 1 H), 1.8-1.4 (m, 8 H)
ESI/FIA/HR and MS/MS : ESI +/- : infusion : [M+H]+ = 222.1
Elemental analysis: C=35.39(35.83);H=5.44(5.11);N=4.60(4.18)
EXAMPLE 2 : 2-(4-Aminobutyl)-l-hydroxy-l-oxo-l-phosphoiane-2-carboxylic acid, trifluoroacetate
Example 2 is obtained starting from intermediate 204 in accordance with procedure A 25 described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 12.5 (si, 1 H), 7.75 (si, 3 H), 2.8 (q, 2 H), 2.21-1.6 (m, 2H), 1.9-1.35 (m, 2H), 1.8-1.5 (m, 6H), 1.6-1.2 (m, 2H)
ESI/FIA/HR and MS/MS : [M+H]+ = 236.1041 (236.1051)
Elemental analysis : C=38.94(37.83):H=5.81(5.48):N=4.50(4.01)
-22EXAMPLE 3 : 2-[(6-Aminopyridin-3-yl)methyl]-l-hydroxy-l-oxo-l-phospholane-2carboxylic acid, trifluoroacetate
Example 3 is obtained starting from intermediate 211 in accordance with procedure A 5 described hereinbefore.
'HNMR: (400 MHz, dmso-d6) δ ppm 13 (si, 2 H), 7.9 (si, 3 H), 7.7 (m, 2 H), 6.85 (d, 1 H),
3.2 (m, 1 H), 2.7 (m, 1 H), 2.05 (m, 1 H), 1.85-1.5 (m, 5 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 271.0842 (271.0847)
Elemental analysis : C=41.20(40.64);H=4.52(4.20);N=8.06(7.29)
EXAMPLE 4 :2-(5-Aminopentyl)-l-hydroxy-l-oxo-l-phospholane-2-carboxylic acid, trifluoroacetate
Example 4 is obtained starting from intermediate 206 in accordance with procedure A described hereinbefore.
XH NMR: (300 MHz, dmso-d6) δ ppm 12.5 (si, 1 H), 2.78 (m, 2 H), 1.8 to 1.4 (m, 4 H), 7.68 (si, 3 H), 2.22/1.65 (m, 2 H), 1.98/1.3 (m, 2 H), 1.52 (t, 2 H), 1.4 to 1 (m, 4 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 250.1209 (250.1208)
Elemental analysis : C=39.69(39.68);H=5.91(5.83);N=4.37(3.86)
EXAMPLE 5 : 2-(3-Ammopropyl)-l-hydroxy-l-oxo-l-phosphinane-2-carboxylic acid, trifluoroacetate
Example 5 is obtained starting from intermediate 205 in accordance with procedure A described hereinbefore.
‘H NMR: (400 MHz, dmso-d6) δ ppm 13.0 (si, 1 H), 7.73 (si, 3 H), 2.77 (m, 2 H), 1.93-1.66-
1.44 (3*(m, 2+10 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 236.1051 (236.1051)
Elemental analysis : C=38.07(37.83);H=5.85(5.48);N=4.11(4.01)
-23EXAMPLE 6 : 2-(5-Aminopentyl)-l-hydroxy-l-oxo-l-phosphinane-2-carboxyiic acid, trifluoroacetate
Example 6 is obtained starting from intermediate 206 in accordance with procedure A described hereinbefore.
'H NMR: (300 MHz, dmso-d6) δ ppm 7.65 (si, 3 H), 2.75 (m, 2 H), 1.9 (m, 2 H), 1.0-1.85 (m,
H)
ESVFIA/HR and MS/MS: ESI +/- : infusion : [M+H]+ = 264.1
Elemental analysis : C=40.84(41.39);H=5.66(6.14);N=3.76(3.71)
EXAMPLE 7 : 2-(4-Aminobutyl)-l-hydroxy-l-oxo-l-phosphinane-2-carboxylic acid, trifluoroacetate
Example 7 is obtained starting from intermediate 204 in accordance with procedure. A described hereinbefore.
1H NMR: (300 MHz, dmso-d6) δ ppm 7.68 (si, 3 H), 2.78 (m, 2 H), 2.02 to 1.16 (m, 14 H) ESI/FIA/HR and MS/MS: ESI +/- : infusion : [M+H]+ = 250.1
Elemental analysis : C=39.61(39.68);H=5.71(5.83);N=3.86(3.86)
EXAMPLE 8 : 2-(4-Ammobutyl)-l-hydroxy-l-oxo-l-phosphepane-2-carboxylic acid, trifluoroacetate
Example 8 is obtained starting from intermediate 204 in accordance with procedure A described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 13 to 11.5 (si, 1 H), 7.75 (si, 3 H), 2.8 (m, 2 H), 2.1 to
1.85 (m, 2 H), 1.85 to 1.2 (m, 14 H)
ESI/FIA/HR and MS/MS: ESI +/- : infusion : [M+H]+ = 264.1
EXAMPLE 9:2-[[4-(Aminomethyl)phenyl]methyl]-l-hydroxy-l-oxo-l-phospholane-2carboxylic acid, trifluoroacetate
Example 9 is obtained starting from intermediate 209 in accordance with procedure A described hereinbefore. '
-24p Tl NMR: (400 MHz, dmso-d6) δ ppm 13 to 12 (si, 1 H), 7.39 (d, 2 H), 2.1 to 1.5 (m, 6 H),
7.22 (d, 2 H), 8.3 (si, 3 H), 3.98 (m, 2 H), 3.39/2.75 (2dd, 2 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 284.1048 (284.1051)
Elemental analysis : C=48.29(48.84);H=5.45(5.99);N=4.64(4.38)
EXAMPLE 10 : 2-(5-Aminopentyl)-l-hydroxy-l-oxo-l-phosphepane-2-carboxylic acid, trifluoroacetate
Example 10 is obtained starting from intermediate 206 in accordance with procedure A described hereinbefore.
Tl NMR: (400 MHz, dmso-d6) Ô ppm 12 (si, 1 H), 7.68 (si, 3 H), 2.76 (m, 2 H), 2.12 to 1.9 (m, 2 H), 1.87 to 1.11 (m, 16 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 278.1518 (278.1521)
Elemental analysis : C=41.99(42.97);H=6.38(6.44);N=3.53(3.58)
EXAMPLE 11 : l-Hydroxy-l-oxo-2-(2-piperidin-4-ylethyl)-l-phosphinane-2-carboxylic acid, trifluoroacetate
Example 11 is obtained starting from JV-Boc-4-bromoethylpiperidîne in accordance with procedure A described hereinbefore.
‘H NMR: (400 MHz, dmso-d6) δ ppm 12 (si, 1 H), 8.49-8.2 (2*(m, 2 H), 3.24 (dl, 2 H), 2.82 (m, 2 H), 1.94-1.65-1.45-1.2 (4*(m, 12 H), 1.79 (tl, 2 H), 1.39 (m, 1 H), 1.2 (m, 2 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 290.1526 (290.1521)
Elemental analysis : C=44.65(44.67);H=5.93(6.25);N=3.41(3.47)
EXAMPLE 12:2-[[3-(Aminomethyl)phenyl]methyl]-l-hydroxy-l-oxo-l-phosphinane-2carboxylic acid, trifluoroacetate
Example 12 is obtained starting from intermediate 208 in accordance with procedure A 25 described hereinbefore.
‘H NMR: (400 MHz, dmso-d6) δ ppm 8.19 (si, 3 H), 7.3 (m, 2 H), 7.22 (s, 1 H), 7.14 (d, 1 H),
3.99 (m, 2 H), 3.32/2.97 (2dd, 2 H), 1.9 to 1.4 (m, 8 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 298.12 (298.120821)
Elemental analysis : C=47.00(46.72);H=4.82(5.15);N=3.39(3.41)
-25EXAMPLE 13 : 2-(6-Aminohexyl)-l-hydiOxy-l-oxo-l-phosphinane-2-carboxyiic acid, trifluoroacetate
Example 13 is obtained starting from intermediate 207 in accordance with procedure A described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.65 (si, 3 H), 2.77 (m, 2 H), 1.93 (m, 2 H), 1.8 to 1.14 (m, 16 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 278.1522 (278.15212)
Elemental analysis : C=42.69(42.97);H=6.26(6.44);N=3.79(3.58)
EXAMPLE 14 : 2-(4-Aminobutyl)-l-hydroxy-l-oxo-l-phosphocane-2-carboxylic acid, trifluoroacetate
Example 14 is obtained starting from intermediate 204 in accordance with procedure A described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.72 (si, 3 H), 2.8 (m, 2 H), 2.11 to 1.32 (m, 18 H) ESI/FIA/HR and MS/MS: [M+H]+ = 278.1522 (278.1521)
Elemental analysis : C=43.34Î42.97):H=6.35(6.44);N=2.91(3.58) .
EXAMPLE 15 : 2- [(2-Aimnopyridin-4-yl)methyl]-1 -hydroxy-l-oxo-1 -phosphinane-2carboxylic acid, trifluoroacetate
Example 15 is obtained starting from intermediate 212 in accordance with procedure A described hereinbefore. .
JH NMR: (400 MHz, dmso-d6) δ ppm 13.5 to 12 (si, 1 H), 7.8 (d, 1 H), 7.87 (si, 3 H), 6.75 (s, 1 H), 6.6 (d, 1 H), 3.25/3 (m, 2 H), 2 to 1.35 (m, 8 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 285.1012 (285.1004)
EXAMPLE 16: 2-[2-(irans-4-Aminocyclohexyl)ethyl]-l-hydroxy-l-oxo-l-phosphmane-
2-carboxylic acid, trifluoroacetate
Example 16 is obtained starting from fert-butyl [frans-4-(2-bromoethyl)cyclohexyl]carbamate, in accordance with procedure A described hereinbefore.
-26Ç ' jH NMR: (300/400/500 MHz, dmso-d6) δ ppm 7.9 (si, 3H), 2.9 (m, 1 H), 2.01 (m, 2 H), 1.91-
1.74 (2m, 4 H), 1.64 (m, 2 H), 1.53 (m, 2 H), 1.39 (m, 2 H), 1.29-0.95 (m, 4 H), 1.11 (m, 4 H), 1.09 (m, 1 H)
1¾ NMR: (300/400/500 MHz, dmso-d6) δ ppm 49.8, 36.8, 31.6, 30.8, 30.5, 30.5, 30.5, 23.6, 5 22.9
ESI/FIA/HR and MS/MS : [M+H]+ = 304.1648 (304.1677)
EXAMPLE 17:2-[2-(cis-4-AminocycIohexyl)ethyl]-l-hydroxy-l-oxo-l-phosphinane-2carboxylic acid, trifluoroacetate
Example 17 is obtained starting from teri-butyl [cis-4-(2-bromoethyl)cyclohexyl]carbamate, in accordance with procedure A described hereinbefore.
1HNMR: (400/500 MHz, dmso-d6) δ ppm 7.9 (si, 3H), 3.15 (m, 1 H), 1.96-1.62 (2m, 2 H), 1.94-1.73 (2m, 2 H), 1.71-1.65 (2m, 2 H), 1.68-1.65 (2m, 2 H), 1.56-1.39 (m, 4 H), 1.49-1.36 (2m, 2 H), 1.38 (m, 1 H), 1.23-1.16 (2m, 2 H) 13C NMR: (400/500 MHz MHz, dmso-d6) δ ppm 173.3, 51, 47.9, 34, 31, 28.7, 27.9, 26.5,
26.5.23.4.21.6 .1.¾ NMR : (400/500 MHz, dmso-d6) δ ppm 173.3, 51, 47.9, 34, 31, 28.7, 27.9, 26.5, 26.5,
23.4.21.6
ESI/FIA/HR and MS/MS : [M+H]+ = 304.1671 (304.1677) 20 Elemental analysis : C=45.47(46.05);H=6.68(6.52);N=3.58(3.36)
EXAMPLE 18 : 2-(5-Aminopeiityl)-l-hydroxy-l-oxo-l-phosphocane-2-carboxylic acid, trifluoroacetate
Example 18 is obtained starting from intermediate 206 in accordance with procedure A described hereinbefore.
ZHNMR: (400 MHz, dmso-d6) δ ppm 12.0-11.0 (si, IH), 7.7 (m, 3 H), 2.8 (m, 2 H), 2.05 (m,
H), 1.9-1.3 (m, 18 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 292.1656 (292.1677)
Elemental analysis : C=44.17(44.45);H=6.69(6.71);N=3.42(3.46)
-27EXAMPLE 19 : 2-(5-Aminopentyl)-l-hydroxy-l-oxo-l-phosphonane-2-carboxyIic acid, trifluoroacetate
Example 19 is obtained starting from intermediate 206 in accordance with procedure A described hereinbefore.
‘HNMR: (400 MHz, dmso-d6) ô ppm 12.4-11 (si, 1 H), 7.7 (si, 3 H), 2.75 (t, 2 H), 2.3 (m, 1 H), 2.05 (m, 1 H), 1.9-1.2 (m, 20 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 306.1834 (306.1834)
Elemental analysis : C=45.54(45.82);H=6.98(6.97);N=3.26(3.34)
Procedure B - Synthesis of the phosphinanes
Step B1 (Intermediate 6)
Ethyl (triphenylphosphorylidene) acetate (100 g, 287 mmol, 1.2 eq) is added in portions to a solution of phenylacetaldehyde (28.74 g, 239 mmol) in DCM (380 mL) and at ambient température. The reaction mixture is stirred for 20 hours at ambient température and then the mixture is concentrated in vacuo. The residue is taken up in heptane (400 mL), stirred for 1 hour, and then the insoluble component is filtered off. The heptane is evaporated off in vacuo and the residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/DCM mixture (60:40). Intermediate 6 (27.25 g, 143 mmol) is obtained in the form of a colourless oil with a yield of 60%.
‘H NMR: (400 MHz, CDC13) δ ppm 7.3 (t, 2 H), 7.25 (t, 1 H), 7.2 (d, 2 H), 7.1 (dt, 1 H), 5.8 (d, 1 H), 4.2 (quad, 2 H), 3.5 (d, 2 H), 1.3 (t, 3 H)
IR (cm’1) : 1716, 1653
Step B2 (Intermediate 7)
OH
Γ·. A solution of IM DIBA1H in THF (355 mL, 355 mmol) is added to a solution of intermediate 6 (28.35 g, 149 mmol) in DCM (375 mL) at ambient température and under an argon atmosphère. After 45 minutes at 0°C, the reaction mixture is stirred for 16 hours at ambient température. The reaction mixture is then cooled to 0°C and treated with 3N HCl (300 mL).
The mixture is extracted with DCM (350 mL), and the organic phase is washed with H2O (2 x 100 mL), dried over Na2SO4 and then evaporated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/AcOEt mixture (75:25). Intermediate 7 (16.05 g, 108 mmol) is obtained in the form of a colourless oil with a yield of
72%.
1_H NMR: (400 MHz, CDC13) δ ppm 7.1-7.4 (m, 5 H), 5.65-5.9 (2m, 2 H), 4.1 (d, 2 H), 3.35 (d, 2 H), 1.5 (m, 1 H) ’ ’ ’
AL (cm4) : 3600-3200,1716, 1650
Step B3 (Intermediate 8)
A mixture of intermediate 7 (3.7 g, 25 mmol) with triethyl orthoacetate (16.2 g, 100 mmol, 4 eq) and propionic acid (5 drops) is stirred for I hour 20 minutes in a microwave (250W) at 14<)°C. The mixture is taken up in EtrO (300 mL) and H,0 (100 mL). The organic phase is then washed with H2O (100 mL), dried over MgSOr and then concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/AcOEt mixture (80:20). Intermediate 8 (4.53 g, 20.7 mmol) is obtained in the form of an oil with a yield of 83%.
—NMR: (4o° MHz’ CDC13> δ PPm 7.15-7.3 (m, 5 H), 5.7 (m, 1 H), 5 (m, 2 H), 4.1 (q, 2 H).
2.85 (m, 1 H), 2.7 (m, 2 H), 2.25-2.4 (m, 2 H), 1.25 (t, 3 H) IR (cm4) : 1732, 699-747
Step B4 (Intermediate 9)
OH
-29LÎA1H4 (6.12 g, 161 mmol, 2 eq) is added in portions to a solution of intermediate 8 (17.58 g,
80.5 mmol) in THF (275 mL) at 0°C and under argon. The reaction mixture is stirred at ambient température for 16 hours. Excess L1AIH4 is hydrolysed by addition of H2O (4.2 mL) and then with a 20% NaOH solution (3.4 mL) and H2O (15.4 mL). The precipitate is filtered off and the filtrate is evaporated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/AcOEt mixture (70:30). Intermediate 9 (8.09 g, 45.9 mmol) is obtained in the form of a colourless oil with a yield of 57%.
Step B 5 (Intermediate 10) :
Triphenylphosphîne (24.07 g, 91.8 mmol, 2 eq) is added in portions to a solution of intermediate 9 (8.09 g, 45.9 mmol) and CBr4 (30.4 g, 91.8 mmol) at ambient température in Et20 (325 mL). The mixture is stirred for 16 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is taken up in heptane (250 mL), stirred for 30 minutes and then filtered. The filtrate is evaporated in vacuo. The residue obtained is purified by flash chromatography on silica gel using heptane as eluant. Intermediate 10 (8.64 g, 36 mmol) is obtained in the form of a colourless oil with a yield of 78%.
'HNMR: (400 MHz, CDCI3) δ ppm 7.28 (t, 2 H), 7.18 (t, 1 H), 7.13 (d, 2 H), 5.53 (ddd, 1 H), 5.02 (d, 1 H), 5 (d, 1 H), 3.42 (m, 1 H), 3.3 (m, 1 H), 2.65 (d, 2 H), 2.53 (m, 1 H), 1.95 (m, 1 H), 1.8 (m, 1 H)
IR (cm-1) : 916, 739-698
Step B6 (Intermediate 11)
Tetraethyl orthosilicate (3.48 g, 16.7 mmol, 1 eq) is added to a solution of hypophosphorous acid (1.1 g, 16.7 mmol) in acetonitrile (25 mL) under argon and at ambient température. The reaction mixture is heated at reflux for 2 hours 30 minutes and then cooled to ambient
-30température. The reaction mixture is degassed with argon and then there are added in succession intermediate 10 (2 g, 8.36 mmol) in solution in MeCN (5 mL), Xantphos (0.048 g, 0.0836 mmol) and then Pd2dba3 (0.038 g, 0.0418 mmol). The mixture is heated at reflux for 16 hours. After évaporation in vacuo, the residue obtained is purified by flash chromatography on silica gel using AcOEt as eluant. Intermediate 11 (1.61 g, 4.85 mmol) is obtained in the form of an oil with a yield of 58%.
H NMR: (400 MHz, dmso-d6) δ ppm centred at 6.95 (d, 1 H), 7.3 (t, 2 H), 7.2 (m, 3 H), 4 (m, 2 H), 3.55 (m, 2 H), 2.59 (d, 2 H), 1.9 (m, 1 H), 1.78 (m, 4 H), 1.45 (m, 2 H), 1.21 (t, 3 H) IR (cm4) : 2343
Step B7 (Intermediate 12)
O O
A solution of 1.06 M LiHMDS in THF (4.53 mL, 4.8 mmol, 1 eq) is added dropwise at -78°C to a solution of intermediate 11 (1.6 g, 4.8 mmol) in 50 mL THF and under an argon atmosphère. The reaction mixture is stirred for 30 minutes at -78°C and then for 4 hours 30 minutes at ambient température, before being treated with a saturated NaCl solution (50 mL). After addition of AcOEt (150 mL), the organic phase is dried over MgSO4 and then evaporated in vacuo. The residue obtained is purified by flash chromatography on silica gel using a DCM/EtOH mixture (95:5) as eluant. Intermediate 12 (0.889 g, 3.52 mmol) is obtained in the form of a colourless oil with a yield of 73%.
iH_NMR: (400 MHz, CDC13) δ ppm 7.3 (t, 2 H), 7.2 (t, 1 H), 7.12 (d, 2 H), 4.08 (m, 2 H), 2.6/2.51 (2d, 2 H), 2.1-1.8 (m, 4 H), 1.8-1.55 (m, 3 H), 1.5-1.3 (m+t, 5 H)
IR (cm1) : 3433
-31Step B 8 (Intermediate 13)
A solution of 2M LDA in THF (2.6 mL, 5.2 mmol, 1.5 eq) is added to a solution of intermediate 12 (0.875 g, 3.47 mmol) in THF (10 mL) at -78°C and under argon. After 5 40 minutes, a solution of dibenzyl carbonate (1.18 g, 4.85 mmol) in THF (5 mL) is added dropwise. The réaction mixture is stirred for 1 hour, and then a further 1.5 eq of 2M LDA in THF (2.6 mL, 5.2 mmol) is added. After 4 hours at -78°C, the reaction mixture is hydrolysed while cold with a 10% aqueous NH4CI solution (9 mL). AcOEt (18 mL) and a 10% aqueous NH4CI solution (18 mL) are then added. After retuming to ambient température, the reaction 10 mixture is extracted with AcOEt (2 x 50 mL). The organic phase is dried over MgSO4 and then concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel using a DCM/EtOH mixture (97.5:2.5) as eluant. Intermediate 13 (0.996 g,
2.58 mmol) is obtained in the form of an oil with a yield of 74%.
1H NMR: (400 MHz, CDC13) δ ppm 7.4-7 (m, 10 H), 5.18 (s, 2 H), 4.15-3.9 (m, 2 H), 3.2-2.8 15 (1 dd, 1 H), 2.58 (d, 2 H), 2.3-1.4 (m, 7 H), 1.25 (t, 3 H)
IRicm·1): 1726
Step B9 (Intermediate 14)
A solution of intermediate 206 (1.11 g, 3.03 mmol, 1.3 eq) in DMSO (5 mL) and a solution of intermediate 13 (0.9 g, 2.33 mmol) in DMSO (4 mL) are added dropwise, in succession, to a 20 suspension of sodium hydride (0.150 g, 3.75 mmol, 1.6 eq) in DMSO (5 mL). After stirring for 4 hours at ambient température, the reaction mixture is added at 0°C to a mixture (1:1) of a 10% NH4CI solution (100 mL) and AcOEt (100 mL). The aqueous phase is re-extracted with AcOEt (2 x 50 mL). The organic phases are combined, dried over MgSÜ4 and then concentrated in vacuo. Intermediate 14 so obtained is used directly without being purified 25 further.
-32( Step BIP (Intermediates 15 and 16)
TMSBr (3.68 mL, 28 mmol, 12 eq) is added to a solution of intermediate 14 (1.56 g,
2.33 mmol) in DCM (125 mL) at ambient température and under argon. The reaction mixture is stirred for 16 hours at ambient température, before being concentrated in vacuo. The oil obtamed is taken up in MeOH (60 mL), stirred for 30 minutes and concentrated in vacuo. The same operation is repeated twice. The residue obtained is purified by reverse-phase chromatography using as eluant an H2O/MeCN/TFA gradient. Intermediates 15 (0.423 g, 0.95 mmol) and then 16 (0.155 g, 0.35 mmol) (in the order of elution) are obtained in the form of white solids after lyophilisation with yields of 41% and 15%, respectively. The 10 absolute configuration of intermediates 15 and 16 has not been verified.
Intermediate 15 : Benzyl 2-(5-aminopentyI)-4-benzyl-l-hydroxy-l-oxo-l-phosphmane-
2-carboxyIate, trifluoroacetate - dia 1 racemic
1HNMR: (400 MHz, dmso-d6) δ ppm 12 (m, 1 H), 7.75 (m, 3 H), 7.35-7.05 (m, 10 H), 5.18/5 (2d, 2 H), 2.6 (m, 3 H), 2.4 (dd, 1 H), 2.1 (m, 1 H), 1.9-1.5 (m, 8 H), 1.4 (m, 2 H), 1.15 (m, 2 15 H), 0.8/0.52 (2m, 2 H) ’ 19F NMR: (400 MHz, dmso-d6) δ ppm -74
IR (cm4) : 3300-2500, 1716, 1678
Intermediate 16 : Benzyl 2-(5-aminopentyI)-4-benzyl-l-hydroxy-l-oxo-l-phosphinane20 2-carboxylate, trifluoroacetate - dia 2 racemic
NMR(400 MHz, dmso-d6) δ ppm 7.4 (m, 5 H), 7.25 (t, 2 H), 7.18 (t, 1 H), 7 (d, 2 H), centred at 5.11 (AB, 2 H), 7.65 (m, 3 H), 2.71 (m, 2 H), 2.4 (d, 2 H), 1.95-1.1 (m, 15 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -74
IR (cm’1) : 3300-2500, 1774, 1716, 1676
EXAMPLE 20:2-(5-Aminopentyl)-4-benzyl-l-hydroxy-l-oxo-l-phosphinane-2i5 carboxylic acid, dia 1 racemic
Intermediate 15 (0.413 g, 0.74 mmol) in solution in 60 mL of a H2O/MeOH mixture (3:1) is stirred at ambient température under an H2 atmosphère, in the presence of 10% Pd/C (41 mg), for 4 hours. The reaction mixture is filtered and then concentrated in vacuo. The residue
-33( ' obtained is purified by reverse-phase chromatography using as eluant an H20/MeCN gradient. Example 20 (0.209 g, 0.591 mmol) is obtained in the form of a white solid after lyophilisation with a yield of 80%.
NMR: (500 MHz, D2O) Ô ppm 7.3 (t, 2 H), 7.24 (d, 2 H), 7.19 (t, 1 H), 2.59/2.37 (m, 2 H), 5 2.41 (t, 2 H), 1.91/1.55 (m, 2 H), 1.77/1.6 (m, 2 H), 1.77/1.35 (m, 2 H), 1.64/1.38 (m, 2 H),
1.63 (m, 1 H), 1.24 (m, 2 H), 1.16/1.1 (m, 2 H), 0.7 (m, 2 H)
-.3C NMR: (500 MHz, D2O) δ ppm 129.2, 128.2, 125.7, 42.5, 40, 35.5, 35.4, 31.3, 31.1, 30.2, 26, 25.9, 22.8
TR (cm1) : 3300-2100,1691, 1631, 1605
1° Elemental analysis : C=60.65(61.18);H=7.58(7.99);N=3.91(3.96) ESJ/FIA/HR and MS/MS : [M+H]+ = 354.1831 (354.1834)
EXAMPLE 21:2-(5-AminopentyI)-4-benzyl-l-hydroxy-l-oxo-l-phosphinane-2carboxylic acid, dia 2 racemic
Intermediate 16 (0.148 g, 0.265 mmol) in solution in 20 mL of an H2O/MeOH mixture (3:1) is stirred at ambient température under an H2 atmosphère, in the presence of 10% Pd/C (15 mg), for 2 hours 30 minutes. The reaction mixture is filtered and then concentrated in vacuo. The residue obtained is purified by reverse-phase chromatography using as eluant an H2OZMeCN gradient. Example 21 (0.053 g, 0.15 mmol) is obtained in the form of a white solid after lyophilisation with a yield of 56 %.
fil NMR: (500 MHz, D2O) δ ppm 7.29 (t, 2 H), 7.2 (d, 2 H), 7.2 (t, 1 H), 2.57 (t, 2 H), 2.45 (m, 2 H), 1.84 (m, 1 H), 1.81/1.33 (m)+(m, 1+1 H), 1.78/1.29 (m)+(m, 1+1 H), 1.69/1.31 (m)+(m, 1+1 H), 1.68/1.27 (m)+(m, 1+1 H), 1.41/1.19 (m)+(m, 1+1 H), 1.38 (m, 2 H), 1.2 (m, 2 H) 13C NMR: (500 MHz, D2O) δ ppm 129.3,128.2, 125.7, 43, 42.4, 40, 35.9, 34,6, 30.4, 29.4,
27, 26.7, 25
IR (cm4) : 3250-1800, 1694+1661, 1618
Elemental analysis : C=61.18(61.18);H=7.90(7.99);N=3.96(3.96)
ESI/FIA/HR and MS/MS : [M+H]+ = 354.1837 (354.1834)
In the same manner, Examples 22 and 23 are obtained in accordance with procedure B described hereinbefore by replacing intermediate 206 by intermediate 204.
-34EXAMPLE 22:2-(4-Aminobutyl)-4-benzyl-l-hydroxy-l-oxo-l-phosphmane-2carboxyhc acid, dia 1 racemic ‘HNMR: (400 MHz, dmso-d6) δ ppm 7.7 (si, 3 H), 7.3 (dd, 2 H), 7.2 (dd+t, 3 H), 2.7 (m, 2 H), 2.55-2.4 (m, 2 H), 1.95 (m, 1 H), 1.8-13 (m, 10 H), 1.1-0.85 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+HJ+ = 340.1677 (340.1677)
Elemental analysis : C=51.00(50.33);H=5.90(6.00);N=3.22(3.09)
EXAMPLE 23 :2-(4-Aminobutyl)-4-benzyl-l-hydroxy-l-oxo-l-phosphinane-2carboxylic acid, dia 2 racemic
NMR: (300 MHz, dmso-d6) δ ppm 15.8 (m, 2 H), 7.95 (m, 2 H), 7.25 (t, 2 H), 7.18 (t, 1 H), 7.1 (d, 2 H), 2.75 (m, 2 H), 2.6-2.35 (m, 2 H), 2.15 (m, 1 H), 1.75-1 (m, 12 H) ESI/FIA/HR and MS/MS : [M+H]+ = 340.1683 (340.1677)
Elemental analysis : C=60.20(60.17);H=7.34(7.72);N=3.96(4.13)
Synthesis of the azaphosphinanes
Intermediate 17 qC
Intermediate 17 was synthesised using a procedure described in the literature by V. Gouverneur et al., J. Or g. Chem. 2005, 70,10803.
A IM solution in THF of vinyl magnésium bromide (170 mL, 170 mmol, 2 eq) is added to a solution of ethyl dichlorophosphinate (10 mL, 84.26 mmol) in 100 mL of THF at -78°C and under argon. Stirring is maintained for 1 hour at -78°C. EtOH (30 mL) is then added dropwise and the reaction mixture is retumed to ambient température. The reaction mixture is then concentrated under reduced pressure and the residue obtained is purified by flash chromatography on silica gel using a DCM/EtOH mixture (96:4) as eluant. Intermediate 17 (6.37 g, 43.6 mmol) is obtained in the form of a colourless oil with a yield of 52 %.
1H NMR: (400 MHz, DMSO - de) δ 6.1-6.4 (m, 6H), δ 3.90 (q, 2H), δ 1.25 (t, 3H).
IR (cm1) : 3500 (OH(H2O)), 1609 (C=C), 1210 (P=O), 1032 and 935 cm’1 (P-O).
GC : tr 5.83 min.
-35Intermediate 18
(V-benzylamine (4.79 mL, 43.6 mmol, 1 eq.) is added in a single batch to a solution of intermediate 17 (6.37 g, 43.6 mmol) in an autoclave and under argon. The reaction mixture is heated to 100°C, stirred for 16 hours and concentrated under reduced pressure. The residue is taken up in AcOEt (100 mL), and the organic phase is washed with a saturated NaCl solution (3 x 100 mL) and dried over MgSO4. The solvent is evaporated off and the residue obtained is purified by flash chromatography on silica gel using a DCMÆtOH mixture (95:5) as eluant. Intermediate 18 (8.68 g, 34.3 mmol) is obtained in the form of a yellowish oil with a yield of 79 %.
-H NMR: (CDC13, 400 MHz) δ 7.31 (m, 5H), 4.08 (m, 2H), 3.60 (s, 2H), 2.98 (m, 2H), 2.64 (m, 2H), 1.97 (m, 2H), 1.85 (m, 2H), 1.35 (t, 3H).
GC : tr 12.29 min.
Intermediate 19
A solution of 2M LDA (75.6 mL, 37.8 mmol, 1.5 eq) in THF is added to a solution of intermediate 18 (6.38 g, 25.19 mmol) in THF (30 mL) at -70°C and under argon. After 15 minutes at -70°C, a solution of Bqc2O (7.68 g, 35.3 mmol, 1.4 eq) in 30 mL of THF is then added dropwise. Stirring is maintained for 90 minutes and 1.5 eq of LDA (75.6 mL, 37.8 mmol) are then added dropwise. When the addition is complété, the reaction mixture is maintained at -70°C for 90 minutes. A saturated NH4C1 solution (30 mL) as well as AcOEt (60 mL) are added and the reaction mixture is slowly retumed to ambient température. The
-36( product is then extracted with AcOEt (2 x 150 mL). The organic phases are combîned, washed with a saturated NaCl solution (2 x 150 mL), dried over MgSO4 and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel using a DCM/THF gradient (95:5 to 40:60) as eluant. Intermediate 19 (6.73 g,
19.04 mmol) is obtained in the form of a yellowish oil with a yield of 76 %.
1H NMR: (CDCh, 400 MHz) δ 7.35 to 7.2 (m, 5H), δ 4.3 to 4.05 (m, 2H), δ 3.60 (dd, 2H), δ
3.3 to 2.5 (m, 5H), δ 2.1 to 1.8 (m, 2H), δ 1.50 (s, 9H), δ 1.35 (t, 3H).
K (cm’1) : 3500 (OH), 1721 (C=O), 1150 (P=O), 1032 and 935 (P-O).
MS : m/z 355 1M+11. .
Procedure C : Procedure for alkylation of intermediate 19
60% NaH (8 mmol, 1.6 eq) at 10°C is added in portions to a solution of intermediate 204 to 212 (5 mmol, 1 eq) in DMSO (10 mL) under argon. Intermediate 19 (5 mmol) in solution in DMSO (5 mL) is then added to the suspension and the mixture is stirred for 4 hours at ambient température. The reaction mixture is then hydrolysed with an aqueous NH4C1 15 solution (50 mL) and extracted with AcOEt (2 x 100 mL). The organic phase is washed with
H2O (2 x 100 mL), dried over MgSO4 and concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant a DCM/AcOEt gradient (90:10 to 50:50). Intermediate 20a-f is obtained in the form of a mixture of 4 diastereoisomers.
Procedure D : Deprotection of the amino and phosphinic functions
TMSBr (7.92 mL, 60 mmol, 12 eq) is added dropwise to a solution of intermediate 20a-f (5 mmol) in DCM (40 mL) under argon and at ambient température. The mixture is stirred for 16 hours at ambient température and then concentrated in vacuo. The residue is taken up in MeOH (40 mL) and stirred for 20 minutes at ambient température, before being evaporated to dryness. The evaporate is dissolved in DCM (20 mL), and trifluoroacetic acid (44.6 mL,
60 mmol, 12 eq) is added. The reaction mixture is stirred for 10 hours at ambient température and then concentrated in vacuo. The residue obtained is purified by reverse-phase chromatography using as eluant an H2O/MeCN gradient. The final product (Examples 24 to 30) (zwitterion or TFA sait), a mixture of 2 enantiomers, is obtained in the form of a white solid after lyophilisation.
„ . -37- ( Intermediate 20a : teri-Butyl 3-{3-[bis(te7ï-butoxycarbonyl)amino]propyl}-l-benzyl-4ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 20a is obtained starting from intermediates 19 and 205 in accordance with procedure C described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) ô ppm 7.35-7.2 (m, 5 H), 4 (m, 2 H), 3.8 (m, 2 H), centred at
3.52 (AB, 2 H), 3-2.25 (m, 4 H), 2-1.8 (m, 4 H), 1.45/1.35 (2s, 27 H), 1.2 (t, 3 H), 1.2 (m, 2
H) ’ ’
EXAMPLE 24 :3-(3-Aminopropyl)-l-benzyl-4-hydroxy-4-oxo-l,4-azaphosphinane-3carboxylic acid
Example 24 is obtained starting from intermediate 20a in accordance with procedure D described hereinbefore.
1H.NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5 H), centred at 4.35 (AB, 2 H), 3.75/3.35 (2m, 2 H), 3.5/3.15 (2dd, 2 H), 2.92 (t, 2 H), 2.3/1.8 (2m, 2 H), 1.95 (m, 1 H), 1.6-1.4 (m, 3 H) ESI/FIA/HR and MS/MS : [M+H]+ = 327.1478 (327.1473) 15 Elemental analysis : C=55.38(55.21);H=6.85(7.10);N=8.41(8.58)
Intermediate 20b : tert-Butyl 3-{4[bis(terAbutoxycarbonyl)amino]butyl}-l-benzyl-4ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 20b is obtained starting from intermediates 19 and 204 in accordance with procedure C described hereinbefore.
1HNMR: (DMSO-dfi, 400MHz) δ 7.30 (m, 5 H), 3.97 (m, 2 H), 3.63-3.43 (dd, 2 H), 3.36 (m,
H), 2.93-2.33 (m, 2 H), 2.79 to 2.47 (m, 2 H), 1.93 (m, 2 H), 1.93 (m, 2 H), 1.43 (m, 2 H),
1.42 (s, 18 H), 1.36 (s, 9 H), 1.21 (t, 3 H), 0.83 (m, 2 H).
IR (cm4) : 1744, 1711 cm1 (C=O), 1276 cm4 (P=O).
EXAMPLE 25 :3-(4-Aminobutyl)-l-benzyi-4-hydroxy-4-oxo-l,4-azaphosphniane-325 carboxylic acid
Example 25 is obtained in accordance with procedure D described hereinbefore starting from intermediate 20b.
-38Ç·- NMR: (400 MHz, dmso-d6) δ ppm 8.2 (si, 3 H), 7.3 (m, 5 H), 3.7/3.5 (2*(d, 1+1 H), 3.05/2.4 (2*(m, 1+1 H), 2.75/2.55 (2*(m, 1+1 H), 2.7 (m, 2 H), 1.8 (m, 1 H), 1.6-1.1 (m, 7 H) ESI/FIA/HR and MSZMS : [M+H]+ = 341.1628 (341.1630)
Elemental analysis : C=55.99(56.46);H=7.14(7.40);N=8.13(8.23)
Intermediate 20c : ieri-Butyl 3-{5-bis(tert-butoxycarbonyl)amino]pentyl}-l-benzyl-4ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 20c is obtained starting from intermediates 19 and 206 in accordance with procedure C described hereinbefore.
]H NMR: (400 MHz, dmso-d6) δ ppm 7.32-7.2 (m, 5 H), 3.99 (m, 2 H), 3.8 (m, 2 H), centred at 3.5 (AB, 2 H), 3-2.3 (m, 4 H), 2-1.8 (m, 4 H), 1.45/1.35 (2s, 27 H), 1.35/1.15 (2m, 4 H), 1.2 (t, 3 H), 0.75 (m, 2 H)
EXAMPLE 26 :3-(5-Aminopentyl)-l-benzyl-4-hydroxy-4-oxo-l,4-azaphosphinane-3carboxylic acid
Example 26 is obtained starting from intermediate 20c in accordance with procedure D described hereinbefore.
. NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5 H), centred at 4.32 (AB, 2 H), 3.7/3.35 (2m, 2 H), 3.5/3.1 (2dd, 2 H), 2.9 (t, 2 H), 2.2/1.78 (2m, 2 H), 1.95/1.45 (2m, 2 H), 1.6 (m, 2 H), 1.3 (m, 2 H), 1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : ΓΜ+Η1+ = 355.1792 (355.1786)
Elemental analysis : C=58.04(57.62);H=7.37(7.68);N=7.95(7.90)
Intermediate 20d : tert-Butyl l-benzyl-3-({6-[bis-iert-butoxycarbonyl)amino]pyridin-3yl}methyi)-4-ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 20d is obtained starting from intermediates 19 and 211 in accordance with 25 procedure C described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 8.18 (s, 1 H), 7.4-7.25 (m, 6 H), 7.18 (d, 1 H), 4 (m, 2 H), 3.8 (m, 2 H), 3.58/3.5 (2d, 2 H), 3-2.6 (m, 4 H), 2.25/2.1 (2m, 2 H), 1.4 (s, 27 H), 1.2 (t, 3 H)
-39EXAMPLE 27 :3- [(6-Aminopyridin-3-yl)methyl] -l-benzyI-4-hydroxy-4-oxo-l,4azaphosphmane-3-carboxyiic acid
Example 27 is obtained starting from intermediate 20d in accordance with procedure D described hereinbefore.
ΓΗ NMR: (400 MHz, D2O) δ ppm 7.51 (dd, 1 H), 7.42 (d, 1 H), 7.4-7.25 (m, 5 H), 6.75 (d, 1 H), centred at 4.25 (AB, 2 H), 3.78 (m, 1 H), 3.4 (dd+m, 2 H), 2.95 (dd, 1 H), 2.7 (dd, 1 H),
2.6 (dd, 1 H), 2.28/1.85 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+= 376.1418 (376.1426)
Elemental analysis : C=57.18(57.60);H=5.82(5.91);N=11.25(11.19)
EXAMPLE 28:3-[(2-Aminopyridin-4-yl)methyl]-l-benzyl-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 28 is obtained starting from intermediates 19 and 212 in accordance with procedures C and D described hereinbefore without intermediate purification.
Ή NMR: (400 MHz, D2O) δ ppm 7.6 (dl, 1 H), 7.4 (m, 5 H), 6.55 (m, 2 H), 4.6/4 (dd, 2 H), 3.9-3.4 (m, 2 H), 3.6/2.75 (dd, 2 H), 3/2.7 (dd, 2 H), 2.3/1.9 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 376.1428 (376.1426)
Elemental analysis : C=56.70(57.60);H=5.45(5.91);N=10.87(11.19)
Intermediate 20e : teri-Butyl l-benzyl-3-(3-{[bis-(iert-butoxycarbonyl)ammo]methyl}benzyI)-4-ethoxy-4-oxo- l,4-azaphosphinane-3-carboxylate
Intermediate 20e is obtained starting from intermediates 19 and 208 in accordance with procedure C described hereinbefore.
jH NMR: (400 MHz, dmso-d6) δ ppm 7.4-7.3 (m, 5 H), 7.15 (t, 1 H), 7.1 (si, 1 H), 7.05/6.95 (d, 2 H), 4.6 (s, 2 H), 4 (m, 2 H), 3.7/3.45 (dd, 2 H), 3.35 (m, 2 H), 2.9/2.15 (m, 2 H), 2.7/2.55 (dd, 2 H), 2.05 (m, 2 H), 1.4 (s, 27 H), 1.2 (t, 3 H) Γ. -40( EXAMPLE 29 : 3-[[3-(Aminomethyl)phenyl]methyl]-l-benzyl-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 29 is obtained starting from intermediate 20e in accordance with procedure D described hereinbefore.
1HNMR: (400 MHz, D2O) δ ppm 7.3 (m, 5 H), 7.3-7.05 (m, 4 H), 4.4/3.95 (dd, 2 H), 4 (dd, 2 H), 3.8-3.3 (m, 2 H), 3.55/2.75 (dd, 2 H), 3/2.7 (dd, 2 H), 2.2/1.8 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 389.1623 (389.1630)
Elemental analysis : C=61.37(61.85);H=6.30(6.49);N=7.05(7.21)
Intermediate 20f : teri-Butyl l-benzyl-3-(4-{[bis(terAbutoxycarbonyl)amino]methyl)}10 benzyl)-4-ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 20f is obtained starting from intermediates 19 and 209 in accordance with procedure C described hereinbefore.
1NMR: (400 MHz, dmso-d6) ô ppm 7.35 (m, 5 H), 6.99 (d, 2 H), 6.91 (d, 2 H), 4.6 (s, 2 H), 3.98 (m, 2 H), 3.5 (s, 2 H), 3.27 (m, 2 H), 2.95/2.22 (2*m, 2 H), 2.75/2.49 (2*m, 2 H), 2.05 15 (m,2H), 1.35 (2*s, 27 H), 1.18 (t, 3 H) ^NMR: <400 MHz> dmso-d6) δ ppm 152, 138, 137, 135, 130, 128, 126, 82, 62, 60, 55.5, 50.5,48.5,34,28,24.5,16 ’
EXAMPLE 30:3-[[4-(AminomethyI)phenyl]methyl]-l-benzyl-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 30 is obtained starting from intermediate 20f in accordance with procedure D described hereinbefore.
-HNMR: (400 MHz’ D2°) δ PPm 7.2 (m, 5 H), 7.1/7 (dd, 4 H), 4.3/3.9 (dd, 2 H), 4 (m, 2 H), 3.7-3.25 (m, 2 H), 3.45/2.65 (dd, 2 H), 2.9/2.65 (dd, 2 H), 2.15/1.75 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 389.1623 (389.1630)
Elemental analysis : C=61.41(61 8S);h=6 36(6.49);N~7.1Q(7.21) . -μIntermediate 20b : ArZ-Butyl 3-{4[bis(ieri-butoxycarbonyl)amino]butyl}-l-benzyl-4ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
DMSO (30 mL) and 60% NaH (8.48 g, 212 mmol, 1.5 eq) are introduced in succession, under an argon atmosphère, into a IL three-necked flask equipped with mechanical stirrîng. The 5 flask is maintained at ambient température by means of a water bath. A solution of intermediate 204 (54.6 g, 155 mmol, 1.1 eq) in DMSO (25 mL) is then added dropwise over a period of 5 minutes. A solution of intermediate 19 (50 g, 141.5 mmol) in DMSO (120 mL) is then added dropwise, the température being maintained below 20°C. When the addition is complété, 100 mL of anhydrous THF are then added in order that stirring can be maintained. 10 After 3 hours, the reaction mixture is cooled by means of an ice-water bath and hydrolysed by addition of 500 mL of a saturated NH4CI solution. The mixture is then extracted with AcOEt (3 x 300 mL). The organic phases are then combined, washed with a saturated NaCi solution (2 x 300 mL) and dried over MgSC>4, before being concentrated under reduced pressure. The yellowish residue (92.5 g) so obtained is then purified by chromatography on silica gel using 15 a CH2C12/AcOEt/MeOH mixture as eluant. The expected product (69.3 g, 110.9 mmol), a mixture of 4 diastereoisomers, is obtained in the form of a white solid with a yield of 78%.
Procedure E : Procedure for débenzylation by hydrogenolysis
Intermediate 21 : teri-Butyl 3-{4-[bis(tot-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-1,4-azaphosphinane-3-carboxylate
Intermediate 20b (73.6 g, 117.8 mmol), éthanol (1 L), Pd/C (7.36 g, 10% by mass) and 37% HCl (7.85 mL, 0.8 eq) are introduced in succession into a 2L flask at ambient température and under a stream of argon. The argon is then replaced by a hydrogen atmosphère. The reaction is monitored by LC/MS. After 4 hours, the reaction is complété and the catalyst is fïltered off over glass fibre. The filtrate is evaporated to dryness in order to obtain a yellow oil, which is 25 taken up in AcOEt (400 mL) and in a 10% NaHCOa solution (400 mL). After décantation, the aqueous phase is extracted with AcOEt (3 x 100 mL). The organic phases are combined and then washed with a saturated NaCi solution (400 mL), dried over MgSO4 and concentrated to yield the expected intermediate 21 in the form of a white solid (57.6 g, 107.7 mmol) with a yield of 91%.
-42Γ 1HNMR: (DMSO-dâ, 400 MHz) S 4.05 to 3.85 (m, 2 H), 3.45 (m, 2 H), 3.1 to 2.6 (m, 4 H),
2.3 -1.7 (m, 4H), 1.45 (s, 18 H), 1.40 (s, 9 H), 1.20 (t, 3 H), 1.5-0.9 (m, 4 H).
IR (cm'1) : 3100-3500 cm ^OH), 3314 cm’1 (NH), 1712-1693 cm'1 (C=O).
Procedure L : Procedure for synthesis of the aldéhydes An-An-CHO by a Suzuki 5 coupling
The non-commercial aldéhydes were prepared in accordance with the procedure described below:
Ethanol (500 mL), boronic acid Ar2-B(OH)2 (92.7 mmol, 1.2 eq) and bromoarylaldehyde or bromoheteroarylaldehyde Br-An-CHO (77.3 mmol) are introduced in succession into a IL 10 flask under argon and at ambient température. The solution is degassed with argon for minutes. Pd(PPh3)4 (1.78 g, 1.55 mmol) and Na2CO3 (92.7 mL of a 2M solution in H2O,
185 mmol, 2.4 eq) are then introduced in a single portion. After the addition, the reaction mixture is heated at reflux for 5 hours. The mixture is then evaporated to dryness. The residue is taken up in DCM (1 L) and H2O (200 mL). After décantation, the aqueous phase is 15 extracted with DCM (200 mL). The organic phases are combined and then washed with a saturated NaCI solution (400 mL), dried over MgSCU and concentrated under reduced pressure. The residue is then purified by flash chromatography on silica gel. The expected product is obtained with yields of from 59 to 94%.
Intermediate 213
!H NMR: (400 MHz, dmso-d6) δ ppm 9.89 (s, 1 H), 7.94 (dd, 1 H), 7.77 (td, 1 H), 7.63 (tl, 1 H), 7.54 (dl, 1 H), 7.54/7.4 (2m, 4 H)
-43Intermediate 214
*Η NMR: (400/500 MHz, dmso-d6) δ ppm 9.72 (s, 1 H), 7.96 (d, 1 H), 7.79 (t, 1 H), 7.65 (t, 1 H), 7.6 (t, 1 H), 7.48 (m, 3 H), 7.4 (d, 1 H)
Intermediate 215
Cl
NMR: (400/500 MHz, dmso-d6) δ ppm 9.91 (s, 1 H), 7.95 (d, 1 H), 7.78 (m, 1 H), 7.78 (m,
H), 7.74 (d, 1 H), 7.64 (t, 1 H), 7.53 (d, 1 H), 7.44 (dd, 1 H)
DEI (70eV) : [M]+. = 250
Intermediate 216
NMR: (400 MHz, dmso-d6) δ ppm 9.59 (s, 1 H), 9.43 (s, 1 H), 8.46 (d, 1 H), 8.26 (d, 1 H), 8.06 (d, 1 H), 7.85 (t, 1 H), 7.81 (t, 1 H), 7.77 (d, 1 H), 7.74 (t, 1 H), 7.51 (d, 1 H), 7.24 (d, 1 H)
Intermediate 217
‘H NMR: (400 MHz, CDC13) δ ppm 9.2 (s, 1 H), 8.1 (dd, 1 H), 7.85 (m, 2 H), 7.4 (m, 2 H),
7.3 (dd+s, 2 H), 7.2 (td, 1 H) . -44( 19F NMR: (400 MHz, CDC13) δ ppm -101.1
GC-EI (70eV) : [M]+. = 256
Intermediate 218
*H NMR: (400 MHz, dmso-d6) δ ppm 9.25 (s, 1 H), 8.8 (d, 1 H), 8 (m, 1 H), 7.85 (m, 1 H), 7.85/7.75 (2m, 2 H), 7.05 (d, 1 H)
Intermediate 219
}H NMR: (400 MHz, dmso-d6) ô ppm 10.05 (s, 1 H), 9.2 (s, 1 H), 8.05 (m, 2 H), 7.7 (m, 3 H) 10 Intermediate 220
CE 1H NMR: (400 MHz, dmso-d6) δ ppm 9.81 (s, 1 H), 8.02 (dd, 1 H), 7.58/7.52 (2d, 4 H), 7.46 (td, 1 H), 7.4 (dd, 1 H)
GC-EI (70e V) : [M]+. = 234
I5 Intermediate 221
,¾ NMR: (400 MHz, dmso-d6) δ ppm 9.82 (s, 1 H), 7.97 (dd, 1 H), 7.42 (d, 2 H), 7.38 (td, 1 H), 7.35 (dd, 1 H), 7.09 (d, 2 H), 3.83 (s, 3 H)
-45Intermediate 222
1H NMR: (400 MHz, dmso-d6) 6 ppm 9.82 (s, 1 H), 7.99 (dd, 1 H), 7.42 (m, 3 H), 7.08/7.01 (2dl, 2 H), 7.06 (si, 1 H), 3.82 (s, 3 H)
Intermediate 223
LH.NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 7.92 (dd, 1 H), 7.78 (td, 1 H), 7.69 (dd, 1 H), 7.65 (dd, 1 H), 7.38 (d, 1 H), 7.07 (d, 1 H), 3.68 (s, 3 H)
Intermediate 224
NMR: (400 MHz, dmso-d6) δ ppm 9.8 (si, 1 H), 7.68 (dd, 1 H), 7.62 (m, 2 H), 7.54 (m, 3 H), 7.5 (d, 1 H)
GC-EI (70eV) : [M]+. = 188
Intermediate 225
O
TH NMR: (400 MHz, dmso-d6) δ ppm 10.35 (s, 1 H), 8.07 (d, 1 H), 7.99 (d, 1 H), 7.88 (m, 2 H), 7.79/7.67 (2*t, 2 H)
Intermediate 226
O
( : TfNMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 7.95 (d, 1 H), 7.8 (m, 1 H), 7.65 (m, 1 H),
7.5 (d, 1 H), 6.85 (s, 1 H), 3.4 (s, 3 H), 2.4 (s, 3 H)
Intermediate 227
Tl NMR: (400 MHz, dmso-d6) δ ppm 9.85 (s, 1 H), 8.15 (m, 1 H), 8.06 (m, 1 H), 7.85 (m, 1 H), 7.74 (s, 1 H), 7.7 (m, 1 H), 7.7 (m, 1 H), 7.7 (m, 1 H), 7.35 (m, 1 H), 6.95 (m, 1 H)
Intermediate 228
O
Tl NMR: (400/500 MHz, dmso-d6) δ ppm 9.53 (s, 1 H), 8.08 (d, 1 H), 8.08 (d, 1 H), 8.02 (dd,
1 H), 7.83 (td, 1 H), 7.71 (tt, 1 H), 7.63 (dd, 1 H), 7.57 (td, 1 H), 7.51 (d, 1 H), 7.49 (d, 1 H),
7.49 (td, 1 H), 7.38 (dt, 1 H) ’
-C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 143.5, 135.5, 135, 134, 133, 132, 128.5,
128.5, 128,128, 127, 127, 126.5,125.5, 125
1HNMR: (400 MHz, CDC13) δ ppm 9.9 (s, 1 H), 8.05 (dd, 1 H), 7.15 (m, 2 H), 7 (d, 1 H), 6.9 (m, 2 H), 3.95 (2 s, 6 H)
DEI (70eV) : [M]+. = 260
-47Intermediate 230
H NMR: (400 MHz, dmso-d6) δ ppm 10.8 (si, 1 H), 9.7 (s, 1 H), 8.2 (d, 1 H), 7.83 (d, 1 H),
7.79 (dd, 1 H), 6.95 (dd, 1 H), 6.91 (d, 1 H), 6.77 (d, 1 H), 3.9 (s, 3 H)
Intermediate 231 ''O
F ίο 1R NMR: (400 MHz, CDC13) δ ppm 10.2 (s, 1 H), 8 (dd, 1 H), 7.75 (t, 1 H), 7.4 (dd, 1 H), 7.2 (m, 2 H), 6.8 (d, 1 H), 3.95 (s, 3 H)
GC-EI(70eV) : ΓΜ1+. = 231
Intermediate 232
F
1]H NMR/ (400 MHz, CDC13) δ ppm 10.5 (m, 1 H), 8.1 (dd, 1 H), 8 (m, 1 H), 7.5 (d, 1 H), 7.4 (dd, 1 H), 7.25 (td, 1 H)
GC-EI (70e V) : [M]+. = 207
Intermediate 233
O
1HNMR: (400 MHz, dmso-d6) δ ppm 10 (s, 1 H), 8.65 (s, 1 H), 8.06 (m, 2 H), 7.6 (m, 3 H)
-48Intermediate 234
F 1r NMR: (400 MHz, CDC13) δ ppm 9.8 (s, 1 H), 8.2 (dd, 1 H), 8 (d, 1 H), 7.8 (d, 1 H), 7.75 (s, 1 H), 7.3 (m, 3 H), 6.95 (t, 1 H)
GC-EI (70eV) : [M]+. = 240
Intermediate 235
ÎHNMR: (400 MHz, dmso-d6) δ ppm 10.15 (d, 1 H), 8.05 (s, 1 H), 7.86 (dd, 1 H), 7.7 (d, 1 H), 7.68 (td, 1 H), 7.53 (dd, 1 H), 7.46 (td, 1 H), 3.91 (s, 3 H) 10 Intermediate 236
1HNMR: (400 MHz, dmso-d6) δ ppm 10 (s, 1 H), 9.25 (s, 1 H), 8.91 (s, 2 H), 8.05 (dd, 1 H),
7.83 (td, 1 H), 7.73 (td, 1 H), 7.58 (dd, 1 H)
Intermediate 237
O
1HNMR: (300 MHz, dmso-d6) δ ppm9.9 (s, 1 H), 8.25 (s, 1 H), 7.95 (d, 1 H), 7.85 (dd, 1 H),
7.75/7.6 (2*m, 2 H), 7.55 (d, 1 H), 6.95 (d, 1 H), 3.9 (s, 3 H)
-49Intermediate 238
Td NMR: (400/500 MHz, dmso-d6) δ ppm 9.64 (s, 1 H), 7.68 (d, 1 H), 7.63 (t, 1 H), 7.57 (t, 1 H), 7.51 (t, 1 H), 7.47 (d, 1 H), 7.45 (t, 1 H), 7.42 (d, 1 H), 7.34 (d, 1 H), 7.17/7.03 (2*m, 5 H)
Intermediate 239
]H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 8 (d, 1 H), 7.8 (t, 1 H), 7.69 (t, 1 H), 7.6 (d, 1 H), 7.55 (m, 2 H), 7.4 (d, 1 H)
GC-EI (70eV) : [M]+. = 250
Intermediate 240
^NMR: (400/500 MHz, dmso-d6) δ ppm 9.95 (s, 1 H), 8.07 (d, 1 H), 8.02 (m, 2 H), 7.99 (d, 1 H), 7.98 (dd, 1 H), 7.8 (td, 1 H), 7.64 (d, 1 H), 7,62 (td, 1 H), 7.62 (m, 1 H), 7.6 (m, 2 H) 13C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 134, 131.5, 129, 128, 128, 128, 128, 127.5, 127
Intermediate 241
‘HNMR: (400/500 MHz, dmso-d6) δ ppm 9.98 (s, 1 H), 7.95 (dd, 1 H), 7.78 (m, 1 H), 7.78 (m, 1 H), 7.75 (d, 2 H), 7.72 (t, 1 H), 7.63 (d, 1 H), 7.62 (t, 1 H), 7.61 (t, 1 H), 7.49 (t, 2 H),
7.44 (dt, 1 H), 7.4 (t, 1 H) 13C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 145.5, 140, 134, 133.5, 131, 129, 129, 128, 128,128, 127.5, 127,127, 127
-50Intermediate 242
NMR: (400 MHz, dmso-d6) δ ppm 9.77 (s, 1 H), 8.05 (dd, 1 H), 7.82 (td, 1 H), Ί.Ί (td, 1 H), 7.6 (d, 2 H), 7.5 (t, 1 H), 7.35 (dd, 1 H)
Intermediate 243
O
‘H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 9.25 (s, 1 H), 8.95 (s, 2 H), 8.15 (dd, 1 H),
7.55 (m, 2 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -102.8
Intermediate 244
Ή NMR: (400 MHz, CDC13) ô ppm 10 (s, 1 H), 8.25 (dd, 1 H), 8.05 (dd, 1 H), 7.7 (td, 1 H),
7.55 (td, 1 H), 7.4 (dd, 1 H), 6.9 (dd, 1 H), 6.75 (dd, 1 H), 4 (s, 3 H)
Intermediate 245
‘H NMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1 H), 7.9 (dd, 1 H), 7.75 (td, 1 H), 7.58 (t, 1 H),
7.43 (d, 1 H), 7.25-7.15 (m, 2 H), 6.91 (dd, 1 H), 3.87 (s, 3 H), 3.38 (s, 3 H)
-51Intermediate 246
Ή NMR: (300/400/500 MHz, dmso-d6) Ô ppm 10.03 (s, 1 H), 7.98 (dd, 1 H), 7.83 (dd, 1 H),
7.46 (dd, 1 H), 7.43 (td, 1 H), 7.36 (dd, 1 H), 7.25 (dd, 1 H) 13C NMR: (300/400/500 MHz, dmso-d6) δ ppm 190.2, 165, 140.3, 137.3, 131.2, 130.7, 130.6,
129,128.4, 117.8, 115.9 19FNMR: (300/400/500 MHz, dmso-d6) δ ppm -103
Intermediate 247
‘HNMR: (300/400/500 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 8.06 (s, 1 H), 8.05 (d, 1 H), 8.048.02 (m, 3 H), 7.64 (dd, 1 H), 7.61 (td, 2 H), 7.51-7.47 (m, 2 H) 13C NMR: (300/400/500 MHz. dmso-d6) δ ppm 190.4, 165, 148.3, 131.2, 130.6, 129.5-128.2, 128.2, 127.7,127.1, 117.9/115.5 19FNMR: (300/400/500 MHz, dmso-d6) δ ppm -103.2
Intermediate 248
NMR: (400 MHz, CDC13) δ ppm 9.88 (s, 1 H), 8.1 (dd, 1 H), 7.74 (s, 1 H), 7.29 (td, 1 H),
7.14 (s, 1 H), 7.1 (dd, 1 H), 3.56 (s, 3 H) -
Intermediate 249
-52p !H NMR: (400 MHz, dmso-d6) δ ppm 9.84 (s, 1 H), 8.27 (d, 1 H), 8.04 (dd, 1 H), 7.5 (td, 1 H), 7.43 (dd, 1 H), 7.1 (dd, 1 H), 6.96 (s, 1 H), 3.91 (s, 3 H) 19FNMR: (400 MHz, CDC13) δ ppm -101.2
Intermediate 250
O
Ή NMR: (400 MHz, dmso-d6) δ ppm 10.1 (s, 1 H), 8.12 (d, 1 H), 7.93 (d, 1 H), 7.78 (dd, 1
H), 7.39 (dd, 1 H), 7.3 (td, 1 H), 3.91 (s, 3 H)
Intermediate 251
O
Cl ]H NMR: (400 MHz, dmso-d6) δ ppm 9.76 (s, 1 H), 7.98 (dd, 1 H), 7.79 (td, 1 H), 7.77 (d, 1
H), 7.68 (td, 1 H), 7.56 (dd, 1 H), 7.47 (d, 1 H), 7.39 (dd, 1 H)
Intermediate 252
NMR: (400 MHz, dmso-d6), δ ppm 9.84 (s, 1 H), 8.59 (d, 1 H), 7.69 (d, 1 H), 7.5-7.3 (m, 5
H)
Intermediate 253
O
Ή NMR: (400 MHz, dmso-d6) δ ppm 9.64 (s, 1 H), 8.04 (dd, 1 H), 7.62 (d, 1 H), 7.5 (m, 1 H), 7.5 (m, 3 H), 7.32 (dd, 1 H)
-53Intermediate 254
ο *Η NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 8 (dd, 1 H), 7.45 (m, 3 H), 7.15 (m, 2 H),
7.1 (dd, 1 H), 5.25. (s, 2 H), 3.4 (s, 3 H)
Intermediate 255
HO
Ο 1HNMR: (400 MHz, dmso-d6) δ ppm 10.75 (s, 1 H), 9.95 (s, 1 H), 7.85 (d, 1 H), 7.75 (d, 1 H), 7.25 (d, 1 H), 7.2 (d, 1 H), 6.95 (dd, 1 H), 6.9 (s, 1 H)
GC-EI (70eV) : [M]+. = 204
Intermediate 256
Ή NMR: (400 MHz, dmso-d6) δ ppm 10.6 (s, 1 H), 9.7 (s, 1 H), 7.8 (d, 1 H), 7.05 (d, 1 H), 7 (s, 1 H), 6.9 (m, 2 H), 6.8 (s, 1 H), 3.8 (2s, 6 H)
Intermediate 257
O
NMR: (300 MHz, CDC13) δ ppm 9.9 (s, 1 H), 8.09 (dd, 1 H), 7.5/7.4 (unresolved peak, 5 H), 7.21 (dd, lH),7.15(dd, 1 H) 19F NMR: (300 MHz, CDC13) δ ppm -103.7
-54Intermediate 258
*H NMR: (400 MHz, CDC13) δ ppm 10 (s, 1 H), 8.73 (d, 2 H), 8.08 (dd, 1 H), 7.71 (dt, 1 H),
7.61 (dt, 1 H), 7.42 (dd, 1 H), 7.35 (d, 2 H)
Intermediate 259
‘H.XMR: (400 MHz, CDC13) δ ppm 10.1 (d, 1 H), 8 (dd, 1 H), 7.62 (dt, 1 H), 7.48 (2*m, 2 H), 7.46 (dd, 1 H), 7.3 (dd, 1 H), 7.2 (dd, 1 H)
Intermediate 260
!H NMR: (400 MHz, CDC13) δ ppm 9.99 (s, 1 H), 8.71 (dd, 1 H), 8.67 (d, 1 H), 8.07 (dl, 1 H), 7.75 (dt, 1 H), 7.7 (tl, 1 H), 7.59 (tl, 1 H), 7.44 (dd, 1 H), 7.43 (dl, 1 H)
Intermediate 261 ,
F
ft-INMR: (300 MHz, CDC13) δ ppm 9.9 (d, 1 H), 8.74 (dd, 1 H), 8.69 (dd, 1 H), 8.12 (dd, 1 H), 7.74 (ddd, 1 H), ΊΑΊ (ddd, 1 H), 7.28 (m, 1 H), 7.15 (dd, 1 H) 19FNMR: (300 MHz, CDC13) δ ppm -102.6
-55Intermediate 262
ΧΗ NMR: (400 MHz, CDC13) δ ppm 9.89 (s, 1 H), 8.75 (d, 2 H), 8.11 (dd, 1 H), 7.33 (d, 2 H),
7.27 (td, 1 H), 7.12 (dd, 1 H)
Intermediate 263
!H NMR: (400 MHz, CDC13) δ ppm 9.82 (s, 1 H), 8.01 (d, 1 H), 7.45 (m, 3 H), 7.38 (m, 2 H),
6.94 (dd, 1 H), 6.85 (df, 1 H), 5.72 (si, 1 H)
Intermediate 264
îH NMR: (400 MHz, CDC13) δ ppm 9.68 (s, 1 H), 9.35 (s, 1 H), 8.5 (s, 1 H), 8.15 (dd, 1 H),
8.1 (m, 1 H), 7.75 (dt, 1 H), 7.67 (2*m, 2 H), 7.65 (dt, 1 H), 7.51 (m, 1 H), ΊΑΊ (dd, 1 H) GC-EI (70eV) : [M]+. = 233.1
Intermediate 265
O
OH ^NMR: (300 MHz, CDC13) δ ppm 9.9 (si, 1 H), 8.03 (dd, 1 H), 7.24 (d, 2 H), 7.12 (td, 1 H),
7.1 (dd, 1 H), 6.95 (d, 2 H), 5.3 (s, 1 H) 19FNMR: (300 MHz, CDC13) δ ppm -102.4
-56Intermediate 266
-H NMR: (40° MHz> dmso-d6) δ ppm 10.65 (s, 1 H), 9.65 (s, 1 H), 7.8 (d, 1 H), 7.3 (s, 4 H), 6.9 (dd, 1 H), 6.75 (s, 1 H), 2.35 (d, 3 H)
Intermediate 267
/H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 8.2 (d, 1 H), 8.05 (d, 1 H), 7.75 (s, 1 H),
7.7 (d, 1 H), 7.35 (t, 1 H), 7.25 (dd, 1 H), 7.2 (s, 1 H), 6.95 (t, 1 H), 3.9 (s, 3 H) Intermediate 268
-ÎBNMR: (400 MHz, dmso-d6) δ ppm 9.75 (s, 1 H), 8.69 (d, 2 H), 7.97 (d, 1 H), 7.7 (dd, 1 H),
7.5 (d, 2 H), 7 (d, 1 H), 3.9 (s, 3 H)
Intermediate 269
]HNMR: (300/400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 8 (dd, 1 H), 7.55 (m, 1 H), 7.5 (m, 1 H), 7.45 (d, 1 H), 7.45 (d, 1 H), 7.35 (m, 1 H), 7.3 (dd, 1 H) 19F NMR: (300/400 MHz, dmso-d6) δ ppm -103.1, -111.7
-57Intermediate 270
HO
Ο 1H NMR: (400 MHz, dmso-d6) δ ppm 10.75 (si, 1 H), 9.65 (s, 1 H), 7.81 (d, 1 H), 7.45 (dd, 2 H), 7.3 (dd, 2 H), 6.93 (dd, 1 H), 6.75 (d, 1 H) 5 Intermediate 271
O
(H NMR: (400 MHz, CDC13) δ ppm 9.88 (s, 1 H), 8.06 (dd, 1 H), 7.36 (dd, 2 H), 7.19 (m, 1 H), 7.19 (dd, 2 H), 7.11 (dd, 1 H)
Intermediate 272
O
*H NMR: (400 MHz, CDC13) δ ppm 9.9 (s, 1 H), 8.05 (dd, 1 H), 7.28 (dd, 4 H), 7.16 (td, 1
H), 7.12 (dd, 1 H), 2.44 (s, 3 H)
Intermediate 273
O
ΧΗ NMR: (400 MHz, dmso-d6) δ ppm 9.82 (s, 1 H), 8 (dd, 1 H), 7.48-7.3 (m, 2 H), 7.48-7.3 (m, 2 H), 7 (ddd, 1 H), 3.9 (s, 3 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -104.4, -135.7
-58Intermediate 274
1H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 8.05 (dd, 1 H), 7.45 (m, 1 H), 7.4 (d, 1 H), 6.9 (s, 1 H), 3.45 (s, 3 H), 2.35 (s, 3 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -102.9
Intermediate 275 %
£>ÇJ '
1HNMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1 H), 7.95 (d, 1 H), 7.15 (dd, 1 H), 7 (s, 1 H),
6.85 (s, 1 H), 3.9 (s, 3 H), 3.4 (s, 3 H), 2.35 (s, 3 H) 0 Intermediate 276
1HNMR: (300/400 MHz, dmso-d6) δ ppm 9.7 (s, 1 H), 7.93 (d, 1 H), 7.8 (s, 1 H), 7.18 (dd, 1 H), 7.03 (d, 1 H), 7 (s, 1 H), 3.9 (s, 3 H), 3.54 (s, 3 H)
Intermediate 277 15 * * *
^NMR: (400 MHz, CDC13) δ ppm 9.85 (s, 1 H), 8.15 (dd, 1 H), 7.6 (s, 1 H), 7.3 (m, 1 H),
7.15 (d, 1 H), 6.35 (s, 1 H), 3.75 (s, 3 H) 19F NMR: (400 MHz, CDC13) δ ppm -101.2
-59Intermediate 278
1H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 7.98 (dd, 1 H), 7.9 (d, 1 H), 7.84 (d, 1 H),
7.78 (td, 1 H), 7.77 (dd, 1 H), 7.67 (tl, 1 H), 7.55 (dd, 1 H)
DEI (70eV) : [M]+. = 284
Intermediate 279
NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 7.9 (d, 1 H), 7.75 (m, 1 H), 7.55 (m, 1 H),
7.5 (d, 1 H), 7.1 (s, 1 H), 7.05 (d, 1 H), 6.85 (dd, 1 H), 6.1 (s, 2 H)
Intermediate 280
Ή NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1 H), 7.99 (d, 1 H), 7.8 (t, 1 H), 7.69 (t, 1 H),
7.58 (d, 1 H), 7.55 (d, 1 H), 6.41 (d, 1 H), 3.69 (s, 3 H) 13C NMR: (400 MHz, dmso-d6) δ ppm 191, 138, 138,136,134,133, 132, 130, 128,109, 37
Intermediate 281
NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1 H), 7.91 (d, 1 H), 7.75 (t, 1 H), 7.59 (t, 1 H),
7.54 (d, 1 H), 7.42 (t, 1 H), 7.05 (dd, 1 H), 7.01 (t, 1 H), 6.98 (dd, 1 H), 3.82 (s, 3 H)
-60Intermediate 282
]H NMR: (400 MHz, dmso-d6) δ ppm 9.66 (s, 1 H), 7.86 (d, 1 H), 7.73 (t, 1 H), 7.54 (t, 1 H),
7.46 (t, 1 H), 7.38 (d, 1 H), 7.31 (d, 1 H), 7.14 (d, 1 H), 7.11 (t, 1 H), 3.69 (s, 3 H)
Intermediate 283
1H NMR: (400 MHz, dmso-d6) δ ppm 9.86 (s, 1 H), 8.17 (d, 1 H), 7.78 (d, 1 H), 7.7-7.55 (m,
H), 7.7-7.55 (m, 5 H), 7.52 (t, 1 H)
Intermediate 284
NMR: (400 MHz, dmso-d6) δ ppm 9.82 (d, 1 H), 8.17 (dd, 1 H), 7.62 (d, 2 H), 7.52 (m, 3 H), 7.43 (d, 1 H)
Intermediate 285
Ή NMR: (400 MHz, CDC13) δ ppm 9.85 (s, 1 H), 8.03 (d, 1 H), 7.5-7.37 (m, 5 H), 7 (dd, 1 H), 6.89 (df, 1 H), 3.9 (s, 3 H)
-61Intermediate 286
F
Ή NMR: (400 MHz, dmso-d6) δ ppm 9.89 (s, 1 H), 7.95 (d, 1 H), 7.77 (t, 1 H), 7.62 (m, 3
H), 7.53 (d, 1 H), 7.49 (d, 2 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -55.59
Intermediate 287
1H..NMR: (400 MHz, CDCB) δ ppm 9.9 (d, 1 H), 8.04 (dd, 1 H), 7.68 (dt, 1 H), 7.56 (t, 1 H),
7.39 (d, 1 H), 7.31 (dt, 1 H), 7.01 (dt, 1 H), 6.95 (dt, 1 H) 19FNMR: (400 MHz, CDCB) δ ppm -109/-110
Intermediate 288
*H NMR: (400 MHz, CDCB) δ ppm 10 (d, 1 H), 8.01 (dd, 1 H), 7.63 (dt, 1 H), 7.48 (t, 1 H),
7.44 (d, 1 H), 7.29 (s, 4 H), 2.43 (s, 3 H) 15 Intermediate 289
JH NMR: (400 MHz, CDCB) δ ppm 10 (s, 1 H), 8.02 (d, 1 H), 7.62 (t, 1 H), 7.45 (d, 1 H),
7.32 (2*d, 4 H), 4.48 (t, 1 H), 2.99 (hept., 1 H), 1.31 (d, 6 H)
-62Intermediate 290
-H NMR: (400 MHz, CDC13) δ ppm 10.27 (d, 1 H), 7.99 (dd, 1 H), 7.61 (dt, 1 H), 7.55 (2*m. 2 H), 7.46 (2*m, 2 H), 6.59 (dd, 1 H)
Intermediate 291
1HNMR: (300 MHz, dmso-d6) δ ppm 9.99 (s, 1 H), 8.86 (d, 1 H), 8.82 (df, 1 H), 7,79 (dd, 1 H), 7.6 (2*d, 4 H)
Intermediate 292
IHNMR: (400MHz, dmso-d6) δ ppm 9.85 (s, 1 H), 7.95 (d, 1 H), 7.65 (dd, 1 H), 7.6 (s, 1 H)
7.55 (d, 2 H), 7.5 (d, 2 H) ’
Intermediate 293
Ή NMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1 H), 8 (dd, 1 H), 7.8 (td, 1 H), 7.7 (td, 1 H),
7.65 (d, 1 H), 7.55 (dd, 1 H), 6.5 (d, 1 H), 5 (dd, 1 H), 3.8/3.25 (2m, 2 H), 2.25/1.8 (2m, 2 H), 1.9/1.5 (2m, 2 H), 1.4 (m, 2 H)
-63f Procedure F : Generic procedure for reductive amination starting from intermediate 21 (synthesis of intermediates 22 to 127).
Intermediate 21 (14 g, 26.2 mmol), anhydrous DCM (280 mL), the aldéhyde (intermediates 213 to 293) (39.3 mmol, 1.5 eq) and MgSÛ4 (14 g) are introduced in succession into a
500 mL three-necked flask at ambient température and under a stream of argon. After stirring for 1 hour, NaBH(OAc)3 (8.32 g, 39.3 mmol, 1.5 eq) is added in portions and the reaction mixture is maintained at ambient température for 16 hours. The reaction is monitored by LC/MS. The insoluble components are filtered off over microfibre and rinsed with DCM (100 mL). The filtrate is then washed with water (1 x 200 mL) and then with a saturated NaCl 10 solution (2 x 200 mL). The organic phase is dried over MgSÛ4 and concentrated under reduced pressure. The oil obtained is then purified by flash chromatography on silica gel (330 g) to yield intermediates 22 to 127.
EX AMPLE 31: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 31 is obtained starting from intermediate 21 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 3.5-3.65 (2m, 2 H), 3.2 (m, 1 H), 3.05 (dd, 1 H), 2.95 (m, 2 H), 2.15 (m, 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.65 (m, 2 H), 1.5 (m, 1 H), 1.4 (m, 1 H), 1.25 . (m, 1 H)
EST/FIA/HR and MS/MS : [M+H]+ = 251.1154 (251.1160)
Elemental analysis : C=42.65(43.20);H=7.23(7.65);N=11.24(11.20)
Intermediate 22 : ieri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(3-fhioro-4hydroxyphenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 22 is obtained starting from intermediate 21 and 3-fluoro-4hydroxybenzaldehyde in accordance with procedure F described hereinbefore.
j-INMR: (400 MHz, dmso-d6) δ ppm 7.0 (d, 1 H), 6.88 (d, 2 H), 3.95 (m, 2 H), 3.5/3.33 (2*d, 2 H), 3.4 (m, 2 H), 2.85/2.3 (2*m, 2 H), 2.8/2.45 (dd, 2 H), 2-1.6 (m, 4 H), 1.42/1.35 (2*s, 27 H), 1.4 (m, 2 H), 1.2 (t, 3 H), 0.9 (m, 2 H)
-64Γ
EXAMPLE 32 :3-(4-Aminobutyl)-l-[(3-fluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4oxo- L4-azaphosphinane-3-carboxylic acid
Example 32 is obtained starting from intermediate 22 in accordance with procedure D described hereinbefore.
/H NMR; (300/400 MHz, D2O) δ ppm 7.24 (dd, 1 H), 7.12 (dd, 1 H), 7.03 (t, 1 H), 4.32/4.12 (2*d, 2 H), 3.68/3.3 (2*m, 2 H), 3.45/3.07 (2*m, 2 H), 2.92 (m, 2 H), 2.22/1.78 (2*m, 2 H), 1.92/1.58 (2*m, 2 H), 1.58/1.46 (2*m, 2 H), 1.23/1.1 (2*m, 2 H) 19FNMR: (300/400 MHz, D2O) δ ppm -135.8
ESI/FIA/HR and MS/MS : [M+H]+ = 375.1455 (375.1480) 10 Elemental analysis : C=51.71(51.34);H=6.44(6.46);N=7.64(7.48)
Intermediate 23 : twt-Butyl 3-{4-[bis(/er/-butoxycarbonyI)aniino]butyl}-l-[(2,4difluorophenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 23 is obtained. starting from intermediate 21 and 2,4-difluorobenzaldehyde in 15 accordance with procedure F described hereinbefore.
1R NMR; (400 MHz, dmso-d6) δ ppm 7.44 (m, 1 H), 7.19 (m, 1 H), 7.07 (m, 1 H), 4 (m, 2 H), 3.57 (m, 2 H), 3-2.6/2.35 (m, 2 H), 3-2.6/2.52 (m, 2 H), 2.78 (m, 2 H), 2-1.6 (m, 2 H), 2-1.6 (m, 2 H), 1.39 (m, 27 H), 1.39 (m, 2 H), 1.2 (m, 3 H), 0.82 (m, 2 H)
EXAMPLE 33: 3-(4-Aminobutyl)-l-[(2,4-difluorophenyI)methyl]-4-hydroxy-4-oxo-l,420 azaphosphinane-3-carboxylic acid
Example 33 is obtained starting from intermediate 23 in accordance with procedure D described hereinbefore.
*H NMR: (400 MHz, D2O) δ ppm 7.51 (m, 1 H), 7.07 (m, 2 H), 4.37 (si, 2 H), 3.69/3.33 (m, 2 25 H), 3.49/3.19 (m, 2 H), 2.95 (m, 2 H), 2.21/1.77 (m, 2 H), 1.95/1.49 (m, 2 H), 1.61 (m, 2 H),
1.28/1.14 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 377.1419 (377.1441)
Elemental analysis : C=50.66(51.06);H=5.79(6.16);N=7.37(7.44) . -65Intermediate 24 : tert-Butyl 3-{4-[Bis(ieri-butoxycarbonyI)amino]butyl}-l-[(3,5difluoro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 24 is obtained starting from intermediate 21 and 3,5-difluoro-4-hydroxybenzaldehyde in accordance with procedure F described hereinbefore, 1H NMR: (300 MHz, dmso-d6) δ ppm 10.1 (si, 1 H), 6.63 (d, 2 H), 4.1-3.8 (m, 2 H), 3.58-3.3 (m, 2 H), 3.58-3.3 (m, 2 H), 3-2.6/2.3 (2*m, 2 H), 3-2.6/2.49 (2*m, 2 H), 2-1.5 (m, 2 H), 2-1.5 (m, 2 H), 1.4 (m, 2 H), 1.4/1.37 (2*s, 27 H), 1.2 (t, 3 H), 1.1-0.8 (m, 2 H)
EXAMPLE 34 :3-(4-Aminobutyl)-l-[(3,5-difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-
4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 34 is obtained starting from intermediate 24 in accordance with procedure D described hereinbefore.
H NMR: (300/400 MHz, D2O) δ ppm 7.1 (m, 2 H), 4.33/4.12 (2*d, 2 H), 3.69/3.31 (2*dd, 2
H), 3.45/3.09 (2*dd, 2 H), 2.94 (m, 2 H), 2.24/1.78 (2*m, 2 H), 1.93/1.6 (2*m, 2 H), 1.6/1,47 (2*m, 2 H), 1.25/1.13 (2*m, 2 H) 19F NMR: (300/400 MHz, D2O) δ ppm-132
ESI/FIA/HR and MS/MS : [M+H]+ = 393.1388 (393.1390)
Elemental analysis : C=48.74(48.98);H=5.90(5.91);N=7.10(7.14)
Intermediate 25 : teri-Butyl 3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-l-[[4(difluoromethyi)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-
3-carboxylate
Intermediate 25 is obtained starting from intermediate 21 and 4-(difluoromethyl)benzaldehyde in accordance with procedure F described hereinbefore.
'H NMR: (400 MHz, dmso-d6) δ ppm 7.55-7.4 (dd, 4 H), 7 (t, 1 H), 4.1-3.85 (m, 2 H), 3.7-3.5 (dd, 2 H), 3.35 (m, 2 H), 3-2.25 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.8 (m, 2 H).
-66EXAMPLE 35:3-(4-Aminobutyl)-l-[[4-(difluoromethyl)phenyl]methyl]-4-hydroxy-4oxo-l,4-azaphosphînane-3-carboxylic acid
Example 35 is obtained starting from intermediate 25 in accordance with procedure D described hereinbefore.
‘H NMR: (400 MHz, D2O) δ ppm 7.7-7.6 (d, 4 H), 6.85 (t, 1 H), 4.5/4.3 (m, 2 H), 3.8-3.65 (m, 1 H), 3.55-3.35 (m, 2 H), 3.15 (m, 1 H), 2.95 (m, 2 H), 2.25 (m, 1 H), 2-1.75 (m, 2 H), 1.65-1.5 (m, 3 H), 1.3-1.1 (m, 2 H) 31PNMR: (400 MHz, D2O) δ ppm 26 19F NMR: (400 MHz, D2O) δ ppm -110
ES1/FIA/HR and MS/MS : [M+H]+ = 391.1583 (391.1598)
Elemental analysis : C=51.85(52.31);H=6.46(6.45);N=7.04(7.18)
Intermediate 26 : ieri-Butyl 3-{4-[bis(ieri-butoxycarbonyl)ammo]butyl}-4-ethoxy-l-[[4hydroxy-3-(trifluoromethyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3 -carboxylate
Intermediate 26 is obtained starting from intermediate 21 and 4-hydroxy-3(trifluoromethyl)benzaldehyde in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 10.45 (unresolved peak, 1 H), 7.4 (si, T H), 7.34 (dl, 1 H), 6.96 (d, 1 H), 4.1-3.85 (m, 2 H), 3.65-3.3 (m, 2 H), 3.65-3.3 (m, 2 H), 3-2.2 (m, 4 H), 2-
1.6 (m, 4 H), 1.38 (m, 29 H), 1.2 (t, 3 H), 0.88 (m, 2 H)
EXAMPLE 36 :3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-3-(trifluoromethyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 36 is obtained starting from intermediate 26 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.68 (df, 1 H), 7.55 (dd, 1 H), 7.09 (d, 1 H), 4.38/4.2 (2*d, 2 H), 3.7/3.3 (2*dd, 2 H), 3.45/3.09 (2*dd, 2 H), 2.92 (m, 2 H), 2.23/1.77 (2*m, 2 H), 1.93/1.6 (2*m, 2 H), 1.6/1.47 (2*m, 2 H), 1.25/1.11 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 425.1453 (425.1453)
Elemental analysis : C=48.19(48.12);H=5.16(5.70);N=6.72(6.60) . -67( Intermediate 27 : tot-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(3-chIoro-5fluoro-4-hydroxyphenyl)methyI]-4-ethoxy-4 -oxo-1,4azaphosphinane-3-carboxylate
Intermediate 27 is obtained starting from intermediate 21 and 3-chloro-5-fluoro-45 hydroxybenzaldehyde in accordance with procedure F described hereinbefore.
-HNMR: (4θθ MHz, dmso-d6) δ ppm 10.26 (si, 1 H), 7.12 (si, 1 H), 7.07 (dl, 1 H), 4.06/3.98 (2quad, 2 H), 3.47 (AB, 2 H), 3.42 (m, 2 H), 3-2.26 (m, 4 H), 1.94 (m, 4 H), 1.41/1.37 (2s, 27 H), 1.4 (m, 2 H), 1.25/1.21 (2t, 3 H), 0.92 (m, 2 H) _F NMR: (400 MHz, dmso-d6) δ ppm -131.7 31P NMR: (400 MHz, dmso-d6) δ ppm -43
ESI/FIA/HR and MS/MS : [M+H]+ = 693.308 (693.3083)
EXAMPLE 37:3-(4-Aminobutyl)-l-[(3-chIoro-5-fluoro-4-hydroxyphenyI)methyl]-4hydroxy-4 -oxo- l,4-azaphosphinane-3-carboxyIic acid
Example 37 is obtained starting from intermediate 27 in accordance with procedure D described hereinbefore.
-U NMIL (400 MHz, D2O) δ ppm 7.3 (m, 1 H), 7.21 (m, 1 H), 4.31/4.12 (2*d, 2 H), 3.69/3.3 (2*dd, 2 H), 3.45/3.09 (2*dd, 2 H), 2.93 (m, 2 H), 2.24/1.77 (2*m, 2 H), 1.93/1.6 (2*m, 2 H), 1.6/1.47 (2*m, 2 H), 1.27/1.13 (2*m, 2 H) ’ ’ _19FNMR: (400 MHz, D2O) δ ppm -131.6
ESI/FIA/HR and MS/MS : [M+H]+ = 409.1091 (409.1095)
Elemental analysis : C=47.25(47.01);H=5.75(5.67);N=6.92(6.85)
Intermediate 28 : ieri-Butyl 3-{4-[bis(W-butoxycarbonyl)amino]biityl}-l-(2,3-dihydro- l-benzofuran-5-yImethyl)-4-ethoxy-4-oxo-l,4-azaphosphinane-3- 25 carboxylate
Intermediate 28 is obtained starting from intermediate 21 and 2,3-dihydrobenzofuran-5carbaldehyde in accordance with procedure F described hereinbefore.
NMR: <400 MHz’ <Lnso-d6) δ ppm 7.13 (d, 1 H), 6.97 (dd, 1 H), 6.68 (d, 1 H), 4.5 (t, 2 H), (m, 2 H), 3.55-3.3 (m, 4 H), 3.15 (m, 2 H), 3-2.2 (m, 4 H), 1.91 (m, 4 H), 1.39 (m, 29 H), 30 1.2 (t, 3 H), 0.87 (m, 2 H) ’ ’ p ’68'
EXAMPLE 38:3-(4-Aminobutyi)-l-(2,3-dihydro-l-benzofuran-5-yImethyl)-4-hydroxy-
4-oxo-1,4-azaphosphi nane-3-carboxylic acid
Example 38 is obtained starting from intermediate 28 in accordance with procedure D described hereinbefore.
1HNMR: (400 MHz, D2O) δ ppm 7.34 (d, 1 H), 7.2 (dd, 1 H), 6.85 (d, 1 H), 4.59 (t, 2 H), 4.14/3.68 (dd, 2 H), 3.68/3.28 (m, 2 H), 3.47/3.06 (m, 2 H), 3.22 (t, 2 H), 2.94 (m, 2 H), 2.22/1.76 (m, 2 H), 1.93/1.47 (m, 2 H), 1.6 (m, 2 H), 1.26/1.12 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 383.1725 (383.1735)
Ejernental analysis : C=55.92(56.54);H=6.71(7.12);N=7.17(7.33)
Intermediate 29 : te/t-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(2-oxo-3H-l,3-benzoxazol-6-yl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 29 is obtained starting from intermediate 21 and 3H-l,3-benzoxazolecarbaldehyde in accordance with procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 12.55 (s, 1 H), 7.15 (s, 1 H), 7.05 (dd, 1 H), 7 (d, 1 H), 4 (m, 2 H), 3.65 (d, 1 H), 3.4 (d, 1 H), 3.35 (m, 2 H), 3.05-2.3 (m, 4 H), 2.05-1.8 (m, 4 H), 1.4 (m, 2 H), 1.4 (3s, 27 H), 1.25 (t, 3 H), 0.9-0.7 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 682.3461 (682.3468)
EXAMPLE 39:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-oxo-3H-l,3-benzoxazol-62θ yDmethyl]-l,4-azaphosphinane-3-carboxylic acid
Example 39 is obtained starting from intermediate 29 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) ô ppm 7.4 (s, 1 H), 7.3 (dd, 1 H), 7.25 (d, 1 H), 4.45/4.25 (2dd, 2 H), 3.8-3.6 (m, 1 H), 3.45 (m, 1 H), 3.35 (m, 1 H), 3.1 (m, 1 H), 2.95 (m, 2 H), 2.25 (m, 2 H), 25 1.95 (m, 1 H), 1.65-1.4 (m, 3 H), 1.25/1.1 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ - 398.1455 (398.1480)
Elemental analysis : C=51.17(51.39);H=5.85(6.09);N=10.49(10.57) , -69C Intermediate 30 : tirt-Butyl 3-{4-[bis(ieri-butoxvcarbonyl)amino]butyl}-l-(lHbenzimidazol-5-ylmethyl)-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 30 is obtained starting from intermediate 21 and lH-benzimidazole-55 carbaldehyde in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 12.4 (si, l H), 8.16 (s, 1 H), 7.7-7.3 (m, 2 H), 7.14 (d, 1 H), 3.97 (m, 2 H), 3.72/3.54 (2*d, 2 H), 3.45-3.2 (m, 2 H), 2.97/2.33 (2*m, 2 H), 2.85/2.48 (2*m, 2 H), 2.02-1.85 (m, 2 H), 2.02-1.85 (m, 2 H), 1.39/1.34 (2*8, 27 H), 1.38 (m, 2 H), 1.2 (t, 3 H), 0.81 (m, 2 H)
EXAMPLE 40 : 3-(4-Aminobutyl)-l-(lH-benzimidazol-5-ylmethyl)-4-hydroxy-4-oxo-
1,4-azaphosphinane-3-carboxylic acid
Example 40 is obtained starting from intermediate 30 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 8.26 (s, 1 H), 7.77 (df, 1 H), 7.72 (d, 1 H), 7.38 (dd, 1 H), 4.53/4.34 (2*d, 2 H), 3.73/3.36 (2*m, 2 H), 3.47/3.12 (2*m, 2 H), 2.88 (m, 2 H), 2.23/1.78 (2*m, 2 H), 1.91/1.55 (2*m, 2 H), 1.55/1.45 (2*m, 2 H), 1.18/1.04 (2*m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 381.1692 (381.1691)
Elemental analysis : C=54.46(53.68);H=6.00(6.62);N=14.67(14.73) 20 Intermediate 31 : W-Butyl 3-{4-[bis(/ert-butoxycarbonyl)amino]butyl}-l-[(2-fluoro-4hydroxyphenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 31 is obtained starting from intermediate 21 and 2-fluoro-4-methoxybenzaldehyde in accordance with procedure F described hereinbefore.
*Η NMR: (400 MHz, dmso-d6) δ ppm 7.25 (t, 1 H), 6.78 (2*m, 2 H), 4.1-3.9 (m, 2 H), 3.76 (s, 3 H), 3.57/3.46 (2*d, 2 H), 3.36 (m, 2 H), 2.93/2.32 (2*m, 2 H), 2.81/2.47 (2*dd, 2 H), 2-
1.8 (m, 2 H), 2-1.8 (m, 2 H), 1.42/1.36 (2*s, 27 H), 1.4 (m, 2 H), 1.2 (t, 3 H), 1-0.75 (m, 2 H)
-70C EXAMPLE 41: 3-(4-Aminobutyl)-l-[(2-fluoro-4-hydroxyphenyl)methyI]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 41 is obtained starting from intermediate 31 in accordance with procedure D described hereinbefore.
Tl NMR: (400 MHz, D2O) δ ppm 7.21 (t, 1 H), 6.63 (m, 1 H), 6.63 (m, 1 H), 4.19 (dd, 2 H), 3.58/3.19 (m, 2 H), 3.38/3.04 (dd, 2 H), 2.84 (m, 2 H), 2.1/1.65 (m, 2 H), 1.84/1.5 (m, 2 H), 1.5/1.38 (m, 2 H), 1.17/1.04 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H] + = 375.1486 (375.1485)
Elemental analysis : C=51.05(51.34);H=5.28(6.46);N=7.76(7.48) 10 Intermediate 32 : tert-Butvl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-1- [(6 -oxo- lH-pyridin-3-yl)methyl] -1,4-azaphosphinane-3carboxylate
Intermediate 32 is obtained starting from intermediate 21 and 6-hydroxynicotinaldehyde in accordance with procedure F described hereinbefore.
Tl NMR: (400 MHz, dmso-d6) δ ppm 11.45 (s, 1 H), 7.35 (dd, 1 H), 7.21 (df, 1 H), 6.31 (d, 1 H), 4.1-3.9 (m, 2 H), 3.4 (m, 2 H), 3.32/3.19 (2*d, 2 H), 2.9/2.28 (2*m, 2 H), 2.8/2.44 (2*dd, 2 H), 2-1.7 (m, 2 H), 2-1.7 (m, 2 H), 1.42/1.38 (2*s, 27 H), 1.4 (m, 2 H), 1.21 (t, 3 H), 1.10.85 (m, 2 H) ’
EXAMPLE 42:3-(4-Aminobutyi)-4-hydroxy-4-oxo-l-[(6-oxo-lH-pyridin-3-yl)methyl]20 l,4-azaphosphinane-3-carboxylic acid
Example 42 is obtained starting from intermediate 32 in accordance with procedure D described hereinbefore.
1H NAÏR: (300 MHz, D2O) δ ppm 7.74 (dd, 1 H), 7.7 (d, 1 H), 6.66 (d, 1 H), 4.17 (AB, 2 H),
3.69/3.31 (2m, 2 H), 3.45/3.09 (2m, 2 H), 2.94 (m, 2 H), 2.24/1.79 (2m, 2 H), 1.94/1.49 (2m,
H), 1.61 (quint., 2 H), 1.29/1.14 (2m, 2 H) 31P NMR: (300 MHz, D2O) δ ppm 25.8
ESI/FIA/HR and MS/MS : [M+HJ+ = 358.1537 (358,1531)
Elemental analysis : C=50.77(50.42);H=6.41(6.77);N=l 1.96(11.76)
-71f Intermediate 33 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-l-(lbenzofuran-5-ylmethyl)-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 33 is obtained starting from intermediate 21 and 5-formylbenzofuran in 5 accordance with procedure F described hereînbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 7.98 (df, 1 H), 7.55 (df, 1 H), 7.53 (d, 1 H), 7.25 (dd, 1 H), 6.91 (df, 1 H), 4.1-3.9 (m, 2 H), 3.72/3.51 (2*d, 2 H), 3.4-3.2 (m, 2 H), 2.98/2.35 (2*dd, 2 H), 2.81/2.48 (2*dd, 2 H), 2-1.65 (m, 2 H), 2-1.65 (m, 2 H), 1.4/1.34 (2*s, 27 H), 1.39 (m, 2 H), 1.21 (t, 3 H), 1-0.7 (m, 2 H)
EXAMPLE 43 : 3-(4-Aminobutyï)-l-(l-benzofuran-5-ylmethyl)-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Exemple 43 is obtained starting from intermediate 33 in accordance with procedure D described hereînbefore.
riï NMR: (400 MHz, D2O) δ ppm 7.79 (df, 1 H), 7.76 (df, 1 H), 7.61 (d, 1 H), 7.39 (dd, 1 H), 15 7.31/4.5 (2*d, 2 H), 6.91 (df, 1 H), 3.72/3.33 (2*dd, 2 H), 3.49/3.11 (2*dd, 2 H), 2.9 (m, 2 H),
2.23/1.77 (2*m, 2 H), 1.91/1.57 (2*m, 2 H), 1.57/1.45 (2*m, 2 H), 1.2/1.15 (2*m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 381.1577 (381.1579)
Elemental analysis : C=56.67(56.84);H=6.52(6.62);N=7.42(7.36)
Intermediate 34 : tert-Butyl 3-{4-[bis(to t-butoxycarbonyl)aminoJbutyl)-4-ethoxy-l-[(420 hydroxy-2-methylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 34 is obtained starting from intermediate 21 and 4-methoxy-2methylbenzaldehyde in accordance with procedure F described hereînbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.05 (d, 1 H), 6.75 (df, 1 H), 6.69 (dd, 1 H), 4.1-3.9 (m, 25 2 H), 3.72 (s, 3 H), 3.5/3.3 (2*d, 2 H), 3.3 (m, 2 H), 2.9/2.41 (2*m, 2 H), 2.8/2.29 (2*m, 2 H),
2.3 (2*s, 3 H), 2.02-1.79 (unresolved peak, 2 H), 2.02-1.79 (unresolved peak, 2 H), 1.42/1.36 (2*8, 27 H), 1.32 (m, 2 H), 1.21 (t, 3 H), 0.68 (m, 2 H)
-72EXAMPLE 44 : 3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxy-2-methylphenyl)methyl]-4oxo- l,4-azaphosphinane-3-carboxylic acid
Exampie 44 is obtained starting from intermediate 34 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.25 (d, 1 H), 6.81 (df, 1 H), 6.77 (dd, 1 H), 4.29/4.22 (2*d, 2 H), 3.69/3.32 (2*dd, 2 H), 3.49/3.18 (2*dd, 2 H), 2.94 (m, 2 H), 2.32 (s, 3 H), 2.19/1.75 (2i;m, 2 H), 1.94/1.6 (2*m, 2 H), 1.6/1.5 (2*m, 2 H), 1.27/1.12 (2*m, 2 H) 31P NMR: (400 MHz, D2O) δ ppm 26
EST/FIA/HR and MS/MS : [M+H]+ = 371.1739 (371.1735)
Elemental analysis : C=54.81(55.13);H=6.88(7.35);N=7.52(7.56)
Intermediate 35 : frrt-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(2-chloro-4fluorophenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 35 is obtained starting from intermediate 21 and 2-chloro-4-fluorobenzaldehyde 15 in accordance with procedure F described hereinbefore.
’H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (dd, 1 H), 7.35 (dd, 1 H), 7.2 (dd, 1 H), 4.1-3.9 (quad., 2 H), 3.65-3.55 (d, 2 H), 3.4-3.3 (m, 2 H), 2.9-2.35 (m, 4 H), 1.9 (m, 4 H), 1.55-1.35 (m, 2 H), 1.4-1.35 (s, 27 H), 1.2 (t, 3 H), 0.85-0.75 (m, 2 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 45 19FNMR: (400 MHz, dmso-d6) δ ppm -112
ESI/FIA/HR and MS/MS : [M+H]+ = 677.3146 (677.3133)
EXAMPLE 45 :3-(4-Aminobutyl)-l-[(2-chloro-4-fluorophenyl)methyl]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 45 is obtained starting from intermediate 35 in accordance with procedure D 25 described hereinbefore.
!H NMR: (400 MHz, D2O) δ ppm 7.56 (dd, 1 H), 7.39 (dd, 1 H), 7.18 (td, 1 H), 4.43 (si, 2 H), 3.7/3.4 (m, 2 H), 3.5/3.26 (m, 2 H), 2.95 (m, 2 H), 2.22/1.78 (m, 2 H), 1.95/1.62 (m, 2 H), 1.62/1.5 (m, 2 H), 1.28/1.12 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 393.1149 (393.1146)
-73Ç- Elemental analysis : C=49.40(48.93);H=5.3 l(5.90);N=7.17(7.13)
Intermediate 36 : ieri-Butyi 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[[2-(4fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 36 is obtained starting from intermediate 21 and 2-(4-fluorophenyl)benzaldehyde in accordance with procedure F described hereinbefore.
]H NMR: (400 MHz, dmso-d6) δ ppm 7.5-7.2 (m, 4 H), 7.5-7.2 (m, 4 H), 4.08-3.73 (m, 2 H), 3.52/3.3 (2*d, 2 H), 3.3 (m, 2 H), 2.8-2.62/2.33 (2*m, 2 H), 2.8-2.62/2.2 (2*m, 2 H), 1.98-
1.63 (m, 2 H), 1.98-1.63 (m, 2 H), 1.4/1.32 (2*8, 27 H), 1.38 (m, 2 H), 1.21/1.18 (2*t, 3 H), 0.9-0.6 (m, 2 H)
EXAMPLE 46 : 3-(4-Aminobutyl)-1 -[[2-(4-fluorophenyl)phenyl] methyl] -4-hydroxy-4 oxo-l,4-azaphosphinane-3-carboxylic acid
Example 46 is obtained starting from intermediate 36 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1 H), 7.52 (m, 2 H), 7.4 (d, 1 H), 7.35 (dd, 2 H),
7.24 (dd, 2 H), 4.41/4.29 (dd, 2 H), 3.39/3.1 (2*m, 2 H), 3.19/2.88 (2*m, 2 H), 2.93 (m, 2 H), 2.09/1.65 (2*m, 2 H), 1.85/1.59 (2*m, 2 H), 1.59/1.35 (2*m, 2 H), 1.2-1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 435.1850 (435.1848)
Elemental analysis : C=60.73(60.82);H=5.96(6.50);N=6.73(6.45)
Intermediate 37 : teri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyi}-l-[[2-(2fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 37 is obtained starting from intermediate 21 and 2-(2-fluorophenyl)benzaldehyde in accordance with procedure F described hereinbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 1 H), 7.45/7.42 (t, 2 H), 7.45 (m, 1 H), 7.35 (m, 3 H), 7.2 (d, 1 H), 3.91 (m, 2 H), 3.5-3.2 (m, 2 H), 3.5-3.2 (m, 2 H), 2.67/2.29 (m, 2 H), 2.67/2.13 (m, 2 H), 1.95-1.6 (m, 2 H), 1.95-1.6 (m, 2 H), 1.42 (s, 18 H), 1.38 (m, 2 H), 1.34 (s, 9 H), 1.17 (t, 3 H), 0.68 (m, 2 H)
-74EXAMPLE 47: 3-(4-Aminobutyl)-l-[[2-(2-fluorophenyl)phenyl]methyl]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 47 is obtained starting from intermediate 37 in accordance with procedure D described hereinbefore.
]H NMR: (400 MHz, D2O) δ ppm 7.66 (m, 1 H), 7.57 (m, 1 H), 7.57 (m, 1 H), 7.51 (m, 1 H), 7.42 (m, 1 H), 7.34 (m, 1 H), 7.34 (m, 1 H), 7.28 (t, 1 H), 4.6-4 (unresolved peak, 2 H), 3.7-
2.7 (unresolved peak, 2 H), 3.7-2.7 (unresolved peak, 2 H), 2.93 (m, 2 H), 2.14/1.69 (m, 2 H), 1.87/1.37 (m, 2 H), 1.59 (m, 2 H), 1.15/1.06 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 435.1855 (435.1848)
Elemental analysis : C=60.87(60.82);H=6.12(6.50);N=6.42(6.45)
Intermediate 38 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-l-[[2-(2,5dichlorophenyi)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-
3-carboxylate
Intermediate 38 is obtained starting from intermediate 21 and 2-(2,515 dichlorophenyl)benzaldehyde in accordance with procedure F described hereinbefore.
ΊΗ NMR: (400 MHz, dmso-d6) δ ppm 7.65-7.1 (m, 7 H), 4.05-3.85 (m, 2 H), 3.5-3.2 (m, 4 H), 2.8-2.3 (m, 4 H), 2.2-1.65 (m, 4 H), 1.5-1.3 (m, 2 H), 1.45 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.8-0.5 (m, 2 H)
EXAMPLE 48 :3-(4-Aminobutyl)-l-[[2-(2,5-dichlorophenyl)phenyI]methyl]-4-hydroxy20 4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 48 is obtained starting from intermediate 38 in accordance with procedure D described hereinbefore.
‘HNMR: (300 MHz, D2O) δ ppm 7.7-7.3 (m, 7 H), 4.45/4.21/4.02 (m, 2 H), 3.75/3.1 (2*m, 2 H), 3.75/3.1 (2*m, 2 H), 2.98 (m, 2 H), 2.2/1.65 (2*m, 2 H), 1.95/1.65 (2*m, 2 H), 1.65/1.15 (2*m, 2 H), 1.45/1.15 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+HJ+ = 485.1184 (485.1163)
Elemental analysis : C=54,33(54.44);H=4.99(5.61);N=5.86(5.77)
-75f Intermediate 39 : ieri-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[[2-(3-phenylphenyl)phenyl]methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 39 is obtained starting from intermediates 21 and 241 in accordance with 5 procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.7 (d, 2 H), 7.65 (d, 1 H), 7.6 (s, 1 H), 7.55 (m, 2 H),
7.45 (m, 2 H), 7.4-7.3 (m, 5 H), 3.9 (m, 2 H), 3.6/3.4 (2*d, 2 H), 3.4-3.2 (m, 2 H), 2.85-2.65 (m, 2 H), 2.35 (m, 1 H), 2.2 (m, 1 H), 1.9 (m, 1 H), 1.85-1.6 (m, 3 H), 1.45-1.3 (m, 2 H), 1.4/1.3 (2*s, 27 H), 1.15 (t, 3 H), 0.65 (m, 2 H)
EXAMPLE 49 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[[2-(3-phenylphenyl)phenyl]methyl]-!,4-azaphosphinane-3-carboxy lie acid
Example 49 is obtained starting from intermediate 39 in accordance with procedure D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.6-7.1 (m, 13 H), 4.25 (d, 1 H), 4.1 (d, 1 H), 3.4-3.2 (m, 1 15 H), 3.15-2.9 (m, 2 H), 2.75-2.55 (m, 3 H), 2.05 (m, 1 H), 1.75 (m, 1 H), 1.55 (m, 1 H), 1.4 (m,
H), 1.25 (m, 1 H), 0.9 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 493.2256 (493.2256)
Elemental analysis : C=68.08(68.28);H=6.02(6.75);N=5.71(5.69)
Intermediate 40 : ieri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(220 naphthaÎen-2-ylphenyI)methyl]-4-oxo-l,4-azaphosphinane-3carboxyiate
Intermediate 40 is obtained starting from intermediates 21 and 240 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.95 (d, 1 H), 7.95 (m, 2 H), 7.9 (s, 1 H), 7.55 (m, 4 25 H), 7.4 (m, 2 H), 7.3 (d, 1 H), 3.9 (m, 2 H), 3.65/3.45 (2*d, 2 H), 3.45-3.2 (m, 2 H), 3.3-2.6 (m, 2 H), 2.35 (dd, 1 H), 2.2 (m, 1 H), 1.9 (m, 1 H), 1.85-1.65 (m, 3 H), 1.8 (m, 2 H), 1.4/1.3 (2*s, 27 H), 1.15 (t, 3 H), 0.7 (m, 2 H)
-76Æ EXAMPLE 50 : 3-(4-Aminobutyl)-4-hydroxy-l-[(2-naphthaIen-2-ylphenyi)methyl]-4oxo- l,4-azaphosphinane-3-carboxylic acid
Example 50 is obtained starting from intermediate 40 in accordance with procedure D described hereinbefore. .
NMR: (300 MHz, D2O) δ ppm 7.9 (d, 1 H), 7.9/7.85 (2*m, 2 H), Ί.Ί (s, 1 H), 7.6-7.4 (m, 5 H), 7.3 (m, 2 H), 4.35/4.2 (2dd, 2 H), 3.4-3.2 (m, 1 H), 3.15-2.9 (m, 2 H), 2.8 (m, 2 H), 2.7 (dd, 1 H), 2 (m, 1 H), 1.75 (m, 1 H), 1.65-1.35 (m, 3 H), 1.25 (m, 1 H), 0.85 (m, 2 H) ESVFIA/HR and MS/MS : [M+H]+ = 467.2090 (467.2099)
Elemental analysis : C=67.58(66.94);H=6.40(6.70);N=5.73(6.00)
Intermediate 41 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-l-[[2-(2,6dichlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane3-carboxylate
Intermediate 41 is obtained starting from intermediates 21 and 242 in accordance with procedure F described hereinbefore.
1H NMR: (300 MHz, dmso-d6) δ ppm 7.65-7.5 (m, 3 H), 7.5-7.3 (m, 3 H), 7.1 (d, 1 H), 4 (m, 2 H), 3.45 (m, 2 H), 3.25 (2*d, 2 H), 2.85-2.1 (m, 4 H), 2-1.75 (m, 4 H), 1.6-1.15 (m, 2 H), 1.45/1.4 (2*s, 27 H), 1.25 (t, 3 H), 0.95 (m, 2 H)
EXAMPLE 51:3-(4-Aimnobutyl)-l-[[2-(2,6-dichlorophenyl)phenyl]methyl]-4-hydroxy-
4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 51 is obtained starting from intermediate 41 in accordance with procedure D described hereinbefore.
!H NMR: (300 MHz, D2O) δ ppm 7.6 (d, 1 H), 7.5/7.2 (m, 3 H), 7.5-7.3 (m, 2 H), 7.12 (d, 1 H), 3.38/3.21 (2*d, 2 H), 2.82/2.38 (2*dd, 2 H), 2.65/2.22 (2*m, 2 H), 2.45 (t, 2 H), 1.85/1.71 (2*m, 2 H), 1.7/1.35 (2*m, 2 H), 1.32/0.8 (2*m, 2 H), 1.32/0.8 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 485.1169 (485.1163)
Elemental analysis : C=54.71(54.44);H=5.14(5.61);N=5.81(5.77)
-τι( Intermediate 42 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-lmethyl-4-oxo-l,4-azaphosphinane-3-carboxyiate
Intermediate 42 is obtained starting from intermediate 21 and formaldéhyde in accordance with procedure F described hereinbefore.
3H NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2 H), 3.48 (m, 2 H), 2.75 (m, 2 H), 2.49/2.2 (2m, 2 H), 2.01 (s, 3 H), 1.92 (m, 4 H), 1.5 (m, 2 H), 1.45/1.4 (2s, 27 H), 1.25/1 (2m, 2 H), 1.2 (t, 3 H)
EXAMPLE 52:3-(4-Aminobutyl)-4-hydroxy-l-methyl-4-oxo-l,4-azaphosphinane-3carboxylic acid
Example 52 is obtained starting from intermediate 42 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 3.7-3.5 (m, 2 H), 3.3 (t, 1 H), 3.2 (dd, 1 H), 3 (t, 2 H), 2.9 (s, 3 H), 2.3 (m, 1 H), 2 (m, 1 H), 1.75 (m, 1 H), 1.7 (m, 2 H), 1.5 (m, 1 H), 1.4/1.25 (2m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 265.1300 (265.1317)
Elemental analysis : C=45.59(45.45);H=7.97(8.01);N=10.61(10.60)
Intermediate 43 : tert-Butyl 3-{4-[bis-(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-(2-phenylethyI)-l,4-azaphosphinane-3-carboxyiate
Intermediate 43 is obtained starting from intermediate 21 and phenylacetaldehyde in 20 accordance with procedure F described hereinbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 7.3-7.15 (m, 5 H), 3.98 (m, 2 H), 3.45 (t, 2 H), 3.05-2.3 (m, 8 H), 2-1.8 (m, 4 H), 1.4 (m+2s, 29 H), 1.2 (t, 3 H), 1.18/0.9 (2m, 2 H)
EXAMPLE 53:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(2-phenylethyl)-l,4azaphosphinane-3-carboxyïic acid
Example 53 is obtained starting from intermediate 43 in accordance with procedure D described hereinbefore.
-78p Ή NMR: (400 MHz, D2O) δ ppm 7.4-7.25 (m, 5 H), 3.7/3.3 (2m, 2 H), 3.52 (m, 1 H), 3.45 (t, 2 H), 3.1 (m, 3 H), 2.95 (m, 2 H), 2.2/1.75 (2m, 2 H), 1.95 (m, 1 H), 1.62 (m, 2 H), 1.5-1.1 (m, 3 H)
ESI/FIA/HR andMS/MS : [M+H]+ = 355.1777 (355.1786)
Elemental analysis : C=57.63(57.62);H=7.36(7.68);N=7.90(7.90)
Intermediate 44 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-pentyl-l,4-azaphosphinane-3-carboxylate
Intermediate 44 is obtained starting from intermediate 21 and 1-pentanal in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2 H), 3.8 (m, 2 H), 3.49 (t, 2 H), 2.85 (m, 2 H), 2.49/2.25 (2m, 2 H), 1.9 (m, 4 H), 1.45/1.4 (2s, 27 H), 1.45 (m, 4 H), 1.25/1 (2m, 6 H),
1.2 (t, 3 H), 0.85 (t, 3 H)
EXAMPLE 54 :3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-pentyl-l,4-azaphosphinane-3carboxylic acid
Example 54 is obtained starting from intermediate 44 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 3.7-3.5 (m, 2 H), 3.3 (m, 1 H), 3.15/3 (2m, 5 H), 2.27 (m, 1 H), 2 (m, 1 H), 1.85-1.6 (m, 5 H), 1.5/1.41 (2m, 2 H), 1.3 (m, 5 H), 0.85 (t, 3 H) ESI/FIA/HR and MS/MS : ΓΜ+Η1+ = 321.1923 (321.1943)
Elemental analysis : C=52.77(52.49);H=8.93(9.12);N=9.00(8.74)
Intermediate 45 : tcri-Butyl 3-{4-[bis(ter/-butoxycarbonyl)amino-butyl}-4-ethoxy-l(naphthalen-l-ylmethyl)-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 45 is obtained starting from intermediate 21 and 1-naphthaldehyde in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 8.29 (d, 1 H), 7.9/7.85 (2d, 2 H), 7.6-7.4 (m, 4 H), 3.95 (AB, 2 H), 4 (m, 2 H), 3.6 (m, 2 H), 3.2-2.8 (m, 4 H), 2.4/2 (2m, 2 H), 1.7 (m, 2 H), 1.4/1.3 (2s, 27 H), 1.22 (t, 3 H), 1.05/0.75 (2m, 2 H), 0.5/0.2 (2m, 2 H)
-79C EXAMPLE 55 : 3-(4-AminobutyI)-4-hydroxy-l-(naphthalen-l-ylmethyl)-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 55 is obtained starting from intermediate 45 in accordance with procedure D 5 described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.9 (m, 3 H), 7.6-7.3 (m, 4 H), 4.55 (s, 2 H), 3.55/3.28 (2m, 2 H), 3.4/3.15 (2dd, 2 H), 2.75 (m, 2 H), 2/1.6 (2m, 2 H), 1.8 (m, 1 H), 1.5-1.25 (m, 3 H), 1/0.9 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 391.1778 (391.1786)
Elemental analysis : C=61.34(61.53);H=6.58(6.97);N=7.01(7.18)
Intermediate 46 : tert-Butyl 3-{4-[bis(/er/-butoxycarbonyl)amino]butyl}-l-(cyclohexylmethyl)-4-ethoxy-4-oxo-l,4-azaphosphinane-3-carboxyiate
Intermediate 46 is obtained starting from intermediate 21 and cyclohexanal in accordance with procedure F described hereinbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 4 (m, 2 H), 3.5 (t, 2 H), 2.8 (m, 2 H), 2.48/2.25 (2m, 2 H), 2.15 (dd, 2 H), 1.95 (m, 2 H), 1.68 (m, 1 H), 1.65/1.4/0.8 (3m, 10 H), 1.45 (m, 3 H), 1.45/1.4 (2s, 27 H), 1.2 (m, 2 H), 1.2 (t, 3 H), 1 (m, 1 H)
EXAMPLE 56 :3-(4-Aminobutyl)-l-(cyclohexylmethyl)-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 56 is obtained starting from intermediate 46 in accordance with procedure D described hereinbefore.
’H NMR: (400 MHz, D2O) δ ppm 3.7/3.25 (2m, 2 H), 3.55/3.15 (2dd, 2 H), 3.1-2.9 (t+2dd, 4 H), 2.25 (m, 1 H), 2 (m, 1 H), 1.85-1.55 (m, 9 H), 1.52/1.41 (2m, 2 H), 1.3/1.1 (m, 4 H), 1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 347.2095 (347.2099)
Elemental analysis : C=55.29(55.48);H=9.08(9.02);N=7.95(8.09)
-80Intermediate 47 : toi-Butyl 3-{4-bis[teri-butoxycarbonyl)amino]butyl}-4-ethoxy-l(naphthalen-2-ylmethyl)-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 47 is obtained starting from intermediate 21 and 2-naphthaldehyde in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.9 (m, 3 H), 7.8 (s, 1 H), 7.5 (m, 3 H), 3.98 (m, 2 H),
3.8 (d, 1 H), 3.6 (m, 3 H), 3.35/3.2 (2m, 2 H), 3.1-2.75 (2m, 2 H), 2.4 (m, 1 H), 2.05-1.8 (m, 3 H), 1.4-0.7 (m, 4 H), 1.38 (3s, 27 H), 1.22 (t, 3 H)
EXAMPLE 57 :3-(4-Aminobutyl)-4-hydroxy-l-(naphthalen-2-yImethyl)-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 57 is obtained starting from intermediate 47 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.95-7.9 (m, 4 H), 7.6-7.5 (m, 3 H), 4.5;4.3 (d, 2*1H H),
3.65 (m, 1 H), 3.45-3.3 (m, 2 H), 3.15 (m, 1 H), 2.8 (m, 2 H), 2.25 (m, 1 H), 1.9-1.7 (m, 2 H), 1.55-1.4 (m, 3 H), 1.15-0.95 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 391.1778 (391.1786)
Elemental analysis : C=61.31(61.53);H=6.56(6.97);N=7.15(7.18)
Intermediate 48 : tert-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(4chlorophenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxyiate
Intermediate 48 is obtained starting from intermediate 21 and 4-chlorobenzaldehyde in accordance with procedure F described hereinbefore.
’H NMR: (400 MHz, dmso-d6) δ ppm 7.4 (d, 2 H), 7.31 (d, 2 H), 3.98 (m, 2 H), 3.65-3.3 (m, 4 H), 3-2.3 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (s+m, 29 H), 1.22 (2t, 3 H), 0.8 (m, 2 H)
EXAMPLE 58 : 3-(4-Aminobutyl)-l-[(4-chlorophenyl)methyI]-4-hydroxy-4-oxo-l,425 azaphosphinane-3-carboxylic acid
Example 58 is obtained starting from intermediate 48 in accordance with procedure D described hereinbefore.
-81P 1H NMR: (400 MHz, D2O) δ ppm 7.5/7.45 (2d, 4 H), 4.41/4.21 (2d, 2 H), 3.7/3.33 (2m, 2 H), 3.45/3.1 (2dd, 2 H), 2.95 (m, 2 H), 2.25/1.78 (2m, 2 H), 1.95/1.5 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 375.1242 (375.1240)
Elemental analysis : C=50.89(51.27);H=6.01(6.45):N-7.44(7.47)
Intermediate 49 : teri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(4fluorophenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 49 is obtained starting from intermediate 21 and 4-fluorobenzaldehyde in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.35 (m, 2 H), 7.15 (t, 2 H), 4 (m, 2 H), 3.65-3.3 (m, 4 H), 3-2.3 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (s+m, 29 H), 1.2 (2t, 3 H), 0.9/0.8 (2m, 2 H)
EXAMPLE 59: 3-(4-Aminobutyl)-l-[(4-fluorophenyl)methyl]-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 59 is obtained starting from intermediate 49 in accordance with procedure D 15 described hereinbefore.
^NMR: (400 MHz, D2O) δ ppm 7.5 (dd, 2 H), 7.2 (t, 2 H), 4.41/4.21 (2d, 2 H), 3.7/3.31 (2m, 2 H), 3.45/3.1 (2dd, 2 H), 2.95 (m, 2 H), 2.25/1.78 (2m, 2 H), 1.95/1.5 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 359.1532 (359.1535)
Elemental analysis : C=53.65(53.63);H=6.20(6.75);N=7.83(7.82)
Intermediate 50 : tert-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-l(furan-2-ylmethyl)-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 50 is obtained starting from intermediate 21 and 2-furaldehyde in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, CDC13) δ ppm 7.41 (s, 1 H), 6.32 (s, 1 H), 6.2 (s, 1 H), 4.09 (s, 2 H), 3.62/3.52 (AB, 2 H), 3.5 (m, 2 H), 3/2.65 (m, 2 H), 2.96/2.52 (m, 2 H), 2.7-1.8 (m, 4 H), 1.5/1.46 (m, 30 H), 1.3 (t, 3 H), 1.01 (m, 1 H) 31P NMR: (400 MHz, CDC13) δ ppm 46.14
-82EXAMPLE 60:3-(4-Aminobutyl)-l-(furan-2-ylmethyl)-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 60 is obtained starting from intermediate 50 in accordance with procedure D 5 described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.6 (si, 1 H), 6.7 (tf, 1 H), 6.5 (tf, 1 H), 4.45/4.32 (2d, 2 H), 3.7/3.3 (2*m, 2 H), 3.52/3.12 (2*m, 2 H), 2.98 (m, 2 H), 2.25/1.8 (2*m, 2 H), 1.95/1.5 (2*m, 2 H), 1.62 (m, 2 H), 1.32/1.2 (2*m, 2 H)
ES1/FIA/HR and MS/MS : [M+H]+ = 331.1422 (331.1422)
Elemental analysis : C=50.48(50.91);H=6.48(7.02);N=8.37(8.48)
Intermediate 51 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[[4-(trifluoromethyl)phenyl]methyl]-l>4-azaphosphinane-3carboxyiate
Intermediate 51 is obtained starting from intermediate 21 and 4-trifluoromethylbenzaldehyde 15 in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 7.71 (d, 2 H), 7.52 (d, 2 H), 4.03 (m, 2 H), 3.72/3.51 (2*d, 2 H), 3.35 (m, 2 H), 3-2.3 (m, 4 H), 1.98 (m, 4 H), 1.4 (s+m, 29 H), 1.2 (t, 3 H), 0.8 (m, 2 H) .
EXAMPLE 61: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-1 - [[4-(trifluoromethyl)phenyl] 20 methyI]-l,4-azaphosphinane-3-carboxylic acid
Example 61 is obtained starting from intermediate 51 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.8 (d, 2 H), 7.65 (d, 2 H), 4.5/4.3 (AB, 2 H), 3.7/3.45 (m, 2 H), 3.39/3.11 (m, 2 H), 2.9 (m, 2 H), 2.28/1.8 (m, 2 H), 1.95/1.49 (m, 2 H), 1.6 (m, 2 H), 25 1.2/1.1 (m, 2 H) 19FNMR: (400 MHz, D2O) δ ppm -62.5 31PNMR: (400 MHz, D2O) δ ppm 24
ESI/FIA/HR and MS/MS : [M+H]+ = 409.1510 (409.1504)
Elemental analysis : C=49.86(50.00);H=5.32(5.92);N=6.83(6.86)
-83Intermediate 52 : tert-Butyl 3-{4-[bis(to/-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(4methoxyphenyl)methyl] -4-oxo-1,4-azaphosphinane-3-carboxylate
Intermediate 52 is obtained starting from intermediate 21 and 4-methoxybenzaldehyde in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 7.2 (d, 2 H), 6.9 (d, 2 H), 3.98 (m, 2 H), 3.72 (s, 3 H), 3.6/3.32 (2*d, 2 H), 3.4 (m, 2 H), 3-2.25 (m, 4 H), 1.9 (m, 4 H), 1.4 (s+m, 29 H), 1.2 (t, 3 H), 0.8 (m, 2 H)
EXAMPLE 62 : 3-(4-Aminobuty 1)-4-hydroxy-1 -[(4-methoxyphenyl)methyl] -4-oxo-1,4azaphosphinane-3-carboxylic acid
Example 62 is obtained starting from intermediate 52 in accordance with procedure D described hereinbefore.
'H NMR: (400 MHz, D2O) δ ppm 7.41 (d, 2 H), 7.02 (d, 2 H), centred at 4.25 (AB, 2 H), 3.8 (s, 3 H), 3.7/3.3 (2m, 2 H), 3.45/3.08 (2dd, 2 H), 2.95 (m, 2 H), 2.25/1.75 (2m, 2 H), 1.95/1.45 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 371.1712 (371.1730)
Elemental analysis : C=54.93(55.13);H=7.41(7.35);N=7.56(7.56)
Intermediate 53 : tert-Butyl 3-{4-[bis(iert-butoxycarbonyI)amino]butyl}-4-ethoxy-4oxo-l-(thiophen-3-ylmethyl)-l,4-azaphosphinane-3-carboxylate
Intermediate 53 is obtained starting from intermediate 21 and 3-thiophenaldehyde in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 7.49 (m, 1 H), 7.31 (m, 1 H), 7.02 (m, 1 H), 3.95 (m, 2 H), 3.6/3.49 (AB, 2 H), 3.4 (m, 2 H), 3/2.8 (m, 2 H), 2.8/2.45 (m, 2 H), 1.9 (m, 4 H), 1.4 (m, 29 H), 1.2 (t, 3 H), 0.95/0.85 (m, 2 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 47/45
-84Λ EXAMPLE 63 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(thiophen-3-ylmethyI)-l,4azaphosphinane-3-carboxylic acid
Example 63 is obtained starting from intermediate 53 in accordance with procedure D described hereinbefore.
^NMR: (400 MHz, D2O) δ ppm 7.61 (d, 1 H), 7.54 (dd, 1 H), 7.2 (d, 1 H), 4.42/4.28 (2*d, 2 H), 3.71/3.32 (m, 2 H), 3.48/3.06 (m, 2 H), 2.94 (m, 2 H), 2.25/1.77 (m, 2 H), 1.93/1.46 (m, 2 H), 1.6 (m, 2 H), 1.26/1.13 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 347.1182 (347.1189)
Elemental analysis : C=48.14(48.55);H=6.55(6.69);N=7.87(8.09);S=8.65(9.26)
Intermediate 54 : tert-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(4hydroxy-3-methoxyphenyl)methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 54 is obtained starting from intermediate 21 and 4-hydroxy-3methoxybenzaldehyde in accordance with procedure F described hereinbefore.
^NMR: (400 MHz, dmso-d6) δ ppm 8.8 (s, 1 H), 6.8 (df, 1 H), 6.7 (d, 1 H), 6.62 (dd, 1 H),
3.95 (m, 2 H), 3.71 (s, 3 H), 3.49/3.31 (2d, 2 H), 3.4 (m, 2 H), 3-2.2 (m, 4 H), 2-1.8 (m, 4 H),
1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 1/0.85 (2m, 2 H)
EXAMPLE 64:3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxy-3-methoxyphenyl)methyl]4-oxo-l,4-azaphosphinane-3-carboxylie acid
Example 64 is obtained starting from intermediate 54 in accordance with procedure D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.09 (m, 1 H), 6.94 (m, 2 H), 4.3/4.13 (2*d, 2 H), 3.7/3.3 (2*m, 2 H), 3.65 (s, 3 H), 3.45/3.07 (2*m, 2 H), 2.92 (m, 2 H), 2.22/1.77 (2*m, 2 H), 1.92/1.6 (2*m,2H), 1.6/1.48 (2*m,2H), 1.23/1.11 (2*m,2H)
ESI/FIA/HR and MS/MS : [M+H]+ = 387.1665 (387.1685)
Elemental analysis : C=53.10(52.85);H=7.01(7.04);N=7.30(7.25)
-85Intermediate 55 : tert-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(2carboxyphenyl)methyl] -4-ethoxy-4-oxo-1,4-azaphosphinane-3 carboxylate
Intermediate 55 is obtained starting from intermediate 21 and methyl 2-formylbenzoate in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.65 (d, 1 H), 7.5 (t, 1 H), 7.38 (m, 2 H), 4.05/3.4 (2d, 2 H), 3.95 (m, 2 H), 3.8 (2s, 3 H), 3.3/3.2 (2m, 2 H), 3-2.35 (m, 4 H), 2 (m, 1 H), 1.8-1.6 (m, 3 H), 1.4/1.3 (2s+m, 29 H), 1.2 (2t, 3 H), 0.5/0.35 (2m, 2 H)
EXAMPLE 65 : 3-(4-Aminobutyl)-l-[(2-carboxyphenyl)methyl]-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxyiic acid
Example 55 is obtained starting from intermediate 65 in accordance with procedure D described hereinbefore.
ESI/F1A/HR and MS/MS : [M+H]+ = 385.1504 (385.1523)
Elemental analysis : C=53.42(53.12);H=6.25(6.56);N=7.40(7.29)
Intermediate 56 : tert-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[(3-chloro-4hydroxyphenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 56 is obtained starting from intermediate 21 and 3-chloro-4hydroxybenzaldehyde in accordance with procedure F described hereinbefore.
’HNMR: (400 MHz, dmso-d6) δ ppm 10.05 (m, 1 H), 7.22 (df, 1 H), 7.02 (dd, 1 H), 6.9 (d, 1 H), 3.98 (m, 2 H), 3.5/3.31 (2d, 2 H), 3.4 (m, 2 H), 3-2.25 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 1.1-0.8 (2m, 2 H)
EXAMPLE 66 :3-(4-AminobutyI)-l-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy-4oxo-1,4-azaphosphinane-3-carboxylic acid
Example 66 is obtained starting from intermediate 56 in accordance with procedure D described hereinbefore.
-86p JH NMR: (400 MHz, D2O) δ ppm 7.42 (df, 1 H), 7.2 (dd, 1 H), 6.97 (d, 1 H), 4.27/4.07 (2*0, 2 H), 3.62/3.22 (2*m, 2 H), 3.39/3 (2*m, 2 H), 2.85 (m, 2 H), 2.18/1.7 (2*m, 2 H), 1.85/1.52 (2*m, 2 H), 1.52/1.4 (2*m, 2 H), 1.18/1.05 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 391.1189 (391.1189)
Elemental analysis : C=49.09(49.17):H=6.02(6.19):N=7.18(7.17)
Intermediate 57 : teri-Butyl 3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[[4hydroxy-3-(trifluoromethoxy)phenyl]methyI]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 57 is obtained starting from intermediate 21 and 4-hydroxy-310 (trifluoromethyl)benzaldehyde in accordance with procedure F described hereinbefore.
Tl NMR: (400 MHz, dmso-d6) δ ppm 10,1 (m, 1 H), 7.15 (df, 1 H), 7.08 (dd, 1 H), 6.95 (d, 1 H), 3.98 (m, 2 H), 3.5/3.4 (2d, 2 H), 3.4 (m, 2 H), 3-2.2 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 1.1-0.8 (2m, 2 H)
EXAMPLE 67 :3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-3-(trifluoromethoxy)15 phenyl]methyl]-4-oxo-l,4-azaphosphmane-3-carboxylic acid
Example 67 is obtained starting from intermediate 57 in accordance with procedure D described hereinbefore.
‘HNMR: (400 MHz, D2O) δ ppm 7.44 (df, 1 H), 7.33 (dd, 1 H), 7.09 (d, 1 H), 4.38/4.13 (2*d, 2 H), 3.7/3.31 (2*dd, 2 H), 3.44/3.07 (2*dd, 2 H), 2.92 (m, 2 H), 2.23/1.78 (2*m, 2 H),
1.94/1.59 (2*m, 2 H), 1.59/1.46 (2*m, 2 H), 1.21/1.1 (2*m, 2 H) 19F NMR: (400 MHz, D2O) δ ppm -58.3 31P NMR: (400 MHz, D2O) δ ppm 26
ESI/FIA/HR and MS/MS : [M+H]+ = 441.1403 (441.1402)
Elemental analysis : C=46.46(46.37);H=4.98(5.49);N=6.42(6.36)
-87f' Intermediate 58 : tert-Butyi 3-{4-[bis(/e/T-butoxycarbonyl)ainino]butyI}-4-ethoxy-l-[(4hydroxy-3,5-dimethy Ip heny Dmethyl] -4-oxo-1,4 -azaphosphinane-3carboxylate
Intermediate 58 is obtained starting from intermediate 21 and 3,5-dimethyl-45 hydroxybenzaldehyde in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmsô-d6) δ ppm 8.09 (s, 1 H), 6.8 (s, 2 H), 3.98 (m, 2 H), 3.49/3.21 (2d, 2 H), 3.35 (m, 2 H), 3-2.2 (m, 4 H), 2.15 (s, 6 H), 2-1.8 (m, 4 H), 1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 0.95-0.82 (2m, 2 H)
EXAMPLE 68: 3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxy-3,5-dimethylphenyl)10 methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 68 is obtained starting from intermediate 58 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.1 (s, 2 H), 4.25-4.1 (d, 2 H), 3.7-3.5 (m, 2 H), 3.25 (m, 1 H), 3.1 (m, 1 H), 2.95 (t, 2 H), 2.2 (s, 6 H), 2.2/1.75 (m, 2 H), 1.95 (m, 1 H), 1.6 (m, 2 H), 1.5 15 (m, 1 H), 1.3-1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 385.1889 (385.1892)
Elemental analysis : C=55.50(56.24);H=7.07(7.60);N=7.16(7.29)
Intermediate 59 : teri-Butyl 3-{4-[bis(ier/-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-(pyridin-4-ylmethyI)-l,4-azaphosphinane-3-carboxylate
Intermediate 59 is obtained starting from intermediate 21 and 4-formylpyridine in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 8.5 (d, 2 H), 7.3 (d, 2 H), 4.1-3.9 (2m, 2 H), 3.65/3.52 (2x2d, 2 H), 3.45 (2m, 2 H), 2.95-2.3 (m, 4 H), 1.98 (m, 4 H), 1.5-1.35 (m+s, 29 H), 1.22 (2t·, 25 3 H), 1.05(m,2H)
-88Γ EXAMPLE 69 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(pyridin-4-yimethyl)-l,4azaphosphinane-3-carboxylic acid
Example 69 is obtained starting from intermediate 59 in accordance with procedure D described hereinbefore.
*Η NMR: (400 MHz, dmso-d6) δ ppm 8.5 (d, 2 H), 8.05 (m, 3 H), 7.3 (d, 2 H), 3.55 (AB, 2 H), 3.05/2.3 (2m, 2 H), 2.7 (m, 3 H), 2.5 (m, 1 H), 1.75 (m, 1 H), 1.65-1.15 (m, 7 H) ESI/FIA/HR and MS/MS : [M+H]+ = 342.1577 (342.1582)
Elemental analysis : C=52.56(52.78);H=6.70(7.09);N=12.22(12.31)
Intermediate 60 : teri-Butyl 3-{4-[bis(/eri-butoxycarbonyl)amino]butyl}-4-ethoxy-410 oxo-l-(pyridin-3-ylmethyl)-l,4-azaphosphinane-3-carboxylate
Intermediate 60 is obtained starting from intermediate 21 and 3-formylpyridine in accordance with procedure F described hereinbefore.
‘HNMR: (400 MHz, dmso-d6) δ ppm 8.5 (d+s, 2 H), 7.7 (2dd, 1 H), 7.35 (m, 1 H), 4.1-3.9 15 (2m, 2 H), 3.65/3.52 (2x2d, 2 H), 3.45 (2m, 2 H), 3-2.3 (m, 4 H), 1.9 (m, 4 H), 1.4 (m+s, 30
H), 1.22 (2t, 3 H), 0.82 (m, 1 H)
EXAMPLE 70:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(pyridin-3-yimethyi)-l,4azaphosphinane-3-carboxylic acid
Example 70 is obtained starting from intermediate 60 in accordance with procedure D 20 described hereinbefore.
^NMR: (400 MHz, D2O) δ ppm 8.6 (s+d, 2 H), 8 (dd, 1 H), 7.52 (dd, 1 H), 4.4 (AB, 2 H),
3.7 (m, 1 H), 3.4 (m, 2 H), 3.18 (dd, 1 H), 2.9 (m, 2 H), 2.28/1.8 (2m, 2 H), 1.91 (m, 1 H), 1.6 (m, 2 H), 1.5 (m, 1 H), 1.21/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 342.1568 (342.1582)
Elemental analysis : C=52.32(52.78);H=6.66(7.09):N=12.32(12.31)
-89Intermediate 61 : tert-Butyi 3-{4-[bis(icri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-(pyridin-2-ylmethyl)-l,4-azaphosphinane-3-carboxylate
Intermediate 61 is obtained starting from intermediate 21 and 2-formylpyridine in accordance with procedure F described hereînbefore.
ti-I NMR: (400 MHz, dmso-d6) δ ppm 8.5 (df, 1 H), 7.75 (t, 1 H), 7.42/7.25 (2dd, 2 H), 4.1-
3.9 (2m, 2 H), 3.71/3.6 (2AB, 2 H), 3.5-3.35 (m, 2 H), 3-2.3 (m, 4 H), 2.0-2.9 (m, 4 H), 1.45/1.35 (3s, 27 H), 1.4/1-0.8 (3m, 4 H), 1.22 (2t, 3 H)
EXAMPLE 71:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(pyridin-2-ylmethyl)-l,4azaphosphinane-3-carboxylic acid
Example 71 is obtained starting from intermediate 61 in accordance with procedure D described hereînbefore.
.¾ NMR: (400 MHz, D2O) δ ppm 8.6 (dd, 1 H), 7.91 (t, 1 H), 7.55 (d, 1 H), 7.45 (dd, 1 H), centred at 4.41 (AB, 2 H), 3.75/3.4 (2m, 2 H), 3.55/3.3 (2dd, 2 H), 2.95 (m, 2 H), 2.3/1.78 (2m, 2 H), 1.98 (m, 1 H), 1,65 (m, 2 H), 1.5 (m, 1 H), 1.3/1.2 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 342.1592 (342.1582)
Elemental analysis : C=52.72(52.78);H=6.92(7.09);N=12.25(12.31)
Intermediate 63 : tert-Butyi 3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-l-(2cycIohexylethyi)-4-ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 63 is obtained starting from intermediate 21 and 2-cyclohexylacetaIdehyde in accordance with procedure F described hereînbefore.
]H NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2 H), 3.48 (t, 2 H), 2.8 (m, 2 H), 2.5-2.2 (m, 4 H), 2-0.8 (m, 19 H), 1.9 (m, 2 H), 1.45/1.4 (2s, 27 H), 1.2 (t, 3 H)
EXAMPLE 73 :3-(4-AminobutyI)-l-(2-cyciohexylethyl)-4-hydroxy-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 73 is obtained starting from intermediate 63 in accordance with procedure D described hereînbefore.
-90HNMR: (400 ΜΗζ> D2°) δ ppm 3.7-3.5 (m, 2 H), 3.3 (m, 1 H), 3.15 (m, 3 H), 3 (t, 2 H), x 2.22/1.8 (2m, 2 H), 2 (m, 1 H), 1.7-0.85 (m, 17 H), 1.65 (m, 1 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 361.2257 (361.2256)
Elemental analysis : C=56.25(56.65);H=8.92(9.23);N=7.49(7.77)
Intermediate 64 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyI)amino]butyl}-4-ethoxy-4oxo-l-[(4-phenylphenyl)methyl]-l,4-azaphosphinane-3-carboxylate
Intermediate 64 is obtained starting from intermediate 21 and 4-phenylbenzaldehyde in accordance with procedure F described hereinbefore.
-H NMR: (400 MHz, dmso-d6) δ ppm 7.69 (2d, 4 H), 7.5-7.3 (m, 5 H), 4 (m, 2 H), 3.7/3.45 10 (2d, 2 H), 3.4 (m, 2 H), 3.05-2,3 (m, 4 H), 2.05-1.65 (m, 4 H), 1.4 (m+2s, 29 H), 1.22 (2t, 3
H), 1-0.7 (m, 2 H)
EXAMPLE 74 :3-(4-AminobutyI)-4-hydroxy-4-oxo-l-[(4-phenylphenyl)methyi]-l,4· azaphosphinane-3-carboxylic acid
Example 74 is obtained starting from intermediate 64 in accordance with procedure D described hereinbefore.
1HNMR: (400 MHz, D2O) δ ppm 7.8 (d, 2 H), 7.7 (d, 2 H), 7.55 (d, 2 H), 7.5 (t, 2 H), 7.41 (t,
H), 4.45/4.28 (2d, 2 H), 3.75/3.35 (2m, 2 H), 3.5/3.15 (2dd, 2 H), 2.9 (m, 2 H), 2.25/1.8 (2m, 2 H), 1.95/1.45 (2m, 2 H), 1.6 (m, 2 H), 1.25/1,1 (2m, 2 H) 20 ESI/FIA/HR and MS/MS : [M+H]+ = 417.1932 (417.1943)
Elemental analysis : C=63.25(63.45);H=6.64(7.02);N=6.55(6.73)
Intermediate 65 : tert-Butyl 3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(3-phenoxyphenyI)methyl]-l,4-azaphosphinane-3-carboxylate
Intermediate 65 is obtained starting from intermediate 21 and 3-phenoxybenzaldehyde in 25 accordance with procedure F described hereinbefore.
^NMR: (400 MHz, dmso-d6) δ ppm 7.38 (2t, 3 H), 7.15 (t, 1 H), 7.05 (d, 1 H), 7.05 (d, 2 H), 6.95 (si, 1 H), 6.9 (d, 1 H), 3.98 (m, 2 H), 3.6/3.45 (2d, 2 H), 3.4 (m, 2 H), 3-2.3 (m, 4 H),
2-1.6 (m, 6 H), 1.4 (2s, 27 H), 1.2 (2t, 3 H), 1-0.75 (m, 2 H)
-91ÇEXAMPLE 75 : 3-(4-AminobutyI)-4-hydroxy-4-oxo-l-[(3-phenoxyphenyl)methyl]-l,4azaphosphinane-3-carboxylic acid
Example 75 is obtained starting from intermediate 65 in accordance with procedure D described hereinbefore.
’H NMR: (400 MHz, D2O) δ ppm 7.5-7.3 (2t, 3 H), 7.2-6.95 (m, 6 H), centred at 4.2 (AB, 2 H), 3.65/3.25 (2m, 2 H), 3.4/3 (2dd, 2 H), 2.82 (m, 2 H), 2.19/1.7 (2m, 2 H), 1.88/1.4 (2m, 2 H), 1.52 (m, 2 H), 1.2-1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 433.1891 (433.1892)
Elemental analysis : C=60.90(61.10);H=6.58(6.76);N=6.34(6.48)
Intermediate 66 : to/Y-Butyl 3-{4-[bis(ter/-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-(3-phenylpropyl)-l,4-azaphosphinane-3-carboxylate
Intermediate 66 is obtained starting from intermediate 21 and 3-phenylpropanal in accordance with procedure F described hereinbefore.
}H NMR: (400 MHz, dmso-d6) δ ppm 7.29 (t, 2 H), 7.15 (d+t, 3 H), 3.98 (m, 2 H), 3.49 (t, 2 H), 2.9-2.2 (m, 4 H), 2.59 (t, 2 H), 2.35 (m, 2 H), 2-1.6 (m, 7 H), 1.5 (m, 1 H), 1.4 (2s, 27 H), 1.25/1 (2m, 2 H), 1.2 (2t, 3 H)
EXAMPLE 76 : 3-(4-Aminobutyi)-4-hydroxy-4-oxo-l-(3-phenylpropyl)-l,4azaphosphinane-3-carboxylic acid
Example 76 is obtained starting from intermediate 66 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.38 (t, 2 H), 7.27 (m, 3 H), 3.62/3.28 (2m, 2 H), 3.52 (dd,
H), 3.11 (m, 3 H), 3 (td, 2 H), 2.7 (t, 2 H), 2.25/1.75 (2m, 2 H), 2.09 (m, 2 H), 1.95/1.5 (2m,
H), 1.65 (m, 2 H), 1.38/1.22 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+HJ+ = 369.195 (369.1943)
Elemental analysis : C=58.46(58.68);H=7.45(7.93);N=7.54(7.60)
-, . -92( Intermediate 68 : tert-Butyl 3-{4-[bis(terributoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(4-phenoxyphenyI)methyÎ]-l,4-azaphosphinane-3-carboxyIate
Intermediate 68 is obtained starting from intermediate 21 and 4-phenoxybenzaldehyde in accordance with procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.4 (t, 2 H), 7.3 (d, 2 H), 7.12 (t, 1 H), 6.98 (2d, 4 H), 3.99 (m, 2 H), 3.6/3.4 (2d, 2 H), 3.38 (m, 2 H), 3-2.25 (m, 4 H), 2-1.65 (m, 6 H), 1.4 (2s, 27 H), 1.2 (2t, 3 H), 1-0.75 (m, 2 H) ’
EXAMPLE 78:3-(4-Aminobutyl)-4-hydroxy.4-oxo-l-[(4-phenoxyphenyI)methyl].l>4azaphosphinane-3-carboxylic acid
Example 78 is obtained starting from intermediate 68 in accordance with procedure D described hereinbefore.
1HNMR: (400 MHz, D2O) ô ppm 7.44 (d, 2 H), 7.41 (t, 2 H), 7.21 (t, 1 H), 7.08 (d, 2 H), 7.08 (d, 2 H), 4.38/4.21 (2d, 1+1 H), 3.7/3.31 (m+m, 1+1 H), 3.5/3.1 (2d, 2 H), 2.93 (m, 2 H), 2.23/1.77 (m+m, 1+1 H), 1.93/1.48 (m+m, 1+1 H), 1.6 (quint., 2 H), 1.24/1.13 (m+m, 1+1 H) 15 2.C NMR: (400 MHz, D2O) δ ppm 177.6, 158.2, 155.7, 132,1, 130, 124.3, 124.1, 119,3,
118.7, 59.4, 51.6, 50.9, 38.8, 27, 26.6, 24.8, 20 ’ 31P NMR: (400 MHz, D2O) δ ppm 25
ESI/FIA/HR and MS/MS : [M+H]+ = 433.1884 (433.1892)
Elemental analysis : C=60.77(61.10);H=6.27(6.76);N=6.42(6.48)
EXAMPLE 79 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(2-phenylmethoxyethyl)-l,4azaphosphinane-3-carboxyIic acid
Example 79 is obtained starting from intermediate 21 and benzyloxyacetaldehyde in accordance with procedures F and D described hereinbefore.
1HNMR: (400 MHz, D2O) δ ppm 7.42 (m, 5 H), 4.63 (d, 1 H), 4.55 (d, 1 H), 3.82 (t, 2 H), 25 3.61 (dd, 1 H), 3.5 (m, 1 H), 3.33 (m, 2 H), 3.26 (m, 1 H), 3.16 (dd, 1 H), 2.92 (t, 2 H), 2.24 (m, 1 H), 1.94 (m, 1 H), 1.71 (m, 1 H), 1.61 (quint, 2 H), 1.48 (m, 1 H), 1.21 (m, 2 H) ^PNMR: (400 MHz, D2O) δ ppm 25.6
ESÏ/FIA/HR and MS/MS : [M+H]+ = 385.1883 (385.1892)
-93Ç~'· EXAMPLE 80 : 3-(4-Aminobutyl)-4-hydroxy-l-(2-hydroxyethyl)-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 80 is obtained starting from Example 79 in accordance with procedure E described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 3.9 (m, 2 H), 3.72 (dd, 1 H), 3.62 (dd, 1 H), 3.32 (m, 1 H),
3.29 (t, 2 H), 3.25 (dd, 1 H), 2.99 (m, 2 H), 2.29 (m, 1 H), 1.99 (m, 1 H), 1.79 (m, 1 H), 1.67 (quint, 2 H), 1.52 (m, 1 H), 1.41 (m, 1 H), 1.29 (m, 1 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 295.1424 (295.1422)
Elemental analysis : C=44.08(44.90);H=7.66(7.88);N=9.23(9.52)
Intermediate 69 : tert-Butyl 3-{4-[Bis(tot-butoxycarbonyI)amino]butyI}-l-[(3chlorophenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphmane-3carboxylate
Intermediate 69 is obtained starting from intermediate 21 and 3-chlorobenzaldehyde in 15 accordance with procedure F described hereinbefore.
'H NMR: (400 MHz, dmso-d6) δ ppm 7.4-7.2 (m, 4 H), 3.99 (m, 2 H), 3.62/3.43 (AB, 1+1 H), 3.38 (m, 2 H), 2.92/2.36 (m)+(m, 1+1 H), 2.73/2.47 (m)+(m, 1+1 H), 1.96 (m, 2 H), 1.89 (m, 2 H), 1.41 (m, 2 H), 1.37/1.33 (2*(s, 27 H), 1.2 (t, 3 H), 0.81 (m, 2 H) 13C NMR: (400 MHz, dmso-d6) δ ppm 127-130, 152.3, 60.9, 60.6, 54.9, 51.6, 45.6, 28.9, 20 28.9, 27.6, 24.7, 20.6, 133.2, 81.8/81.1
EXAMPLE 81:3-(4-AminobutyI)-l-[(3-chlorophenyl)methyl]-4-hydroxy-4-oxo-l,4azaphosphmane-3-carboxylic acid
Example 81 is obtained starting from intermediate 69 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.52-7.35 (m, 4 H), centred at 4.32 (AB, 2 H), 3.7/3.32 (2m, 2 H), 3.5/3.12 (2dd, 2 H), 2.93 (m, 2 H), 2.25/1.8 (2m, 2 H), 1.95/1.48 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.11 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 375.1256 (375.1240)
Elemental analysis : C=51.26(51.27);H=6.32(6.45);N=7.43(7.47) . -94O Intermediate 70 : tol-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(3hydroxyphenyl)methyI]-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 70 is obtained starting from intermediate 21 and 3-hydroxybenzaldehyde in accordance with procedure F described hereinbefore.
jHNMR: (400MHz, dmso-d6) δ ppm 9.25 (s, 1 H), 7.1 (t, 1 H), 6.7-6.55 (m, 3 H), 3.98 (m, 2 H), 3.52/3.4 (2d, 2 H), 3.4 (m, .2 H), 3-2.2 (m, 4 H), 2-1.65 (m, 6 H), 1.4 (2s, 27 H), 1.2 (2t, 3 H), 0.95/0.82 (2m, 2 H)
EXAMPLE 82:3-(4-Aminobutyl)-4-hydroxy-l-[(3-hydroxyphenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 82 is obtained starting from intermediate 70 in accordance with procedure D described hereinbefore.
ÎHNMR: (400 MHz, D2O) δ ppm 7.38 (t, 1 H), 7-6.9 (m, 3 H), centred at 4.18 (AB, 2 H), 3.7/3.32 (2m, 2 H), 3.45/3.1 (2dd, 2 H), 2.91 (m, 2 H), 2.25/1.8 (2m, 2 H), 1.92/1.48 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.1 (2m, 2 H) 15 ESVFIA/HR and MS/MS : [M+H]+ = 357.1573 (357.1579)
Elemental analysis : C=53.22(53.93);H=6.98(7.07);N=7.72(7.86)
Intermediate 71 : tert-Butyl 3-{4-[bisfrcrt-butoxycarbonyl)amino]hutyl}-4-ethoxy-l-[(4hydroxyphenyi)methyl] -4-oxo- l,4-azaphosphinane-3-carboxylate
Intermediate 71 is obtained starting from intermediate 21 and 4-hydroxybenzaldehyde in 20 accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 9.25 (s, 1 H), 7.05 (d, 2 H), 6.7 (d, 2 H), 3.98 (m, 2 H), 3.49/3.3 (2d, 2 H), 3.4 (m, 2 H), 3-2.2 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 0.95/0.82 (2m, 2 H)
EXAMPLE 83 :3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxyphenyl)methyl]-4-oxo-l,425 azaphosphinane-3-carboxyiic acid
Example 83 is obtained starting from intermediate 71 in accordance with procedure D described hereinbefore.
-95‘ ( JLNMR: (400 MHz, D2O) δ ppm 7.38 (d, 2 H), 6.95 (d, 2 H), centred at 4.25 (AB, 2 H), 3.7/3.3 (2m, 2 H), 3.48/3.05 (2dd, 2 H), 2.95 (m, 2 H), 2.21/1.75 (2m, 2 H), 1.95/1.5 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.11 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 357.1572 (357.1579)
Elemental analysis : C=53.24(53.93);H=6.89(7.07);N=7.57(7.86)
Intermediate 72 : fort-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyI}-l-(furan-3ylmethyI)-4-ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 72 is obtained starting from intermediate 21 and 3-furaldehyde in accordance with procedure F described hereinbefore.
]H NMR:. (400 MHz, dmso-d6) δ ppm 7.61/7.55 (2sl, 2 H), 6.39 (si, 1 H), 3.98 (m, 2 H), 3.49/3.33 (2d, 2 H), 3.45 (m, 2 H), 3-2.2 (m, 4 H), 2-1.8 (m, 4 H), 1.4 (2s+m, 29 H), 1.2 (2t, 3 H), 1.05/0.9 (2m, 2 H) ’ ’
EXAMPLE 84:3-(4-AminobutyI)-l-(furan-3-ylmethyl)-4-hydroxy-4-oxo-l,4· azaphosphinane-3-carboxylic acid
Example 84 is obtained starting from intermediate 72 in accordance with procedure D described hereinbefore.
-HNMR: (400 MHz’ D2°) δ PPm 7-71 (si, 1 H), 7.59 (si, 1 H), 6.58 (si, 1 H), centred at 4.22 (AB, 2 H), 3.7/3.35 (2m, 2 H), 3.55/3.08 (2dd, 2 H), 2.95 (m, 2 H), 2.25/1.8 (2m, 2 H), 1.95/1.5 (2m, 2 H), 1.62 (m, 2 H), 1.31/1.18 (2m, 2 H) 20 ESI/FIA/HR and MS/MS : [M+H]+ = 331.1431 (331.1422)
Elemental analysis : C=50.45(50.91);H=6.72(7.02);N=8.39(8.48)
Intermediate 73 : fort-Butyl 3-{4-[bis(A//-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[(2hydroxyphenyl)methyi]-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 73 is obtained starting from intermediate 21 and 2-hydroxybenzaldehyde in 25 accordance with procedure F described hereinbefore.
2HNMR: (400 MHz, dmso-d6) δ ppm 9.45 (s, 1 H), 7.1 (d+t, 2 H), 6.78 (d+t, 2 H), 4 (m, 2 H), 3.62/3.52 (2d, 2 H), 3.4 (m, 2 H), 3-2.3 (m, 4 H), 2-1.8 (m, 4 H), 1.42/1.38 (m+2s, 29 H),
1.21 (2t, 3 H), 0.98/0.85 (2m, 2 H) ’
-96EXAMPLE 85 : 3-(4-Aminobutyl)-4-hydroxy-l-[(2-hydroxyphenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 85 is obtained starting from intermediate 73 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 7.39 (t, 1 H), 7.3 (d, 1 H), 6.95 (d+t, 2 H), 4.28 (AB, 2 H), 3.65/3.28 (2m, 2 H), 3.52/3.2 (2dd, 2 H), 2.95 (m, 2 H), 2.2/1.72 (2m, 2 H), 1.98/1.5 (2m, 2 H), 1.62 (m, 2H), 1.3/1.18 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 357.1591 (357.1579)
Elemental analysis : C=53.22(53.93);H=6.97(7.07);N=7.71(7.86)
Intermediate 74 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[[2(4-hydroxyphenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 74 is obtained starting from intermediate 21 and 2-(4hydroxyphenyl)benzaldehyde in accordance with procedure F described hereinbefore.
.¾ NMR: (400 MHz, dmso-d6) δ ppm 9.45 (s, 1 H), 7.45 (dd, 1 H), 7.3 (td, 2 H), 7.16 (dd, 1 H), 7.13 (d, 2 H), 6.81 (d, 2 H), 3.93 (quad., 2 H), 3.54/3.36 (d, 2 H), 3.28 (t, 2 H), 2.85-2.15 (m, 2 H), 2.85-2.15 (m, 2 H), 1.84 (m, 2 H), 1.84 (m, 2 H), 1.47-1.3 (s, 27 H), 1.47-1.3 (s, 2 H), 1.17 (t, 3 H), 0.7 (m, 2 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 45.3
EXAMPLE 86 :3-(4-Ammobutyl)-4-hydroxy-l-[[2-(4-hydroxyphenyl)phenyl]methyl]-4oxo-1,4-azaphosphinane-3-carboxylic acid
Example 86 is obtained starting from intermediate 74 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 7.56 (dd, 1 H), 7.55-7.45 (2td, 2 H), 7.37 (dd, 1 H), 7.25 (d, 2 H), 7 (d, 2 H), 4.36 (dd, 2 H), 3.35/3.1 (2m, 2 H), 3.2/2.85 (2m, 2 H), 2.95 (m, 2 H), 2.05/1.65 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.6 (m, 2 H), 1.2-0.95 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 433.1893 (433.1892)
Elemental analysis : C=61.11(61.10);H=6.10(6.76);N=6.68(6.48) . -97Intermediate 75 : teri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(3-phenyl-lH-pyrazol-4-yl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 75 is obtained starting from intermediate 21 and 3-phenyl-lH-pyrazole-45 carboxaldehyde in accordance with procedure F described hereinbefore.
jHNMR: (400 MHz, dmso-d6) δ ppm 13-12.5 (m, 1 H), 7.9-7.3 (m, 6 H), 4.05-3.9 (m, 2 H),
3.45 (dd, 2 H), 3.3 (m, 2 H), 3.1-2.2 (m, 6 H), 2-1.7 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (m, 2 H), 1.2 (t, 3 H), 1-0.7 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 691.3829 (691.3835)
EXAMPLE 87 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(3-phenyI-lH-pyrazol-4yl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 87 is obtained starting from intermediate 75 in accordance with procedure D described hereinbefore.
1H.NMR: (400 MHz, D2O) δ ppm 7.95 (si, 1 H), 7.6-7.5 (m, 5 H), 4.45 (dd, 2 H), 3.55/3.15 (2m, 2 H), 3.05/2.7 (2m, 2 H), 2.9 (m, 2 H), 2.2/1.7 (m, 2 H), 1.8/1.25 (2m, 2 H), 1.5 (m, 2 H), 0.95/0.7 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 407.1865 (407,1848)
Elemental analysis : C=55.99(56.15);H=6.40(6.70);N=13.79(13.79) 20 Intermediate 76 : teri-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[[2(4-methoxyphenyÎ)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 76 is obtained starting from intermediate 21 and 2-(4methoxyphenyl)benzaldehyde in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 7.47 (d, 1 H), 7.32 (m, 2 H), 7.27 (d, 2 H), 7.19 (d, 1 H), 7 (d, 2 H), 3.93 (m, 2 H), 3.8 (s, 3 H), 3.54/3.37 (2*d, 2 H), 3.32 (m, 2 H), 2.74/2.22 (m, 2 H), 2.74/2.33 (m, 2 H), 1.95-1.75 (m, 2 H), 1.95-1.75 (m, 2 H), 1.41 (s, 18 H), 1.37 (m, 2 H),
1.34 (s, 9 H), 1.18 (t, 3 H), 0.7 (m, 2 H)
-98O EXAMPLE 88 : 3-(4-Aminobutyl)-4-hydroxy-l-[[2-(4-methoxyphenyl)phenyl]methyl]-4oxo-1,4-azaphosphinane-3-carboxylic acid
Example 88 is obtained starting from intermediate 76 in accordance with procedure D described hereinbefore.
*Η NMR: (400 MHz, D2O) δ ppm 7.59 (dd, 1 H), 7.51 (m, 2 H), 7.38 (dd, 1 H), 7.31 (d, 2 H),
7.1 (d, 2 H), 4.44/4.29 (2*d, 2 H), 3.36 (s, 3 H), 3.19/2.94 (m, 2 H), 3.19/2.84 (m, 2 H), 2.94 (m, 2 H), 2.08/1.65 (m, 2 H), 1.85/1.35 (m, 2 H), 1.58 (m, 2 H), 1.13/1.05 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 447.2046 (447.2048)
Elemental analysis : C=62.04(61.87);H=6.38(7.00);N=6.05(6.27) 10 Intermediate 77 : ter/-Butyl 3-{4-[bis(/er/-butoxycarbonyi)amino]butyl}-4-ethoxy-4oxo-l-[(4-phenyl-lH-pyrazol-3-yl)methyl]-l,4-azaphosphmane-3carboxylate
Intermediate 77 is obtained starting from intermediate 21 and 4-phcnyl-lH-pyrazole-3carboxaldehyde in accordance with procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 13-12.5 (m, 1 H), 8 (m, 1 H), 7.62 (d, 2 H), 7.35 (t, 2 H), 7.2 (t, 1 H), 4.1-3.9 (m, 2 H), 3.8-3.35 (m, 2 H), 3.25 (m, 2 H), 3.15-2.3 (m, 4 H), 2.1-1.9 (m, 2 H), 1.8 (m, 2 H), 1.4-1.2 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 89:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(4-phenyl-lH-pyrazol-3yl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 89 is obtained starting from intermediate 77 in accordance with procedure D described hereinbefore.
jH-NMR: (400 MHz, D2O) δ ppm 7.9 (s, 1 H), 7.55-7.35 (m, 5 H), 4.65-4.4 (dd, 2 H), 3.55/3.15 (2m, 2 H), 3.15/2.9 (2m, 2 H), 2.9 (m, 2 H), 2.15/1.65 (2m, 2 H), 1.8/1.25 (m, 2 H),
1.5 (m, 2 H), 0.95/0.75 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H] + = 407.1844 (407,1848)
Elemental analysis : C=56.58(56.15);H=6.24(6.70);N=13.79(13.79) . -99Ç Intermediate 78 : terAButyl 3-{4-[bis(icr/-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-1 -[(5-phenyl- l,3-oxazol-4-yl)methyl] - l,4-azaphosphinane-3carboxylate
Intermediate 78 is obtained starting from intermediate 21 and 5-phenyl-1,3-oxazole-4carboxaldehyde in accordance with procedure F described hereinbefore.
lH NMR:. (300 MHz, dmso-d6) δ ppm 8.29 (s, 1 H), 7.78 (m, 2 H), 7.5 (m, 2 H), 7.4 (m, 1 H), 4 (m, 2 H), 3.68 (dd, 2 H), 3.3 (m, 2 H), 3.05/2.5 (2m, 2 H), 2.95/2.65 (2m, 2 H), 2.05-1.7 (m, 4 H), 1.45 (s, 18 H), 1.35 (s, 9 H), 1.25 (m, 2 H), 1.25 (t, 3 H), 0.9 (m, 2 H)
EXAMPLE 90 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(5-phenyl-l,3-oxazol-4yl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 90 is obtained starting from intermediate 78 in accordance with procedure D described hereinbefore.
1H NMR: t400 MHz, D2O) δ ppm 8.28 (s, 1 H), 7.68 (d, 2 H), 7.6-7.5 (m, 3 H), 4.55 (dd, 2
H), 3.65/3.3 (2m, 2 H), 3.4/3.1 (2dd, 2 H), 2.9 (m, 2 H), 2.2/1.71 (2m, 2 H), 1.9/1.35 (2m, 2
H), 1.55 (m, 2 H), 1.05/0.95 (2m, 2 H) '
ESI/FIA/HR and MS/MS : [M+H]+ = 408.1689 (408.1688)
Elemental analysis : C=55.52(56.02);H=6.16(6.43);N=10.20(10.31)
Intermediate 79 : terAButyl 3-{4-[bis(terAbutoxycarbonyl)amino]butyl}-4-ethoxy-l-[[220 ^>2-oxazol-5-yi)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 79 is obtained starting from intermediates 21 and 218 in accordance with procedure F described hereinbefore.
1HNMR: (300 MHz, dmso-d6) δ ppm 8.6 (d, 1 H), 7.65 (m, 1 H), 7.55-7.4 (m, 3 H), 6.75 (d,
1 H), 4 (m, 2 H), 3.85/3.5 (dd, 2 H), 3.3 (m, 2 H), 2.95/2.4 (2m, 2 H), 2.8/2.55 (2m, 2 H), 2.1-
1.6 (2m, 4 H), 1.45 (s, 18 H), 1.35 (m, 2 H), 1.35 (s, 9 H), 1.22 (t, 3 H), 0.9-0.5 (m, 2 H)
-100r EXAMPLE 91:3-(4-Aminobutyl)-4-hydroxy-l-[[2-(l,2-oxazol-5-yl)phenyl]methyI]-4oxo-1,4-azaphosphinane-3-carboxyIic acid
Example 91 is obtained starting from intermediate 79 in accordance with procedure D described hereinbefore.
‘H NMR: (400 MHz, D2O) δ ppm 8.55 (d, 1 H), 7.85 (m, 1 H), 7.65-7.55 (m, 3 H), 6.85 (d, 1 H), 4.7/4.4 (dd, 2 H), 3.85/3.2 (2m, 2 H), 3.5/3.2 (2dd, 2 H), 2.9 (m, 2 H), 2.3/1.8 (2m, 2 H), 1.9/1.45 (2m, 2 H), 1.6 (m, 2 H), 1.2/1.05 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 408.1685 (408.1688)
Elemental analysis : C=55.14(56.02);H=5.95(6.43);N=10.14(10.31)
Intermediate 80 : teri-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(2-pyrazol-l-yiphenyl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 80 is obtained starting from intermediate 21 and 2-(lH-pyrazol-l-yl)benzaldehyde in accordance with procedure F described hereinbefore.
JjNMR: (400 MHz, dmso-d6) δ ppm 8.04 (d, 1 H), 7.7 (d, 1 H), 7.55-7.35 (m, 4 H), 6.5 (m, 1 H), 3.95 (m, 2 H), 3.65/3.35 (dd, 2 H), 3.3 (m, 2 H), 2.8-2.6 (2m, 2 H), 2.4-2.15 (2m, 2 H),
2-1.65 (m, 4 H), 1.5-1.3 (m, 2 H), 1.41 (s, 18 H), 1.35 (s, 9 H), 1.19 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 92: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-pyrazol-l-ylphenyl)methyl]· l,4-azaphosphinane-3-carboxylic acid 20 * * * * 25 *
Example 92 is obtained starting from intermediate 80 in accordance with procedure D described hereinbefore.
^NMR: (400 MHz’ D2°) δ PP™ 8.05 (d, 1 H), 7.9 (d, 1 H), 7.7-7.45 (m, 4 H), 6.6 (t, 1 H),
4.25 (dd, 2 H), 3.5/3.1 (2dd, 2 H), 3.35/3.15 (2m, 2 H), 2.95 (m, 2 H), 2.3/1.8 (2m, 2 H),
1.9/1.5 (2m, 2 H), 1.6 (m, 2 H), 1.3/1.1 (2m, 2 H) 25 ESI/FIA/HR and MS/MS : [M+H] + = 407.1869 (407.1848)
Elemental analysis : C=56.00(56.15);H=6.16(6.70);N=l3.77( 13.79)
Z- . -101( Intermediate 81 : /eri-Butyl 3-{4-[bis(ier/-butoxycarbonyl)amino]butyl}-4-ethoxy-l-[[2fluoro-6-(4-methoxyphenyl)phenyl]methyI]-4-oxo-1,4azaphosphinane-3-carboxylate
Intermediate 81 is obtained starting from intermediate 21 and 2-fluoro-6-(45 methoxyphenyl)benzaldehyde in accordance with procedure F described hereinbefore.
~- NMR: (400 MHz’ D2°) δ PPm 7-4 (d, 2 H), 7.4 (dd, 1 H), 7.18 (t, 1 H), 7.08 (d, 1 H), 7 (d, 2 H), 3.92 (m, 2 H), 3.8 (s, 3 H), 3.46 (s, 2 H), 3.22 (m, 2 H), 2.7/2.38 (dd, 2 H), 2.65/2.25 (2*m, 2 H), 2-1.6 (m, 4 H), 1.4 (s, 18 H), 1.34 (s, 9 H), 1.25 (m, 2 H), 1.18 (t, 3 H), 0.63/0.5 (2*m, 2 H)
EXAMPLEW:3.(4.Aminobutjl).l-[[2.ilUoro-6.(4.nieth.1x.v|>hen.vl)phen5l1methyl]-4hydroxy-4 -oxo-1,4-azaphospbinane-3-carboxylie acid
Example 93 is obtained starting from intermediate 81 in accordance with procedure D described hereinbefore.
\HNMR: (400 MHz, D2O) δ ppm 7.54 (m, 1 H), 7.3 (d, 2 H), 7.28 (m, 1 H), 7.21 (d, 1 H), 7.11 (d, 2 H), 4.42 (dd, 2 H), 3.86 (s, 3 H), 3.46/3.09 (m, 2 H), 3.2/2.9 (m, 2 H), 2.95 (m, 2 H), 2.11/1.67 (m, 2 H), 1.87/1.37 (m, 2 H), 1.6 (m, 2 H), 1.11 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 465.1955 (465.1954) Elemental analysis : C=59.31(59.48);H=5.75(6.51);N=6.10(6.03)
Intermediate 82 : te/T-Butyl 3-{4-[bis(^-butoxycarbonyl)amino]butyI}-4-ethoxy-l-[[2(l-methylpyrazoI-4-yl)phenyl]methyl]-4-oxo-lf4-azaphosphinane-3carboxylate
Intermediate 82 is obtained starting from intermediates 21 and 235 in accordance with procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.9 (s, 1 H), 7.65 (s, 1 H), 7.4-7.35 (m, 2 H), 7.3-7.2 (m, 2 H), 4 (m, 2 H), 3.9 (s, 3 H), 3.61/3.4 (dd, 2 H), 3.3-3.15 (m, 2 H), 2.9/235 (2m, 2 H), 2.8/2.45 (2dd, 2 H), 2.05-1.9 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.25 (m, 2 H),
1.2 (t, 3 H), 0.65 (m, 2 H) ( EXAMPLE9Î : 3-(4-Anùnobutyl)-^^ nietllyl]-4-oxo-l,4-azaphosphinane-3-carb()xylic acid
Example 94 is obtained starting from intermediate 82 i ’ described hereinbefore. * _
». «, MH,. , Ηξ , , , Ηχ
BSVFIAÆR and MS/MS_: [M+HJ+ = 421.2016 (421.2004)
Elemental analysis : C=56.61(57.13);H=6.36(6.95);N=13.O8(13.33) in accordance with procedure D
InlenneM : fert-Butyl 3-(4-^^^DamlnolbulyD^thn^. oxo-l-[(2-pyrimidin.5-yIphenyI)inethyl]-l,4-azaphosphinane-3carboxylate
Intermediate 83 is obtained starting from intermediates 21 procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) S ppm 9.2 (s, 1 H), 8.86 (s, 2 H), 7.5-7.3 (m 4 H) 3 93 ta 2 H). 3.46 (dd. 2 H). 3.3 (m. 2 H), 2.78-2.6 (2. 2 H). 2.4 (dd, 1 H), 2.2 (J 1' Χζ £
H), 1.65 (m, 2 H), 1.4 (m, 2 H). 1.4 (s, 18 H), 1.33 (s, 9 H), 1.18 (t, 3 H), 0.6 (m. 2 H)
EXAMPLE95 : ^.AminobuV·^^
E4-azaphosphinane-3-carboxylic acid and 236 in accordance with , 1 H), 7.68-7.59 (m, 2 (2m, 2 H), 2.9 (m, 2 H),
Example 95 is obtained starting from intermediate 81 in a ..
described hereinbefore. -termedrate 83 m accordance wtth procedum D ~ NMR: (400 MHz’ D2O> 5 PPm 9.19 (s, 1 H), 8.85 (s, 2 H) 7 7 (m
H), 7.45 (m, 1 H), 4.38 (dd, 2 H), 3.52/3.15 (2m, 2 H), 3.25/2.9
2.1/1.7 (2m, 2 H), 1.85/1.4 (2m, 2 H), 1.6(m,2H), 1.1 (m,2H)
ESI/FIA/HR and MS/MS : [M+H]+ = 419.1856 (419.1848)
Ëlementalanalysis : C=57.94(57.41);H=6.37(6.50);N=13.40(13.39) ’ Intermediate 84: tert-Butyl 3.{4.[bWerfrbut0xycarbony^^ (2-'ethylp.yrazol-3.yl)phenyllmethyl].4-oxo.l,4-azaph„Sphinane-3carboxylate
Intermediate 84 is obtained starting from intetmediates 21 and 280 in accordance with 5 procedure F described hereinbefore.
ÏLNMR: (400 MHz, dmso-d6) δ ppm 7.56 (dd, 1 H), 7.5 (d, 1 H), 7.47 (td, 1 H) 7 39 (td 1 H), 7.28 (dd, ! H), 6.25 (d, 1 H), 3.95 (m, 2 H), 3.58 (s, 3 H), 3.45-3.25 (m, 4 H), 2.8/2.2 (2m 2 H), 2.7/2.35 (2dd, 2 H), 2-1.75 (m, 4 H), 1.4 (m, 2 H), 1.4 (s, 18 H), 1.35 (s. 9 H) 1 2 (t 3
H), 0.7 (m, 2 H) Λ ( ’
EXAMPLE 96:3-(4.AnünobutyI).4-hydroxy-l.^ methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Exemple 96 is obtained starting from intermediate 84 in accordance with procedure D described hereinbefore.
ÜINm (400 MHz, D2O) δ ppm 7.7-7.4 (m, 4 H). 7.63 (d, 1 H), 6.45 (d, 1 H), 4.2 (dd 2 H)
3.58 (s, 3 H), 3.55-3.05 (m, 4 H), 2.8 (m, 2 H), 2.1/1.7 (2m, 2 H), 1.85/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.3-1 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 421.2019 (421.2004)
Elemental analysis : C=57.47(57.13);H=6.44(6.95);N=13.24(13.33)
Intermediate 85: tert-Butyl 3.{4-[bis(tert.butoxycarbonyl)amino]butyl)-l-[[2.(2c^l<,ropbenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3· carboxylate
Intermediate 85 is obtained starting from intermediates 21 and 214 in accordance with procedure F described hereinbefore.
(HW (400 MHz, dmso-d6) δ ppm 7.56 (m, 1 H), 7.56/7.49 (d, 1 H), 7.42 (m, 2 H), 7.42 (m, 1 H), 7.34 (m, 1 H), 7.27 (m, 1 H), 7.12 (m, 1 H), 3.92 (m, 2 H), 3.5-3.15 (m, 2 H), 3 5-
3.15 (m, 2 H), 2.68/2.1 (m, 2 H), 2.68/2.31 (m, 2 H), 2-1.7 (m, 2 H), 2-1.7 (m, 2 H), 1.42 (s, 18 H), 1.39 (m, 2 H), 1.34 (s, 9 H), 1.16 (2*t, 3 H), 0.73 (m, 2 H) ’
C ' EXAMPLE 97 :3.(4.Ammobutyl).l.[[2-(2.cMorophenyl)phenyl]methyl]^.hydroxy-|. oxo-1,4-azaphosphinane-3-carboxylic acid
Example 97 is obtained starting from intermediate 85 in accordance with procedure D described hereinbefore.
]HNMR: (400 MHz, D20) δ ppm 7.7-7.25 (m, 4 H), 7.7-7.25 (m, 4 H), 4.45-3.9 (m, 2 H), 3.75-3 (m, 2 H), 3.45-2.75 (m, 2 H), 2.95 (m, 2 H), 2.15/1.69 (m, 2 H), 1.87/1.38 (m, 2 H),
1.59 (m, 2 H), 1.3-1 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1545 (451.1553)
Elemental analysis : C=58.81(58.60);H=6.24(6.26);N=6.36(6.21)
Intermediate 86 t tert-Butyl 3-(4.[bis(tert.butoxycarbonyl)amino]butyl).4.ethoxy.l.((2^ iimdazol-l-ylphenyl)methyI]-4-oxo-l,4-azapfaosphinane-3carboxylate
Intermediate 86 is obtained starting from intermediate 21 and 2-imidazol-l-ylbenzaldehyde in 15 accordance with procedure F described hereinbefore.
‘HNMR:·(400 MHz’ « ppm 7.81 (t, 1 H), 7.53 (m, 1 H), 7.5-7.42 (2m, 2 H) 7 41 (t
H), 7.35 (m, 1 H), 7.1 (t, 1 H), 4.05-4 (m, 2 H), 3.4 (dd, 2 H), 3.3 (m, 2 H). 2.9/2.4 (2m, 2 H), 2.68/2.6 (2dd, 2 H), 1.9-1.6 (m, 4 H), 1.45 (s, 18 H), 1.35 (m, 2 H), 1.35 (s, 9 H), 1.21 (t 3 H), 1-0.65 (2m, 2 H) ’ ’
EXAMPLE 98 :3.(4.AminobUtyl).4.hydrOxy.l.[(2.inùdazol-l.ylphenyl)methyl]-t-oxo. l54-azaphosphinane-3-carboxylic acid
Example 98 is obtained starting from intermediate 86 in accordance with procedure D described hereinbefore.
LH-NMR: (400 MHz, D2O) δ ppm 7.9 (si, 1 H), 7.7-7.45 (m, 4 H), 7.36 (si, 1 H), 7.25 (si, 1
H), 4.25 (dd, 2 H), 3.5-3 (m, 4 H), 2.95 (m, 2 H), 2.1/1.7 (2m, 2 H), 1.85/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.15 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 407.1852 (407.1848)
Elemental analysis : C=56.41(56.15);H=5.89(6.70);N=13.55(13.79) ( Intermediate 87 : toi-Butyl 3-(4.[bisrtert.butoxyearbonyl)aoii11o]butyl).4-ethoxy-4.
oxo-l.[(2-piperazin-l.ylphenyl)methyl].l,4-azaphosphinane.3. carboxylate
Intermediate 87 is obtained starting from intermediate 21 and l-Boc-4(25 formylphenyijpiperazine in accordance with procedure F described hereinbefore.
TINMIL (400 MHz, dmsû-d6) δ ppm 7.35 (dd, 1 H), 7.24 (td, 1 H), 7.11 (dd, 1 H), 7.07 (td,
H), 4.1-4 (m, 2 H), 3.58 (dd, 2 H), 3.46 (m, 4 H), 3.3 (m, 2 H), 2.9-2.5 (m, 8 H), 1 9 (m 2
H), 1.75 (m, 2 H), 1.4 (s, 18 H), 1.4 (s, 9 H), 1.35 (s, 9 H), 1.35 (m, 2 H), 1.25 (t, 3 H), 0.85
EXAMPLE99 : ^Am^uty^^ l,4-azaphosphinane-3-carboxylicacid
Example 99 is obtained starting from intermediat? «7 j , ë mrermeaiate 87 m accordance with procedure D described hereinbefore.
1HNMR: (400MHz, D2O) δ ppm 7.6-7.25 (m, 4H), 4.3 (dd, 2 H), 3.75-3.05 (m 12 H) 2 9 15 (m, 2 H), 2.2/1.75 (2m, 2 H), 1.9/1.5 (2m, 2 H), 1.6 (m, 2 H), 1.3/1.15 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 425.2317 (425.231768)
Elemental analysjs : C=47.64(47.53);H=6.01(6.78);N=11.07(U.09);Br-=15.70(15.81) latermedtatess :tm-Butyl^[bie^-bu^^ 1-i[2-<2-ox»-l>3-oxazolidm-3-yl)plienyl]methyl]-l,4-azaphosplimane-3- 20 carboxylate
Intermédiare 88 is obtained starting from intermediate 21 and 2-(2-oxooxazoIidin-3yl)benzaldehyde m accordance with procedure F described hereinbefore.
iNMR: (400 MHz, dmSo-d6) δ ppm 7.5-7.3 (m, 4 H), 4.5 (t, 2 H), 4.15-4 (m, 2 H), 4-3.85 (2m, 2 H), 3.5 (dd, 2 H), 3.35 (m, 2 H), 2.9-2.5 (m, 4 H), 2-1.7 (m, 4 H), 1.42 (s, 18 H), 1.4 25 (m, 2 H), 1.38 (s, 9 H), 1.25 (t, 3 H), 0.85 (m, 2 H)
EXAMPLE 100 : 3 yl)phenyl]methyI]-l,4-azaphosphinane-3-carboxylic acid
Exampte 100 is obta,„ed starting ftom intermediate 88 in accordance with β described hereinbefore.
MNMR; (400 MHz, D2O) 8 ppm 7.71-7.42 (m, 4 H), 4.64 (t, 2 H), 4.38 (s, 2 H) 4 12/4 03 m. 2 H), 3.65/3.38 (dd, 2 H), 3.46/3.16 (dd, 2 H), 2.94 (t. 2 H), 2.24/1.76 (m, 2 H) 1 93/1 47 (m, 2 H), 1.6 (t, 2 H), 1.26/1.12 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+HJ+ = 426.1782 (426.1793)
Elemental analysis : C=53.51(53.64);H=6.34(6.63);N=9.71(9.88)
H—iateS, :te/7-Biityl3-{4.[bis(te„.butoxycarboByl)amino]butylH.ethM2. (',-m«l'yl™idilz(,l-4.yl)pheI1.vIJmethylJ.4-oxo.|,4.azaphoSphinane-3. carboxylate totonnaiiate 89 is obtamcd starting from intermediate 21 and 3-(methylimidazol-4yllbenzaldehyde m accordance with procedure F described hereinbefore.
toMR: (400 MHz, dmso-d6) δ ppm 7.7 (s, I H), 7.52 (dd, 1 H), 7.4/7.35 (2t, 2 H) 7 25 (dd H), 6.86 (s, 1 H), 4.1-4 (m, 2 H), 3.45-3.25 (m, 2 H), 3.4 (s, 3 H), 3.35 (m, 2 « 2 95/2 < 2m 2 H), 2.85-2.6 (2m, 2 H), 1.95-1.8 (m, 2 H), 1.75 (m, 2 H), 1.45 (s, 18 H), L4 m 2 H)
1.35 (s, 9 H), 1.25 (t, 3 H), 0.9-0.7 (2m, 2 H)’ 101 1 3-(4’AminObl,tî'lj-4-hydroïy.l.[[2-(3.methyliraidaz0I.4.yIJpbenyl|.
methyl]-4-oxo4,4-azaphosphinane-3-carboxylic acid
Example 101 is obtained starting from intermediate RO i« α <
, ë intermediate 89 in accordance with procedure D described hereinbefore.
2HNMR: (400 MHz, D20) δ ppm 7.8 (s, 1 H), 7.65 (m, 1 H), 7.59 (m, 2 H) 7 45 (m 1 H) 08 (.1 H), 424 (dl, 2 H), 3.43 (s, 3 H), 3.36/3.02 (dd. 2 H), 3.19 (m, 2 HX 2941 H
2.15/1.73 (m, 2 H), 1.9/1.44 (m, 2 H), 1.6 (m, 2 H), 1.15 (dl, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 421.1999 (421.2004)
Elemental analysis : C=58.05(57.I3);H=6.09(6.95);N=13.62(13.33)
-107
IflÎÊirnsHaieSO :fcrt-Butyl3.{4.[biS(to^^^ (l-methylin1idazol-2.yI)phenylJmethyl].4-oxo.l,4.azaphoSphiiiane.3.
carboxylate
Intermediate 90 is obtained starting from intermediates 21 and 223 in accordance with procedure F described hereinbefore.
1HNMR. (400MHz, dmso-d6) δppm 7.55 (dd, 1 H), 7.45/7.35 (2t, 2 H), 7 31 (dd 1 H) 7 25
SAMPLE102:3-(4.Aminobutyl).4-hyd^^ methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 102 is obtained starting from intermediate on in a .
described hereinbefore. “æ D plRi (400 MHz, D2O) 8 ppm 7.7.7.5 (m_ 4 H), w (d> ,
). 3.61 (s, 3 H), 3.46/3.26 (2m, 2 H), 3.3W3.09 (dd, 2 H), 2.8 (m, 2 H), 2.11/1 83 (2m 2 H) 1.94/1.4 (2m, 2 H), 1.5 (m, 2 H), l(m, 2 H) ’’
ESI/FIA/HR and MS/MS: [M+HJ+ = 421.2013 (421.2004)
Elemental analysis : C=57.28(57.13);H=7.10(6.95);N=13.21(13.33)
ÏSienaedtateSl :te«-BntylSWbi^-but^^ fluoro-2-(4-metfaoxyphenyl)phenyl]methyl]-4-oxo-1,4azaphosphinane-3-carboxyIate
Intermediate 91 is obtained starting from intermediates 21 and 221 in accordance with procedure F described hereinbefore.
' ”” 748 (dd'1 7 33 (d’2 H’· 7·16 «“1 H). (dd, 1 ), 71)2 (d, 2 H), 4.03 (m, 2 H), 3.8 (s, 3 H), 3.4 (AB, 2 H), 3.32 (m, 2 H), 2.66/2.51/2.41 (3m, 4 H), 1.91-1.66 (m, 4 H), 1.41 (s, 18 H), 1.37 (m, 2 H), 1.34 (s, 9 H), 1 22 (t 3 H) 0.88/0.76 (2m, 2 H) ' ’ H)’ p EXAMPLEW3 : S-^A.nin.bn.y·).^ ydroxy-4-oxo-l,4-azaphosphinane-3-carboxylicacid
ΧΧΖ1ΤΓ ......... ” -°
IHNMR: (300 MHz. D2O) δ ppm 7.62 (dd. j H) 7J5
W (. 2 H), 4.36 (AB, 2 H), 3.89 (s, 3 H), 3^ 2£ (m, 2 H), 2.09/1.66 (2m, 2 H), 1.88/1.38 (2m, 2 H), 1.62 (m, 2 H), 1 09 (m 2 H) ’’ '
EmâZffijnd MS/MS.: [M+H]+ = 465.1965 (465.1954)’
ElSfflSBBUnalysB : C=59.91(59.48);H=6.23(6.51);N=6 25(6 03)
ÊMMPLE104 : ;’^nobutyl)-!.^^ ydroxy-4-oxo4,4-azaphosphinane-3-carboxylic acid
2ΖΓ “ '™“51 -l» (300 MHz, D2O) δ ppm 7.62 (dd, 1 H), 7.3 (d, 2 H), 7.25 «d, 1 H), 7 !8 (dd ! H) ZT <AB’ 2 ** 3'4/3·13 (2”’ 2 H)· ™ 2 H) -9 (m H
2.12/1.68(2.^2^,1.89/1.38(2^211),1.63(,,.,2^,1.12^ 2H) ÎSÎHAÆIRand MS/MS.: [M+H]+ = 451.1816 (451.1798) fiiSfflSMiUMb™ : C=58.99(58.66);H=6.33(6.27);N=6.27(6.22) ^2“P'1en3'I^1* *0Pl|en‘3-yI)methyl]-l,4.azaphosphinane-3-carboxylate
IntermeÆate 92 is obtained starting ta intennediates 21 and 224 in a procedure F described heminbefore.
laWB: (400 MHz, dmso-dô) δ ppm 7.55-7.34 (m. 5 H), 7.55-7.34 (m. 1 H) 7 09 (d 1 H) ^Γι:η;:Μ2^\3·34(”’2Η,·2·88·2·52(“^4• (. ^^-38^.2^,1.35(5,9^,1,23 0,3^,0.89^,2^
-109( EXAMPLE 105 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-phenylthiophen-3-yI)methyl]- l,4-azaphosphinane-3-carboxyIic acid '
Example 105 is obtained starting from intermediate 92 in accordance with procedure D described hereinbefore.
iHNMR: (300 MHz, D2O) δ ppm 7.52 (d, 1 H), 7.4 (m, 5 H), 7.2 (d, 1 H), 4.4-4.25 (m, 2 H), 3.6-3.4 (m, 1 H), 3.2-3.1 (m, 2 H), 2.9 (m, 2 H), 2.7 (m, 1 H), 2.15 (m, 1 H), 1.85 (m, 1 H), 1.65-1.5 (m, 3 H), 1.3 (m, 1 H), 1 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+HJ+ = 423.1511 (423.1507)
Elemental analysis : C=56.99(56.86);H=6.31(6.44);N=6.79(6.63);S=7.29(7.59)
Intermediate 93 : A/AButyi 3-{4-[bis(ier/-butoxycarbonyi)amino]butyl}-4-ethoxy-4-oxol[(4-phenyIthiophen-3-yl)methyl]-l,4-azaphosphinane-3-carboxyiate
Intermediate 93 is obtained starting from intermediates 21 and 252 in accordance with procedure F described hereinbefore.
’HNMR: (400 MHz, dmso-d6) δ ppm 7.53 (d, 2 H), 7.5/7.47 (2d, 2 H), 7.41 (t, 2 H), 7.33 (t, 15 1 H), 4.04 (m, 2 H), 3.47 (AB, 2 H), 3.32 (m, 2 H), 2.92-2.4 (m, 4 H), 1.94-1.6 (m, 4 H\
1.43/1.41 (2s, 18 H), 1.34 (2s, 9 H), 1.33 (m, 2 H), 1.22 (t, 3 H), 0.8 (m, 2 H) '
EXAMPLE 106 · 3-(4-Aminobutyl)-4-hydroxy-4-oxo.l-[(4-phenylthiophen-3-yl)methyl]-
1.4-azaphosphinane-3-carboxyIic acid
Example 106 is obtained starting from intermediate 93 in accordance with procedure D described hereinbefore.
^NMR: (30° MHz’ D20> δ PP™ 7.75 (d, 1 H), 7.45 (m, 5 H), 7.42 (d, 1 H), 4.4-4,3 (2*d, 2 H), 3.45/3.15 (m, 2 H), 3.15/2.75 (m, 2 H), 2.9 (m, 2 H), 2.1 (m, 1 H), 1.8 (m, 1 H), 1.7-1.5 (m, 3 H), 1.25 (m, 1 H), 0.95 (m, 2 H) 25 ESI/FIA/HR and MS/MS : [M+H] + = 423.1503 (423.1507)
Elemental analysis : C=57.35(56.86);H=6.30(6.44);N=6.53(6.63);S=7.56(7.59) . -noΓ Intermediate 94 : toï-Butyl 3-{4-[bis(teri-butoxycarbonyI)amino]butyl}-4-ethoxy-4-oxo- l-(thiophen-2-ylmethyi)-l,4-azaphosphinane-3-carboxylate
Intermediate 94 is obtained starting from intermediate 21 and 2-formylthiophene in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.43 (m, 1 H), 6.97 (m, 2 H), 4.05 (m, 2 H), 3.77 (AB, 2 H), 3.41 (m, 2 H), 2.85/2.55 (2m, 2 H), 2.85/2.66 (2m, 2 H), 2-1.7 (m, 4 H), 1.43 (s, 18 H),
1.41 (m, 2 H), 1.39 (s, 9 H), 1.24 (t, 3 H), 1.01 (m, 2 H)
EXAMPLE 107:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-(thiophen-2-ylmethyl)-l,4azaphosphinane-3-carboxylic acid
Example 107 is obtained starting from intermediate 94 in accordance with procedure D described hereinbefore.
1R NMR: (400 MHz, D2O) δ ppm 7.6 (dl, 1 H), 7.25 (dl, 1 H), 7.12 (t, 1 H), 4.6/4.5 (d, 2 H), 3.75/3.3 (m, 2 H), 3.6/3.12 (m, 2 H), 2.95 (m, 2 H), 2.25/1.8 (m, 2 H), 1.95/1.5 (m, 2 H), 1.6 (m, 2 H), 1.3-1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 347.1205 (347.1194)
Elemental analysis : C=48.94(48.55);H=5.79(6.69);N=7.90(8.09);S=9.22(9.26)
Intermediate 95 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)ammo]butyl}-4-ethoxy-4-oxo- l-[[2-(l,3-thiazol-2-yl)phenyl]methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 95 is obtained starting from intermediates 21 and 225 in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 7.98 (d, 1 H), 7.85 (d, 1 H), 7.7 (d, 1 H), 4.45 (m, 3 H), 4.05 (quad., 2 H), 3.45/3.35 (d, 2 H), 3.4/2.5 (m, 2 H), 3.3 (m, 2 H), 2.7/2.5 (m, 2 H), 1.8-1.55 (m, 4 H), 1.45-1.35 (m, 2 H), 1.4/1.3 (s, 27 H), 1.2 (t, 3 H), 0.65-0.3 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 708.3453 (708.3447)
C OAMPLE108:3-«-A™nobutyl)-4-hydrX'.4-<,x(,.l-1|2.(l,3-tl1iaz„l.2.yl)phenylj.
methyI]-l,4-azaphosphmane-3-carboxyiic acid
Example 108 is obtained starting from intermédiare <K i„ a described hereinbefore. Pm“dU“ D
1HNMRJ300 MHz, D2O) δ ppm 7.98 (m, 2 H), 7.85 (m, 4 H), 4.6 (d 1 H) 42 (d 1 m
ESKFIAmR and MS/MS: [M+HJ+ = 424.1443 (424.1459)
ÊlanenlaUMl^ : C=54.17(53.89);H=5.57(6.19);N=9.91(9.92);S=7.38(7.57)
ÈMîMeSi :t^-Bntv!344-tM^-buto^^ naP^iIhalen-l-y|phenyl)methyl]^l.oxo-l,4.azaphosphinane-3· carboxylate
Intermediate 96 is obtained starting fom intermediates 21 and 228 in accordance with procedure F described hereinbefore.
1I1NMR; (400 MHz, dmso-d6) δ ppm 8-7.15 (m, 11 H), 4.05-3.8 (m, 2 H) 3 5-3 3 (m 2 H) oxo-M-azaphosphinane-3-carboxylic acid 8“η8 θ'” % ta ““ D D Z Γ8 (d·2 H)·7·75’7·3 <m·9 H)· “ (2’d·1 «> 3-95/3·8 1.35-0ZT ( ' H)' W (”· 1 H’’ ' H’· 1 H»' 3 H),
1.35-0.7(111, 3 H)
ESI/FIA/HR and MS/MS.: [M+HJ+ = 467.2109 (467.2099)
Elemental analysis : C=67.08(66.94):H=6.21(6.70);N=5.75(6.00) l-[(4-phenylthiophen-2-yl)inethv]l 1 J 37 i, .. f ^methyl|-l,4.azaphosphinane-3-carboxylate taermediate 97 is obtained starting from tatennediate thiophenecarboxaldehyde in accordance with procedure F de h a / ‘•-Phenyl-JiNMR: (500 MHz, dmso-d6) 8 ppm 7.75 (d 1 H) 7 67 L Γ
7-27 (t, 1 H), 4.07 (m, 2 H), 3 8 (AB 2 H) 3 4 < ' H)’7 39 (t>2 W’
H), 2-1.74 (m, 4 H), Ι.43/1.4/1.39Λ.37 (5s 27^) H (2m, 2 H) ’ ’ 4 (m· 2 H)· 1-24/1.2 (2t, 3 H), 1.1/1 .3.^^.bydn^^^^ l^-azaphosphinane-S-carboxylic acid
Example 110 is obtained starting from intermediate 97 in accorda · t.
described hereînbefore. accordance with procedure D
ÎXZX 2 H?3 s^5 3 ' H)' 7'65 <d’ 2 H)’ 7 6 (S’1 H)· 742 (d· 2 H). « -Vi.45 (m, 2 H), (m, 2W>· 1 Ηλ 2'85 2 «’ 2 H).
[M+H]+ = 423.151 (423 1507) : C=57.05(56.86);H=6.10(6.44);N=6.67(6.63);S=7.51(7.59) taM = ^3.{4“0)Wert-butoxycarbonyl)ainino]butyl}.l.[(2-b1Onlo-4 mtennedtate 98 is obtained sMng méthoxybenzaldéhyde in accordance with proceduæ F de b a n 2-bromo-4(300 MHz, dmso-dô) 8 ppm 7 3 71 ^7 2 “
75 (s, 3 H), 3.6-3.5 (d, 2 H), 3.4-3 3 (m 2 H) 3 2 6 ( \ 1 2 H)’ 27 H)’1-4 (m, 2 H), 1,22 (t, 3 H), 0.75 (m, 2 H)’3^^^^^^-^^^42/1.35(5, ^PNMR: (300 MHz, dmso-d6) δ ppm47.5
-113EXAMPLEm :^-AminobutyD-l.^.bromo.ihydrraypteiyDTOthyIl-H,ydn>xy^ oxo-1,4-azaphosphinane-3-carboxylic acid
Example 111 is obtained starting from intermediate os λ .
ë iiuui imermeoiate 98 m accordance with procedure D described hereinbefore.
1HNMR: (400 MHz, D2O) δppm 7.38 (d, 1 H), 7.2 (s, 1 H), 6.9 (dd, 1 H), 44-4 3 (2*d 2 H) J - On. 1 H). 3.6-3.4 (m, 2 H), 3.25 (dd, 1 H), ,95 (m, 2 H), 2.25 (m, 1 H), l,i (m 1 i
1.8 (m, 1 H), 1.65-1.5 (m, 3 H), 1.3 (m, 1 H), 1,15 (m, 1 H)
ESOTIAÆR and MS/MSj [M+H]+ = 435.067 (435.0684)
Elemental analysis : C=44.16(44.15);H=5.06(5.56);N=6.05(6.44)
Iü!s™diate99 :/ert-Butyl^-[bis^.butoxyearbonyDaminoJbutyD-l.ff^.
ehIorophenyl)Pyridin.3-yIJniethyl].4-ethoxy^.0xo.l,4.
azaphosphinane-3-carboxylate
Intermediate 99 is obtained starting from intermediates 21 and 291 in accordance with procedure F described hereinbefore.
1HNMR,(400 MHz, dmso-db) δppm 8.58 (m, I H), 7.9/7.89 (2dd, 1 H), 7.63/7.61 (2d,2 H),
2^ Γ’ 7/'7 4 1 H)> 4 04/3,94 (2m’ 2 H)’ 3'56/3'33 <2AB- 2 H)· 332 2 «λ 2-76•25 (m, 4 H), 1.95-1.65 (m, 4 H), 1.43/1.41 (2s, 18 H), 1.35 (m, 2 H),
1.23/1.18 (2t, 3 H), 0.9/0.74 (2m, 2 H)
1.33/1.32 (2s, 9 H),
EXAMPLE 112 : ^-Aminobutyll-l-fp·^^ hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 112 is obtained starting fæm intermediate 99 in accordance with procedure D described hereinbefore.
(300 MHz, D2O) δ ppm 8.61 (dd, 1 H), 8.09 (dd, 1 H). 7.56/7.43 (2d, 4 H) 7 55
H), 1.82/1.33 (2m, 2 H), 1.55 (m, 2 H), 1.03 (m, 2 H)
ESI/FIA/HR and MS/MS: [M+H]+ = 452.1508 (452.1505)
Elemental analysis : C=55.90(55.82);H=6.11(6.02);N=8.95(9.30)
C Intermediate ÎOQ ·
-1143(4 ’,biSfe’bUtoX)CarbOnyl}an,i,1Ol',ul5''>-l-rM.chlor<, -(4-chlorophenyl)phenyI]metliylJ.4-ethoxy.4-oxo.l,4.
azaphosphinane-3-carboxyiate '
Intermediate 100 is obtained starting from intennediates procedure-F described hereinbefore.
and 292 in accordance with (3t, 27 H), 1.25 (t, 3 H), 1.15-0.75
3.3(m, 4 H), 2.95-2.4 (m, 4 H), 1.95-1.6 (m, 6 H) , 5./ (S’1 H’2 (”· 2 H), 3.5(m, 2 H) ’ y roxy 4-oxo-l,4-azaphosphinane-3-carboxyIic acid
Example 113 is obtained starting from intermediatP inn · described hereinbefore “ aCCOrdance with procedure D ss ™ tzt: · “ “=* » « - » « ». . »>. »». 2 «> !,«.,» 0., 2 2 m 2 2 >» » 2 > 2 » «
EæmisLMSM: [M+H)+ = 485.1172 (485.1163)
Eisaentalanalysis : C=54.57(54.44);H=5.31(5.61);N=5.84(5.77)
ÏU1MU10I :
°XO’’'^2'(2-phenyIphenyI)phenyl]niethyl]-l,4-a2ap|loSpi|jn 3_ carboxylate
Intermediate 101 is obtained starting from intennediates 21 and 238 in h procedure F described hereinbefore. 8 aCCOrdance with
X'XS” 7·6’7 <m' 13 H)’ 4J5-3·9 ta· 2 Η>· 3·«·3 (æ. 2 H), (t,3H),1.2-0.7(m,2H) ’ ’ 4 H)’ (m>2 H)’ 145 (3s, 27 H), 1.25
-115
EXAMPLEH4 : ^Anünobutyl^hyd^^ IIle‘hyl]-l,4-azaphosphinane-3-carboxylic acid
-—· ” - —- -—»
Ι1 000 MHZ’ “0) 6 13 H). 3.8/3.6/3.55 (2¾ 2 H) 3 3/3 (2¾ 2
ESI/FIA/HR and MS/MS_: [M+HJ+ = 493.2273 (493.2256)
ËlTOtaUnalysn, .· C=68.12(68.28);H=6.31(6.75);N=5.77(5.69)
Intermediate 102 :
*ertButyl 3-{4-[bis(tert-b,itoxycarbonyl)amîno]butyl}-4-ethoXy.4. oxo.l.[[2.[3.(trinuoromethoxy)phenyl]phenyl]methyl].l,4.
azaphosphinane-3-carboxylate
Intermediate 102 (tnfluoromethoxyphenyl)Jbenzaldehyde i hereinbefore.
1HNMR: (400 MHz, dmso-dd) d ppra 7.59 (t, 1 H), 7.42 (m, 3 H), 7.42 (m, 3 H), 7.28 ta 1 , 3.99 (m, 2 H), 3.54/3.32 (m, 2 H), 3.32 (m, 2 H), 3.1-2.2 (m, 2 H), 3 1-2 2 (m 2 H) 2 1 6 is obtained starting from . in accordance intermediate 21 and 2-[3with procedure F described
SAMPLEH5..
Phenyi]methyl]-l,4-azaphosphinane-3-carboxylic acid x “· -.....—- - -- -—°
1HNMR;(400MHz, dmso-d6) δ ppm7.63 (m, 1 H), 7.59 (t, 1 H) 755 (m 2H) 741 < 1 xxî/i : <2’d·2 h)·—-2 x
ElSmaManalysis : C=54.63(55.2O);H=5.24(5.64);N=5.43(5.6O) latonrediareioa : te„.Butyl3.{4.[bis(/«Xxyearbo^^^^ [(4-fluoro-2-phenylplienyl)methyl]-|.oxo-l)4.azaphoSphinane.3. carboxylate
Intermediate 103 is obtained starting ftom intermédiares 21 and 257 in accordance with procedure F described hereinbefore 2122 , „ ,J4 , Hi , „ t 7 a t . · ( . ), 7.2 (dt, 1 H), 7.04 (dd, 1 H), 4-3.7 (m, 2 H), 3.52/3 32 (2*d 2 H) 3 32 <
H). 2.7/2.32 (2*m, 2 H), 1.95-1.72 (m, 2 H), 1.95-1,2 (m, 2 H), 1.41/1 Z (m. 2 H), 1.17 (t, 3 H), 0.8-0.6 (m, 2 H)
SAMPLEU6 : 3-(4oxo-1,4-azaphosphinane-3-carboxylic acid
Example 116 is obtained starting from intermediate mv , described hereinbefore. “““ WiÜ1 D
1MJ300 MHZ D20) 6 ppm 7.6 (dd, t H), 7.49 (m, 3 7 M (m, 2 (ω, t (dd, 1 H), 4.31 (AB, 2 H), 3.32/3.06 (2m, 2 H), 3.16/2.8 (2m, 2 H) 2 92 (m 2 Hi
2-05/(.6 (2m, 2 H), 1.82/1.33 (2m, 2 H), 1.56 (m. 2 H), ,,, (m, 2 2
-T NMR: (300 MHz, D20) 5 ppm -111.5
BSVFIAÆJR and MS/MS : [M+HJ+ = 435.1854 (435.1848)
EifflentaUnalEis : C=60.79(60.82);H=6.07(6.50);N=6.19(6.45) fotermediateW : tert.Butyl S-f^tbis^butoxycarbonyOami™]^,).^^.!. ((4.hydroxy.2.phenylphenyl)methyl].4.Oxo.l,4.azaphoSphinane-3. carboxylate
Intermédiare 104 is obtained starting ftom intermédiares 21 and 285 in accordance with procedure F described hereinbefore.
dmso-d6) 6 ppm 7.45-7.32 (m, 5 H), 7.42 (d, 1 H), 6.95 (dd, 1 H), 6 74 W 6^ 2 ( Τ' “t3'7’ (S' 3 HJ’ 3'46/3·27 (2*d' 2 “>·3·34 2 2·™. 15 (2*m, 2 X7 H) Γ H t65 (“' 2 H)’ 1·85-1·65 (· 2 H)· 169 2 «· (2 s, 27 H), 1.39 (m, 2 H), 1.17 (t, 3 H)
C EXAMPLE H 7 : 3-(4-Aminobutyi)-4-hydroxv-l IY4 hvH.· u . y t(4_hydroxy-2-phenylphenyl)methyl]4-oxo-l,4-azaphosphinane-3-carboxylic acid
H), 1.8/1.55 (2*m, 2 H), 1.55/1.3 (2-m. 2 H), 1.05 (m, 2 H) ' ’ ESm^g^dMSZMS · [M+H]+ = 433.1888 (433.1892)
Eteaentalanah^ : C=60.92(61.10);H=6.44(6.76);N=6.43(6.48) : fe„-ButyI 2'{4-[bis(/ert-butoxycarb0nyl)anrino]butyI}-4-ethoxy-l^^2-yl)ptenynI«tIWl]M^l^a^hospUna^3.
carboxylate and 2-(2-furyl)benzaldehyde in
Intermediate 105 is obtained starting from intermediate accordance with procedure F described hereinbefore.
AnMR: (400 MHz, dmso-d6) δ ppm 7.77 (d, 1 H), 7.62 (d, 1 H) 7 41 (d 1 H) 7 37/7 3, (2«m, 2 H), 6.77 (d, 1 H), 6.61 (dd, 1 H), 3.96 (m, 2 H), 3.84/3.49 (2*d 2 H) 3 3 3 tS
H), 2.95/2.38 (2*m, 2 H), 2.77/2.45 (2*m 2 Ht 2 05 , Λ , o „ (m’ 2 <- - H)· -1.15 (m. 2 H), .2 i
MAm^!3(4.Ami.nobuW
M-azaphosphinane-3-carboxylic acid
Example 118 is obtained starting from intermediate ins · described hereinbefore. accordance with procedure D iLNMR^MOO MHz, D2O) δ ppm 7 75 M , m 7 ,, , , , «· 1 H), 6.88 (d, ! H), 6.63 (d, 1 H), 4.63/4.33 2*d 2H) 3 8M T‘
H), 2.9 (m, 2 H), 2.26/1.8 (2-m, 2 H), !.9/l 8 (2^2 H Z 2 h ’’ H) ' m’ 2 H>’ * * * * * * 16 * * * * (m, 2 H), 1.2/1.05 (2*m, 2
ÈaÆIA/HRjindMS/MS : [M+HJ+ = 407.1729 (407 1735)
Ssmsntalaflabsis : C=59.18(59.11);H=6.65(6.70);N=6.86(6.89) f Intermediate 106 : iert-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyI}-4-ethoxy-4. oxo-l-[(2-thiophen-2-ylphenyl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 106 is obtained starting from intermediate 21 and 2-(2-thienyl)benzaldehyde in 5 accordance with procedure F described hereinbefore.
- NMR·' (400 MHz' dmso-d6) δ ppm 7.62 (dd, 1 H), 7.46-7.33 (m, 4 H), 7.23 (dd, 1 H), 7.14 (dd, 1 H), 4.03-3.88 (m, 2 H), 3.65/3.42 (2*d, 2 H), 3.32-3.15 (m, 2 H), 3-2.7/2.4 (2*m, 2 H),
3-2.7/2.4 (2*m, 2 H), 2.05-1.75 (m, 2 H), 2.05-1.75 (m, 2 H), 1.4/1.34 (2*s, 27 H), 1.39 (m 2 H), 1.2 (t, 3 H), 0.7-0.45 (m, 2 H) ’
EXAMPLE 119 : 3-(4-Ammobutyl).4-hydroxy^.OxO.l.[(2.thiophen-2.ylphenyl)methyl]-l,4-azaphosphinane-3-carboxyIic acid
Example 119 is obtained starting from intermediate 106 in accordance with procedure D described hereinbefore.
]H_NMR: (400 MHz, D2O) δ ppm 7.6 (m, 1 H), 7.57 (d, 1 H), 7.52 (m, 2 H), 7.52 (m, 1 H), 15 7.2 (d, 1 H), 7.15 (d, 1 H), 4.52/4.42 (2*d, 2 H), 3.48/3.22 (2*m, 2 H), .3.3/2.98 (dd, 2 H), 2.93 (m, 2 H), 2.13/1.68 (2*m, 2 H), 1.88/1.4 (2*m, 2 H), 1.6 (m, 2 H), 1.2/1.05 (2*m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 423.1493 (423.1507)
Elemental analysis : C=56.66(56.86);H=6.32(6.44);N=6.64(6.63);S=7.48(7.59)
Intermediate 107 : tor-Butyl 3-{4.[bis(ttrt.buto^^ 20 oxo-l-[(2-pyridin^-ylphenyl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 107 is obtained starting from intennediates 21 and 258 in accordance with procedure F described hereinbefore.
-WR: (40° MH2· δ ppm 8.62 (d, 2 H), 7.5 (dd, 1 H), 7.46-7.37 (m, 2 H), 7.4 (d,
2 H), 7.26 (dd, 1 H), 3.92 (m, 2 H), 3.58/3.38 (2*d, 2 H), 3.3 (m, 2 H), 2.82/2.22 (2»m, 2 H\
2.68/2.37 (2*m, 2 H), 1.85-1.65 (m, 2 H), 1.85-1.65 (m, 2 H), 1.41/1.33 (2»s, 27 H), 1.38 (m,
H), 1.18 (t, 3 H), 0.63 (m, 2 H) ’ —C NMR: (400 MHz, dmso-d6) δ ppm 107, 67, 29/23
-119ÊXAMPLEUO : 3'i4-Aniinobutyl)-4-hydroxy.4-oxo.l-[(2-pyridin-4.ylphenyI)methyl]- l,4-azaphosphinane-3-carboxylic acid
Example 120 is obtained starting from intermpdiai-P im · , described hereinbefore. “ ““ D
1^(400 MHz, D2O) g ppm 8.59 (d, 2 H), 7.62 (m, 1 H), 7.55 (m, 2 Ηχ γ „ (d 2
7.41 (m, 1 H), 4.4/4.29 (2*d, 2 H), 3.42/3.09 (2*m, 2 H), 3.18/2.85 (2*tn, 2 H) 2 91 (m 2 H)’
2-08/1.65 (2*m, 2 H), 1.82/1.55 (2*m, 2 H). 1.55/1.32 (2*m, 2 H), ! 05 (m, 2 Î) BSVFWHR and MS/MS : [M+H]+ = 418.1891 (418.1895)
Elemental analysis : C=59.87(60.42);H=6.51(6.76);N=9.86(10.07)
Intermédiare 108 : 3·(4-[Μ^^ oxOl-[(2Pyridin-3-ylphenyl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 108 is obtained starting ftom intermediate 21 and 2-(3.pyridyl)benzaidehyde in accordance with procedure F described hereinbefore.
te® (400 MHz, dmso-d6) δ ppm 8.58 (dd, 1 H), 8.56 (d, 1 H), 7.81 (dt, 1 H), 7.48 (m 1 H),. m 'HU41W H).7.27(UB).3.,3(m,2H),3.55M(,UH).^
H). 2.71/2.2 (m, 2 H), 2.71/2.35 (m, 2 H), 1.95-1.7 (m, 2 H), 1.95-1.7 (m, 2 H), 1.41 (s 18 H)
1.36 (m, 2 H), 1.34 (s, 9 H), 1.18 (t, 3 H), 0.64 (m, 2 H) ’ ’
EWMPLE12, : ^AHlinobu^^ >4-azaphosphinane-3-carboxylic acid
121 is obtained starting from intermediate 108 in accordance with procedure D described hereinbefore.
IHNMR^MOO MHz, D2O) δ ppm 8.58 (dd, 1 H), 8.51 (d, 1 H), 7.86 (dt, 1 H) 7 67 (m 1 H) χ· ÏZT2 H)'743 (œ·1 H)’ ™2 H)·— ESI/FIA/HR ^2,117165^2^ L86/1·36 2H), 1.59(m,2H), 1.08(m,2H)
ESI/FIA/HR and MS/MS : [M+H]+ = 418.1898 (418.1895)
EtanSsUlfeis t C=60.58(60.42);H=6.51(6.76);N=10.09(10.07)
F IntermediatelO!) : /ert-Buty!
oxo-l-[[2-[4-(trifluoromethyl)phenyl]phenyl]methyl]-l,4. azaphosphinane-3-carboxylate
Intermediate 109 is obtained starting ftom (trifluoromethyl)phenyl]benzaldehyde in accordance hereinbefore.
i intermediate 21 with procedure F described » (400 MHz, dmso-d6) δ ppm 7.81 (d, 2 H), 7.62 (d, 2 H), 7.5 (d, i H), 7.4! (m, 2 H), 27Lt ; f (m' λ 158/3·34 (2*“· 2 3'28 2 2-74/2.36 (m, 2 H)
M7 c, 3 *2 H)’W·7 <m'2 *14 <”18 H)·136 <”·2 *- * ’ * and 2-[4EXAMPLE122 : ^.AminobutyiM-hyd^^
Phen-vllmethyI]-L4-azaphosphinane-3-carboxylic acid
Example 122 is obtained starting from intermediate 109 in accordance with procedure D described hereinbefore. procedure D »-(400 MHz, D2O) δ ppm 7.83 (d. 2 H), 7.64 (m, 1 H), 7.56 (m, 2 H) 7 53 (d 2 H) • 3 (m, 1 H), 4.42/4.28 (2*d, 2 H), 3.42/3.09 (m, 2 H), 3.18/2.84 (i, 2 H), 2^1 2 Ξ) • /1-64 (m, 2 H), 1.85/1.35 (m, 2 H), 1.59 (m, 2 H), 1.13/1.05 (m, 2 H) ’
ESI/FIA/HR ;i„d MS/MS. [M+H]+ = (4gJJ81?) asmentalanabsis : C=56.24(57.02);H=5.26(5.83);N=5.65(5 78)
Intermediate 110 ;
^ri-Butyl3-{4-[bis(^.butoxycarbonyl)amino]butyl}.l-[(2c^cIohexylPhenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane“3carboxyiate
Intermediate 110 is obtained starting from intermediate 21 and 2-cycIohexylheuzaldehyde in accordance with procedure F described hereinbefore.
i™. (400 MHz, dmso-d6) δ ppm 7.28/7.17 (2*d, 2 H), 7.22/7.1 (2¾. 2 H), 3 98 (m 2 (2 m. 2 H), 1.9-1.65 (m, 2 H), 1.9-1.65 (m, 6 H), 1.45-1.25 (m, 2 H), I 45-1 25 (m 4 H)
1.41/1.37 (2*s, 27 H). 1.21 (t, 3 H), 0.85-0.65 (m, 2 H)
-121î EXAMPLE 123 : 3-(4-Aminobutyl)-l-[(2-cyclohexylphenyl)methyl]-4-hydroxy-4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 123 is obtained starting from intermediate 110 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.52-7.4 (m, 2 H), 7.52-7.4/7.3 (2*m, 2 H), 4.4 (t, 2 H), 3.6/3.4 (2*m, 2 H), 3.49/3.24 (2*m, 2 H), 2.93 (m, 2 H), 2,66 (m, 1 H), 2.21/1.75 (2*m, 2 H), 1.95/1.5 (2*m, 2 H), 1.85-1.1 (m, 10 H), 1.85-1.1 (m, 4 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 423.2408 (423.2412)
Elemental analysis : C=62.46(62.54);H=8.23(8.35);N=6.61(6.63)
Intermediate 111 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-l(lH-indazol-5-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxy late
Intermediate 111 is obtained starting from intermediate 21 and lH-indazole-5-carbaldehyde in accordance with procedure F described hereinbefore.
‘H NMR: (400 MHz, dmso-d6) δ ppm 13 (si, 1 H), 8 (s, 1 H), 7.62 (df, 1 H), 7.48 (d, 1 H), 7.3 15 (dd, 1 H), 3.97 (m, 2 H), 3.72/3.52 (2*d, 2 H), 3.4-3.2 (m, 2 H), 2.96/2.32 (2*m, 2 H),
2.83/2.47 (2*m, 2 H), 2-1.8 (m, 2 H), 2-1.8 (m, 2 H), 1.39/1.33 (2*s, 27 H), 1.36 (m, 2 H), 1.2 (t, 3 H), 0.9-0.7 (m, 2 H)
EXAMPLE 124 : 3-(4-Aminobutyl)-4-hydroxy-l-(lH-indazol-5-ylmethyl)-4-oxo-l,4azaphosphinane-3-carboxylic acid
Example 124 i s obtained starting from intermediate 111 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 8.16 (s, 1 H), 7.91 (s, 1 H), 7.68 (d, 1 H), 7.49 (d, 1 H), 4.51/4.32 (2*d, 2 H), 3.64/3.35 (2*m, 2 H), 3.48/3.11 (2*m, 2 H), 2.89 (m, 2 H), 2.25/1.77 (2*m, 2 H), 1.91/1.55 (2*m, 2 H), 1.55/1.45 (2*m, 2 H), 1.19/1.05 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 381.1697 (381.1691)
Elemental analysis : C=53.27(53.68);H=6.55(6.62);N= 14.52(14.73) , . -122Intermediate 112 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)an1i„o]|,„tyiH.ethoxy^.
oxo-l.[(2.thioPhen-3.ylphenyl)niethyl].l,4^zaphosPhiiiane.3.
carboxylate
Intermédiare 112 is obtained starting from intennediates 21 and 259 in accordance with procedure F described hereinbefore.
i» (400 MHz, dmso-dô) δ ppm 7.61 (dd, 1 H), 7.59 (dd, 1 H), 7.44/7.32 (2*m, 4 H)
7.25 (dd, ! H), 3.95 (m, 2 H), 3.6/3.4 (2-d, 2 H), 3.3 (m, 2 H), 2.8/2.29 (2*m 2 H) 8/2 ' ^2 H), 2.79 (m, 2 H), 2-1.79 (m, 2 H), 1.7 (m, 2 H), 1.4/1.34 „ H),
EXAMPLE 125: 3-(4-AimnobutyI)-4.hydroxy^^^^^ methyl]-!,4-azaphosphinane-3Carboxylic acid
Example 125 is obtained starting from intermediate il? in a , ë mrermeaiate 112 in accordance with procedure D described hereinbefore.
».(400 MHz, D2O) 8 ppm 7.63-7.43 (m, 2 H), 7.63-7.43 (m, 4 H), 7.19 (dd 1 H) 4.49/4.34 (2*d, 2 H), 3.39/3.17 (2*m, 2 H), 3.25/2.94 (2*m, 2 H), 2.94 (m, 2 2 VI 68 (2*m, 2 H), 1.87/1.59 (2‘m, 2 H), 1.59/1.39 (2*m, 2 H), 1.18/1.05 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 423.1504 (423.1507)
Hfflenalapaly^ : C=57.17(56.86);H=6.48(6.44);N=6.67(6.63);S=7.11(7.59)
Intermediate 113 ;
tert-ButyI3.{4-[bis(tert-butoxycarbonyl)ainino]butyl}-4.ethoxy-l[[2-(3.flUOr0phenyl)phenyl]methyI]^.oxo.l,4.azaphoSphtaane.3carboxylate
Intermediate 113 fluorophenyl)benzaldehyde in accordance with procedure F described____ ~(400 “k· δ ppm 7.48 (m, 1 H), 7.48 (m, 1 H), 7.38 (m. H), 7.23 (m, I H), 3.93 (m, 2 H), 3.56/3.36 (2»d. 2 H), 3.29 (m 2 H) ‘ “ 2.73/2.23 (m, 2 H), 2-1.7 (m, 2 H), 2-L7 (m, 2 H), 1.41 (s, 18 H), i.36 1 33 (s 9 H)
1.17 (t, 3 H), 0.66 (m, 2 H) ’ ’ is obtained starting from intermediate 21 and 2-(3l hereinbefore.
. i, 2 H), 7.23 (m, 3 , 2.73/2.36 (m, 2 H),
-123EXAMPLE 126: 3-(4-Aminobutyi)-l-[[2-(3-fluorophenyl)phenyl]methyl]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 126 is obtained starting from intermediate 113 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 7.62 (m, 1 H), 7.54 (m, 2 H), 7.5 (m, 1 H), 7.41 (m, 1 H),
7.21 (m, 1 H), 7.16 (m, 1 H), 7.14 (m, 1 H), 4.44/4.31 (2*d, 2 H), 3.43/3,11 (m, 2 H), 3.21/2.86 (m, 2 H), 2.94 (m, 2 H), 2.11/1.64 (m, 2 H), 1.86/1.36 (m, 2 H), 1.59 (m, 2 H), 1.09 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 435.1841 (435.1848)
Elemental analysis : C=61.58(60.82);H=5.84(6.50);N=6.51(6.45)
Intermediate 114 : teri-Butyl 3-{4-[bis(ter/-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(5-phenyl-l,2-oxazol-4-yl)methyl]-l,4-azaphosphinane-3carboxyiate
Intermediate 114 is obtained starting from intermediates 21 and 219 in accordance with procedure F described hereinbefore.
1H.NMR: (400 MHz, dmso-d6) δ ppm 8.6 (s, 1 H), 7.9 (m, 2 H), 7.55 (m, 3 H), 4 (m, 2 H),
3.6 (dd, 2 H), 3.3 (m, 2 H), 3/2.35 (2m, 2 H), 2.8/2.5 (2dd, 2 H), 2 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.35 (m, 2 H), 1.2 (t, 3 H), 0.8 (m, 2 H)
EXAMPLE 127: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(5-phenyl-l,2-oxazol-4yl)methyl] -1,4-azaphosphinane-3-carboxylic acid
Example 127 is obtained starting from intermediate 114 in accordance with procedure D described hereinbefore.
1r NMR: (400 MHz, D2O) δ ppm 8.66 (s, 1 H), 7.75-7.55 (m, 5 H), 4.5 (dd, 2 H), 3.6/3.28 (2m, 2 H), 3.2/2.9 (dd, 2 H), 2.85 (m, 2 H), 2.2/1.7 (2m, 2 H), 1.85/1.25 (2m, 2 H), 1.5 (m, 2 H), 0.9/0,7 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 408.1661 (408.1688) p Intermediate 115 :
-124<ert-Butyl3-{4-[bis(ftH.butoxycarbonyl)ainino]butyl}.l.[(5-broino2'Phenylphenyl)methyI]-4-ethoxy-4-oxo-L4-azaphospliinane-3carboxylate
Intermediate 115 and 5-bromo-2is obtained starting from intermediate 21 , phenylbenzaldehyde in accordance with procedure F described hereinbefore pR; (400 MHz, dmso-d6) δ ppm 7.71 (df, 1 H), 7.53 (dd, 1 H), 7.45 (t, 2 H), 7.4 (dd, 1 ) 7.3 (d, 2 H), 7.16 (t, t H), 3.92 (m, 2 H), 3.58/3.35 (2* *d, 2 H), 3.4 (m, 2 H) 2 74/2 22
H), 1.17 (t, 3 H), 0.78 (m, 2 H)
EXAMPLE 128 : 3-(4-A.ninobutyl).l.[(5^^ oxo-1,4-azaphosphinane-3-carboxylic acid
Example 128 is obtained starting from intermediate 115 in . i , ë miermeaiate 115 m accordance with procedure D described hereinbefore. .
1HNMRL(400 MHz, D2O) δ ppm 7.81 (d, 1 H), 7.7 (dd, 1 H), 7.52 (t, 2 H), 749 (t 1 H) 2 95 Γ 2,m7·31 id’ ‘ <4/4·28 (2<d' 2 H)’ 3-32/2·88 <2’m· 2 H)· 3-2/3-‘ (2*m' 2 H)’ (2.m,TH) 2'08/L67 (2’”' 2 H>’ L88/1'6 <2’m' 2 Ηλ tM·37 (2’m· 2
ESI/FIA/HR and MS/MS : [M+H]+ = 495.1041 (495.1048)
Elemental analysis : C=53.71(53.34);H=5.72(5,0);N=5.89(5.66) 11<j : /ert-Bu^ 3-14-[bistert-|>utoxycarbo„yl)ami„ulbutyl|.4-eth(,xy-4. oxo-l-[[2-t4-(trifluoromethoxy)phenyl]phenyl]methyl]-l,4. azaphosphinane-3 -carboxylate
Intermediate 116 is obtained starting from intennediates 21 and 286 in accordance with procedure F described hereinbefore.
pa (400 MHz, dmso-d6) δ ppm 7.65-7.33 (m, 4 H), 7.65-7.33 (m, 3 H), 7.25 (dd, 1 H) • 4 (m, 2 H), 3.57/3.3 (2-d, 2 H), 3.3 (m, 2 H), 2,2/2.23 (2*m, 2 H), 2,2/2.37 (2^ 2 H)
2-1.7 (m, 2 H), 2-1.7 (m, 2 H), 1.4/1.34 (2*s, 24 H), 1.35 (m, 2 H), 1.17 (t, 3 H), 0.65 (m; 2 H)’
-125c EXAMPLE 129 : 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[[2-[4-(trifluoromethoxy)phenyl]phenyl]methyl] -1,4-azaphosphinane-3-car boxylic acid
Example 129 is obtained starting from intermediate 116 in accordance with procedure D described hereinbefore.
jHNMR: (400 MHz, D2O) δ ppm 7.62 (m, 1 H), 7.54 (m, 2 H), 7.44 (s, 4 H), 7.4 (m, 1 H), 4.42/4.28 (2*d, 2 H), 3.4/3.12 (2*m, 2 H), 3.2/2.88 (2*m, 2 H), 2.94 (m, 2 H), 2.1/1.64 (2*m, 2 H), 1.86/1.59 (2*m, 2 H), 1.59/1.38 (2*m, 2 H), 1.15/1.05 (2*m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 501.1773 (501.1766)
Elemental analysis : C=55.71(55.20);H=5.27(5.64);N=5.62(5.60)
Intermediate 117 : fort-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyi}-4-ethoxy-l[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 117 is obtained starting from intermediates 21 and 271 in accordance with procedure F described hereinbefore.
^NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.42 (dd, 2 H), 7.29 (t, 2 H), 7.21 (dt, 1 H), 7.06 (dd, 1 H), 3.93 (m, 2 H), 3.49/3.3 (2*d, 2 H), 3.3 (m, 2 H), 2.72/2.21 (2*m, 2 H), 2.69/2.34 (2*m, 2 H), 1.95-1.7 (unresolved peak, 2 H), 1.95-1.7 (unresolved peak, 2 H), 1.68 (m, 2 H), 1.41/1.33 (2*s, 27 H), 1.38 (m, 2 H), 1.18 (t, 3 H)
EXAMPLE 130: 3-(4-Aminobutyl)-l-[[4-fluoro-2-(4-fluorophenyI)phenyl]methyi]-420 hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 130 is obtained starting from intermediate 117 in accordance with procedure D described hereinbefore.
-H NMR: (4Q0 MHz, D2O) δ ppm 7.66 (dd, 1 H), 7.38 (dd, 2 H), 7.27 (t, 2 H), 7.25 (df, 1 H),
7.18 (dd, 1 H), 4.39/4.28 (2*d, 2 H), 3.38/3.09 (2¼ 2 H), 3.18/2.87 (2*m, 2 H), 2.95 (m, 2
H), 2.09/1.68 (2*m, 2 H), 1.86/1.6 (2*m, 2 H), 1.6/1.37 (2*m, 2 H), 1.15/1.07 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 453.1741 (453.1754) Elemental analysis : C=58.67(58.40);H=5:99(6.01);N=6.46(6.19)
P iBtacmediate 118 : toi-Buty! 344-[bis(to^b^^ chl'»''>-3-<trif1uor<>methyl)phenyl]phenyl]met(,y|]^.ed]oxW<iji(| l,4-azaphosphinane-3-carboxylate
Intermediate 118 is obtained starting ftom intennediates 21 and 278 in accordance with procedure F described hereinbefore.
ILNMR: (400 MHz, dmso-d6) δ ppm 7.9 (d, 1 H), 7.81 (d, 1 H), 7.75 (dd, 1 H), 7.42/7 32 (2m, 3 H), 3.95 (m, 2 H), 3.41 (AB, 2 H), 3.2 (m, 2 H), 2.79/2.37 (2m, 2 H), 2 69/2 27 (2m 2
H), 1.95/1.7 (2m, 2 H), I.8/1.7 (2m, 2 H), !.39 (s, !8 H), 1.33 (s, 9 H), 1.2 m 2
H), 0.61/0.48 (2m, 2 H) λ ( ’
EXAMPLE131 = 3<*Anrfn0b„tyD-l.a2-r4^ro.3.(trifluoromethyl)pI»enylJphei.yl].
methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
ΓΤΖ1 1S °btaÜœd StarÜ”8 frO” intemediate 118 in accordance with procedure D described hereinbefore.
1H^(300 MHz, D2O) δ ppm 7.76 (si, 1 H), 7.71 (d, 1 H), 7.63 (tu, 1 H), 7.54 (dl, 1 H) (m, 2 H), 7.38 (m, 1 H), 4.31 (AB, 2 H), 3.46/3.08 (2m, 2 H), 3.13/2.83 (2m. 2 H) 2 92 m. 2 H), 2.11/1.64 (2m, 2 H), 1.83/1.34 (2m, 2 H), 1.57 (m, 2 H), 1.06 (m, 2 H) —F NMR: (300 MHz, D2O) δ ppm -62.3
EST/FIA/HRancl MS/MS : [M+H]+ = 519.1442 (519,1427)
Elemental analysis : C=53.40(53.24);H=4.76(5.24);N=5.43(5.40)
Intermediate 1J9 : tert-Butyl 3.{4.[bis(tert.butoxycarbonyl)aminojbntyl}.l.[[2.(3. eh,oroPhenyl)phenyl]niethyl]-4-ethoxy-4-oxo-l,4.azaphosphinane-
3-carboxylate
Intermediate 119 is obtained starting from intermédiares 21 and 213 in accordance with procedure F described hereinbefore.
iUMO MHz, dmso-d6) δ ppm 7.52 (t, ! H), 7.45 (m, 3 H), 7.4/7.37 (2td, 2 H), 7 33 H)’2 7/i'25 m 3'94 <m’ 2 H)' 3·5Μ·32 (AB· 2 H)’125 2 HX 2-76/2·37 <2m- 2
H), 2,7/2.25 (2m, 2 H), 1.95/1.78 (2m, 2 H), 1.82/1.75 (2m, 2 H), 1.41 (s, 18 H), 1 33 (s 9 H)
1.33 (m, 2 H), 1.18 (t, 3 H), 0.66/0.57 (2m, 2 H)
-127C' EXAMPLE 132 : 3-(4-Aminobutyl)-l-[[2-(3-chlorophenyl)phenyl]methyl]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 132 is obtained starting from intermediate 119 in accordance with procedure D described hereinbefore.
..H NMR: (300 MHz, D2O) Ô ppm 7.6 (m, 1 H), 7.52 (m, 2 H), 7.5-7.35 (m, 4 H), 7.26 (m, 1 H), 4.33,(AB, 2 H), 3.41/3.09 (2m, 2 H), 3.16/2.81 (2m, 2 H), 2.92 (m, 2 H), 2.09/1.64 (2m, 2 H), 1.83/1.34 (2m, 2 H), 1.56 (m, 2 H), 1.05 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1556 (451.1553)
Elemental analysis : C=58.91(58.60);H=5.83(6.26);N=6.32(6.21)
Intermediate 120 : tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyi}-4-ethoxy-l[[2-(4-methylphenyI)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 120 is obtained starting from intermediates 21 and 288 in accordance with procedure F described hereinbefore.
jHNMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.33 (2*m, 2 H), 7.23 (2*d, 4 H), 7.18 (dd, 1 H), 3.92 (m, 2 H), 3.54/3.35 (2*d, 2 H), 3.3 (m, 2 H), 2.74/2.2 (2*m, 2 H), 2.74/2.32 (2*m, 2 H), 2.36 (s, 3 H), 1.95-1.75 (m, 2 H), 1.95-1.75 (m, 2 H), 1.41/1.33 (2*s, 27 H), 1.38 (m, 2 H), 1.17 (t, 3 H), 0.71 (m, 2 H)
EXAMPLE 133: 3-(4-Aminobutyl)-4-hydroxy-l-[[2-(4-methylphenyl)phenyl]methyl]-4oxo-1,4-azaphosphinane-3-carboxylic acid
Example 133 is obtained starting from intermediate 120 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 7.6 (dd, 1 H), 7.52/7.5 (2*m, 2 H), 7.39 (dd, 1 H), 7.35 (d, 2 H), 7.25 (d, 2 H), 4.43/4.28 (2*d, 2 H), 3.36/3.1 (2*dd, 2 H), 3.22/2.83 (2*dd, 2 H), 2.94 (m, 2 H), 2.38 (s, 3 H), 2.09/1.64 (2*m, 2 H), 1.86/1.6 (2*m, 2 H), 1.6/1.35 (2*m, 2 H), 1.15/1.05 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 431.2103 (431.2099)
Elemental analysis : C=64.12(64.17);H=7.45(7.26);N=6.50(6.51) r . 428' f Intermediate 121 : tert-Butyi 3-{4-[bis(ierf-butoxycarbonyl)amino]butyl}-l-[[2-(2,4dichlorophenyl)phenyI]methyI]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxyiate
Intermediate 121 is obtained starting from intermediates 21 and 251 in accordance with 5 procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.73 (m, 1 H), 7.51 (m, 1 H), 7.51 (m, 1 H), 7.42/7.35 (m, 2 H), 7.31 (m, 1 H), 7.12 (m, 1 H), 3.92 (m, 2 H), 3.5-3.2 (m, 2 H), 3.5-3.2 (m, 2 H), 2.68/2.12 (m, 2 H), 2.68/2.35 (m, 2 H), 1.81 (m, 2 H), 1.81 (m, 2 H), 1.42 (2*s, 18 H), 1.38 (m, 2 H), 1.35 (2*s, 9 H), 1.17 (2*t, 3 H), 0.74 (m, 2 H) 10 EXAMPLE 134 : 3-(4-Aminobutyl)-l-[[2-(2,4-dichlorophenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 134 is obtained starting from intermediate 121 in accordance with procedure D described hereinbefore.
]H NMR: (400/500 MHz, D2O) δ ppm 7.7-7.63 (m, 2 H), 7.6-7.5 (m, 2 H), 7.46 (dd, 1 H), 15 7.33 (m, 1 H), 7.3/7.28 (2*d, 1 H), 4.42/4.19/3.99 (m, 2 H), 3.64/3.41/3.14 (m, 2 H\
3.38/3.12/2.99/2.84 (m, 2 H), 2.95 (m, 2 H), 2.14/1.67 (m, 2 H), 1.9/1.4 (m, 2 H), 1.58 (m, 2 H), 1.19/1.11 (m, 2 H) ’ 13C NMR: (400/500 MHz, D2O) δ ppm 132.1, 130.6, 129.5, 127.3, 57, 57, 51.8, 38.6, 27, 26.4,24.5,20 ’ ’ ’ ’ 20 ESI/FIA/HR and MS/MS : [M+H]+ = 485.1166 (485.1163)
Elemental analysis : C=54.26(54.44);H=5.33(5.61);N=5.83(5.77)
Intermediate 122 : tert-Butyl 3-{4-[bis(/eri-butoxycarbonyl)amino]butyl}-4-ethoxy-l[[2-(2-methoxyphenyl)phenyi]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate 25 * * *
Intermediate 122 is obtained starting from intermediates 21 and 282 in accordance with procedure F described hereinbefore.
1HNMR: (300 MHz, dmso-d6) 5 ppm 7.5 (d, 1 H), 7.4-7.2 (m, 2 H), 7.4-7.2 (m, 1 H), 7.09 (m, 1 H), 7.09 (m, 2 H), 7.01 (t, 1 H), 3.96 (m, 2 H), 3.7 (s, 3 H), 3.42 (m, 2 H), 3.34 (dd, 2
-129Λ Η), 2.73/2.23 (m, 2 Η), 2.73/2.46 (m, 2 Η), 2-1.7 (m, 2 Η), 2-1.7 (m, 2 Η), 1.47 (s, 18 Η), 1.42 (m, 2 Η), 1.4 (s, 9 Η), 1.21 (t, 3 Η), 0.96 (m, 2 Η)
EXAMPLE 135: 3-(4-Aminobutyl)-4-hydroxy-l.[[2-(2-methoxyphenyl)phenyi]methyl]-
4-oxo-l,4-azaphosphinane-3-carboxylicacid
Example 135 is obtained starting from intermediate 122 in accordance with procedure D described hereinbefore.
. H NMR. (400 MHz, D2O) δ ppm 7.7-7.1 (m, 4 H), 7.7-7.1 (m, 4 H), 4.4-3.9 (m, 2 H), 3.74 (s, 3 H), 3.7-3 (m, 2 H), 3.25-2.65 (m, 2 H), 2.94 (m, 2 H), 2.3-1.3 (m, 2 H), 2.3-1.3 (m, 2 H), 1.61 (m,2H), 1.3-0.9 (m, 2 H) 10 ESI/FIAZHR and MS/MS : [M+H]+ = 447.2031 (447.2048)
Elemental analysis : C=62.34(61.87);H=6.65(7.00);N=6.46(6.27)
Intermediate 123 : tert-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyI}-4-ethoxy-l[[2-(3-methoxyphenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 123 is obtained starting from intermediates 21 and 281 in accordance with procedure F described hereinbefore.
^H-NMR: (400 MHz, dmso-d6) δ ppm 7.49 (d, 1 H), 7.35 (m, 2 H), 7.35 (m, 1 H), 7.21 (d, 1 H), 6.95 (dd, 1 H), 6.89 (d, 1 H), 6.86 (si, 1 H), 3.93 (m, 2 H), 3.79 (s, 3 H), 3.55/3.37 (2*d, 2 H), 3.29 (m, 2 H), 2.74/2.21 (m, 2 H), 2.74/2.33 (m, 2 H), 2-1.7 (m, 2 H), 2-1.7 (m, 2 H), 1.41 (s, 18 H), 1.37 (m, 2 H), 1.33 (s, 9 H), 1.17 (t, 3 H), 0.68 (m, 2 H)
EXAMPLE 136: 3-(4-AmmobutyI)-4-hydroxy-l-[[2-(3-methoxyphenyl)phenyI]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 136 is obtained starting from intermediate 123 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 7.6 (m, 1 H), 7.53 (m, 2 H), 7.46 (t, 1 H), 7.4 (m, 1 H), 7.07 (dd, 1 H), 6.95 (m, 2 H), 4.43/4.28 (2*d, 2 H), 3.84 (s, 3 H), 3.38/3.1 (m, 2 H), 3.2/2.85 (m, 2 H), 2.94 (m, 2 H), 2.1/1.64 (m, 2 H), 1.86/1.36 (m, 2 H), 1.59 (m, 2 H), 1.13/1.06 (m, 2 H) ’
-130ESI/FIA/HR and MS/MS : [M+H]+ = 447.2064 (447.2048)
Elemental analysis : C=61.90(61.87);H=6.25(7.00);N=6.35(6.27)
Intermediate 124 : iW-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[[2-(4-propan-2-ylphenyl)phenyl]methyl]-l,4azaphosphinane-3-carboxylate
Intermediate 124 is obtained starting from intermediates 21 and 289 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.33 (2*m, 2 H), 7.31 (d, 2 H), 7.27 (d, 2 H), 7.21 (dd, 1 H), 3.93 (m, 2 H), 3.6/3.35 (2*d, 2 H), 3.33 (m, 2 H), 2.95 (hept., 1 H), 2.73/2.23 (2*m, 2 H), 2.73/2.34 (2*m, 2 H), 1.9-1.75 (m, 2 H), 1.9-1.75 (m, 2 H), 1.41/1.32 (2*s, 27 H), 1.38 (m, 2 H), 1.25 (d, 6 H), 1.18 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 137: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[[2-(4-propan-2-ylphenyl)phenyl]methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 137 is obtained starting from intermediate 124 in accordance with procedure D described hereinbefore.
-H NMR: (400 MHz, D2O) δ ppm 7.61 (dd, 1 H), 7.52 (2*t, 2 H), 7.43 (d, 2 H), 7.38 (dd, 1 H), 7.29 (d, 2 H), 4.42/4.24 (2*d, 2 H), 3.35/3.11 (2*m, 2 H), 3.22/2.83 (2*m, 2 H), 2.97 (m, 1 H), 2.95 (m, 2 H), 2.09/1.67 (2*m, 2 H), 1.85/1.6 (2*m, 2 H), 1.6/1.35 (2*m, 2 H), 1.24 (d, 6 H), 1.15/1.05 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 459.2418 (459.2412)
Elemental analysis : C=65.54(65.49);H=7.39(7.69);N=6.12(6.11)
Intermediate 125 : A/Z-Butyl 3-{4-[bis(ier/-butoxycarbonyi)amino]butyl}-4-ethoxy-l(lH-indazol-4-ylmethyl)-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 125 is obtained starting from intermediate 21 and lH-indazole-4-carbaldehyde in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 13.01 (s, 1 H), 8.19 (s, 1 H), 7.44 (d, 1 H), 7.27 (dd, 1 H), 6.99 (d, 1 H), 3.98 (m, 2 H), 3.93/3.71 (2*d, 2 H), 3.29/3.16 (m, 2 H), 3.03/2.37 (m, 2 H),
EXAMPLE138: 3-<4-Ami„„but.vl).4.hydroxy.l-(1H.inda2ol.4.ylme(hv|H oxü_M_ azaphosphinane-3-carboxylic acid zxz:·“ ”“ » —- -—» ^^(300 MHz, D2O) δ ppm 8.29 (s, 1 H), 7.71 (dl, 1 H), 7.49 (dd, 1 H), 7.3 (dl, 1 H) I 91/1 45 (21^2 HU «T”1,2 Γ’ 3 5OT 21 2 H)’ 2'87 2 Hl- 2'19/1'74 (2”’ 2 H)’
l.yi/1.4J (2m, 2 H), 1.54 (quint., 2 H), 1.08 (m, 2 H)
ESPFLVHR and M.S/A4S .· [M+HJ+ = 381.1707 (381.1691) aæSlMÜ® : C=53.52(53.68);H=6.73(6.62);N=14.77(14,73)
Intermediate .26 : rert-Butyl Wbisf/erributoxyearboayijaminojbutyi}.!-®.^ chIor°PhenyFpyridm-4-yl]methylJ.4-ethoxy-4-oxo-l,4. azaphosphinane-3-carboxylate taennediate 126 is obtained starting from intermediate 2] 3.(4.chlorophenyl) 4 baldehyde m accordance with procedure F described hereinbefore.
HNMR: (400MHz,dmso-d6)δppm8.57 (d, 1 H), 8.42 (s, 1 H), 7.56 (d 2 H) 7 54(d 1 H1 7-44 (d, 2 H), 3,4 (m, 2 H), 3.53 (AB, 2 H), 3.36 (m, 2 H). 2.7/45 (2m 2 H)’ ζ ’ ‘ ' 4H),i.41(s,18H),
É^AMPLEW : 3.(4-A„ünobutyi).l4[3.(4^^ hvdroxy-4-oxo-l,4-azaphosphinane-3-carboxyIicacid
Example 139 is obtained starting from intermedi^ , described hereinbefore. »-—te 126 m accoirianee with procedure D
1SNW: (400 MHz, D2O) δ ppm 8.62 (d, 1 H). 8.54 (s, 1 H), 7.67 (d, 1 H) 7 58 (d 2 H) •38 (d, 2 H), 4.46/4.35 (2’d, 2 H), 3.47/3.12 (2*m, 2 H), 3.17/2,5 (2‘m, 2 H) 2,5 < 7
N15/1 68 (2*m’2 H>’ h87/1'61 2 H)’ L59/1·38 (2*“- 2 108 (m 2 H)
2ΡΝΜ&(400ΜΗζ,Β20)δρρ„25.Ι ‘ W “J.JZr _ÇNMR: (400 MHz, D2O) δ ppm 147.4, 146.1, 128.3, 126.4, 122.2, 55, 53.2,49 9 36 243
23.9,22.1,17.3 ’ ’ *'
ESI/FIA/HR and MS/MS : [M+H]+ = 452.1516 (452.1505)
Elemental analysis : C=55.97(55.82);H=5.86(6.02);N=9.28(9.30)
Intermediate 127 : fert-Butyl 3-{4-[bis(^rt-hutoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(3-phenyI-l-benzothiophen-2-yl)methyI]-l,4azaphosph inane-3 -carboxyiate
Intermediate 127 is obtained starting from intermediates 21 and 283 in accordance with procedure F described hereinbefore.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.95 (m, 1 H), 7.55 (t, 2 H), 7.47 (t, 1 H) 745-7 3 (m 3 H), 7.45-7.3 (m, 2 H), 4.05 (m, 2 H), 3.81 (dd, 2 H), 3.42/3.33 (m, 2 H), 2.88/2.53 (m, 2 H),' 2.88/2.7 (m, 2 H), 2-1.7 (m, 2 H), 2-1.7 (m, 2 H), 1.49 (m, 2 H), 1.39 (s, 27 H), 1.23 (t 3 H)’ 1.14/1.02 (m, 2 H) ’ ’
EXAMPLE 140 : 3.(4-Anünobutyl)-4.hydr0xy^^ yl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 140 is obtained starting ftom intermediate 127 in accordance with procedure D described hereinbefore.
a NMR: (400 MHz, D2O) δ ppm 7.97 (d, 1 H), 7.56 (m, 3 H), 7.49 (d, 1 H), 7.45 (t, 1 H) 7.35 (m, 1 H), 7.35 (m, 2 H), 4.6/4.51 (dd, 2 H), 3.55/3.18 (m, 2 H), 3.26/2.9 (m, 2 H) 2 9 (m’
2 H), 2.18/1.68 (m, 2 H), 1.86/1.34 (m, 2 H), 1.56 (m, 2 H), 1.04 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+HJ+ = 473.1669 (473.1663)
Elemental analysis : C=61.52(61.00);H=5.76(6.19);N=5.51(5.93);S=6.56(6.79)
EXAMHÆ141: 3-(4-AnûnObutyl).4.hyd^^ azaphosphinane-3-carboxyiîc acid
Example 141 is obtained starting from intermediate 21 and 3-phenyIbenzaIdehyde in accordance with procedures F and D described hereinbefore.
r !» (400 MHz. D20) δ ppn] 7.79-7.4 Ηλ 4 49 , H) i Z1 ίΐ \H58 ( 39 (m;1 d H)·313 (dd·1 H)’2,89 (m·2 H>·2·27 (nt 1
HsiBSatalanabas : C=64.07(63.45);H=6.72(7.02);N=6.86(6.73)
KAMPLEH2 : 3‘(4-AminobutyI)-4-hydroxy-4H>xo-I.(4-phenyibutyl)-l,4.
azaphosphinane-3-carboxylic acid
Example 142 is obtained starting from intermediate λ λ k
... „ d hmi“ = -4*·*·- lHNMR:(400MHz,D2O)6ppm7.29(t,2H),7.21(d.2H) 719(t
ESHEIAZHRandMSaiS : [M+H]+ =383.2092(383.2099)
EaBaMMalysis : 059.51(59.67)^=8.12(8.17)^=7.34(7.33)
EXAMPLE 143: 3<4-An>inobutyl).4.hydmy.4-oxo.l.(5.plienylpentyl).1.4.
azaphosphinane-3-carboxylic acid
Example 143 is obtained starting from intermediate 21 and s h . withproceduresFandDdescribedheæinbefore
H), 1.8-1.6 (unresolved peak, 2 H), 1.8-1.15 (m, 10 H) ( ’
ËSEFIAZHKandMS/MS : [M+HJ+ = 397.2251 (397.2256)
Elemental analyse : O61.01(60.59);H=7.98(8.39);N=7.12(7.07)
SAMOE145 .· ^'^'AmlnobiitylJ^-hydroxy-l-ffA-niethylsuIphaiiylphenyDinethyl]-
4-oxo-l,4-azaphosphinane-3-earboxyIic acid ^ΖΖ^ΣΤ··1'··1·-'···’.....
r J1NMR (400 MHz, D2O) δ ppm 7.41/7.37 (2*d, 4 H), 4.38/4.17 (2«d 2 H) 3 TO 31 z2.
2 Η)· 3·45/3·ϋ9 2 H3· (m, 2 H), 2.49 (s, 3 H), 2.22/1 78 2^ , 2 (2*m, 2 H), 1.58/1.47 (2*m, 2 H), 1.22/1.1 (2·». 2 H)
ÜENMR: (400 MHz, D2O) δ ppm 25.9 5 BSIEAÆIRandMSAJS : [M+HJ+ = 387.1512(387.1507)
SemalaU^ : C=52.52(52.84);H=6.70(7.04)^7.35(7.25);S=8.34(8.30)
SAMPLE146:
azaphosphinane-3-carboxylic acid
Example 146 is obtained starting fæm intennediate 21 and methyi 3-formylbenzoate in accordance wrth procedures F and D described hereinbefore
S^3~’2 D2°’ 8 PPm 8 03 (2’m· 2 H’’ 7'7 (d’ 1 H’· ™ * H)· 4-52/4.3 (2*d, (2*ηΐ 2 H) I 62 1 43 ( 1 2 ( m’2H). 1-62-1.43 (unresolvedpeak,2H), 1.2/1.1 (2*m 2H)
ÜNMR:(400MHz,D20)Sppm25 ’
ESIQAfflRand MS/MS.· (M+H]+ = 385.1522(385.1528)
ElemenraLanalysis ; C=53.60(53.12);H=6.54(6.56);N=7.42(7.29)
EXAMPLEU7 : ^-Anifaobuty^^ azaphosphinane-3-carboxylic acid
Exampie 147 is obtained starting from intermediate 21 ccordance with procedures F and D described hereinbefore.
ΖΤΓ5 PPm 8 (d’2 H)’76 (d’2 H)’ 4'52/4·3 (2*d’2 H)· 3-7M·4
H),' 1.2/1.1 S ’ 2·9 2 H)· 2'28/1·8 (2’m'2 H)· 3 H)· 1.55H.5 (m,
ESjglAÆiR and MS/MS. : [M+HJ+ = 385.1524 (385.1528)
Elansntalamljsis ; C=52.66(53.12);H=6.04(6.56);N=7.33(7.29)
-135-mjMPLEU* : 3-M-An>in„b„tyl).].[l4.(diflu„rometh„xy)pheny|Jmethyij^.l,ydr(,xy.
4-oxo-l,4-azaphosphinane-3-carboxyIic acid
Example 148 is obtained starting from m.ermedlate 21 and 4-(difluoromethoxy)ben2aldehyde in accordance with procedures F and D described hereinbefore D2°> 5 PP” ™ « 2 H). 7.25 (d, 2 H), 6.83 (t, 1 H), 4.4/4.22 (2*d, 2 2 H) 1Î (dd' 2 H)' W 2 H)· 2-25/1'78 (2‘”· 2 H)· >·’·* <2*m.
H), 1.6/1.46 (2*m, 2 H), 1.22/1.1 (2»m, 2 H)
ESVFIA/HR and MS/MS. : (M+H]+ = 407.1551 (407.1547)
Elemental analysis : C=50.33(50.25);H=5.97(6.20);N=7.02(6.89)
EXAMPLE 149: 3-(4.AminObulyl).4.h^^ azaphosphinane-3-carboxyiic acid
Exemple 149 is obtained starting from intermediate 21 and aeetophenone in aceordanee with procedures F and D described hereinbefore.
2HJffiffiL.(4OO MHz, D2O) δ ppm 7.5 (m, 5 H), 4.67 (quai, 1 H), 3.72/3 53 (2*m I H) Γ Z?/ H)’ 3'29/3'13 (2’m·1 H)’309-2·9 1 2 hÎ Xn (2 m, 1 H), 2-1.65 (m, 1 H), 2-1.65 (m, 2 H), 1.7 (2*d, 3 H), 1.7-1.05 (m, 2 H), 1.7-1.05 (m, 2 ^P-NMR: (400 MHz, D2O) δ ppm 26.4/26.2
ESI/FIA/HR and MS/MS : [M+H]+ = 355.1807 (355.1781) fenentaUna^ : C=57.43(57.62);H=7.57(7.68);N=7.96(7.90) ^AMPLE15I! : dttluoropha.yOn.ethrtl^hyd^^ l,4-azaphosphinane-3-carboxylic acid
Example 150 is obtained starting from intennediate 21 and 3,4-difluorobenzaldehyde in accordance with procedures F and D described hereinbefore.
J»(300 Mhz, D20) δ ppm 7 4M 22 (mi 3 Ηλ 4 2g (ab 2 3 6s/3 2
3.34 3.J (ra+dd. 2 H), 2.92 (m, 2 2 23/] ?7 (2m, 2 Ηλ t 92/i
H), 1.22/1.09 (2m, 2 H) (quint., 2
2!FNMR: (300 MHz, D2O) δ ppm -135.5
2ÎPNMR: (300MHz, D2O) δ ppm 23 “136
EStFIAÆR and MS/MS : [M+H]+ = 377.1416 (377.1441)
Elemental analysis : C=50.40(5I.06);H=6.20(6.16);N=7.38(7.44)
OAMPLE151 : ^-Anûnobmy!)-!^^ methyI].4-hydroxy-4-oxo-l,4-azaphosPhinane-3-carboxylic acid
Exampie 151 ts obtained starting from intermédiare 21 and 3-(dimethylaminomethyl).4H nZ Z 6 “ Wi‘h ProCedUreS F “d ° deSCribed hereinbefore.
(40“ D20) 5 P- ™ <d· 1 H), 7.43 (s, 1 H), 7.02 (d, 1 H), 4.35/4.18 (2*d 2 ’ 4.32/4.28 (2*d, 2 H), 3.7/3.3 (2»m, 2 H), 3.44/3.08 (dd, 2 H) 2 9 (m 2 H) 2 8 td 6 m
2-2/1.75 (2-m, 2 H). 1.9/1.45 (2.m, 2 H), 1.6 (m, 2 H), ,.25/1., (^ ESI/FIA/HR and MS/MS.: [M+H]+ = 414.2155 (414.2157) Elemental analysis : C=46.97(47.82);H=5.90(6.31);N=7.67(7.97)
SAMPLE152 : 3.(4.Aminobutyl).l.[(2.^^ azaphosphinane-3-carboxyIic acid
Exampie 152 is obtained starting from intermédiare 21 and 2-flnorobenzaldebyde in accordance with procedures F and D described hereinbefore ppm 7.5 (m, 2 H), 7.26 (m. 2 H), 4.41 (si, 2 H), 3.7/3.35 (2m, 2
J^FNMR: (300MHz, D2O) δppm-115 ^PNMR: (300MHz, D2O) δ ppm 25.6
ESI/FIA/HR and MS/MS : [M+H]+ = 359.1530 (359.1535)
Elemental analysis : C=53.34(53.63);H=6.46(6.75);N=7.77(7.82) —^153 · ^^A^^butyl/'l'lcl'fluorophenyonlethylj^-hydroxy-i-oxo-l^.
azaphosphinane-3-carboxylic acid
Example 153 is obtained starting froffi intermédiare 21 and 3-flnorobenzaldehyde in accordance with procedures F and D described hereinbefore.
±HNMRl(300 MHz, D2O) δ ppm 748 (m’’/m 7 74 < , „ y . ». —. i r» (quint., 2 H), 1.22/1.1 (2m, 2 H) ’ 2 H)’158 ^ENMR: (300 MHz, D2O) δ ppm -112
2PNMR: (300MHz, D2O) δppm22.9
ESI£IAÆRandMS/MS : [M+HJ+ = 359.1536 (359.1535)
SanenlaUnalyas : C=53.15(53.63);H=6.41(6.75);N=7.83(7.82) «^.·3(4-Α^^ i,4-azaphosphinane-3-carboxyIic acid
H), 1.59 (quint., 2 H), 1.25/1.11 (2m, 2 H) ( '
2ENMR: (400 MHz, D2O) δ ppm 23.2
EW2A/HR™IMs/ms ; [M+HJ+ = 357.1696 (357.1691) asosmanalyas : C=51.09(50.56);H=6.51(7.07);N=15.78(15.72)
EXAMPI.E 155 : 3-(4.AniinobutylM-hydroxy.4-oxo 1 1/2 nh y xo-1'l(2-phenoxyphenyl)-inethyn-l,4azaphosphinane-3-carboxylic acid
-HNMR: (300MHz, D2O) δ ppm 7.47 (t, 1 H) 741 (, 2 H) 7 77 7no , h .«/1.40 (2m, 2 H), 1.6 (quint, 2 H), 1.15 (m, 2 H) iPNMR: (300 MHz, D2O) δ ppm 25.8 : [M+H]+ = 433.1894 (433.1892) ^aBSntalanalysis : C=61.51(61.10);H=6.57(6.76);N=6.61(6.48) r EXAMPLE156.· Xd-Amim-butyl)-!.^^^ oxo-1,4-azaphosphinane-3-carboxylic acid
Ta ΖΓ 2> -d 2_(4-chloroPhenÿl)benzaldehyde n accordance with procedures F and D described hereinbefore » (300 MHz, D2O) δ ppm 7.6/7.52/7,4 (m, 3 H), 7.52/7.34 (2d, 4 H), 4 35 (AB 2 H)
3.4/3.1 (2m, 2 H), 3.17/2.86 (2m. 2 H), 2.94 (m, 2 H), 2.09/1.64 (2m. 2 H), LS5/135 .^ 2
H), 1.58 (m, 2 H), 1.08 (m, 2 H) ^Slæ^HRandMSAlS : [M+HJ+ = 451.1559 (451.1553) aaBentalanMyss : C=58.24(58.60);H=5.82(6.26);N=6.48(6.21) ^AMOE157 :
azaphosphinane-3-carboxylic acid
Example 157 is obtained starting fan intermediate 21 Md 2.bromobe & ccordance with procedures F and D described hereinbefore
S-2 : 5 PPm 7 75 (dt 1 H)' 7 53 1 «>· - * 1 H). 7.39 (td, 1 H).
1,95/1 5 (2^ H) ( 2 3'5/3,28 (2”· 2 H)’ 2 94 2 2-24/1·79 <2”· 2 H>.
i.yo/1.3 (Zm, 2 H), 1.6 (m, 2 H), 1.26/1.1 (2m, 2 H)
ËSimÆiRmLMSWS : [M+H]+ = 419.0732(419.0735) aEBSntaLæalysis : &45.33(45.84);H=5.29(5.77);N=7.00(6.68)
EXAMPLE 159: 3-<4-Ami''b'«jl)-4-hyd1oxy^.Ox„.1.li2.„xo.i j.dihydr()indü| 5 ybmethylJ.I,4-aZaphOSphinane-3-carboxylic add
Example 159 is obtained starting from intermediate 21 and oxindole-5-carboxaIdehvde i„ accordance with procedures F and D described hereinbefore.
iLNMRU300 MHz, D2O) S ppm 7.35 (d, 1 H), 7.3 (dd, 1 H), 7 (d, 1 H) 4 35/4 15 (dd 2 m
ESj/FtA/HR andXf&MS : [M+H]+ = 396.1692 (396.1688) : C=54.70(54.68);H=6.42(6.63);N=10.57(10.63)
-139r EXAMPLE160: 3-W-Aminobutyl).^^ -'’l)P1'«>.'Un,ethyl|.4-ox0.I,4-azaphoSpt,taa,1e.3.ca,b0xylicadd
ΙΤζ16° iS “ S,ming fmm in“te 21 “> ^--«hyl-u^adiazpwyDbenzaldehyde m accordance with procedures F and D described hereinbefore «400 MHz, D20) 5 ,26 (d, t 7 ?2 (mi 2 H)> 7 m ( 4
X Γ X (m' 2 H)’ 2'91 <m· 2 H)· “ 3 (>· 2 H)
1.88/1.49 (m, 2 H), 1.58 (m, 2 H), 1.22/1.02 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 423.1801 (423.1797)
SementaLanal^is : C=53.57(54.02);H=6.25(6.44);N=12.77(13.26) —AMt,Lni<il 3-^'Ambl<)bllty^'4-hydroxy.l.[[2-[2.niethyl.5-(trifluoromethyI)pyraz01.3.yl]phenyI]methyi].4.oxo.l,4.azaphoSphinane.3.carboxyUc acid lZ‘e M StMi”8 fr°m 21 Md ^n-thyl-S^uoremetbyi).
hereLZrê F “d D “d
».(400 MHz. D2O) S ppm ,71 (d, , H), 7.67 (ζ , η & γ S’ ’ 3/418 (dI> 2 H)’3,53/3 21 (“'2 H)’ 3·27 (s’ 3 H)’ 2*27/3,03 (m, 2 H) 2 94 (m
H), 2.18/1.71 (m, 2 H), 2.18/1.43 (m, 2 H), 1.6 (tn, 2 H), 1.18/1.1 (œ, 2 H) ESh'FWHR and MS/MS : [M+H]+ = 489.1903 (489.1878)
Elemental analyses : C=51.66(51.64);H=5.61(5.78);N=11.25(11.47) maue : 3-M-Ami nbu'ylM-[[2.(2,4.dinuoroPhCnyl)phen}IJmcth}l|.4.
hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 162 is obtained starting fom intemediates 21 287 procedures F and D described hereinbefore.
KWfc (4«) MHZ, D2O) δ ppm 7.65 (m, 1 H), 7.57 (m, 2 H), 7.4 (m, 1 H) 7 34 (m ! H) (ZX XT2 *3·7-2·8 (m·2 Ηλ 3·7-2·8 (m·2 * (2 m, 2 H), 1.88/1.6 (2*m, 2 H), 1.6/1.38 (2»m, 2 H), 1.15/1.05 (2*m, 2 H) ESIÆTAÆÏR and MS/MS : [M+H]+ = 453.1745 (453.1754)
Elaaemalanalysis : C=58.27(58.40);H=6.09(6.01);N=6.17(6.19)
-140EXAMPLKM : ^44Amin.butyl)-l.I[2-fluon>-6.(4.hy<|roXyp|leny|jp|len^y_m^y|^ hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 163 is obtained starting from intermediate hydroxyphenyDbenzaldehyde in accordance with procedures F · _ 1HNMRL(4OO MHz, D2O) 5 ppm 7.52 (m, 1 H), 7.27 (m, 1 H) 712 (d
6-98 (d, 2 H), 4.41 (dd, 2 H), 3.45/3.09 (m, 2 H), 3.16/2.9 (m, 2 H), (m, 2 H), 1.86/1.35 (m, 2 H), 1.59 (m, 2 H), 1.08 (m, 2 H) ES1ZFIAÆR and MS/MS : [M+HJ+ = 451.1813 (451.1798) aSBaitalanalysis : C=58.33(58.66);H=5.35(6.27);N=6.49(6.22) and 2-fluoro-6-(4and D described hereînbefore.
. UH),7.19 (m, 1 H),
2.94 (m, 2 H), 2.09/1.64 «W1H : 3-(4-Aminobutyl)-I-[[2-(I,3-benzodioxol-5-yl)pheiiyl]inethyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 164 is obtained starting from intermédiares 21 and 279 in accordance with procedures F and D described hereînbefore.
ΙΗΝΜΛΜΟΟ MHZ, dmso-d6) δ ppm 8.2-7.9 (s, 3 H), 7.45 (d, 1 H), 7.3 (m 2 H) 7 15 (d 1 X 7^ Ht 2?5 (S' 1 H)' M <dd’ 1 6 05 (S· 2 H>· - X ’ ' ’ H), 2.55 (m, 1 H), 2.35 (m, 1 H), 2.25 (m, I H), 1.7 (m, 1 H) 1 6-1 (m 7 H) ESJEâfflRsildMSAiS : [M+HJ+= 461.1854 (461.1841) ’ ’ ’
Bemental analysis : C=60.04(59.99);H=6.06(6.35);N=5.62(6.08)
EXAMPLE 165 : 3-(4-Aminobutyi)-4-hvdroxv 1 rr? m «.
y ) nyûr°xyl-[[2-(6-methoxypyndin-3-yl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylicacid
Example 165 is obtained starting from intermediate 21 and 2-(6-methoxy 3 •Hrx:Tdeinaccordancew“
----.. (300 MHz, D2O) δ ppm 8.05 (s, 1 H), 7.75 (dd, 1 H), 7.6 (m, 1 H) 7 5 (m 2 H) •35 (m, 1 H), 6.95 (d, 1 H), 4.4 (d, 1 H), 4.25 (d, 1 H), 3.9 (s, 3 H), 3 55-3 3 (m 1 H) 3 3 3 1’ («.IH), 3-1 (m, 1 H), 2.95 (t, 2 H), 2.85 (m, 1 H), 2.1 (m, 1 H),
H), 1.35 (m, 1 H), 1.2-0.95 (m, 2 H) ' ’3
ESPFIAÆRandMS/MS,: [M+H]+ = 448.1996 (448.2001)
ElememaUn^ : C=59.45(59.05);H=6.75(6.76);N=9.12(9.39)
-141: 3 (^
Exampie 166 is obtained starting from intermediates 2] procedures F and D described hereinbefore. accordance with
MNMR; (300/400MHz, D2O) S ™ 77.™ ,,
H)· «5 (tu, 2 H), ,6-3.4 (m. ! “ X ' ’ 2’ >85 (fo, i H), 1.7 (m, I H), 1.6 (m, 2 H), 1.4 (m,'l jjj j 25 0’9J ES^MRandMSAîS:[M+H]+ = 434.I860(434.1844)’
Hfflffltalanabsis : C=58.86(58.!9);H=6.27(6.51);N=9.89(9.69) « J] oxo-l,4-azaphosphinane-3-carboxylicaci<I
Example 167 is obtained starting ftom inlemediates 2[ md procedures F and D described hereinbefore. accordance with HNMR' (30° MHz· D2°) 5 Ppm 7.98 (d, 1 H) 7 68 (s 1 Hi 7 fis m i
7-52 (m, 1 H), 7.45 (dd, 1 H). 7.22 (m, 1 H), 6 98 (t 1H) “ 7 , T ’’
2-9 (m, 2 H), 2.85 (m, 2 H), 2.12/1.55 (2»m 2 H) i 8/1 55 /2* , B 2
1.28/0.95 (2*m, 2 H) '55 2 2 H)’ 155/®-95 (2«m, 2 H), ^EÎMiRandhiSZ^: tM+H]+ = 457.2004 (457.20046) : C=59.82(60.52);H=5.48(6.40);N=l 1.98(12.27) : 3X“b“W^ 4.
azaphosphinane-3-carboxyIic acid ’ accordancewithprocedure^X^X“Xr * 21 ^“nzaidehyde in (2‘m, 2H), 1.6/1.49 (2*m, 2 H), 1.28/!.Il (2*m, 2 H)' 8 2 ^ENMR:(400MHz,D2O)5ppni.25.5 ’
ESJÆÎMÎKandjT^ : [M+HJ+ = 375.1235 (375.1240)
-142Elemental analysis : C=51.58(51.27);H=6.22(6.45);N=7.65(7.47)
EXAMPLEHW : 3‘(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(lÆ)-l.phenyIethyl]-l,4.
azaphosphinane-3-carboxyiic acid
Example 169 is obtained starting from intermédiare ?ι < i.
procedures F and D described hereinbefore “
JUm (400 MHz, D2O) δ ppm 7.5 (m, 5 H), 4.67 (quad. 1 H), 3.72/3.53 (2-m, 1 H) ZX Z13 (2‘m'1 3·09·2·9 (m·1 H)·3M-2·9 (m·2 H>-—' (2 -, 1 H), 2-1.65 (m, 1 H), 2-1.65 (m, 2 H), 1.7 (2-d, 3 H), 1.7-1.05 (m, 2 H), 1.7-1.05 (m, 2 iNMR: (400 MHz, D2O) δ ppm 26.4/26.2
ESI/FIA/HR and MS/MS : [M+HJ+ = 355.1783 (355.1786)
Elemental analysis : C=58.22(57.62);H=7.85(7.68);N=8.04(7.90)
MAMPLE170: 3'(4-Aminobutyl)-4-hydr.xy-4-oxo-l-[(2-phe„ylpheny1)methyl]-l,4azaphosphinane-3-carboxylic acid
Example 170 is obtained starting from intermediate 21 accordance with procedures F and D described hereinbefore (400 MHz, dmso-d6) δ ppm 7,65.7 3 (m> 6 Ηλ 4 (ab> 2 3 3 (m> W 1 H), 2.82 (m, 2 H), 2.06/1.57 (2m, 2 H), 1.83/1.33 (2m, 2 H), 1.57 (m, 2 H), 1.08
ESI/FIA/HR and MS/MS : [M+H]+ = 417.1945 (417.1943)
Elemental analysis : C=63.68(63.45);H=6.84(7.02);N=6.85(6.73) and 2-phenylbenzaldehyde in : 3-(4-Aminobutyl)-l-[[2-(ftiran-3-yI)phenyl]methyl]-4-hydroxy-4-oxo- l,4-azaphosphinane-3-carboxy!ic acid
Example 171 is obtained starting from intermediates 21 procedures F and D described hereinbefore.
MNMR; (400 MHz, D2O) δ ppm 7.68 (m, 1 H), 7.65 (m, 1 H), 7.58-7.44 (m 4 H) 6 63 (m S2 Ηλ 3-5/3·22 (2*m·2 H)· 3-34/3·01 2 * - 2 * ™ (2 m, 2 H), 1.69/1.6 (2*m, 2 H), 1.59/1.41 (2*m, 2 H), 1.18/1.08 (2*m, 2 H) and 290 in accordance with
X-- -143( ESI/FIA/HR and MS/MS : [M+H]+ = 407.1736 (407.1735)
Elemental analysis : C=59.20(59.11);H=7.12(6.70);N=7.00(6.89)
EXAMPLE 172: S-ii-AmtaobutyM-hy^^
4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 172 is obtained starting ftom intermediates 21 and 281 in accordance with procedures F and D described hereinbefore.
—NMR: (40° D2o) δ PP' 7 52 <“· 2 H), 7.39 (m, 1 H), 7.39 (m, 1 H), 7.29 (d, 1 H),
6.95 (dd, 1 H). 6.9 (dl, 1 H), 6.85 (si, 1 H), 4.44/4.29 (d, 2 H), 3.38/3.13 (m, 2 H), 3.2/2.85 io w 2 H)’3 13/136 <m'2 H)’2'94 <m’2 H)' 2'μΐ'65 <m’2 H)’1,59 2 H)*I13/1·05 (m·2
ESI/FIA/HR and MS/MS : [M+H]+ = 433.1895 (433.1892)
Elemental analysis : C=61.64(61.10);H=6.51(6.76);N=6.73(6.48)
EXAMPLE 173: 3-(4.Anünobutyl).l.[[2.(4-chIo^^ hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 173 is obtained starting from intermediates 21 and 220 in accordance with procedures F and D described hereinbefore.
'HNMRi (40° MHz· D2O) δ PP” 7·59 (<M. 1 H), 7.51 (d, 2 H), 7.32 (d, 2 H), 7.23 (td I H)
7.14 (dd, 1 H), 4.3 (AB, 2 H), 3.37/3.06 (2m, 2 H), 3.11/2.81 (2m, 2 H), 2.92 (m ’2 H)’ 2.06/1.62 (2m, 2 H), 1.83/1.33 (2m, 2 H), 1.56 (m, 2 H), 1.05 (m, 2 H) ’ 20 ESI/PTA/HR and MS/MS : [M+H]+ = 469.1470 (469.1459)
Elemental analysis : C=56.07(56.35);H=5.39(5.80);N=6.03(5.97) gAMPLE m : 3“(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-propan-2-ylphenyl)methyl]l?4-azaphosphinane-3-carboxylic acid
Example 174 is obtained starting from intermediate 21 and 2-isopropylbenzaldehyde in 25 accordance with procedures F and D described hereinbefore.
-N',1R: (50° MHz· D20> 8 PP” 7·4’ (d. 1 H), 7.45 (t, 1 H), 7.38 (d, 1 H) 7 28 (t 1 H)
4.39 (dd, 2 H), 3.65 (dd, 1 H), 3.5 (dd, 1 H), 3.35 (m, 1 H), 3.21 (dd, 1 H), 3.09 (m 1 H) 2 91 (m, 2 H), 2.17 (m, 1 H), 1.93 (m, 1 H), 1.74 (m, 1 H), 1.58 (m, 2 H), 1.47 (m, I H), 1 24 (m 1
H), 1.2/1.18 (2*s, 6 H), 1.1 (m, 1 H) ’
C ESI/FIA/HR and MS/MS : (M+H]+ = 383.2097 (383.2099)
Elemental analysis : C=59.45(59.67);H=8.00(8.17);N=7.60(7.33)
EXAMPLE175: ^Ambmhtrtyl).!^^ hydroxy-4-oxo-l,4-azaphosphmane-3-carboxyIic acid
Example 175 is obtained starting tant intermediates 21 and 215 in accordanee with procedures F and D described hereinbefore
1» (300 MHz, D2O) 5 ppm 7.62 Ά 1 H), 7.6 (m, I H), 7.54 (d, 1 H) 7 52 (m 2 H) .37 (m, 1 H), 7.24 (dd, 1 H), 4.34 (AB, 2 H), 3.45/3.07 (2m, 2 H), 3.12/2.83 (2m 2 H) 2 93 (m, 2 H). 2.1/1.63 (2m, 2 H), 1.84/1.33 (2m. 2 H), 1.57 (m. 2 H), 1.04 (m 2 H) ’ ESOTIAÆR and MS/MS.: [M+H]+ = 485.1158 (485.1163)
Hemental analysis : C=54.91(54.44);H=5.37(5.61);N=5.35(5.77)
SAMHÆ176 : ^-AminobutyM-hyd^^ yl)methyl]-l,4-azaphosphmane-3-carboxylic acid
Example 176 is obtained starting from intermediates procedures F and D described hereinbefore (3°° D2°> 5 PP” (4 « H), 7.49 (t, 2 H), 7.44 (t, 1 H) 7 4 (d 2 H) 7 17 • 1 H), 4.6 (AB, 2 H), 3.52/3.,3 2 H), 3.13/2.73 (2m. 2 H) 2.91 H) 2^Z (2m, 2 H), 1.81/1.26 (2m. 2 H), 1.55 (m, 2 H), 0.97 (m, 2 H) Ea/EIA/HROTdMWS : (M+HJ+ = 423.1525(423.1507) ElSfflentalanabsis : C=56.76(56.86);H=6.46(6.44);N=7.19(6.63)®
Procedure G : Chiral séparation of the diastereoisomers of intermediate 20b and 284 in accordance with =7.30(7.59)
Intermediate 12g:
i^-ButyI(3S)-3-{4-[bis(/^.butoxycarbonyI)amino]butyl}-l.
benzyl-4.ethoxy.4.oxo-l,4-azaphOSphinane.3-carboxylate
DMSO (30 mL) and 60% NaH (6.78 g, 186 6 mmol 1 6 + λ \ ë, 100.0 mmol, 1.6 eq) are introduced in succession under an argon atmosphère into a IL three-necked fla.tr M a · .
The flA.tr qulpped Wlth m«tanical stüring.
T e flask rs matntamed at ambient température by means of a water bath. A solution of minutes. A solution of mtennediate 19 (37.54 g, 106 mmol) in DMSO (100 mL) . -145is then added dropwise, the température being maintained below 20°C. The addition in fact causes pronounced heating as well as pronounced thickening of the reacüon mixture. When the addition is complété, 100 mL of anhydrous THF are then added in order that sttaing can be maintained. After 3 hours, the reaction mixture is cooled by means of an ice-water bath and hydrolysed by addition of 500 mL of a saturated NHÆl solution. The mixture is then extracted with AcOEt (3 x 300 mL). The organic phases are then combined, washed with a saturated NaCl solution (2 x 300 mL) and dried over MgSOr. before being concentrated under reduced pressure to yield a yellowish solid (69.94 g), a mixture of 4 diastereoisomers The 4 diastereoisomers of intermediate 20b are separated on a 2.5 kg chiral column of type (R Wheik-O-1 in batches of 8 g, each batch requiring 2 passes under the following conditions: Ist pass:
The mixture containing the 4 diastereoisomers of intermediate 20b (8 g of crude product) is applied to a chiral column of type W«)-Whelk-O-1 of 2.5 kg using as mobile phase DCM/heplane (55:45) + 10% NEb in order to isolate diastereoisomer 4 (number allocated 15 according to the order of discharge from the column) of intermediate 20b.
2nd pass:
The mixture containing the remaining 3 diastereoisomers of intermediate 20b is applied to a 2.5 kg chiral column of type («,S)-Whelk-O-1 using as mobile phase MTBE + 10% DEA in order to isolate diastereoisomer 2.
After 9 injections, the fractions containing diastereoisomers 2 and 4 of intermediate 20b are then collected and evaporated under reduced pressure to yield intermediate 128 (25.2 g,
40.3 mmol), quatemary carbon of the (S) configuration with a yield of 38%. '
1HNMK (400 MHz, dmso-d6) δ ppm 7.3 (m, 5 H), 4 (m, 2 H), 3.6 (d, 1 H), 3.4 (d 1 H) 3 35 (m, 2 H), 2.9 (m, IH), 2.8 (dd, 1 H), 2.45 (dd, 1 H), 2.3 (m, 1 H), 1.9 (m, 4 H), 1.4 (m,2 H),
1.38 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.8 (3, 2 H). ’
IR (cm1) : 1760-1680 cm’1 (C=O), 1124 cm’1 (P=O), 1124 cm ^C-O-C).
Intermediate 129. fm-Butyl (3S)-3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4ethoxy-4-oxo-l,4-azaphosphinane-3-carboxylate
Intermediate 128 (30.35 g, 48.6 mol), éthanol (200 mL), Pd/C (3.03 g, 10% by mass) and 37% 30 HCl (3 mL, 0.8 eq) are introduced in succession into a 500 mL flask at ambient température and under a stream of argon. The argon is then replaced by a hydrogen atmosphère The reaction is monitored by LC/MS. After 4 hours, the reaction is complété and the catalyst is p filtered off over glass fibre. The fihrate is evaporated to dryness in order to obtain a yellow oil, which is taken up in AcOEt (200 mL) and in a 10% NaHCOi solution (200 mL). After décantation, the aqueous phase is extracted with AcOEt (3 x 100 mL). The organic phases are combined and then washed with a saturated NaCl solution (400 mL), dried over MgSOe and concentrated to yield intermediate 129 in the form of a white solid (23.12 g, 43.24 mmol) with a yield of 89%.
1HNMR: (DMSO-ds, 400 MHz) δ 4.01 to 3.88 (m, 2 H), 3.47 (m, 2 H), 2.95-2.68 (2m, 2 H),
2.95 (m, 2 H), 2.23 (m, 1 H), 1.92-1.68 (m, 4 H), 1.48 (m, 2 H), 1.44 (s, 9 H), 1.41 (s, 9 H),
1.3 (s, 9 H), 1.27/0.97 (2m, 2 H), 1.24/0.97 (2t, 3 H).
IR (cm4) : 1715-1692 cm’1 (C=O), 1125 cm^C-O-C).
EXAMPLE 177: (3S).3.(4.Aminobutyl).l.benzyM.hydroxy-4-oxo.l,4.azaphoSphinaiie.
3-carboxylic acid
Example 177 is obtained starting from intermediate 128 in accotdance with procedure D described hereinbefore.
_H NMR: (400 MHz, D2O) δ ppm 7.49 (m, 5 H), 4.41/4.21 (2d, 2 H), 3.7/3.32 (2m, 2 H), 3.5/3.1 (2m, 2 H), 2.91 (m, 2 H), 2.22/1.78 (2m, 2 H), 1.92 (m, 1 H), 1.6 (m, 2 H), 1 45 (m 1 H), 1.22/1.1 (2m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 341.1638 (341.1630) Elemental analysis : C=56.43(56.46);H=7.33(7.40);N=8.20(8.23)
RP2 -45.630 (589 nm,T=20°C,C=l.l)
Intermediate 131: tert-Butyl (3S)-3-{4-[bis(rert-butoxycarbonyl)aminO]butyl)-l.[[2. (3»4-dimethoxyphenyl)-4-flUorophenyl]methyl]-4-ethoxy-4-oxo-l,4. azaphosphinane-3-carboxylate
Intermediate 131 is obtained starting from intermediates 129 and 229 in accotdance with procedure F described hereinbefore.
~HNMR:·(400 δ ppm 7.5 (dd, 1 H), 7.15 (m, 1 H), 7.05 (m, 2 H), 6.9 (m, 2
H), 3.95 (m, 2 H), 3.8 (2s, 6 H), 3.55 (d, 1 H), 3.35 (d, 1 H), 3.3 (m, 2 H), 2.85-2.65 (m, 2 H),
2.35 (dd, 1 H), 2.25 (m, 1 H), 2-1.75 (m, 4 H), 1.45-1.3 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H),
1.2 (t, 3 H), 0.8-0.6 (m, 2 H).
< % nxr à n IH·/Γ EXAMPLE 179: (3S)-3.(4-Aminobutyl).l.[[2^^ methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 179 is obtained starting from intermediate 131 in accordance with procedure D 5 described hereinbefore.
—NMR: (3°° MHZ' D2C” δ PPm 7.6 (dd, 1 H), 7.2 (td, 1 H), 7.1 (m, 1 H), 7 (dd 1 H) 6 9 (dd, 1 H), 4.4/4.25 (2 d, 2 H), 3.8 (2 s, 6 H), 3.35 (m, 1 H), 3.2-2.75 (m, 5 H), 2.05 (m, 1 H),
1.8 (m, 1 H), 1.6 (m, 3 H), 1.3 (m, 1 H), 1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 495.2056 (495.2060)
Elemental analysis : C=58.64(58.29);H=6.44(6.52);N=5.72(5.67)
RP : -23.170 (589 nm, T=21°C, C=0.8)
Intermediate 132: /«-Butyl (35)-3-(4-^(^^^ 1-Îr4-HuolO-2-(4-methylphenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 132 is obtained starting from intermediates 129 and 272 in accordance with procedure F described hereinbefore.
1HNMR: (400MHz,dmso-d6) δ ppm7.51 (dd, 1 H), 7.26 (s, 4H), 7.18(td, 1 H) 701 (dd 1 H), 3.93 (m, 2 H), 3.42 (AB, 2 H), 3.34 (m, 2 H), 2.72/2.2 (2m, 2 H), 2.72/2.32 (2m, 2 H),
2.36 (s, 3 H), 1.9-1.7 (m, 4 H), 1.41 (s, 18 H), 1.37 (m, 2 H), 1.34 (s, 9 H), 1.17 (t, 3 H) 07 (m,2H) ‘
EXAMPLE 180: (3S)-3-(4-Aininobutyl).l.[[4-nuoro.2.(4-niethylPhenyl)phenyl]. me<hyll.4.hy<lr<>Xy.4-oxo-l,4.azaphoSphinane.3-carb<IXylicacid
Example 180 is obtained starting from intermediate 132 in accordance with procedure D described hereinbefore.
Tj NMR, (400 MHz, D2O) δ ppm 7.61 (dd, 1 H), 7.36 (d, 2 H), 7.26 (d, 2 H), 7.23 (td 1 H)
7.15 (dd, 1 H), 4.41/4.26 (2% 2 H), 3.35/3.09 (m, 2 H), 3.17/2.81 (m, 2 H), 2.95 (m,’ 2 H),’
2.37 (s, 3 H), 2.08/1.64 (m, 2 H), 1.85/1.35 (m, 2 H), 1.6 (m, 2 H), 1.13/1.05 (m, 2 H) ' ESVFIA/HR and MS/MS : [M+H]+ = 449.2005 (449.2005) ’
Elemental analysis : C=61.57(61.60);H=6.53(6.74);N=6.45(6.25)
RP : -15.640 (589 nm, T=20°C, C=1.0)
-148Intermediate 133: zm-Butyl (3S).3.(4.[bis(tert-botoxyearbonyl)an1ino]butyIH. ethoxy-4-oxo.l-[(2-phenylphenyl)methyl]-l,4-azaphosphinane-3carboxylate
Intermediate 133 is obtained starting from imerrnediate 129 and 2-phenylbenzaldehyde in accordance with procedure F described hereinbefore.
(400 mh,, dmso-d6) 5 ppm 7 52 7 2 (m> 9 4 06 3 86 (m_ 2 H)_ 3 55/3 3g
H . 3.36 (m, 2 H), 2.71/2.32/2.19 (3m, 4 H), 1.95-1.65 (m, 4 H), 1.42/1.34 (2s, 27 H) 1 37 (m, 2 H), 1.21/1.17 (2t, 3 H), 0.68 (m, 2 H) ^AMHÆlSl: (3S)-3-(4-A„ünobutyl)^^
1,4 -azaphosphinane-3-carboxyIic acid
Example 181 is obtained starting from intermediate m · , , u . g m mtermedlate 133 in accordance with procedure D described hereinbefore.
IHNMR: (400MHz, dmso-d6) δ ppm 7.65-7.3 (m, 9 H), 4.3 (AB, 2 H), 3.43/3 (m 3 H) 2 92 £ · H), 2.82 (m, 2 H), 2.06-1.57 (2m, 2 H), 1.83/1.33 (2m, 2 H) 1.57 (m, 2 £ 1.08 (^
ESI/FIA/HR and MS/MS : [M+HJ+ = 417.1938 (417.1943)
Elemental analysis : C=62.99(63.45);H=6.45(7.02);N=6.93(6.73)
Intermediate 134:
^-Butyl(3S)-3-{4-[bis(ieri.butoxycarbonyl)amino]butyl}.4. ethoxy-4-oxo-l-[(2-pyrimidin-5-yIphenyi)methyl]-lJ4azaphosphinane-3-carboxylate
Intermediate 134 is obtained starting from intermediates 129 and procedure F described hereinbefore.
»1 (300 MHz, dmso-d6) δ ppm 9.2 (s, 1 H), 8.85 (s, 2 H), 7.45 (m, 3 H), 7.35 (d, I H) »5 m H , 3.55 (d, 1 H). 3.4 (d, 1 H), 3.3 (m, 2 H), 2.8-2.55 (m. 2 H), 2.45-2.15U, 2 ), 2.15-1.7 (m, 2 H), 2-1.55 (m, 4 H), 1.5-1.25 (3s, 27 H), 1.2 (t, 3 H), 0.6 (m, 2 H)
236 in accordance with _ -149‘ ( _XAMPLE 182: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-pyrimidiii-5-yÎphenyl)methyI]4,4-azaphosphinane-3-carboxylic acid
Example 182 is obtained starting from intermediate 134 in accordance with procedure D described hereinbefore.
.‘H NMR: (400 MHz, D2O) δ ppm 9.15 (s, 1 H), 8.82 (s, 2 H), 7.7-7.55 (m, 3 H), 7.43 (d, 1
H), 4.4/4.3 (2d, 2 H), 3.6-3.35 (m, 1 H), 3.3-3.1 (m, 1 H), 3.1 (m, 1 H), 2.95 (m, 3 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.62-1.45 (m, 2 H), 1.35 (m, 1 H), 1.15-1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 419.1855 (419.1848)
Elemental analysis : C=57.01(57.41);H=6.57(6.50);N=13.45(13.39)
RP : -20.520 (589 nm, T=20°C, C= 1.0)
Intermediate 135: toi-Bntyl (3®-3.{4.[6ί8»ηΛ.^^ 4H>xo-l-[(2-thiophen-2-ylphenyl)methyl].l,4-azaphosphinane-3carboxyiate
Intermediate 135 is obtained starting from intermediate 129 and 2-(2-thienyl)benzaldehyde in 15 accordance with procedure F described hereinbefore.
-HNMR: (300 MHz, dmso-d6) δ ppm 7.62 (d, 1 H), 7.45-1.3 (m, 4 H), 7.25 (d, 1 H), 7.15 (t,
H), 4.1-3.9 (quai, 2 H), 3.65/3.45 (d, 2 H), 3.4-3.2 (m, 2 H), 2.9-2.7 (m, 2 H)’ 2.4-2.3 (m, 2 H), 1.9-1.7 (m, 4 H), 1.5-1.3 (m, 2 H), 1.4/1.35 (2*s, 27 H), 1.2 (t, 3 H), 0.7-0.5 (m, 2 H)
EXAMPLE 183: (3S)-3.(4-Aminobutyl)-|.hydroxy.4rt>xo-l-[(2.thiophen.2-ylphenyl)methyl]-l,4-azaphosphÎnane-3-carboxylic acid
Example 183 is obtained starting from intermediate 135 in accordance with procedure D described hereinbefore.
-NMR:' (40° MHz· D2°j PP™ ’-6 (d. 1 H), 7.55 (d, 1 H), 7.48 (m, 2 H), 7.45 (d, 1 H),
7.15 (dd, 1 H), 7.1 (t, 1 H), 4.5/1.4 (2*d, 2 H), 3.5-3.2 (m, 3 H), 3-2.85 (m, 3 H), 2.15/1.7 (m,’ 4 H), 1.88 (m, 1 H), 1.55 (m, 2 H), 1.2-1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 423.1505 (423.1507)
Elemental analysis : C=57.14(56.86);H=6.12(6.44);N=6.61(6.63);S=7.33(7.59)
RP :-18.340 (589 nm, T=20°C, C=0.9) ' Intermediate 136: icrt-Butyl (3S)-3-{4.[bis(tert.butoxycarbonyl)amino]butyl}4ethoxy4'®xnl-[(2-pyridin-3-ylphenyl)methyl]-l,4-azaphosphinane-
3-carboxylate
Intermediate 136 is obtained starting from intermediates 129 and 260 in accordance with procedure F described hereinbefore, — (4°° drnsn·^ δ PPm 8·59 (dd, 1 H), 8.56 (dd, 1 H), 7.82 (dt, 1 H) 7 49 (dd
H), 7.48 (ddd, 1 H), 7.42/7.39 (2td, 2 H), 7.27 (dd, 1 H), 3.92 (m, 2 H), 3.44 (AB, 2 H), 3.3 (m, 2 H), 2.7/2.2 (2m, 2 H), 2.7/2.35 (2m, 2 H), 1.95-1.66 (m, 4 H), 1.42 (s, 18 H), 1.35 (m, 2
H), 1.33 (s, 9 H), 1.17 (t, 3 H), 0.63 (m, 2 H) ’
EXAMPLE 184: (3S)-3-(4.Aminobntyl).4-hydroxy.4^^ methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 184 is obtained starting from intermediate 136 in accordance with procedure D described hereinbefore.
Ti NMR: (400 MHz, dmso-d6) δ ppm 8.57 (d, 1 H), 8.48 (s, 1 H), 7.83 (d, 1 H), 7.65 (m, 1 H), 7.57 (m, 1 H), 7.57 (m, 2 H), 7.4 (m, 1 H), 4.41/4.29 (dd, 2 H), 3.44/3.12 (dd 2 H) 3.2/2.86 (dd, 2 H), 2.93 (m, 2 H), 2.1/1.67 (2«m, 2 H), 1.85/1.35 (2*m, 2 H), 1 59 (m 2 H)’ 1.08 (m, 2 H) ’
ESI/FIA/HR and MS/MS : [M+H]+ = 418.1871 (418.1895) 20 Elemental analysis : C=60.35(60.42);H=6.74(6.76);N=9.70( 10.07)
RP_: -20.940 (589 nm, T=28°C, C=0.9)
Intermediate 137: tert-Butyl (3S).3.{4.[biS(terrtutoxycarbonyl)amino]bntylHethoxy-l-[[4-fluoro-2-(3-methoxyphenyl)phenyl]niethyI].4-oxo-l> azaphosphinane-3-carboxylate
Intermediate 137 is obtained starting from intermediates 129 and 222 in accordance with procedure F described hereinbefore.
—NMR: (400 MHz’ <ta«<M16) δ ppm 7.51 (dd, 1 H), 7.36 (t, 1 H), 7.2 (td, 1 H) 7 05 (dd 1 H), 6.97 (d, 1 H), 6.91 (m. 1 H), 6.9 (m, 1 H), 3.93 (m, 2 H), 3.79 (s, 3 H), 3.52/3 33 (2M 2 H), 3.33 (m, 2 H), 2.72/2.21 (m, 2 H), 2.72/2.32 (m, 2 H), 2-1.75 (m, 4 H), 1.4 (s, 18 H), 1.37 (m, 2 H), 1.34 (s, 9 H), 1.17 (t, 3 H), 0.69 (m, 2 H)
-151EXAMPLE 185: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(3-methoxyphenyl)phenyi]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 185 is obtained starting from intermediate 137 in accordance with procedure D described hereinbefore,
1£LNMR: (400 MHz, D2O) δ ppm 7.62 (dd, 1 H), 7.46 (t, 1 H), 7.25 (td, 1 H), 7.16 (dd, 1 H), 7.08 (dd, 1 H), 6.97 (dl, 1 H), 6.96 (si, 1 H), 4.41/4.27 (2*d, 2 H), 3.84 (s, 3 H), 3.37/3.09 (m, 2 H), 3.16/2.83 (m, 2 H), 2.95 (m, 2 H), 2.09/1.66 (m, 2 H), 1.86/1.35 (m, 2 H), 1.66 (m, 2 H), 1.13/1.06 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 465.1941 (465.1949)
Elemental analysis : C=59.94(59.48);H=6.44(6.51);N=6.11(6.03)
RP : -19.240 (589 nm, T=20°C, C=0.6)
Intermediate 138: tert-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyi)amino]butyl}-l-[[3-(4chlorophenyl)pyridin-2-yI]methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 138 is obtained starting from intermediates 129 and 291 in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 8.55 (d, 1 H), 7.68 (d, 1 H), 7.55 (m, 4 H), 7.42 (dd, 1 H), 3.94 (m, 2 H), 3.63/3.44 (2*d, 2 H), 3.19 (m, 2 H), 2.98/2.51 (2*m, 2 H), 2.64/2.36 (2*m, 2 H), 1.91/1.75 (2*m, 2 H), 1.75/1.62 (2*m, 2 H), 1.4 (s, 18 H), 1.33 (s, 9 H), 1.23 (m, 2 H),
1.18 (t, 3 H), 0.59/0.34 (m, 2 H)
EXAMPLE 186: (3S)-3-(4-Aminobutyl)-l-[[3-(4-chlorophenyl)pyridin-2-yl]methyl]-4hydroxy-4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 186 is obtained starting from intermediate 138 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 8.6 (d, 1 H), 7.8 (d, 1 H), 7.5 (m, 3 H), 7.3 (d, 2 H), 4.4 (m, 2 H), 3.5-3.3 (m, 2 H), 3.2 (m, 2 H), 2.95 (m, 2 H), 2.2 (m, 1 H), 1.9 (m, 1 H), 1.65 (m, 1 H),
1.6 (m, 2 H), 1.45 (m, 1 H), 1.3-1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 452.1502 (452.1500)
-152C Elemental analysis : C=55.89i55.82):H=5.56(6.02):N=9.17(9.30)
RP : -5.260 (589 nm, T=20°C, C=1.0)
Intermediate 139 : tert-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4ethoxy-l-[ [4-fluoro-2- (4 -methoxypheny l)phenyl]methyl] -4-oxo-1,4azaphosphinane-3-carboxylate
Intermediate 139 is obtained starting from intermediates 129 and 221 in accordance with procedure F described hereinbefore.
?H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.31 (d, 2 H), 7.17 (m, 1 H), 7.01 (m, 1 H), 7.01 (d, 2 H), 3.93 (m, 2 H), 3.8 (s, 3 H), 3.5/3.32 (2*d, 2 H), 3.32 (m, 2 H), 2.75/2.21 (2*m, 2 H), 2.72/2.33 (2*m, 2 H), 2-1.78 (unresolved peak, 2 H), 2-1.78 (unresolved peak, 2 H), 1.4/1.33 (2*s, 27 H), 1.38 (m, 2 H), 1.18 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 187: (3S)-3-(4-AminobutyI)-l-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 187 is obtained starting from intermediate 139 in accordance with procedure D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.57 (dd, 1 H), 7.3 (d, 2 H), 7.19 (td, 1 H), 7.12 (dd, 1 H), 7.08 (d, 2 H), 4.32 (AB, 2 H), 3.84 (s, 3 H), 3.33/3.07 (2m, 2 H), 3.13/2.8 (2m, 2 H), 2.92 (m, 2 H), 2.05/1.62 (2m, 2 H), 1.83/1.32 (2m, 2 H), 1.57 (m, 2 H), 1.05 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 465.1960 (465.1954)
Elemental analysis : C=59.41(59.48);H=6.76(6,51);N=6.09(6.03)'
RP: -13.770 (589 nm, T=20°C, C=0.9)
Intermediate 140: te/ï-Buty 1 (3S)-3 -{4- [bis(ieri-butoxycarbonyl)amino]butyl }-4-ethoxy-
-[[2- (4-methylphenyl)phenyl] methyl]-4-oxo-1,4 -azaphosphinane-3carboxylate
Intermediate 140 is obtained starting from intermediates 129 and 288 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.33 (2*m, 2 H), 7.23 (2*d, 4 H), 7.18 (dd, 1 H), 3.92 (m, 2 H), 3.54/3.35 (2*d, 2 H), 3.3 (m, 2 H), 2.74/2.2 (2*m, 2 H), 2.74/2.32
-153p (2*m, 2 H), 2.36 (s, 3 H), 1.95-1.75 (m, 2 H), 1.95-1.75 (m, 2 H), 1.41/1.33 (2*s, 27 H), 1.38 (m, 2 H), 1.17 (t, 3 H), 0.71 (m, 2 H)
EX AMPLE 188: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[2-(4-methylphenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Exemple 188 is obtained starting from intermediate 140 in accordance with procedure D described hereinbefore.
'H NMR: (300 MHz, D2O) δ ppm 7.6-7.35 (m, 4 H), 7.33/7.22 (2d, 4 H), 4.33 (AB, 2 H), 3.33/3.07 (2m, 2 H), 3.19/2.8 (2m, 2 H), 2.91 (m, 2 H), 2.35 (s, 3 H), 2.06/1.58 (2m, 2 H), 1.82/1.32 (2m, 2 H), 1.57 (m, 2 H), 1.07 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 431.2097 (431.2099)
Elemental analysis : C=64.03(64.17);H=6.92(7.26);N=6.45(6.51)
RP: -13.150 (589 nm, T=20°C, C=0.9)
Intermediate 141: teri-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4ethoxy-l-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 141 is obtained starting from intermediates 129 and 271 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1 H), 7.42 (dd, 2 H), 7.29 (t, 2 H), 7.21 (td, 1 H), 7.06 (dd, 1 H), 3.92 (m, 2 H), 3.49/3.32 (2*d, 2 H), 3.32 (m, 2 H), 2.71/2.2 (2*m, 2 H), 2.7/2.34 (2*m, 2 H), 1.9-1.65 (m, 2 H), 1.9-1.65 (m, 2 H), 1.4/1.33 (2*s, 27 H), 1.38 (m, 2 H),
1,18 (t, 3 H), 0.67 (m, 2 H)
EXAMPLE 189: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-
4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 189 is obtained starting from intermediate 141 in accordance with procedure D described hereinbefore.
*H NMR: (300 MHz, D2O) δ ppm 7.59 (dd, 1 H), 7.35 (m, 2 H), 7.23 (td, 1 H), 7.23 (t, 2 H), 7.14 (dd, 1 H), 4.31 (AB, 2 H), 3.36/3.07 (2m, 2 H), 3.16/2.83 (2m, 2 H), 2.92 (m, 2 H), 2.06/1.58 (2m, 2 H), 1.84/1.33 (2m, 2 H), 1.58 (m, 2 H), 1.07 (m, 2 H)
-15419F NMR: (300 MHz, D2O) δ ppm -111.4/-114.1
ESI/FIA/HR and MS/MS : [M+H]+ = 453.1750 (453.1754)
Elemental analysis : C=58.26(58.40):H=5.79(6.01):N=6.18(6.19)
RP : -17.770 (589 nm, T=20°C, C=1.2)
Intermediate 142: tert-Butyl (3S)-3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-4-ethoxy- l-[(4-fluoro-2-pyridin-3-ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-
3-carboxylate
Intermediate 142 is obtained starting from intennediates 129 and 261 in accordance with procedure F described hereinbefore.
'H NMR: (400 MHz, dmso-d6) δ ppm 8.6 (dd, 1 H), 8.58 (dl, 1 H), 7.84 (dt, 1 H), 7.51 (m, 2 H), 7.26 (td, 1 H), 7.15 (dd, 1 H), 3.93 (m, 2 H), 3.42 (AB, 2 H), 3.33 (m, 2 H), 2.67/2.2 (2m, 2 H), 2.67/2.35 (2m, 2 H), 1.96-1.62 (m, 4 H), 1.41 (s, 18 H), 1.36 (m, 2 H), 1.34 (s, 9 H), 1.17 (t, 3 H), 0.65 (m, 2 H)
EX AMPLE 190: (3S) -3-(4-Aminobutyl) -1 -[(4-fluoro-2-pyridin-3-ylphenyl)methyl] -4 hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 190 is obtained starting from intermediate 142 in accordance with procedure D described hereinbefore.
Tl NMR: (300 MHz, D2O) δ ppm 8.62 (dd, 1 H), 8.54 (d, 1 H), 7.89 (dt, 1 H), 7.7 (dd, 1 H),
7.6 (dd, 1 H), 7.34 (td, 1 H), 7.23 (dd, 1 H), 4.35 (AB, 2 H), 3.46/3.12 (2m, 2 H), 3.18/2.87 (2m, 2 H), 2.97 (m, 2 H), 2.12/1.67 (2m, 2 H), 1.88/1.37 (2m, 2 H), 1.61 (m, 2 H), 1.11 (m, 2 H) 19F NMR: (300 MHz, D2O) δ ppm -111
ESI/FIA/HR and MS/MS : [M+H]+ = 436.1794 (436.1801)
Elemental analysis : C=57.69(57.93);H=5.69(6.25);N=9.60(9.65)
RP : -19.680 (589 nm, T=20°C, C=0.7)
-155Intermediate 143: iert-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy- l-[(4-methoxy-2-phenylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 143 is obtained starting from intermediates 129 and 285 in accordance with 5 procedure F described hereinbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 7.47-7.32 (m, 5 H), 7.35 (d, 1 H), 6.95 (dd, 1 H), 6.75 (d, 1 H), 3.92 (quad., 2 H), 3.77 (s, 3 H), 3.47/3.27 (dd, 2 H), 3.32 (t, 2 H), 2.75/2.28 (dd, 2 H), 2.67/2.16 (dd, 2 H), 1.85/1.72 (dd, 2 H), 1.79 (t, 2 H), 1.41 (s, 18 H), 1.36 (m, 2 H), 1.34 (s, 9 H), 1.16 (t, 3 H), 0.68 (m, 2 H)
EXAMPLE 191: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxy-2-phenyiphenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxyiic acid
Example 191 is obtained starting from intermediate 143 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.54-7.44 (m, 3 H), 7.54-7.44 (m, 1 H), 7.34 (d, 2 H), 6.97 (dd, 1 H), 6.86 (df, 1 H), 4.34/4.19 (2*d, 2 H), 3.33/3.05 (2*m, 2 H), 3.19/2.78 (2*m, 2 H),
2.95 (m, 2 H), 2.07/1.63 (2*m, 2 H), 1.85/1.35 (2*m, 2 H), 1.59 (m, 2 H), 1.2-1 (2*m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+= 433.1887 (433.1887)
Elemental analysis : C=60.81(61.10):H=6.31(6.76);N=6.49(6.48)
RP : -39.130 (589 nm, T=20°C, C=0.9)
Intermediate 144: teri-Butyl (3S)-3-{4-[bis(/er/-butoxycarbonyl)amino]butyl}-4ethoxy-1 - [(4-fluoro-2-pyridin-4-ylphenyl)methyi] -4 -oxo-1,4azaphosphinane-3-carboxylate
Intermediate 144 is obtained starting from intermediates 129 and 262 in accordance with procedure F described hereinbefore.
Tl NMR: (400 MHz, dmso-d6) δ ppm 8.65 (m, 2 H), 7.53 (dd, 1 H), 7.44 (m, 2 H), 7.28 (td, 1 H), 7.14 (dd, 1 H), 3.93 (m, 2 H), 3.44 (AB, 2 H), 3.32 (m, 2 H), 2.69/2.21 (2m, 2 H), 2.69/2.35 (2m, 2 H), 1.96-1.62 (m, 4 H), 1.41 (s, 18 H), 1.36 (m, 2 H), 1.33 (s, 9 H), 1.17 (t, 3 H), 0.66/0.58 (2m, 2 H)
-156Ç EX AMPLE 192: (3S’)-3-(4-Aminobutyl)-l-[(4-fluoro-2-pyridin-4-ylphenyl)methy]]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 192 is obtained starting from intermediate 144 in accordance with procedure D described hereinbefore.
]H NMR: (400 MHz, D2O) δ ppm 8.63 (d, 2 H), 7.67 (dd, 1 H), 7.45 (d, 2 H), 7.33 (td, 1 H),
7.21 (dd, 1 H), 4.4/4.29 (2*d, 2 H), 3.44/3.08 (m, 2 H), 3.16/2.88 (m, 2 H), 2.95 (m, 2 H), 2.1/1.65 (m, 2 H), 1.86/1.36 (m, 2 H), 1.6 (m, 2 H), 1.08 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 436.1804 (436.1801)
Elemental analysis : C=58.11(57.93);H=5.71(6.25);N=9.79(9.65) .
RP : -16.250 (589 nm, T=20°C, C=1.0)
Intermediate 146: ieri-Butyl (3S)-3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-l-[[2-(3chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 146 is obtained starting from intermediates 129 and 213 in accordance with 15 procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (si, 1 H), 7.45 (m, 2 H), 7.45/7.38/7.25 (3m, 4 H),
7.33 (dt, 1 H), 3.94 (m, 2 H), 3.53/3.32 (AB, 2 H), 3.25 (m, 2 H), 2.76/2.37 (2m, 2 H), 2.7/2.25 (2m, 2 H), 1.95/1.78 (2m, 2 H), 1.82/1.75 (2m, 2 H), 1.41 (s, 18 H), 1.33 (s, 9 H),
1.33 (m, 2 H), 1.18 (t, 3 H), 0.66/0.57 (2m, 2 H)
EXAMPLE 194: (3S)-3-(4-Aminobutyl)-l-[[2-(3-chlorophenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 194 is obtained starting from intermediate 146 in accordance with procedure D described hereinbefore.
Ή NMR: (300 MHz, D2O) δ ppm 7.63-7.23 (m, 8 H), 4.33 (AB, 2 H), 3.42/3.1 (2m, 2 H), 3.17/2.82 (2m, 2 H), 2.93 (m, 2 H), 2.1/1.63 (2m, 2 H), 1.84/1.34 (2m, 2 H), 1.57 (m, 2 H), 1.07 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1539 (451.1548)
Elemental analysis : C=58.76(58.60):H=6.46(6.26):N=6.38(6.2n
RP : -15.780 (589 nm, T=20°C, C=1.2)
-157Intermediate 147: terf-Butyl (3S)-3-{4-[bis(iert-butoxycarbonyi)amino]butyl}-l-[[4chloro-2-(4-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 147 is obtained starting from intermediates 129 and 292 in accordance with procedure F described hereinbefore.
!H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 2 H), 7.5 (d, 1 H), 7.45 (dd, 1 H), 7.41 (d, 2 H), 7.27 (d, 1 H), 3.94 (m, 2 H), 3.5/3.33 (dd, 2 H), 3.3 (m, 2 H), 2.8-2.6 (2m, 2 H), 2.35 (dd, 1 H), 2.2 (m, 1 H), 2-1.7 (m, 4 H), 1.41 (s, 18 H), 1.4-1.3 (m, 2 H), 1.33 (s, 9 H), 1.18 (t, 3 H), 0.68 (m, 2 H)
EXAMPLE 195: (3S)-3-(4-Aminobutyl)-l-[[4-chloro-2-(4-chlorophenyi)phenyl]methyl]-
4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 195 is obtained starting from intermediate 147 in accordance with procedure D described hereinbefore.
1H NMR: (300 MHz, D2O) δ ppm 7.55-7.5 (2d, 2 H), 7.5 (d, 2 H), 7.4 (d, 1 H), 7.28 (d, 2 H),
4.3 (dd, 2 H), 3.35/3.05 (2m, 2 H), 3.15/2.8 (2m, 2 H), 2.9 (m, 2 H), 2.05/1.65 (2m, 2 H), 1.8/1.3 (2m, 2 H), 1.55 (m, 2 H), 1.05 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 485.1162 (485.1163)
Elemental analysis : C=55.11(54.44);H=5.26(5.61);N=5.87(5.77)
RP : -17.410 (589 nm, T=19°C, C=1.0)
Intermediate 148: tert-Butyl (3S)-3-{4-[bis(iert-butoxycarbonyl)amino]butyI}-4-ethoxy- l-[2-(6-methoxypyridin-3-yI)benzyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 148 is obtained starting from intermediates 129 and 237 in accordance with procedure F described hereinbefore.
1H.NMR: (400 MHz, dmso-d6) δ ppm 8.1 (d, 1 H), 7.75 (dd, 1 H), 7.5-7.2 (m, 4 H), 6.9 (d, 1 H), 3.9 (s, 3 H), 3.9 (m, 2 H), 3.55/3.35 (dd, 2 H), 3.3 (m, 2 H), 2.75/2.2 (2m, 2 H), 2.7/2.35 (2dd, 2 H), 1.9/1.8 (2m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (m, 2 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.65 (m, 2 H)
-158EXAMPLE 196: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[2-(6-methoxypyridin-3yl)benzyl] -4-oxo-l,4-azaphosphinane-3-carboxylic acid
Ex ample 196 is obtained starting from intermediate 148 in accordance with procedure D described hereinbefore.
T-I NMR: (400 MHz, D2O) δ ppm 8.05 (d, 1 H), 7.75 (dd, 1 H), 7.6 (m, 1 H), 7.5 (m, 2 H),
7.4 (m, 1 H), 7 (d, 1 H), 4.3 (dd, 2 H), 3.9 (s, 3 H), 3.45/3.15 (2m, 2 H), 3.2/2.85 (2dd, 2 H),
2.9 (m, 2 H), 2.1/1.7 (2m, 2 H), 1.8/1.35 (2m, 2 H), 1.6 (m, 2 H), 1.1 (m, 2 H) ,
ESI/FIA/HR and MS/MS : [M+H]+ = 448.2009 (448.2001)
Elemental analysis : C=58.81(59.05);H=6.79(6.76);N=9.31(9.39)
RP : -11.510 (589 nm,T=19°C, C=0.9)
Intermediate 149: teri-Butyl (3S)-3-{4-[bis(ieri-butoxycarbonyl)ammo]butyl}-4-ethoxyl-[[2-(4-fluorophenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 149 is obtained starting from intermediate 129 and 2-(4fluorophenyl)benz aldéhyde in accordance with procedure F described hereinbefore.
]H NMR: (400 MHz, dmso-d6) δ ppm 7.47 (dd, 1 H), 7.39/7.33 (2*m, 2 H), 7.39 (dd, 2 H),
7.27 (t, 2 H), 7.21 (dd, 1 H), 3.93 (m, 2 H), 3.52/3.34 (2*d, 2 H), 3.38-3.22 (m, 2 H), 2.75/2.21 (2*m, 2 H), 2.7/2.35 (2*m, 2 H), 1.98-1.72 (m, 2 H), 1.98-1.72 (m, 2 H), 1.41/1.34 (2*s, 27 H), 1.37 (m, 2 H), 1.19 (t, 3 H), 0.68 (m, 2 H)
EXAMPLE 197: (3S)-3-(4-Ammobutyl)-l-[[2-(4-fluorophenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylicacid
Example 197 is obtained starting from intermediate 149 in accordance with procedure D described hereinbefore.
!H NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1 H), 7.52 (m, 2 H), 7.4 (d, 1 H), 7.35 (dd, 2 H), 7.24 (dd, 2 H), 4.41/4.29 (dd, 2 H), 3.39/3.1 (2*m, 2 H), 3.19/2.88 (2*m, 2 H), 2.93 (m, 2 H), 2.09/1.65 (2*m, 2 H), 1.85/1.59 (2*m, 2 H), 1.59/1.35 (2*m, 2 H), 1.2-1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 435.1843 (435.1843)
Elemental analysis : C=60.70(60.82);H=6.56(6.50);N=6.49(6.45)
-159Ç' RP : -23.350 (589 nm, T=20°C, C=0.7)
Intermediate 150: ter/-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[[2-(4chlorophenyl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 150 is obtained starting from intermediates 129 and 220 in accordance with procedure F described hereinbefore.
lELNMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 2 H), 7.5 (m, 1 H), 7.42 (d, 2 H), 7.22 (dt, 1
H), 7.07 (dd, 1 H), 4-3.86 (m, 2 H), 3.5/3.32 (2*d, 2 H), 3.4-3.25 (m, 2 H), 2.71/2.21 (2*m, 2 H), 2.71/2.35 (2*m, 2 H), 1.99-1.72 (m, 2 H), 1.99-1.72 (m, 2 H), 1.41/1.33 (2*s, 27 H), 1.38 10 (m,2H), 1.19 (t, 3 H), 0.68 (m, 2 H)
EXAMPLE 198: (3S)-3-(4-AminobutyÎ)-l-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-
4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 198 is obtained starting from intermediate 150 in accordance with procedure D described hereinbefore.
*H NMR: (400 MHz, D2O) δ ppm 7.62 (dd, 1 H), 7.54 (d, 2 H), 7.35 (d, 2 H), 7.25 (td, 1 H),
7.17 (dd, 1 H), 4.39/4.28 (2*d, 2 H), 3.4/3.09 (2*m, 2 H), 3.13/2.84 (2*m, 2 H), 2.95 (m, 2
H), 2.09/1.65 (2*m, 2 H), 1.86/1.36 (2*m, 2 H), 1.6 (m, 2 H), 1.09 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 469.1452 (469.1454)
Elemental analysis : C=56.19(56.35);H=5.57(5.80);N=5.97(5.97)
RP : -12.560 (589 nm, T=20°C, C=0.7)
Intermediate 151: iert-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(2-naphthalen-l-ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 151 is obtained starting from intermediates 129 and 228 in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 8 (m, 2 H), 7.65-7.2 (m, 9 H), 3.85 (m, 2 H), 3.4 (m, 2
H), 3.35-3 (2dd, 2 H), 2.65/2.2 (2m, 2 H), 2.5/2 (2m, 2 H), 1.9-1.5 (m, 4 H), 1.4 (2s, 18 H),
1.35 (m, 2 H), 1.3 (2s, 9 H), 1.1 (t, 3 H), 0.65 (m, 2 H)
-160EXAMPLE 199: (35)-3-(4-Aminobutyl)-4-hydroxy-1 - [(2-naphthalen-1 -ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 199 is obtained starting from intermediate 151 in accordance with procedure D described hereinbefore.
'HNMR: (400 MHz, D2O) δ ppm 8 (m, 2 H), 7.75-7.3 (m, 9 H), 4.35-3.8 (2dd, 2 H), 3.4/2.95 (2m, 2 H), 3.2/2.7 (2m, 2 H), 2.9 (m, 2 H), 2.05/1.55 (2m, 2 H), 1.75/1.25 (2m, 2 H), 1.5 (m, 2 H), 1.2-0.7 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 467.2109 (467.2099)
Elemental analysis : C=66.50(66.94);H=6.26(6.70);N=6.08(6.00)
RP : -25.420 (589 nm, T=19°C, C=1.0)
Intermediate 152: tert-Butyl (3S)-3-{4-[bis(icrt-butoxycarboxy)amino]butyl}-l-[(2-icrtbutylphenyl)methyl]-4-ethoxy-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 152 is obtained starting from intermediate 129 and 2-teri-butylbenzaldehyde in accordance with procedure F described hereinbefore.
'H NMR: (400 MHz, dmso-d6) δ ppm 7.6-7.15 (3m, 4 H), 4 (m, 2 H), 3.75 (dd, 2 H), 3.45-3.3 (m, 2 H), 3-2.75 (2m, 2 H), 2.5 (dd, 2 H), 2.4 (m, 2 H), 2-1.85 (m, 2 H), 1.4 (m, 2 H), 1.4 (s, 18 H), 1.4 (t, 9 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.95-0.7 (m, 2 H)
EXAMPLE 200: (35)-3-(4-AminobutyI)-l-[(2-terfrbutylphenyl)methyl]-4-hydroxy-4oxo-l,4-azaphosphinane-3-carboxylic acid
Example 200 is obtained starting from intermediate 152 in accordance with procedure D described hereinbefore.
'HNMR: (300 MHz, D2O) δ ppm 7.57/7.46 (2m, 2 H), 7.36 (m, 2 H), 4.65 (AB, 2 H), 3.68/3.41 (2m, 2 H), 3.46/3.22 (2m, 2 H), 2.89 (m, 2 H), 2.25/1.75 (2m, 2 H), 1.9/1.46 (2m, 2 H), 1.56 (quint., 2 H), 1.35 (s, 9 H), 1.13 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 397.2253 (397.2256)
Elemental analysis : C=61.19(60.59);H=8.40(8.39);N=7.29(7.07)
RP : -41.120 (589 nm, T=19°C, C=0.9)
-161Intermediate 153: teri-Butyl ( 3S)-3-{4-[bis(teri-butoxycarbonyi)ammo]butyl}-4-ethoxyl-[[4-fluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxyiate
Intermediate 153 is obtained starting from intermediates 129 and 273 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.51 (dd, 1 H), 7.28 (dd, 1 H), 7.21 (dt, 1 H), 7.09 (m, 1 H), 7.09 (m, 1 H), 6.93 (m, 1 H), 3.93 (m, 2 H), 3.88 (s, 3 H), 3.52/3.35 (2*d, 2 H), 3.4-3.25 (m, 2 H), 2.72/2.21 (2*m, 2 H), 2.72/2.34 (2*m, 2 H), 1.9-1.65 (m, 2 H), 1.9-1.65 (m, 2 H), 1.41/1.33 (2*s, 27 H), 1.38 (m, 2 H), 1.18 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 201: (35)-3-(4-Aminobutyl)-1 -[[4-fluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 201 is obtained starting from intermediate 153 in accordance with procedure D described hereinbefore.
'HNMR: (400 MHz, dmso-d6) δ ppm 7.6 (dd, 1 H), 7.25 (m, 2 H), 7.15 (m, 2 H), 6.95 (m, 1 H), 4.4/4.3 (2*d, 2 H), 3.9 (s, 3 H), 3.5-3.3 (m, 1 H), 3.2-3.05 (m, 2 H), 2.95 (m, 2 H), 2.9 (dd, 1 H), 2.05 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.6 (m, 2 H), 1.35 (m, 1 H), 1.2-1 (m, 2 H) ESI/FIA/HR and MS/MS: [M+H]+ = 483.1854 (483.1855)
Elemental analysis : C=57.37(57.26);H=5.95(6.06);N=5.86(5.81)
RP :-21.910 (589 nm, T=21°C, C=l.l)
Intermediate 154: /eri-Butyl (3$)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(2-isoquinolin-4-ylphenyl)methyl]-4-oxo-l,4-azaphosphmane-3carboxylate
Intermediate 154 is obtained starting from intermediates 129 and 264 in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 9.35 (d, 1 H), 8.32 (d, 1 H), 8.21 (m, 1 H), 7.71 (m, 2 H), 7.6 (2*d, 1 H), 7.5 (2% 1 H), 7.42 (t, 1 H), 7.31 (m, 1 H), 7.25 (m, 1 H), 3.87 (m, 2 H),
-162p 3.45-3.3 (m, 2 H), 3.32/3.2/3.05 (m, 2 H), 2.62/2.2 (m, 2 H), 2.58/2 (m, 2 H), 1.8-1.25 (m, 6
H), 1.6 (m, 2 H), 1.42/1.4 (2*s, 18 H), 1.32/1.3 (2*s, 9 H), 1.1 (m, 3 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 44.94
EXAMPLE 202: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(2-isoquinolin-4-ylphenyl)5 methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 202 is obtained starting from intermediate 154 in accordance with procedure D described hereinbefore.
3H NMR: (400 MHz, D2O) δ ppm 9.3 (s, 1 H), 8.35/8 (2*s, 1 H), 8.2 (m, 1 H), 7.8-7.4 (m, 7 H), 4.4-3.8 (2AB, 2 H), 3.6-3.2/3 (m, 2 H), 3.1/2.7 (m, 2 H), 2.91 (m, 2 H), 2.1/1.55 (m, 2 H), 10 1.75/1.25 (m, 2 H), 1.6 (m, 2 H), 1.15-0.75 (m, 2 H) 31P NMR: (400 MHz, D2O) δ ppm 25.29
ESI/FIA/HR and MS/MS : [M+H]+ = 468.2046 (468.2047)
Elemental analysis : C=64.83(64.23);H=5.86(6.47);N=9.17(8.99)
Intermediate 155: tert-Butyl (3S)-3-{4- [bis (teri-butoxycarbonyl)ammo]butyl}-4-ethoxy15 1 - [[2-(2-methoxypyridin-4-yl)phenyl]methyl] -4-oxo-1,4azaphosphinane-3-carboxyIate
Intermediate 155 is obtained starting from intermediates 129 and 244 in accordance with procedure F described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 8.2 (d, 1 H), 7.5 (m, 1 H), 7.45-7.3 (2m, 2 H), 7.25 (m, 20 1 H), 7 (dd, 1 H), 6.8 (si, 1 H), 3.9 (m, 2 H), 3.9 (s, 3 H), 3.6/3.35 (dd, 2 H), 3.3 (m, 2 H),
2.75/2.35 (dd, 2 H), 2.7/2.25 (2m, 2 H), 1.95/1.75 (2m, 2 H), 1.75 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.3 (m, 2 H), 1.2 (t, 3 H), 0.7-0.5 (m, 2 H)
EXAMPLE 203: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[2-(2-methoxypyridin-4yl)phenyl] methyl] -4-oxo-1,4-azaphosphinane-3-carboxylic acid
Example 203 is obtained starting from intermediate 155 in accordance with procedure D described hereinbefore.
-163Γ ΧΗ NMR: (400 MHz, D2O) δ ppm 8,18 (d, 1 H), 7.65-7.35 (m, 4 H), 7.02 (d, 1 H), 6.85 (s, 1 H), 4.35 (dd, 2 H), 3.9 (s, 3 H), 3.65-3 (m, 3 H), 3-2.8 (m, 3 H), 2.1/1.7 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.6 (m, 2 H), 1,1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 448.1989 (448.2001)
Elemental analysis : C=59.15(59.05);H=6.25(6.76);N=9.64(9.39)
RP : -11.440 (589 nm, T=19.5°C, C=0.9)
EXAMPLE 204: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[[2-(2-oxo-l£I-pyridin-4yl)phenyl]methyl] -l,4-azaphosphinane-3-carboxyIic acid
Example 204 is obtained starting from intermediate 155 in accordance with procedure D 10 described hereinbefore, 1H NMR: (300 MHz, D2O) δ ppm 7.65-7.3 (m, 4 H), 7.6 (d, 1 H), 6.55 (s, 1 H), 6.5 (d, 1 H),
4,35 (dd, 2 H), 3.5 (2m, 2 H), 3.25/2.9 (2m, 2 H), 2.9 (m, 2 H), 2.15/1.7 (2m, 2 H), 1.85/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 434.1838 (434.1839)
Elemental analysis : C=58.88(58.19):H=6.31(6.51):N=9.95(9.69)
RP :-10.530 (589 nm, T=19°C, C=1.0)
Intermediate 156: teri-Butyl (3S)-3-{4-[bis(/er/-butoxycarbonyl)amino]butyl}-4-ethoxy4-oxo-l-{2-[l-(tetrahydro-2H-pyran-2-yl)-LH-pyrazol-5-yl]benzyl}- l,4-azaphosphinane-3-carboxylate
Intermediate 156 is obtained starting from intermediates 129 and 293 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.6 (d, 1 H), 7.6-7.2 (m, 4 H), 6.3 (d, 1 H), 4.9-4.8 (dd, 1 H), 4-3.8 (m, 4 H), 3.5-3.2 (m, 4 H), 2.85-2.6 (m, 2 H), 2.5-2.1 (m, 3 H), 2-1.65 (m, 6 H),
1.5-1.25 (m, 5 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.85-0.6 (m, 2 H)
EXAMPLE 205: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[2-(lH-pyrazol-3-yI)bénzyl]- l,4-azaphosphinane-3-carboxylic acid
Example 205 is obtained starting from intermediate 156 in accordance with procedure D described hereinbefore. .
-164P !H NMR: (300/400/500 MHz, dmso-d6) δ ppm 7.62 (d, 1 H), 7.6 (d, 1 H), 7.38 (t, 1 H), 7.33 (d, 1 H), 7.26 (t, 1 H), 6.55 (d, 1 H), 4.32/4.05 (dd, 2 H), 3.59/3.19 (dd, 2 H), 3.33/2.93 (dd, 2 H), 2.74 (m, 2 H), 2.11/1.61 (2*m, 2 H), 1.73/1.29 (2*m, 2 H), 1.41 (m, 2 H), 1.04/0.88 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 407.1843 (407.1848)
Elemental analysis : C=56.28(56.15);H=6.42(6.70);N=13.82(13.79)
RP : -84.390 (589 nm, T=19°C, C=l.l)
Intermediate 157: iert-Butyl (3S)-3-{4-[bis(ier£-butoxycarbonyl)ammo]butyl}-l-[[2-(2chloropheny l)-4-fluorophenyl]methyl] -4 -ethoxy-4-oxo-1,410 azaphosphinane-3-carboxyIate
Intermediate 157 is obtained starting from intermediates 129 and 253 in accordance with procedure F described hereinbefore.
‘H NMR: (300/400 MHz, dmso-d6) δ ppm 7.65-7.4 (m, 4 H), 7.25 (m, 2 H), 7 (m, 1 H), 3.9 (m, 2 H), 3.35 (d, 1 H), 3.3 (m, 2 H), 3.15 (d, 1 H), 2.8-2.55 (m, 2 H), 2.3 (m, 1 H), 2.1 (m, 1
H), 1.95-1.7 (m, 4 H), 1.45 (m, 2 H), 1.45/1.35 (2*s, 27 H), 1.15 (t, 3 H), 0.75 (m, 2 H) 19F NMR: (300/400 MHz. dmso-d6) δ ppm -114.5 ‘
ESI/FIA/HR and MS/MS : [M+H]+ = 753.3436 (753.3441)
EXAMPLE 206: (35)-3-(4-Aminobutyl)-1-[[2-(2-chlorophenyl)-4-fluorophenyl]methyl] 4-hydroxy-4-oxo-l,4-azaphosphmane-3-carboxylic acid
Example 206 is obtained starting from intermediate 157 in accordance with procedure D described hereinbefore.
!H NMR: (300/400 MHz, dmso-d6) δ ppm 7.7-7.35 (m, 4 H), 7.35-7.2 (m, 2 H), 7.1 (m, 1 H),
4.1 (si, 2 H), 3.7-3 (m, 3 H), 3-2.7 (m, 3 H), 2.2-2 (m, 1 H), 1.8 (m, 1 H), 1.65 (m, 1 H), 1.55 (m,2H), 1.45-1 (m, 3 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 469.1456 (469.1454)
Elemental analysis : C=56.86(56.35);H=5.21(5.80);N=5.91(5.97)
RP : -15.060 (589 nm, T=20°C, C=1.0)
-165Intermediate 158: ieri-ButyI (3S)-3-{4-[bis(tert-butoxycarbonyl)amino ] butyl}-1 -[[2-(2,3dimethoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4azaphosphmane-3-carboxylate
Intermediate 158 is obtained starting from intermediate 129 and 2-(2,3dimethoxyphenylbezaldehyde) in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 7.5 (m, 1 H), 7.35-7.2 (2m, 2 H), 7.1 (m, 1 H), 7.05-7 (2m, 2 H), 6.7 (dd, 1 H), 3.9 (m, 2 H), 3.85 (s, 3 H), 3.45 (s, 3 H), 3.4 (m, 2 H), 3.35 (dd, 2 H), 2.7/2.4 (2m, 2 H), 2.65/2.2 (2m, 2 H), 1.95-1.7 (m, 4 H), 1.45 (s, 18 H), 1.4 (m, 2 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.9 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 761.4136 (761.4142)
EXAMPLE 207: (3S)-3-(4-Aminobutyi)-l-[[2-(2,3-dimethoxyphenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 207 is obtained starting from intermediate 158 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.65-7.35 (m, 4 H), 7.25 (m, 1 H), 7.2 (m, 1 H), 6.9-6.8 (2dd, 1 H), 4.35-3.9 (2dd, 2 H), 3.86 (s, 3 H), 3.7-2.65 (m, 4 H), 3.4-3.35 (2s, 3 H), 2.9 (m, 2 H), 2.5-1.6 (m, 4 H), 1.6 (m, 2 H), 1.5-0.9 (m, 2 H)
EST/FTA/HR and MS/MS : [M+H]+ = 477.2149 (477.2154)
Elemental analysis : C=61.06(60.50);H=6.99(6.98);N=5.97(5.88)
Intermediate 159: teri-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl)-4hydroxy-l-[[2-(2-methylsulphonylphenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 159 is obtained starting from intermediate 129 and 2-(2methylsulphonylphenyl)benzaldehyde in accordance with procedure F described hereinbefore.
NMR: (300/400 MHz, dmso-d6) δ ppm 8.1 (d, 1 H), 7.8-7.65 (2*m, 2 H), 7.55 (d, 1 H),
7.45 (m, 1 H), 7.3 (d, 1 H), 7.25 (d, 1 H), 7.25 (m, 1 H), 3.95 (m, 2 H), 3.5-3.25 (m, 4 H), 3.1 (dd, 1 H), 2.9-2.6 (2*m, 2 H), 2.85 (2*s, 3 H), 2.45 (m, 1 H), 2.3 (m, 1 H), 2.1 (m, 1 H), 2-
1.65 (m, 4 H), 1.5-1.3 (4s, 27 H), 1.2 (m, 3 H), 0.75 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 779.3696 (779.3701)
-166EXAMPLE 208: (3S)-3-(4-AminobutyI)-4-hydroxy-l-[[2-(2-methylsulphonylphenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxyIic acid
Example 208 is obtained starting from intermediate 159 in accordance with procedure D described hereinbefore.
XH NMR: (400 MHz, dmso-d6) δ ppm 8.2 (d, 1 H), 7.9/7.8 (2*m, 2 H), 7.8-7.4 (m, 4 H), 7.55 (d, 1 H), 4.4-3.8 (4d, 2 H), 3.8-3.5 (m, 1 H), 3.5-2.85 (m, 5 H), 3.1/3 (2*s, 3 H), 2.4-1.85 (m, 2 H), 1.8 (m, 1 H), 1.7 (m, 2 H), 1.6-1.1 (m, 3 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 495.1716 (495.1713)
Elemental analysis : C=55.39(55.86);H=5.77(6.32);N=5.61(5.66);S=6.24(6.48)
Intermediate 160: tert-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(2-naphthalen-2-ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 160 is obtained starting from intermediates 129 and 240 in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 8-7.3 (m, 11 H), 3.9 (m, 2 H), 3.6/3.4 (dd, 2 H), 3.3 (m, 2 H), 2.75/2.3 (2dd, 2 H), 2.7/2.2 (2m, 2 H), 1.9/1.7 (2m, 2 H), 1.75 (m, 2 H), 1.4 (s, 18 H),
1.3 (m, 2 H), 1.3 (s, 9 H), 1.15 (t, 3 H), 0.65 (m, 2 H)
EXAMPLE 209: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(2-naphthalen-2-ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxylie acid
Example 209 is obtained starting from intermediate 160 in accordance with procedure D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 8-7.4 (m, 11 H), 4.35 (dd, 2 H), 3.35/3 (2m, 2 H), 3.1/2.7 (2dd, 2 H), 2.8 (m, 2 H), 2/1.6 (2m, 2 H), 1.75/1.2 (2m, 2 H), 1.5 (m, 2 H), 0.9 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 467.2095 (467.2099)
Elemental analysis : C=67.07(66.94);H=6.46(6.70);N=5.88(6.00)
RP : -8.570 (589 nm, T=19°C, 00.8)
-167Ç Intermediate 161: te/ï-Butyl (3S)-3-{4-[bis(iert-butoxycarbonyl)amino]butyl}-l-[[4chIoro-2-(4-fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 161 is obtained starting from intermediate 129 and 4-chloro-2-(45 fluorophenyl)benzaldehyde in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (d, 1 H), 7.45 (dd, 1 H), 7.4 (dd, 2 H), 7.29 (t, 2 H),
7.25 (d, 1 H), 3.92 (m, 2 H), 3.5/3.3 (AB, 2 H), 3.3 (m, 2 H), 2.72/2.2 (2*m, 2 H), 2.67/2.35 (2*m, 2 H), 2-1.7 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (m, 2 H), 1.32 (s, 9 H), 1.18 (t, 3 H), 0.7 (m, 2 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 44.88, -113.8
EXAMPLE 210: (3S)-3-(4-Aminobutyl)-l-[[4-chloro-2-(4-fluorophenyl)phenyl]methyl]4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 210 is obtained starting from intermediate 161 in accordance with procedure D described hereinbefore.
te NMR: (400 MHz, D2O) Ô ppm 7.57 (d, 1 H), 7.51 (dd, 1 H), 7.45 (d, 1 H), 7.36 (m, 2 H), 7.24 (t, 2 H), 4.4/4.27 (AB, 2 H), 3.38/3.1 (m, 2 H), 3.2/2.85 (m, 2 H), 2.94 (m, 2 H), 2.09/1.65 (m, 2 H), 1.85/1.35 (m, 2 H), 1.59 (m, 2 H), 1.1 (m, 2 H) 31P NMR: (400 MHz, D2O) δ ppm 25.4, -110.5
ESI/FIA/HR and MS/MS : [M+H]+ = 469.1455 (469.1454)
Elemental analysis : C=56.27(5635);H=5.43(5.80);N=5.97(5.97);Cl=7.28(7.56)
RP : -28.440 (589 nm, T=20°C, C=0.9)
Intermediate 162: /eri-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[[4-fluoro-2-(4-hydroxyphenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 162 is obtained starting from intermediates 129 and 265 in accordance with procedure F described hereinbefore.
te NMR: (400 MHz, dmso-d6) δ ppm 9.6 (si, 1 H), 7.49 (dd, 1 H), 7.18 (d, 2 H), 7.12 (td, 1 H), 6.98 (dd, 1 H), 6.81 (d, 2 H), 3.92 (m, 2 H), 3.5/3.3 (AB, 2 H), 3.3 (m, 2 H), 2.72/2.2
-168(2*m, 2 H), 2.67/2.35 (2*m, 2 H), 2-1.7 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (m, 2 H),
1.32 (s, 9 H), 1.18 (t, 3 H), 0.7 (m, 2 H) 31P NMR: (400 MHz, dmso-d6) δ ppm 45.1, -114.8
EXAMPLE 211: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(4-hydroxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 211 is obtained starting from intermediate 162 in accordance with procedure D described hereinbefore.
ΧΗ NMR: (400 MHz, D2O) δ ppm 7.47 (dd, 1 H), 7.12 (d, 2 H), 7.09 (td, 1 H), 7.01 (dd, 1 H), 6.88 (d, 2 H), 4.3/4.16 (AB, 2 H), 3.23/2.98 (m, 2 H), 3/2.7 (m, 2 H), 2.81 (m, 2 H), 1.96/1.55 (m, 2 H), 1.72/1.21 (m, 2 H), 1.49 (m, 2 H), 0.95 (m, 2 H) 31P NMR: (400 MHz, D2O) δ ppm 25.4, -113
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1794 (451.1793)
Elemental analysis : C=58.16(58.66);H=5.71(6.27);N=6.30(6.22)
RP : -16.520 (589 nm, T=20°C, C=0.9)
Intermediate 163: teri-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyI)amino]butyl}-4-ethoxy-
- [4-fluoro-2-(l -methy1-IH-py razol-4-y l)benzy I] -4-oxo-1,4azaphosphinane-3-carboxylate
Intermediate 163 is obtained starting from intermediates 129 and 250 in accordance with procedure F described hereinbefore.
]H NMR: (300 MHz, dmso-d6) δ ppm 8 (s, 1 H), 7.7 (s, 1 H), 7.4 (dd, 1 H), 7.2 (dd, 1 H), 7.05 (td, 1 H), 3.97 (m, 2 H), 3.9 (s, 3 H), 3.6/3.4 (dd, 2 H), 3.25 (m, 2 H), 3/2.35 (2m, 2 H), 2.8/2.45 (2m, 2 H), 2 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.3 (m, 2 H), 1.2 (t, 3 H), 0.65 (m, 2 H)
EXAMPLE 212: (3S)-3-(4-AminobutyI)-l-[4-fluoro-2-(l-methyi-lH-pyrazol-4yl)benzyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 212 is obtained starting from intermediate 163 in accordance with procedure D described hereinbefore.
-169C NMR: (300 MHz, D2O) δ ppm 7.81 (s, 1 H), 7.7 (s, 1 H), 7.6 (dd, 1 H), 7.2 (m, 2 H), 4.45 (dd, 2 H), 3.95 (s, 3 H), 3.5/3.25 (2m, 2 H), 3.3/3 (2m, 2 H), 3 (m, 2 H), 2.1/1.75 (2m, 2 H), 1.9/1.4 (2m, 2 H), 1.65 (m, 2 H), 1.15 (m, 2 H) 19F NMR: (300 MHz, D2O) δ ppm -110.5
ESI/FIA/HR and MS/MS : [M+H]+ = 439.1905 (439.1910)
Elemental analysis : C=54.79(54.79);H=6.05(6.44);N=12.61(12.78)
RP: -18.620 (589 nm, T=19°C, C=0.9)
Intermediate 164: iert-Butyl (35)-3-{4-[bis(/erf-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(4-fluoro-2-thiophen-2-ylphenyl)methyl]-4-oxo-l,410 azaphosphinane-3-carboxylate
Intermediate 164 is obtained starting from intermediates 129 and 246 in accordance with procedure F described hereinbefore.
*H NMR: (300 MHz, dmso-d6) δ ppm 7.66 (dd, 1 H), 7.47 (dd, 1 H), 7.31 (dd, 1 H), 7.25 (dd, 1 H), 7.2 (dd, 1 H), 7.16 (td, 1 H), 3.97 (m, 2 H), 3.63/3.4 (dd, 2 H), 3.25 (m, 2 H), 2.88/2.32 (2m, 2 H), 2.79/2.42 (dd, 2 H), 2.05-1.9 (m, 2 H), 1.82 (m, 2 H), 1.39 (s, 18 H), 1.33 (s, 9 H),
1.3 (m, 2 H), 1.2 (t, 3 H), 0.7-0.4 (2m, 2 H) 19F NMR: (300 MHz, dmso-d6) δ ppm -113.9
EXAMPLE 213: (3S)-3-(4-AminobutyI)-l-[(4-fluoro-2-thiophen-2-ylphenyl)methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 213 is obtained starting from intermediate 164 in accordance with procedure D described hereinbefore.
NMR: (300 MHz, dmso-d6) δ ppm 7.65 (dd, 1 H), 7.55 (dd, 1 H), 7.29 (dd, 1 H), 7.2 (td, 1 H), 7.15 (m, 2 H), 4.5 (dd, 2 H), 3.5/3.2 (2m, 2 H), 3.3/2.9 (2m, 2 H), 2.9 (m, 2 H), 2.1/1.75 (2m, 2 H), 1.85/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.1 (m, 2 H) 19F NMR: (300 MHz, dmso-d6) δ ppm -110
ESI/FIA/HR and MS/MS : [M+H]+= 441.1405 (441.1413)
Elemental analysis : C=54.66(54,54):H=5.90(5.95);N=6.35(6.36):S=7 27(7 9.R)
RP : -13.110 (589 nm, T=19.5°C, C=0.7)
-170( Intermediate 165: ieri-Butyl (3S)-3-{4-bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(2-isoquinoIin-5-ylphenyI)methyI]-4-oxo-l,4-azaphosphinane-3carboxylate
Intermediate 165 is obtained starting from intermediates 129 and 216 in accordance with 5 procedure F described hereinbefore.
MNMR: (400 MHz, dmso-d6) δ ppm 9.4 (s, 1 H), 8.45 (d, 1 H), 8.2 (m, 1 H), 7.75 (m, 1 H),
7.65 (m, 1 H), 7.6-7.4 (m, 3 H), 7.2 (m, 1 H), 7.15 (2*d, 1 H), 3.95-3.7 (m, 2 H), 3.5-3 (m, 4 H), 3.5-3.3 (m, 2 H), 2.7-2.4 (m, 2 H), 2.2 (m, 1 H), 2 (m, 1 H), 1.85 (m, 1 H), 1.8 (m, 2 H), 1.7-1.5 (m, 1 H), 1.5-L25 (4s, 27 H), 1.1 (t, 3 H), 0.75-0.5 (m, 2 H)
EX AMPLE 214: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(2-isoquinolin-5-ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 214 is obtained starting from intermediate 165 in accordance with procedure D described hereinbefore.
]Η NMR: (400 MHz, D2O) δ ppm 9.25 (s, 1 H), 8.3 (dd, 1 H), 8.2 (m, 1 H), 7.85-7.55 (m, 5 15 H), 7.35 (m, 1 H), 7.3 (d, 1 H), 4.45-3.8 (4d, 2 H), 3.65-3.05 (m, 2 H), 3.05-2.8 (m, 3 H), 2.7 (m, 1 H), 2.1 (m, 1 H), 1.75 (m, 1 H), 1.7-1.5 (m, 3 H), 1.35-0.6 (m, 3 H)
ESI/FIA/HR and MS/MS : [M+H]+= 468.2051 (468.2047)
Elemental analysis : C=64.96(64.23);H=6.08(6.47);N=9.03(8.99)
Intermediate 166: ieri-Butyl (3S)-3-{4-[bis(ier/-butoxycarbonyl)amino]butyl}-4-ethoxy20 l-[(4-fluoro-2-naphthaÎen-2-ylphenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 166 is obtained starting from intermediates 129 and 247 in accordance with procedure F described hereinbefore.
’HNMR: (400 MHz, dmso-d6) δ ppm 8-7.9 (m, 3 H), 7.9 (si, 1 H), 7.6-7.5 (m, 4 H), 7.25 (td, 25 1 H), 7.15 (dd, 1 H), 3.9 (m, 2 H), 3.6/3.4 (dd, 2 H), 3.3 (m, 2 H), 2.75/2.3 (2m, 2 H), 2.7/2.2 (2m, 2 H), 1.9/1.75 (2m, 2 H), 1.75 (m, 2 H), 1.4 (s, 18 H), 1.3 (s, 9 H), 1.3 (m, 2 H), 1.15 (t, 3 H), 0.7 (m, 2 H)
-171EXAMPLE 215: (3S)-3-(4-AminobiityI)-l-[(4-fluoro-2-naphthaien-2-ylphenyl)methyl]4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 215 is obtained starting from intermediate 166 in accordance with procedure D described hereinbefore.
1H NMR: (400 MHz, D2O) δ ppm 8.08 (d, 1 H), 8 (m, 2 H), 7.95 (d, 1 H), 7.7 (dd, 1 H), 7.65 (m, 2 H), 7.54 (dd, 1 H), 7.3 (m, 1 H), 7.3 (dd, 1 H), 4.65-4.2 (m, 2 H), 3.35/3.05 (2m, 2 H), 3.05/2.8 (2m, 2 H), 2.85 (m, 2 H), 2/1.65 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.55 (m, 2 H), 0.9 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 485.2002 (485.2005)
Elemental analysis : C=63.97(64.45);H=6.21(6.24);N=5.93(5.78)
RP : -6.790 (589 nm, T=19°C, C=0.7)
Intermediate 167: teri-Butyl (3S)-3-{4-[bis(tert-butyloxycarbonyl)amino]butyl}-l-[[2-(lbenzothiophen-2-yl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-l>4azaphosphinane-3-carboxylate
Intermediate 167 is obtained starting from intermediates 129 and 217 in accordance with procedure F described hereinbefore.
!Η NMR: (400 MHz, dmso-d6) δ ppm 8.05 (d, 1 H), 7.9 (d, 1 H), 7.6 (s, 1 H), 7.55 (dd, 1 H),
7.4 (m, 2 H), 7.35 (d, 1 H), 7.3 (m, 1 H), 3.95 (m, 2 H), 3.75 (d, 1 H), 3.5 (d, 1 H), 3.25 (m, 2 H), 2.95 (m, 1 H), 2.8 (m, 1 H), 2.45 (dd, 1 H), 2.35 (m, 1 H), 2.05-1.6 (m, 4 H), 1.42 (m, 2 20 H), 1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.65 (m, 1 H), 0.55 (m, 1 H)
EXAMPLE 216: (3S)-3-(4-Aminobutyl)-l-[[2-(l-benzothiophen-2-yl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 216 is obtained starting from intermediate 167 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.95/7.9 (2*d, 2 H), 7.65 (m, 1 H), 7.45 (m, 2 H), 7.4 (s, 1 H), 7.3 (m, 2 H), 4.55/4.4 (2*d, 2 H), 3.6-3.4 (m, 1 H), 3.25 (m, 1 H), 3.15 (m, 1 H), 2.9 (dd, 1 H), 2.85 (m, 2 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.6-0.85 (m, 5 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 491.1565 (491.1564)
Elemental analysis : C=59.10(58.77);H=5.38(5.75);N=5.84(5.71);S=6.42(6.54)
-172O RP : 0.930 (589 nm, T=20.5°C, C=1.0)
Intermediate 168: teri-Butyl (35)-3 -{4- [bis(iert-butoxycarbonyl)aniino]butyl}-4-ethoxyl-[4-fluoro-2-(l-metbyl-lH-imidazol-5-yl)benzyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 168 is obtained starting from intermediates 129 and 248 in accordance with procedure F described hereinbefore.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.75 (s, 1 H), 7.56 (2d, 1 H), 7.29 (2t, 1 H), 7.15 (2d, 1 H), 6.9 (s, 1 H), 3.95 (m, 2 H), 3.5-3.25 (m, 4 H), 3.4 (s, 3 H), 2.9/2.2 (2m, 2 H), 2.65/2.3 (2m, 2 H), 1.95/1.85 (2m, 2 H), 1.85 (m, 2 H), 1.4 (m, 2 H), 1.4 (2s, 18 H), 1.35 (2s, 9 H), 1.2 (t, 3 H), 1.1-0.65 (m, 2 H)
EXAMPLE 217: (3S)-3-(4-Ammobutyl)-l-[4-fluoro-2-(l-methyi-l£Limidazol-5yl)benzyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 217 is obtained starting from intermediate 168 in accordance with procedure D described hereinbefore.
‘HNMR: (400 MHz, D2O) δ ppm 7.8 (s, 1 H), 7.68 (dd, 1 H), 7.33 (td, 1 H), 7.22 (dd, 1 H),
7.1 (s, 1 H), 4.25/4.18 (AB, 2 H), 3.6/3.2 (2m, 2 H), 3.45 (s, 3 H), 3.3/3 (2m, 2 H), 2.95 (m, 2 H), 2.12/1.71 (2m, 2 H), 1.9/1.42 (2m, 2 H), 1.6 (m, 2 H), 1.3-1 (m, 2 H) 19F NMR: (400 MHz, D2O) δ ppm -109.75
ESI/FIA/HR and MS/MS : [M+H]+ = 439.1905 (439.1905)
Elemental analysis : C=54.41(54.79);H=6.12(6.44);N=12.74(12.78)
RP : -27.720 (589 nm, T=20°C, C=0.7)
Intermediate 169: tert-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-l-[[4chloro-2-(4-methylphenyl)phenyl]methyl]-4-ethoxy-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 169 is obtained starting from intermediate 129 and 4-chloro-2-(4methylphenyl)benzaldehyde in accordance with procedure F described hereinbefore.
NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 1 H), 7.4 (dd, 1 H), 7.25 (dd, 4 H), 7.2 (d, 1 H), 3.9 (m, 2 H), 3.5/2.8 (dd, 2 H), 2.8 (m, 2 H), 2.75/2.2 (2m, 2 H), 2.65/2.3 (2dd, 2 H), 2.35
-173ç- (s, 3 H), 1.95/1.8 (2m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (m, 2 H), 1.35 (s, 9 H), 1.18 (t, 3 H), 0.7 (m, 2 H)
EXAMPLE 218: (3S)-3-(4-Aminobutyl)-l-[[4-chloro-2-(4-methylphenyl)phenyl]methyl]4-hydroxy-4 -oxo-1,4-azaphosphinane-3-carboxylic acid
Example 218 is obtained starting from intermediate 169 in accordance with procedure D described hereinbefore.
‘HNMR: (400 MHz, D2O) δ ppm 7.58 (d, 1 H), 7.5 (dd, 1 H), 7.42 (d, 1 H), 7.38 (d, 2 H), 7.23 (d, 2 H), 4.4/4.25 (AB, 2 H), 3.35/3.1 (2m, 2 H), 3.2/2.81 (2m, 2 H), 2.95 (m, 2 H), 2.39 (s, 3 H), 2.09/1.68 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.6 (m, 2 H), 1.2-1 (m, 2 H)
ESI/FIA/HR and MS/MS : ΓΜ+Η1+ = 465.1707 (465.1704)
Elemental analysis : C=60.11(59.42);H=6.34(6.50);N=6.09(6.03)
RP : -26.100 (589 nm, T=20°C, C=0.3)
Intermediate 170: tert-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]buty!}-l-[2(1,2-dimethyl-l H-imidazol-5 -yl) -4-fluorobenzyl] -4-ethoxy-4-oxo15 l,4-azaphosphinane-3-carboxyiate
Intermediate 170 is obtained starting from intermediates 129 and 274 in accordance with procedure F described hereinbefore.
NMR: (300/400 MHz, dmso-d6) δ ppm 7.55 (dd, 1 H), 7.2 (m, 1 H), 7 (d, 1 H), 6.75 (s, 1 H), 4.05-3.7 (m, 4 H), 3.5-3.3 (2*d, 2 H), 3.25 (s, 3 H), 3-2.2 (m, 4 H), 2.35 (s, 3 H), 2-1.3 (m,
6 H), 1.4 (3s, 27 H), 1.25 (m, 3 H), 0.85 (m, 2 H)
EXAMPLE 219: (3S)-3-(4-Aminobutyl)-l-[2-(l,2-dimethyl-lH-imidazol-5-yl)-4fluorobenzyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
F.x ample 219 is obtained starting from intermediate 170 in accordance with procedure D described hereinbefore.
!H NMR: (400 MHz, D2O) δ ppm 7.75 (dd, 1 H), 7.55 (s, 1 H), 7.5 (m, 1 H), 7.3 (dd, 1 H),
4.25 (s, 2 H), 3.55 (m, 1 H), 3.45 (s, 3 H), 3.4 (m, 1 H), 3.25 (m, 1 H), 3.15 (dd, 1 H), 2.95 (t, 2 H), 2.65 (s, 3 H), 2.15 (m, 1 H), 1.9 (m, 1 H), 1.75 (m, 1 H), 1.65 (m, 2 H), 1.45 (m, 1 H),
1.3 (m, 1H), 1.15 (m, 1 H)
-174ESI/FIA/HR and MS/MS : [M+H]+ = 453.2058 (453.2061)
Elemental analysis : C=46.18(47.29);H=5.24(5.86);N=10.02(10.50)
RP : -28.200 (589 nm, T=20°C, C=1.0)
Intermediate 171: to t-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxyl-[(4-fluoro-2-imidazo[l,2-a]pyridin-3-y!phenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 171 is obtained starting from intermediates 129 and 234 in accordance with procedure F described hereînbefore.
Ή NMR: (300 MHz, dmso-d6) δ ppm 7.9 (d, 1 H), 7.65 (m, 2 H), 7.65 (s, 1 H), 7.35-7.2 (m, 3 H), 6.9 (m, 1 H), 3.9 (quad., 2 H), 3.35 (t, 2 H), 3.35/3.25 (2*d, 2 H), 2.8-2.4 (m, 3 H), 2.4 (dd, 1 H), 2.2 (m, 1 H), 1.9-1.6 (m, 3 H), 1.5-1.3 (m, 2 H), 1.45 (s, 18 H), 1.35 (s, 9 H), 1.15 (t, 3 H), 1-0.75 (m, 2 H)
EXAMPLE 220: (3S)-3-(4-Aminobutyl)-l-[(4-fluoro-2-imidazo[l,2-a]pyridin-3ylphenyl)methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 220 is obtained starting from intermediate 171 in accordance with procedure D described hereînbefore.
NMR: (400 MHz, D2O) δ ppm 8.05 (d, 1 H), 7.75 (dd, 1 H), 7.7 (d, 1 H), 7.7 (s, 1 H), 7.45 (m, 1 H), 7.4 (m, 1 H), 7.3 (d, 1 H), 7 (m, 1 H), 4.6-4 (m, 2 H), 3.45 (m, 1 H), 3.05 (m, 2 H),
2.9 (m, 2 H), 2.8 (dd, 1 H), 2.1 (m, 1 H), 1.8 (m, 1 H), 1.65 (m, 1 H), 1.55 (m, 2 H), 1.3 (m, 1 H), 0.95 (m, 2 H) .
ESVFIA/HR and MS/MS : [M+H]+ = 475.1906 (475.1905)
Elemental analysis : C=58.69(58.22);H=5.71(5.95);N=11.94(11.81)
RP : -27.190 (589 nm, T=20°C, C=1.0)
-175C Intermediate 172: teri-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[[4-fluoro-2-(2-methoxypyridin-4-yl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 172 is obtained starting from intermediates 129 and 249 in accordance with procedure F described hereinbefore.
'HNMR: (400 MHz, dmso-d6) δ ppm 8.23 (d, 1 H), 7.52 (dd, 1 H), 7.26 (td, 1 H), 7.11 (dd, 1
H), 7.01 (dd, 1 H), 6.85 (si, 1 H), 3.94 (m, 2 H), 3.9 (s, 3 H), 3.53/3.34 (dd, 2 H), 3.31 (m, 2 H), 2.74/2.24 (2m, 2 H), 2.68/2.37 (2dd, 2 H), 1.93/1.75 (2m, 2 H), 1.86-1.66 (m, 2 H), 1.41 (s, 18 H), 1.36 (m, 2 H), 1.35 (s, 9 H), 1.19 (2m, 2 H), 0.69/0.61 (t, 3 H)
EXAMPLE 221: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(2-methoxypyridin-4-yl)phenyl]methy 1] -4-hydroxy-4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 221 is obtained starting from intermediate 172 in accordance with procedure D described hereinbefore.
ffiNMR: (400 MHz, D2O) δ ppm 8.17 (d, 1 H), 7.64 (dd, 1 H), 7.29 (td, 1 H), 7.17 (dd, 1 H),
7.01 (dd, 1 H), 6.86 (s, 1 H), 4.32 (dd, 2 H), 3.9 (s, 3 H), 3.45/3.07 (2m, 2 H), 3.17/2.84 (2m,
H), 2.9 (m, 2 H), 2.1/1.68 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.6 (m, 2 H), 1.07 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 466.1905 (466.1902)
Elemental analysis : C=56.79(56.77);H=6.15(6.28);N=8.94(9.03)
RP: -9.530 (589 nm, T=19°C, C=1.0)
EXAMPLE 222: (3S)-3-(4-Ammobutyl)-l-[[4-fluoro-2-(2-oxo-lH-pyridin-4-yi)phenyl]methyl] -4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 222 is obtained starting from intermediate 172 in accordance with procedure D described hereinbefore.
!H NMR: (400 MHz, D2O) Ô ppm 7.64 (dd, 1 H), 7.62 (d, 1 H), 7.29 (td, 1 H), 7.18 (dd, 1 H),
6.57 (d, 1 H), 6.53 (dd, 1 H), 4.3 (dd, 2 H), 3.51/3.15 (2m, 2 H), 3.24/2.95 (2m, 2 H), 2.92 (m,
H), 2.13/1.7 (2m, 2 H), 1.86/1.38 (2m, 2 H), 1.58 (m, 2 H), 1.1 (m, 2 H) 19FNMR: (400 MHz, D2O) δ ppm -109.6
ESI/FIA/HR and MS/MS : [M+H]+ = 452.1745 (452.1745)
Elemental analysis : C=56.06(55.87);H=5.96(6.03);N=9.21(9.31)
-176P RP : -10.270 (589 nm, T=19°C, C=0.9)
Intermediate 173; ier/-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[[4-hydroxy-2-(4-methylphenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 173 is obtained starting from intermediates 129 and 266 in accordance with procedure F described hereinbefore.
jH NMR: (400 MHz, dmso-d6) δ ppm 9.4 (s, 1 H), 7.2 (s, 4 H), 7.2 (d, 1 H), 6.75 (dd, 1 H),
6.7 (t, 1 H), 6.55 (s, 1 H), 3.95 (m, 2 H), 3.4 (d, 1 H), 3.25 (d, 1 H), 2.8 (m, 3 H), 2.7 (dd, 1 H), 2.35 (s, 3 H), 2.25 (dd, 1 H), 2.15 (m, 1 H), 1.9 (m, 1 H), 1.85-1.7 (m, 3 H), 1.35 (2s, 18
H), 1.25 (m, 2 H), 1.2 (t, 3 H), 0.75 (m, 2 H)
EXAMPLE 223: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-2-(4-methylphenyl)phenyl]methyl] -4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 223 is obtained starting from intermediate 173 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.47 (d, 1 H), 7.35 (d, 2 H), 7.22 (d, 2 H), 6.95 (dd, 1 H), 6.83 (d, 1 H), 4.32/4.19 (AB, 2 H), 3.32/3.05 (2m, 2 H), 3.18/2.77 (2m, 2 H), 2.95 (m, 2 H),
2.38 (s, 3 H), 2.09/1.68 (2m, 2 H), 1.85/1.35 (2m, 2 H), 1.6 (m, 2 H), 1.2-1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 447.2045 (447.2043)
Elemental analysis : C=62.20(61.87);H=6.77(7.00);N=6.19(6.27)
RP : -32.320 (589 nm, T=20°C, C=0.7) .
Intermediate 174: ieri-Butyl (3S)-3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[4-methoxy-2-(imidazo[l,2-a]pyridin-3-yl)benzyl]-4-oxo-l,4azaphosphinane-3 -carboxylate
Intermediate 174 is obtained starting from intermediates 129 and 267 in accordance with 25 procedure F described hereinbefore.
‘HNMR: (400 MHz, dmso-d6) δ ppm 7.98 (d, 1 H), 7.66 (d, 1 H), 7.63 (d, 1 H), 7.5 (s, 1 H),
7.29 (t, 1 H), 7.1 (dd, 1 H), 6.98 (d, 1 H), 6.9 (t, 1 H), 3.9 (m, 2 H), 3.8 (s, 3 H), 3.35 (m, 2 H),
-177P 3.35/3.19 (AB, 2 H), 2.7/2.25 (m, 2 H), 2.62/2.1 (m, 2 H), 1.85/1.7 (m, 2 H), 1.65 (m, 2 H),
1.4 (s, 18 H), 1.35 (m, 2 H), 1.3 (s, 9 H), 1.15 (t, 3 H), 0.65 (m, 2 H)
EX AMPLE 224: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[4-hydroxy-2-(imidazo[l,2-«]py ridin-3-y l)benzyl] -4-oxo-1,4-azaphosphinane-3-carboxylie acid
Example 224 is obtained starting from intermediate 174 in accordance with procedure D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 8 (d, 1 H), 7.67 (s, 1 H), 7.65 (d, 1 H), 7.59 (d, 1 H), 7.42 (t, 1 H), 7.09 (dd, 1 H), 6.99 (t, 1 H), 6.96 (df, 1 H), 4.15 (m, 2 H), 3.4/3.02 (m, 2 H), 3.02/2.72 (m, 2 H), 2.9 (m, 2 H), 2.1/1.6 (m, 2 H), 1.75/1.22 (m, 2 H), 1.5 (m, 2 H), 0.92 (m, 2 10 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 473.1950 (473.1948)
Elemental analysis : C=58.82(58.47);H=6.00(6.19);N=11.80(11.86)
RP : -34.930 (589 nm, T=18°C, C=0.9)
Intermediate 175: teri-Butyl (3S)-3-{4-[bis(iert-butoxycarbonyl)amino]butyI}-4-ethoxy15 l-[(4-methoxy-2-pyridin-4-ylphenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 175 is obtained starting from intermediates 129 and 268 in accordance with procedure F described hereinbefore.
‘HNMR: (400 MHz, dmso-d6) δ ppm 8.61 (d, 2 H), 7.41 (d, 2 H), 7.38 (d, 1 H), 7 (dd, 1 H), 20 6.8 (d, 1 H), 3.92 (m, 2 H), 3.79 (s, 3 H), 3.49/3.3 (AB, 2 H), 2.73/2.18 (m, 2 H), 2.73 (m, 2
H), 2.67/2.3 (m, 2 H), 1.95-1.8 (m, 2 H), 1.7 (m, 2 H), 1.35 (2s, 18 H), 1.22 (m, 2 H), 1.18 (t, 3 H), 0.69/0.55 (m, 2 H)
EXAMPLE 225: (3S)-3-(4-AminobutyI)-4-hydroxy-l-[(4-hydroxy-2-pyridin-425 ylphenyl)methyl]-4-oxo-l94-azaphosphinane-3-carboxylic acid
Example 225 is obtained starting from intermediate 175 in accordance with procedure D described hereinbefore.
-178p *H NMR: (400 MHz, D2O) δ ppm 8.6 (d, 2 H), 7.5 (d, 1 H), 7.41 (d, 2 H), 7.01 (dd, 1 H), 6.88 (d, 1 H), 4.31/4.2 (AB, 2 H), 3.41/3.05 (m, 2 H), 3.15/2.8 (m, 2 H), 2.97 (m, 2 H), 2.09/1.65 (m, 2 H), 1.85/1.35 (m, 2 H), 1.6 (m, 2 H), 1.09 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 434.1841 (434.1839)
Elemental analysis : C=58.51(58.19);H=5.87(6.51);N=9.77(9.69)
RP : -28.730 (589 nm, T=18°C, C=0.6)
Intermediate 176: teri-Butyl (3S)-3-{4-[bis(ter/-butoxycarbonyl)amino]butyl}-4-ethoxyl-[[4-fluoro-2-(3-fluorophenyl)phenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 176 is obtained starting from intermediates 129 and 269 in accordance with procedure F described hereinbefore.
'H NMR: (400 MHz, dmso-d6) δ ppm 7.52-7.08 (m, 7 H), 3.92 (m, 2 H), 3.51/3.32 (AB, 2 H),
3.3 (m, 2 H), 2.72/2.21 (m, 2 H), 2.69/2.36 (m, 2 H), 2-1.85 (m, 2 H), 1.78 (m, 2 H), 1.4 (s, 18 H), 1.34 (m, 2 H), 1.31 (s, 9 H), 1.18 (m, 3 H), 0.65 (t, 2 H) 19F NMR: (400 MHz, dmso-d6) δ ppm -112/-114
EXAMPLE 226: (3S)-3-(4-aimnobutyI)-l-[[4-fluoro-2-(3-fluorophenyi)phenyl]methyl]4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 226 is obtained starting from intermediate 176 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.65 (dd, 1 H), 7.5 (m, 1 H), 7.25 (m, 1 H), 7.25 (d, 1 H), 7.25-7.1 (m, 3 H), 4.4 (d, 1 H), 4.3 (d, 1 H), 3.5-3.35 (m, 1 H), 3.2 (m, 1 H), 3.15 (m, 1 H),
2.95 (m, 2 H), 2.85 (dd, 1 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.7 (m, 1 H), 1.6 (m, 2 H), 1.35 (m, 1 H), 1.2-1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 453.1748 (453.1749)
Elemental analysis : C=58.06(58.40);H=6.00(6.01);N=6.14(6.19)
RP : -15.830 (589 nm, T=20.5°C, C=1.0)
-179Intermediate 177: teri-Butyl (3S)-3-{4-[Bis(ieri-butoxycarbonyl)ammo]butyl}-4-ethoxyl-[(4-hydroxy-2-thiophen-2-ylphenyl)methyl]-4-oxo-l,4azaphosphinane-3-carboxylate
Intermediate 177 is obtained starting from intermediates 129 and 255 in accordance with procedure F described hereinbefore.
Ή NMR: (400 MHz, dmso-d6) δ ppm 9.55 (s, 1 H), 7.55 (d, 1 H), 7.25 (d, 1 H), 7.2 (d, 1 H),
7.1 (m, 1 H), 6.8 (s, 1 H), 6.75 (dd, 1 H), 4 (m, 2 H), 3.5 (d, 1 H), 3.3 (d, 1 H), 3.25 (m, 2 H), 2.95-2.8 (m, 2 H), 2.4 (dd, 1 H), 2.25 (m, 1 H), 2.05-1.8 (m, 4 H), 1.4 (s, 18 H), 1.35 (s, 9 H),
1.3 (m, 2 H), 1.2 (t, 3 H), 0.65 (m, 2 H)
EXAMPLE 227: (3S)-3-(4-Aminobutyi)-4-hydroxy-l-[(4-hydroxy-2-thiophen-2ylphenyl)methyl] -4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 227 is obtained starting from intennediate 177 in accordance with procedure D described hereinbefore.
‘HNMR: (400 MHz, D2O) δ ppm 7.55 (d, 1 H), 7.45 (d, 1 H), 7.2 (m, 1 H), 7.15 (d, 1 H),
6.95 (m, 2 H), 4.45 (d, 1 H), 4.35 (d, 1 H), 3.55-3.4 (m, 1 H), 3.35-3.25 (m, 1 H), 3.15 (m, 1 H), 2.95 (m, 2 H), 2.9 (dd, 1 H), 2.15 (m, 1 H), 1.85 (m, 1 H), 1.7 (m, 1 H), 1.6 (m, 2 H), 1.4 (m, 1 H), 1.2 (m, 1 H), 1.1 (m, 1 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 439.1450 (439.1451)
Elemental analysis : C=55.29(54.78);H=6.41(6.21);N=6.46(6.39);S=7.06(7.31)
RP : -36.090 (589 nm, T=20.5°C, C=1.0)
Intermediate 178: teri-Butyl (3$)-3-{4-[bis(/eri-butoxycarbonyl)amino]butyl}-4-ethoxyl-[[2-(4-fluorophenyl)-4-hydroxyphenyl]methyl]-4-oxo-l,4azaphosphinane-3-carboxyiate
Intermediate 178 is obtained starting from intermediates 129 and 270 in accordance with procedure F described hereinbefore.
3Η NMR: (400 MHz, dmso-d6) δ ppm 9.5 (si, 1 H), 7.39 (dd, 1 H), 7.24 (dd, 1 H), 7.2 (d, 1 H), 6.75 (dd, 2 H), 6.6 (d, 2 H), 3.92 (m, 2 H), 3.31/3.21 (AB, 2 H), 3.3 (m, 2 H), 2.72/2.12 (2*m, 2 H), 2.67/2.3 (2*m, 2 H), 2-1.8 (m, 2 H), 1.8 (m, 2 H), 1.4 (s, 18 H), 1.35 (m, 2 H),
1.32 (s, 9 H), 1.18 (t, 3 H), 0.7 (m, 2 H).
-180pi 31P NMR: (400 MHz, dmso-d6) δ ppm -114.8
EXAMPLE 228: (3S)-3-(4-Aminobutyl)-l-[[2-(4-fluorophenyl)-4-hydroxyphenylJmethyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 228 is obtained starting from intermediate 178 in accordance with procedure D 5 described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.47 (d, 1 H), 7.32 (dd, 2 H), 7.22 (dd, 2 H), 6.98 (dd, 1 H), 6.85 (d, 1 H), 4.32/4.2 (AB, 2 H), 3.37/3.05 (m, 2 H), 3.15/2.8 (m, 2 H), 2.95 (m, 2 H), 2.09/1.65 (m, 2 H), 1.85/1.35 (m, 2 H), 1.59 (m, 2 H), 1.1 (m, 2 H) 19F NMR: (400 MHz, D2O) δ ppm -113.5
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1792 (451.1793)
Elemental analysis : C=58.29(58.66);H=6.12(6.27);N=6.20(6.22)
RP : -36.630 (589 nm, T=21°C, C=1.0)
Intermediate 179: teri-Butyl (3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-l-[[2-(3,4dimethoxyphenyl)-4-hydroxyphenyl]methyl]-4-ethoxy-4-oxo-l,415 azaphosphinane-3-carboxylate
Intermediate 179 is obtained starting from intermediates 129 and 256 in accordance with procedure F described hereinbefore.
!Η NMR: (400 MHz, dmso-d6) δ ppm 9.4 (m, 1 H), 7.2 (d, 1 H), 7 (d, 1 H), 6.85 (m, 2 H), 6.7 (dd, 1 H), 6.6 (dd, 1 H), 3.95 (m, 2 H), 3.8 (2s, 6 H), 3.4/3.25 (2d, 2 H), 3.3 (m, 2 H), 2.8 (m,
1 H), 2.7 (m, 1 H), 2.3 (dd, 1 H), 2.15 (m, 1 H), 1.9 (m, 1 H), 1.8 (m, 3 H), 1.4/1.25 (2m, 2 H),
1.4 (s, 18 H), 1.35 (s, 9 H), 1.2 (t, 3 H), 0.75 (quint, 2 H)
EXAMPLE 229: (3S)-3-(4-Aminobutyl)-l-[[2-(3,4-dimethoxyphenyl)-4-hydroxyphenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 229 is obtained starting from intermediate 179 in accordance with procedure D described hereinbefore.
*H NMR: (400 MHz, dmso-d6) δ ppm 7.05 (s, 1 H), 7-6.85 (dd;d, 2 H), 6.85 (d, 1 H), 6.25 (dd, 1 H), 6.15 (s, 1 H), 3.75 (s, 6 H), 3.2 (d, 1 H), 3.05 (d, 1 H), 3-2.85 (m, 1 H), 2.8-2.65 (m,
-181P; 1 Η), 2.45-2.25 (m, 3 Η), 2.15 (m, 1 Η), 1.85-1.7 (m, 2 Η), 1.65 (m, 1 Η), 1.3-1.15 (m, 3 Η), 0.9 (m, 1 Η), 0.8 (m, 1 Η)
ESI/FIA/HR and MS/MS : ESI-HR +/- : [M+H]+ = 493.2098 (493.2098)
Elemental analysis : C=58.52(58.53);H=6.32(6.75);N=5.48(5.69)
RP : -32.470 (589 nm, T=20°C, C=0.9)
EXAMPLE 230: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(4-hydroxyphenyl)methyï]-4-oxo- l,4-azaphosphinane-3-carboxylic acid
Example 230 is obtained starting from intermediate 129 and 4-hydroxybenzaldehyde in accordance with procedures F and D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.32 (d, 2 H), 6.9 (d, 2 H), centred at 4.2 (AB, 2 H), 3.7/3.28 (2m, 2 H), 3.45/3.05 (2dd, 2 H), 2.9 (m, 2 H), 2.21/1.75 (2m, 2 H), 1.9/1.45 (2m, 2 H), 1.59 (m, 2 H), 1.22/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 357.1577 (357.1574)
Elemental analysis : C=54.12(53.93);H=6.96(7.07);N=7.93(7.86)
RP : -56.580 (589 nm, T=20°C, C=1.0)
EXAMPLE 231: (3S)-3-(4-Aminobutyl)-l-[[2-(4-chlorophenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 231 is obtained starting from intermediate 129 and 2-(4-chlorophenyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.59 (m, 1 H), 7.51 (m, 2 H), 7.51 (d, 2 H), 7.38 (m, 1 H), 7.31 (d, 2 H), 4.33 (AB, 2 H), 3.39/3.08 (2m, 2 H), 3.15/2.83 (2m, 2 H), 2.92 (m, 2 H), 2.07/1.62 (2m, 2 H), 1.83/1.34 (2m, 2 H), 1.56 (m, 2 H), 1.06 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1541 (451.1553)
Elemental analysis : C=58.91(58.60);H=6.12(6.26);N=5.85(6.21)
RP: -10.140 (589 nm,T=20°C,C=0.8)
-182EX AMPLE 232; (3S)-3-(4-Aimnobutyl)-4-hydroxy-l-[[2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yI]phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxyhc acid
Example 232 is obtained starting from intermediate 129 and 2-[l-methyl-3-(trifluoromethyl)lH-pyrazol-5-yl]benzaldehyde in accordance with procedures F and D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.63/7.46 (m, 4 H), 6.81 (s, 1 H), 4.21 (AB, 2 H), 3.65 (s, 3
H), 3.5/3.19 (2m, 2 H), 3.26/3 (2m, 2 H), 2.91 (m, 2 H), 2.15/1.69 (2m, 2 H), 1.87/1.4 (2m, 2 H), 1.58 (m, 2 H), 1.11 (m, 2 H) 19F NMR: (300 MHz, D2O) δ ppm -61.8 .
ESI/FIA/HR and MS/MS : [M+H]+ = 489.1869 (489.1878)
Elemental analysis : C=51.64(51.64);H=6.03(5.78);N=l 1.47(11.47)
RP: -27.030 (589 nm,T=20°C,C=0.9)
EX AMPLE 233: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[[2-(trifluoromethyl)phenyl]methyl]-l,4-azaphosphinane-3-carboxyIic acid
Example 233 is obtained starting from intermediate 129 and 2-trifluoromethylbenzaldehyde in accordance with procedures F and D described hereinbefore.
NMR: (300 MHz, D2O) δ ppm 7.88-7.6 (m, 4 H), 4.51 (AB, 2 H), 3.69/3.43 (2m, 2 H), 3.48/3.25 (2m, 2 H), 2.92 (m, 2 H), 2.22/1.78 (2m, 2 H), 1.93/1.49 (2m, 2 H), 1.59 (m, 2 H), 1.23/1.09 (2m, 2 H) .
19F NMR: (300 MHz, D2O) δ ppm -58.3
ESI/FIA/HR and MS/MS : [M+H]+ = 409.1492 (409.1499)
Elemental analysis : C=49.52(50.00);H=5.85(5.92);N=7.00(6.86)
RP: -38.120 (589 nm,T=20°C,C= 1.0
EXAMPLE 234: (3S)-3-(4-Aminobutyl)-l-[(4-fluoro-2-pyrimidin-5-ylphenyl)methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 234 is obtained starting from intermediate 129 and 4-fluoro-(2-pyrimidin-5yl)benzaldehyde in accordance with procedures F and D described hereinbefore.
-183NMR: (300 MHz, D2O) δ ppm 9.2 (s, 1 H), 8.82 (s, 2 H), 7.7 (dd, 1 H), 7.35 (td, 1 H), 7.2 (dd, 1 H), 4.38/4.28 (2*d, 2 H), 3.5/3.15 (2*m, 2 H), 3.25/2.9 (2*m, 2 H), 2.9 (t, 2 H), 2.1/1.6 (2*m, 2 H), 1.85/1.6 (2*m, 2 H), 1.6/1.1 (2*m, 2 H), 1.38/1.1 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 437.1740 (437.1753)
Elemental analysis : C=54.96(55.04);H=4.82(6.00);N= 12.78(12.84)
RP: -23.070 (589 nm, T=20°C, C=l.l)
EX AMPLE 235: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[2-(2-methylpyrazol-3yl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 235 is obtained starting from intermediates 129 and 280 in accordance with procedures F and D described hereinbefore.
*Η NMR: (300 MHz, D2O) δ ppm 7.7-7.35 (m, 4 H), 7.65 (d, 1 H), 6.45 (d, 1 H), 4.25/4.15 (dd, 2 H), 3.6 (s, 3 H), 3.5/3.2 (2m, 2 H), 3.3/3 (dd, 2 H), 2.9 (m, 2 H), 2.15/1.7 (2m, 2 H), 1.9/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.3-1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 421.1998 (421.2004)
Elemental analysis : C=57.19(57.13);H=7.08(6.95);N=13.43( 13.33)
RP: -29.970 (589 nm,T=19.5°C,C=1.0)
EXAMPLE 236: (3S,)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(2-methylpyrazol-3-yl)phenylJmethyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 236 is obtained starting from intermediates 129 and 277 in accordance with procedures F and D described hereinbefore.
^NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1 H), 7.65 (d, 1 H), 7.39 (td, 1 H), 7.24 (dd, 1 H),
6.5 (d, 1 H), 4.25/4.13 (AB, 2 H), 3.61 (s, 3 H), 3.48/3.18 (m, 2 H), 3.29/3 (m, 2 H), 2.94 (m, 2 H), 2.17/1.7 (m, 2 H), 1.9/1.41 (m, 2 H), 1.6 (m, 2 H), 1.2/1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 439.1903 (439.1905)
Elemental analysis : C=54.74(54.79);H=6.38(6.44);N=12.57(12.78)
RP : -26.790 (589 nm, T=21°C, C=1.0)
-184(' EXAMPLE 237: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[(2-imidazo[l,2-a]pyridin-3ylphenyl)methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 237 is obtained starting from intermediates 129 and 227 in accordance with procedures F and D described hereinbefore.
te NMR: (300 MHz, D2O) δ ppm 7.98 (d, 1 H), 7.68 (s, 1 H), 7.65 (d, 1 H), 7.65 (m, 2 H), 7.52 (m, 1 H), 7.45 (dd, 1 H), 7.22 (m, 1 H), 6.98 (t, 1 H), 4.25 (m, 2 H), 3.45/3.1 (2*m, 2 H),
2.9 (m, 2 H), 2.85 (m, 2 H), 2.12/1.55 (2*m, 2 H), 1.8/1.55 (2*m, 2 H), 1.55/0.95 (2*m, 2 H), 1.28/0.95 (2*m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 457.1993 (457.1999)
Elemental analysis : C=60.73(60.52);H=6.00(6.40);N= 12.29(12.27)
RP: -33.550(589nm,T=19°C,C=0.9)
EXAMPLE 238: (3S)-3-(4-Aminobutyl)-1- [[4-fluoro-2-(3-hydroxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 238 is obtained starting from intermediates 129 and 254 in accordance with 15 procedures F and D described hereinbefore.
te NMR: (400 MHz, dmso-d6) δ ppm 7.6 (dd, 1 H), 7.4 (m, 1 H), 7.25 (m, 1 H), 7.15 (d, 1 H), 6.95 (dd, 1 H), 6.9 (dd, 1 H), 6.85 (s, 1 H), 4.4 (d, 1 H), 4.25 (d, 1 H), 3.5-3.3 (m, 1 H), 3.25-3 (m, 2 H), 2.95 (m, 2 H), 2.85 (dd, 1 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.6 (m, 2 H), 1.35 (m, 1 H), 1.2-1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 451.1794 (451.1793)
Elemental analysis : C=58.81(58.66);H=5.81(6.27);N=6.19(6.22)
RP : -19.520 (589 nm, T=21°C, C=1.0)
EX AMPLE 239: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(6-methoxypyridm-3-yl)phenyl]methyl] -4-hy droxy-4 -oxo- l,4-azaphosphinane-3-carboxylic acid
Example 239 is obtained starting from intermediate 129 and 4-fIuoro-2-(6-methoxy-3pyrîdinyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
te NMR: (400 MHz, D2O) δ ppm 8.1 (d, 1 H), 7.8 (dd, 1 H), 7.65 (dd, 1 H), 7.3 (td, 1 H),
7.15 (dd, 1 H), 7 (d, 1 H), 4.4/4.3 (2 d, 2 H), 3.9 (s, 3 H), 3.45 (m, 1 H), 3.2 (dd, 1 H), 3.1 (m,
-185Ç 1 H), 2.95 (m, 2 H), 2.85 (dd, 1 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.6 (m, 2 H),
1.35 (m, 1 H), 1.1 (m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 466.1903 (466.1902)
Elemental analysis : C=57.18(56.77);H=6.17(6.28);N=9.05(9.03) '
RP : -11.850 (589 nm,T=20°C.C=0.9)
EXAMPLE 240: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[2-(6-hydroxypyridin-3yl)phenyl]methyl]-4-oxo-l,4-azaphosphmane-3-carboxylic acid
Example 240 is obtained starting from intermediate 129 and 2-(6-methoxy-3pyridinyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1 H), 7.6 (d, 1 H), 7.55-7.4 (2 m, 4 H), 6.7 (d, 1 H), 4.4 (2 d coal., 2 H), 3.5 (m, 1 H), 3.3 (dd, 1 H), 3.2 (m, 1 H), 3 (dd, 1 H), 2.95 (m, 2 H),
2.1 (m, 1 H), 1.9 (m, 1 H), 1.7 (m, 1 H), 1.6 (m, 2 H), 1.4 (m, 1 H), 1.1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 434.1840 (434.1839)
Elemental analysis : C=58.14(58.19);H=6.38(6.51);N=9.60(9.69)
RP: -8.440 (589 nm,T=20°C,C=0.8)
EXAMPLE 241: (3S)-3-(4-Aininobutyl)-l-[[4-fluoro-2-(6-hydroxypyridin-3-yl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 241 is obtained starting from intermediate 129 and 4-fluoro-2-(6-methoxy-3pyridinyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
‘H NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1 H), 7.6 (m, 2 H), 7.3 (td, 1 H), 7.2 (dd, 1 H), 6.7 (d, 1 H), 4.35 (2 d coal., 2 H), 3.5 (m, 1 H), 3.25 (m, 1 H), 3.2 (m, 1 H), 3 (dd, 1 H), 2.95 (m, 2 H), 2.1 (m, 1 H), 1.9 (m, 1 H), 1.7 (m, 1 H), 1.6 (quint, 2 H), 1.4 (m, 1 H), 1.1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 452.1746 (452.1745)
Elemental analysis : C=55.62(55.87);H=5.85(6.03);N=9.16(9.31)
RP: -7.630 (589 nm,T=20°C,C=0.7)
-186f EXAMPLE 242: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-2-(6-methoxypyridin-
3-yl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 242 is obtained starting from intermediates 129 and 230 in accordance with procedures F and D described hereinbefore.
1HNMR: (400 MHz, D2O) δ ppm 7.95 (d, 1 H), 7.6 (dd, 1 H), 7.4 (d, 1 H), 6.9 (m, 2 H), 6.7 (d, 1 H), 4,2-4.l(2d., 2 H), 3.8 (s, 3 H), 3.3-2.95 (2m, 2 H), 3.1-2.7 (2m, 2 H), 2.85 (m, 2 H), 2.0-1.5 (2m, 2 H), 1.75-1.25 (2m, 2 H), 1.5 (m, 2 H), 1.0 (m, 2 H)
Elemental analysis : C=56.79(57.01);H=6.62(6.52);N=8.99(9.07)
RP: -27.320 (589 nm,T=20°C,C=0.8)
EXAMPLE 243: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-oxo-l,3-dihydrobenzimidazol-5-yl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 243 is obtained starting from intermediate 129 and 2-oxo-l,3-dihydrobenzothiazole-
5-carbaldehyde in accordance with procedures F and D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.25 (s, 1 H), 7.2 (m, 2 H), 4.45 (d, 1 H), 4.25 (d, 1 H),
3.8-3.65 (m, 1 H), 3.55-3.4 (m, 1 H), 3.35 (m, 1 H), 3.1 (dd, 1 H), 2.95 (m, 2 H), 2.3-2.15 (m,
H), 2-1.85 (m, 1 H), 1.85-1.7 (m, 1 H), 1.6 (m, 2 H), 1.55-1.4 (m, 1 H), 1.3-1 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 397.1635 (397.1635)
EXAMPLE 244: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(6-methoxypyridin-2-yl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid
Example 244 is obtained starting from intermediates 129 and 231 in accordance with procedures F and D described hereinbefore.
1H NMR: (300 MHz, D2O) δ ppm 8.2 (t, 1 H), 7.8 (dd, 1 H), 7.7 (dd, 1 H), 7.55 (m, 2 H), 7.2 (d, 1 H), 4.7 (d, 1 H), 4.5 (d, 1 H), 4.2 (s (+m, 3 H), 3.9 (m, 1 H), 3.6 (m, 3 H), 3.2 (t (+m, 2 H), 2.6 (m, 1 H), 2.05 (m, 2 H), 1.8 (m, 2 H), 1.7 (m, 1 H), 1.4/1.3 (2m, 2 H) 19F NMR: (300 MHz. D2O) δ ppm -110.9
ESI/FIA/HR and MS/MS : 1M+H1+ = 466.1901 (466.1902)
Elemental analysis : C=57.09(56.77);H=6.16(6.28);N=8.87(9.03)
RP : -69.790 (589 nm,T=19°C,C=0.8)
-187Ç EX AMPLE 245: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(l,3-thiazol-2-yl)phenyl]methyl]-
4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid
Example 245 is obtained starting from intermediates 129 and 232 in accordance with procedures F and D described hereinbefore.
*H NMR: (300 MHz, D2O) δ ppm 8 (d, 1 H), Ί.Ί (m, 2 H), 7.7 (dd, 1 H), 7.3 (td, 1 H), 4.5 (d, 1 H), 4.3 (d, 1 H), 3.85 (m, 1 H), 3.45 (m, 2 H), 3.15 (dd, 1 H), 2.9 (m, 2 H), 2.3 (m, 1 H),
1.85 (m, 2 H), 1.55 (m, 3 H), 1.2 (m, 1 H), 1 (m, 1 H) 19F NMR: (300 MHz, D2O) δ ppm -109
ESI/FIA/HR and MS/MS : [M+H]+ = 442.1358 (442.1360)
Elemental analysis : C=51.13(51.69);H=5.30(5.71);N=9.42(9.52);S=7.25(7.26)
RP : -99.540 (589 nm,T=18°C;C=0.8)
EXAMPLE 246: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-2-(3-methyliinidazol4-yl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid, hydrobromide
Example 246 is obtained starting from intermediates 129 and 276 in accordance with procedures F and D described hereinbefore.
1h NMR: (300 MHz, D2O) δ ppm 8.85 (s, 1 H), 7.65 (d, 1 H), 7.6 (s, 1 H), 7.2 (dd, 1 H), 7 (d, 1 H), 4.4 (m, 1 H), 4.15 (m, 1 H), 3.7 (m, 1 H), 3.6 (s, 3 H), 3.55-3.2 (2 m, 2 H), 3.1 (m, 1 H),
2.9 (m, 2 H), 2.15 (m, 1 H), 1.9 (m, 2 H), 1.6 (m, 3 H), 1.25 (2 m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 437.1947 (437.1948)
Elemental analysis : C=39.13(40.15);H=5.22(5.22);N=8.85(9.37)
RP :-15.390 (589 nm, T=21°C, C=1.0)
EXAMPLE 247: (3S)-3-(4-Aminobutyl)-4-hydroxy-l-[[4-hydroxy-2-(2-methylpyrazoI-3yi)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 247 is obtained starting from intermediate 129 and 4-hydroxy-2-(2-methylpyrazol-3yl)benzaldehyde in accordance with procedures F and D described hereinbefore.
NMR: (400 MHz, D2O) δ ppm 7.63 (s, 1 H), 7.52 (dd, 1 H), 7.08 (d, 1 H), 6.9 (s, 1 H),
6.44 (d, 1 H), 4.18/4.05 (2m, 2 H), 3.61 (s, 3 H), 3.45/3.15 (2m, 2 H), 3.26/2.95 (2dd, 2 H),
2.95 (m, 2 H), 2.15/1.68 (2m, 2 H), 1.9/1.4 (2m, 2 H), 1.6 (m, 2 H), 1.2/1.1 (2m, 2 H)
-188ESI/FIA/HR and MS/MS : [M+H]+ = 437.1947 (437.1948)
Elemental analysis : C=55.22(55.04);H=6.48(6.70);N=12.72(12.84)
RP: -44.210 (589 nm,T=20°C,C=1.0)
EXAMPLE 248: (3S)-3-(4-Aminobutyl)-l-[[2-(3>4-dimethoxyphenyl)phenyl]methyl]-4hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 248 is obtained starting from intermediate 129 and 2-(3,4dimethoxyphenyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
Td NMR: (300 MHz, D2O) δ ppm 7.6 (dd, 1 H), 7.5 (m, 2 H), 7.35 (dd, 1 H), 7.1 (d, 1 H), 7 (d, 1 H), 6.9 (dd, 1 H), 4.45/4.3 (2 d, 2 H), 3.85 (2 s, 6 H), 3.35/3.1 (2 m, 2 H), 3.1/2.9 (m + dd, 2 H), 2.95 (m, 2 H), 2.1/1.65 (2 m, 2 H), 1.85/1.35 (2 m, 2 H), 1.6 (m, 2 H), 1.05 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 477.2147 (477.2149)
Elemental analysis : C=60.13(60.50);H=6.84(6.98);N=5.68(5.88)
RP : -21.710 (589 nm.T=18°C,C=1.0)
EXAMPLE 249: (3S)-3-(4-Aminobutyl)-l-[[2-(2,3-dimethylimidazol-4-yl)-4-hydroxyphenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxylic acid
Example 249 is obtained starting from intermediates 129 and 275 in accordance with procedures F and D described hereinbefore.
'H NMR: (400 MHz, D2O) δ ppm 7.55 (d, 1 H), 7.45 (s, 1 H), 7.15 (dd, 1 H), 6.95 (s, 1 H),
4.15 (si, 2 H), 3.65-3.5 (m, 1 H), 3.45 (s, 3 H), 3.35 (m, 1 H), 3.2 (m, 1 H), 2.95 (dd, 1 H),
2.95 (t, 2 H), 2.65 (s, 3 H), 2.15 (m, 1 H), 1.9 (m, 1 H), 1.75 (m, 1 H), 1.6 (m, 2 H), 1.45 (m, 1 H), 1.35-1.05 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 451.2102 (451.2105)
Elemental analysis : C=46.98(47.47);H=6.05(6.07);N=10.40(10.54)
RP : -37.730 (589 nm, T=20.5°C, C=1.0)
-189EXAMPLE 250: (3S)-3-(4-Aminobutyl)-l-[[2-(2,3-dimethylimidazol-4-yl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-carboxyIic acid
Example 250 is obtained starting from intermediates 129 and 226 in accordance with procedures F and D described hereinbefore.
’H NMR: (400 MHz, D2O) ô ppm 7.75-7.45 (m, 4 H), 7.45 (s, 1 H), 4.25 (m, 2 H), 3.5/3.2 (2m, 2 H), 3.4/3.1 (m, 2 H), 3.4 (s, 3 H), 2.9 (m, 2 H), 2.65 (s, 3 H), 2.1/1.7 (2m, 2 H), 1.9/1.45 (2m, 2 H), 1.6 (m, 2 H), 1.25/1.1 (2m, 2 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 435.2179 (435.2161)
Elemental analysis : C=49.57(50.37);H=5.92(5.88);N=9.92(10.21)
RP : -23.310 (589 nm, T=20°C, C=0.9)
EXAMPLE 251: (3S)-3-(4-Aminobutyl)-l-[[4-fluoro-2-(4-fluoro-3-hydroxyphenyl)phenyljmethyl] -4-hydroxy-4 -oxo- 1,4-azap hosphinane-3-carboxy lie acid
Example 251 is obtained starting. from intermediate 129 and 4-fluoro-2-(4-fluoro-3hydroxyphenyl)benzaldehyde in accordance with procedures F and D described hereinbefore. 1HNMR: (400 MHz, D2O) δ ppm 7.6 (d, 1 H), 7.25 (2*m, 2 H), 7.15 (d, 1 H), 6.95 (d, 1 H),
6.8 (m, 1 H), 4.4 (d, 1 H), 4.3 (d, 1 H), 3.5-3.35 (m, 1 H), 3.2-3.05 (m, 2 H), 2.95 (m, 2 H),
2.85 (dd, 1 H), 2.1 (m, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.6 (m, 2 H), 1.35 (m, 1 H), 1.2-1 (m, 2 H)
EST/FIA/HR and MS/MS : [M+H]+ = 469.1696 (469.1698)
Elemental analysis : C=56.82(56.41);H=5.77(5.81);N=6.02(5.98)
RP : -12.950 (589 nm, T=21°C, C=1.0)
EXAMPLE 252: (3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-pyridin-4-ylphenyl)methyl]-l,4-azaphosphinane-3-carboxylic acid
Example 252 is obtained starting from intermediate 129 and 2-(4-pyridyl)benzaldehyde in accordance with procedures F and D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 8.6 (d, 2 H), 7.64 (m, 1 H), 7.57 (m, 2 H), 7.42 (d, 2 H),
7.41 (m, 1 H), 4.42/4.3 (dd, 2 H), 3.44/3.09 (dd, 2 H), 3.18/2.88 (dd, 2 H), 2.93 (m, 2 H), 2.09/1.64 (2*m, 2 H), 1.85/1.35 (2*m, 2 H), 1.59 (m, 2 H), 1.08 (m, 2 H)
-190p ESI/FIA/HR and MS/MS : [M+HJ+ = 418.1897 (418.1895)
Elemental analysis : C=61.00(60.42);H=6.62(6.76);N=10.20(10.07)
RP: -17.980 (589 nm,T=28°C,C=0.9)
Procedure H : Synthesis of the azaphosphepanes
A solution of N-Boc allylamine (30 g, 190 mmol) in THF (170 mL) is added dropwise to a 60% NaH suspension (11.45 g, 285 mmol, 1.5 eq) in THF (100 mL) and under an argon atmosphère. The mixture is left in contact for 1 hour 30 minutes, and then benzyl bromide 10 (34 mL, 285 mmol, 1.5 eq) in solution in THF (30 mL) is added. The reaction mixture is stirred at ambient température for 48 hours. The THF is evaporated off under reduced pressure and the evaporate is taken up in DCM (10 mL) cooled in an ice-water bath and then poured slowly onto H2O (100 mL). The organic phase is separated off, and the aqueous phase is re-extracted with DCM (2 x 100 mL). The combined organic phases are washed with H2O 15 (2 x 50 mL), dried over MgSCk and then evaporated. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/DCM gradient (from 50:50 to 0:100).
Intermediate 180 is obtained in the form of a colourless oil (39.8 g, 160.92 mmol) with a yield of85%.
Ή NMR: (400 MHz, DMSO-d6) δ ppm 7.65 (t, 2 H), 7.22 (m, 3 H), 5.75 (m, 1 H), 5.1 (m, 2 20 H), 4.33 (s, 2 H), 3.75 (m, 2 H), 1.39 (s, 9 H)
Intermediate 181 :
-191f~\ Tetraethoxysilane (38.35 mL, 173 mmol, 2 eq) is added dropwise to a solution of hypophosphorous acid (11.42 g, 173 mmol, 2 eq) in acetonitrile (224 mL) at O C and under an argon atmosphère. After returning to ambient température, there are added to the reaction mixture (degassed with argon) intermediate 180 (21.4 g, 86.5 mmol) in solution in MeCN (44.7 mL), Xantphos (0.55 g, 11 mmol) and then Pdadbas (0.396 g, 5 mmol). The mixture is heated at reflux for 16 hours. After concentration under reduced pressure, the residue obtained is purified by flash chromatography on silica gel using as eluant an AcOEt/EtOH gradient (from 95:5 to 90:10). Intermediate 181 is obtained in the form of a colourless oil (10.1 g, 29.58 mmol) with a yield of 34%.
‘H NMR: (400 MHz, DMSO-d6) δ ppm 7.32 (t, 2 H), 7.22 (m, 3 H), 6.95 (d, 1 H), 4.38 (s, 2 H), 3.99 (m, 2 H), 3.19 (m, 2 H), 1.65 (m, 4 H), 1.4 (m, 9 H), 1.21 (t, 3 H) 31P NMR: (400 MHz, DMSO-d6) δ ppm 40.7
Intermediate 182 :
A solution of IM LiHMDS in THF (29.6 mL, 29.6 mmol, 1 eq) is added to a solution of intermediate 181 (10.1 g, 29.6 mmol) in THF (100 mL) previously degassed with argon. After stirring for 30 minutes at -70°C, allyl bromide (2.56 mL, 29.6 mmol, 1 eq) is added. The reaction mixture is stirred for 2 hours at ambient température and then poured onto a saturated aqueous NH4CI solution. The mixture is extracted with DCM (3 x 100 mL), and the organic phase is washed with H2O (2 x 100 mL) and dried over Na2SÜ4. After concentration under reduced pressure, the residue obtained is purified by flash chromatography on silica gel using as eluant an AcOEt/EtOH gradient (from 100% - 90:10). The expected intermediate 182 is obtained in the form of a colourless oil (9.3 g, 24.3 mmol) with a yield of 82%.
Ή NMR: (400 MHz, DMSO-d6) δ ppm 7.4-7.2 (m, 5 H), 5.2 (m, 1 H), 5.18 (2dd, 2 H), 4.4 (s, 2 H), 3.91 (quad, 2 H), 3.15 (m, 2 H), 2.6 (dd, 2 H), 1.6 (m, 4 H), 1.4 (si, 9 H), 1.2 (t, 3 H)
-192Intermediate 183 :
A 4% solution of OsCU in H2O (4.64 mL, 0.73 mmol) at ambient température is added dropwise to a solution of intermediate 182 (9.3 g, 24.3 mmol) and 4-methylmorpholine TVoxide (3.14 g, 26.7 mmol, 1.1 eq) in 100 mL of an acetone/H2O mixture (2:1). The reaction mixture is stirred at ambient température for 16 hours and then poured onto a 10% solution of sodium metabisulphite in H2O (100 mL). The mixture is extracted with AcOEt (2 x 100 mL). The organic phases are combined and washed with H2O (1 x 100 mL), dried over MgSÛ4 and then concentrated in vacuo. Intermediate 183 (9.8 g, 23.58 mmol) is obtained without further purification in the form of a dark-coloured oil with a yield of 97%.
NMR: (400 MHz, DMSO-d6) δ ppm 7.35-7.2 (m, 5 H), 4.8/4.78 (2d, 1 H), 4.65 (2t, 1 H),
4.36 (s, 2 H), 3.9 (m, 2 H), 3.75 (m, 1 H), 3.35-3.2 (m, 2 H), 3.15 (m, 2 H), 1.9/1.7 (m, 2 H),
1.63 (m, 4 H), 1.4 (m, 9 H), 1.17 (t, 3 H) 31P NMR: (400 MHz, DMSO-d6) δ ppm 58.6/57.7
Intermediate 184 :
Sodium periodate (20.16 g, 94.25 mmol, 4 eq) is added in portions to a solution of intermediate 183 (9.79 g, 23.5 mmol) in 320 mL of a THF/H2O mixture (3:1) at ambient température. Stirring is maintained for 72 hours at ambient température. The reaction mixture is then extracted with AcOEt (2 x 150 mL), and the organic phases are combined and washed with H2O (1 x 100 mL), dried over MgSO4 and then concentrated in vacuo. Intermediate 184 (8.13 g, 21.2 mmol) is obtained without further purification in the form of an oil with a yield of90%.
ffiNMR: (400 MHz, dmso-d6) δ ppm 9.6 (m, 1 H), 7.35-7.2 (m, 5 H), 4.38 (s, 2 H), 4-3.75 (m, 2 H), 3.25 (dd, 2 H), 3.15 (m, 2 H), 1.65 (m, 4 H), 1.4 (m, 9 H), 1.2 (m, 3 H)
-193Intermediate 186 :
N
O O jp'
A solution of intermediate 184 (8.13 g, 21.2 mmol) in 2N HCl (53 mL, 106 mmol, 5 eq) is stirred for 4 hours at ambient température. The reaction mixture is concentrated in vacuo to yield intermediate 185, which is used directly without being purified further. Intermediate 185 is dissolved in DCM (150 mL) and stirred for 1 hour with MgSCL (10 g). NaBH(OAc)a (6.75 g, 31.8 mmol, 1.5 eq) is then added in portions at 0°C, and the reaction mixture is stirred at ambient température for 16 hours. After filtering off the insoluble components, the organic phase is washed with a 10% saturated aqueous NaHCCh solution (2 x 100 mL) and then with
H2O (1 x lOOmL), and dried over MgSCU. After concentration under reduced pressure, the residue obtained is purified by flash chromatography on silica gel using as eluant a
DCM/EtOH gradient (98:2 to 94:6). The expected product is obtained in the form of a colourless oil (1.9 g, 7.1 mmol) with a yield of 33%.
‘H NMR: (400 MHz, DMSO-d6) δ ppm 7.3 (m, 5 H), 3.9 (quadd, 2 H), 3.7 (s, 2 H), 2.7 (m, 4 15 H), 2-1.6 (m, 6 H), 1.2 (t, 3 H) 31PNMR: (400 MHz, DMSO-d6) δ ppm 62
Intermediate 186
Intermediate 187
Intermediate 188
-194p 2N LDA in THF (5.33 mL, 10.6 mmol, 1.5 eq) is added dropwise to a solution of intermediate 186 (1.9 g, 7.1 mmol) in THF (18 mL) at -78 °C under an argon atmosphère. After 30 minutes, di-iert-butyl dicarbonate (2.17 g, 9.95 mmol, 1.4 eq) dissolved in THF (9 mL) is added. The reaction mixture is stirred for 1 hour 30 minutes, the température beîng 5 maintained at -78°C. A further 1.5 eq of 2N LDA in THF (5.33 mL, 10.6 mmol) is added dropwise. After 2 hours, the reaction mixture is hydrolysed while cold with an aqueous NH4CI solution (10 mL) followed by AcOEt (10 mL). After retuming to ambient température, the reaction mixture is extracted with AcOEt (2 x 100 mL). The organic phases are combined, washed with H2O (100 mL), dried over MgSO4 and then concentrated in vacuo. The residue 10 obtained is purified b y flash chromatography on silica gel using as eluant an AcOEt/THF gradient (from 100% to 70:30). The expected intermediates 187 and 188 are obtained in the form of an oily mixture (1.7 g, 4.62 mmol) with a yield of 63%.
Intermediate 187 Intermediate 188
Intermediate 189
Intermediate 190
60% NaH (0.287 g, 7.18 mmol, 1.6 eq) is added, at 10°C and in portions, to a solution of 15 intermediate 204 (1.74 g, 4,94 mmol, 1.1 eq) in DMSO (10 mL) under argon. Intermediates
187 and 188 (1.65 g, 4.49 mmol) in solution in DMSO (5.9 mL) are then added to the suspension and the mixture is stirred for 6 hours at ambient température. The reaction mixture is then hydrolysed with an aqueous NH4C1 solution (30 mL) and extracted with AcOEt (2 x mL). The organic phase is washed with H2O (2 x 50 mL), dried over MgSO4 and 20 concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant a DCM/AcOEt gradient (90:10 to 50:50). Intermediate 189 (0.342 g,
0.54 mmol) and intermediate 190 (1 g, 1.6 mmol) are obtained in the form of a mixture of diastereoisomers with a yield of 36% and 12%, respectively.
-195O EXAMPLE 253 : 5-(4-Aminobutyl)-l-benzyI-4-hydroxy-4-oxo-ls4-azaphosphepane-5carboxylic acid
TMSBr (0.87 mL, 6.6 mmol, 12 eq) is added dropwise to a solution of intermediate 189 (0.342 g, 0.54 mmol) in DCM (4 mL) under argon and at ambient température, The mixture is 5 stirred for 16 hours at ambient température and then concentrated in vacuo. The residue is taken up in MeOH (20 mL) and stirred for 20 minutes at ambient température, before being evaporated to dryness. The evaporate is dissolved in DCM (4 mL), and trifluoroacetic acid (0.81 mL, 10.9 mmol, 20 eq) is added. The reaction mixture is stirred for 10 hours at ambient température and then concentrated in vacuo. The residue obtained is purified by reverse-phase 10 chromatography using as eluant an H2O/MeCN gradient. Example 253 (0.11 g, 0.31 mmol) is obtained in the form of a white solid with a yield of 57%.
!H NMR: (400 MHz, D2O) δ ppm 7.42 (s, 5 H), 4.32 (AB, 2 H), 3.5-3.2 (m, 4 H), 2.9 (m, 2
H), 2.1-1 (m, 10 H) 31P NMR: (400 MHz, D2O) δ ppm 40.25
ESI/FIA/HR and MS/MS : [M+H]+ = 355,1780 (355.1786)
Elemental analysis : C=57.16(57.62);H=7.28(7.68);N=7.83(7.90)
EXAMPLE 254 :3-(4-Aminobutyl)-l-benzyl-4-hydroxy-4-oxo-l,4-azaphosphepane-3carboxylic acid
TMSBr (2.53 mL, 19.2 mmol, 12 eq) is added dropwise to a solution of intermediate 190 (1 g, 20 1.61 mmol) in solution in DCM (5 mL) under argon and at ambient température. The mixture is stirred for 16 hours at ambient température and then concentrated in vacuo. The residue is taken up in MeOH (20 mL) and stirred for 20 minutes at ambient température, before being evaporated to dryness. The evaporate is dissolved in DCM (4 ml), and trifluoroacetic acid (2.37 mL; 32 mmol, 20 eq) is added. The reaction mixture is stirred for 10 hours at ambient 25 température and then concentrated in vacuo. The residue obtained is purified by reverse-phase chromatography using as eluant an H2O/MeCN gradient. Example 254 (0.34 g, 0.96 mmol) is obtained in the form of a white solid with a yield of 60%.
3H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5 H), 4.35 (m, 2 H), 3.75-3.1 (m, 4 H), 2.95 (t, 2 H), 2.15-1.4 (m, 4 H), 2.1 (m, 2 H), 1.6 (m, 2 H), 1.35/1.2 (m)+(m, 1+1 H)
ESI/FIA/HR and MS/MS : [M+H]+ = 355.1780 (355.1786)
Elemental analysis : C=57.16(57.62);H=7.28(7.68);N=7.83(7.90)
-196EXAMPLE 255 :5-(5-Aminopentyl)-l-benzyI-4-hydroxy-4-oxo-l,4-azaphosphepane-5carboxylic acid
Exampie 255 is obtained in accordance with procedure H described hereinbefore, replacing intermediate 204 by intermediate 206.
Td NMR: (500 MHz, D2O) δ ppm 7.54 (m, 5 H), 4.41/4.34 (d)+(d, 1+1 H), 3.7/3.63 (m)+(m, 1+1 H), 3.51/3.22 (m)+(m, 1+1 H), 2.99 (t, 2 H), 2.16/1.58 (m)+(m, 1+1 H), 2.14/1.51 (m)+(m, 1+1 H), 2.11/1.82 (m)+(m, 1+1 H), 1.67 (quint, 2 H), 1.39 (quint., 2 H), 1.35/1.18 (m)+(m, 1+1 H) 13C NMR: (500 MHz, D2O) δ ppm 129.4, 61, 54.7, 51.8, 39.1, 32.3, 29.4, 26, 26, 25.8, 23.
31P NMR: (500 MHz, D2O) δ ppm 37
ESI/FIA/HR and MS/MS : [M+H]+ = 369.1955 (369.1943)
Elemental analysis : C=58.53(58.68);H=7.80(7.93);N=7.51(7.60)
Intermediate 191 : iW-Butyl 5-{4-[bis(/eri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-1 - [(3-phenyiphenyl)methyl] -1,4-azaphosphepane-5-carboxylate
Intermediate 191 is obtained în accordance with procedure H described hereinbefore, replacing benzyl bromide by 3-phenylbenzyl bromide.
NMR; (400/500 MHz, dmso-d6) δ ppm 7.65 (d, 2 H), 7.63 (t, 1 H), 7.59 (s, 1 H), 7.53 (d, 1 H), 7.46 (t, 2 H), 7.41 (t, 1 H), 7.31 (d, 1 H), 4.06 (m, 2 H), 3.69/3.63 (2*d, 2 H), 3.44 (t, 2 H),
2.83/2.71 (2*m, 2 H), 2.8/2.67 (2*m, 2 H), 2.21/1.6 (2*m, 2 H), 2.12/1.88 (2*m, 2 H),
1.9/1.67 (2*m, 2 H), 1.42 (m, 2 H), 1.41 (s, 18 H), 1.39 (s, 9 H), 1.22 (t, 3 H), 1.22/0.99 (2*m, 2 H) 13C NMR: (400/500 MHz, dmso-d6) δ ppm 129.1, 128.9, 127.9, 127.6, 127, 126.7, 125.4,
61.5, 60.3, 50.8, 48.2, 45.8, 31.2, 31.2, 29, 28.3, 28, 28, 21.6, 16.6
EXAMPLE 256 : 5-(4-AminobutyI)-4-hydroxy-4-oxo-l-[(3-phenylphenyl)methyl]-l,4azaphosphepane-5-carboxylic acid
Example 256 is obtained starting from intermediate 191 in accordance with procedure D described hereinbefore.
-197Ο ‘H NMR: (400 MHz, D2O) δ ppm 7.8-7.4 (m, 9 H), 4.45/4.35 (d, 2 H), 3.7-3.2 (m, 4 H), 2.95 (m, 2 H), 2.2-1.75 (m, 4 H), 1.6-1.2 (m, 6 H) 31P NMR: (400 MHz, D2O) δ ppm 86
ESI/FIA/HR and MS/MS : [M+H]+ = 431.2092 (431.2094)
Elemental analysis : C=63.35(64.17);H=6.85(7.26);N=6.42(6.51)
Intermediate 192 : Avï-Butyl 3-{4-[bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(3-phenylphenyl)methyl]-l,4-azaphosphepane-3-carboxylate
Intermediate 192 is obtained in accordance with procedure H described hereînbefore, replacing benzyl bromide by 3-phenylbenzyl bromide.
1HNMR: (400 MHz, dmso-d6) δ ppm 7.7 (s, 1 H), 7.66 (d, 2 H), 7.5 (t, 1 H), 7.42 (t, 2 H), 7.35 (m, 2 H), 7.32 (t, 1 H), 4.06 (m, 2 H), 4.01/3.8 (2*d, 2 H), 3.45 (t, 2 H), 3.32/2.76 (dd, 2
H), 2.62-2.45 (m, 2 H), 2-1.3 (m, 8 H), 1.4/1.1 (2*m, 2 H), 1.4 (s, 27 H), 1.25 (t, 3 H)
EXAMPLE 257: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(3-phenylphenyl)methyl]-l,4azaphosphepane-3-carboxylic acid
Example 257 is obtained starting from intermediate 192 in accordance with method D described hereînbefore.
NMR: (400 MHz, D2O) δ ppm 7.8-7.4 (m, 9 H), 4.45/4.35 (d, 2 H), 3.6-3.25 (m, 4 H), 2.8 (m, 2 H), 2.1-1.9 (m, 4 H), 1.75-1.1 (m, 6 H) 31P NMR: (400 MHz, D2O) Ô ppm 86
ESI/FIA/HR and MS/MS : [M+H]+ = 431.2095 (431.2094)
Elemental analysis : C=63.89(64.17);H=6.92(7.26);N=6.50(6.51)
Intermediate 193 : teri-Butyl 3-{4-bis(teri-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxol-[(4-phenylphenyl)methyl]-l,4-azaphosphepane-3-carboxylate
Intermediate 193 is obtained in accordance with procedure H described hereînbefore, 25 replacing benzyl bromide by 4-phenylbenzyl bromide.
.‘.HNMR: (400 MHz, dmso-d6) δ ppm 7.7-7.55 (2d, 4 H), 7.5 (m, 2 H), 7.45 (d, 2 H), 7.35 (m, 1 H), 4.1 (m, 2 H), 3.95 (d, 1 H), 3.8 (d, 1 H), 3.45 (t, 2 H), 3.3 (m, 1 H), 2.8 (m, 1 H), 2.55 (m, 1 H), 2-1.35 (m, 9 H), 1.4 (3s, 27 H), 1.25 (t, 3 H), 1.25 (m, 1 H), 1.1 (m, 1 H)
-198Π
EXAMPLE 258: 3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(4-phenylphenyl)methyl]-l,4azaphosphepane-3-carboxylic acid
Example 258 is obtained starting from intermediate 193 in accordance with procedure D 5 described hereinbefore.
1H.NMR: (400 MHz, D2O) δ ppm 7.7 (2d, 4 H), 7.5 (t+d, 4 H), 7.4 (td, 1 H), 4.35 (2d, 2 H),
3.5-3.2 (m, 4 H), 2.85 (m, 2 H), 2.15-1 (m, 10 H)
ESI/FIA/HR and MS/MS : ESI-HR +/- : [M+H]+ = 431.2093 (431.2094)
Elemental analysis : C=63.92(64.17);H=7.15(7.26);N=6.47(6.51) 10 Intermediate 62 : tert-Butyl 5-{4-[bis(ter/-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(4-phenylphenyl)methyl]-l,4-azaphosphepane-5-carboxylate
Intermediate 62 is obtained in accordance with procedure H described hereinbefore, replacing benzyl bromide by 4-phenylbenzyl bromide.
EXAMPLE 259:5-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(4-phenylphenyl)methyl]-l,415 azaphosphepane-5-carboxylic acid
Example 259 is obtained starting from intermediate 62 in accordance with procedure D described hereinbefore.
1R NMR: (400 MHz, D2O) δ ppm 7.75 (d, 2 H), 7.7 (d, 2 H), 7.6 (d, 2 H), 7.5 (m, 2 H), 7.45 (m, 1 H), 4.45/4.35 (2d, 2 H), 3.75-3.1 (m, 4 H), 2.95 (t, 2 H), 2.2-1.85 (m, 3 H), 1.8 (m, 1 H), 20 1.7-1.05 (m, 6 H)
ESI/FIA/HR and MS/MS : EI-HR : [M+H]+ = 431.2093 (431.2094)
Elemental analysis : C=64.46(64.17);H=7.17(7.26);N=6.46(6.51)
Intermediate 194 : teri-Butyl 3-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-4-ethoxy-4oxo-l-[(2-phenylphenyl)methyl]-l,4-azaphosphepane-3-carboxylate
Intermediate 194 is obtained in accordance with procedure H described hereinbefore, replacing benzyl bromide by 2-phenylbenzyl bromide.
-199- .
Ή NMR: (400 MHz, dmso-d6) δ ppm 7.88 (d, 1 H), 7.48-7.2 (m, 5 H), 7.35 (m, 2 H), 7.15 (d, 1 H), 4.05 (m, 2 H), 3.9/3.7 (2*d, 2 H), 3.42 (t, 2 H), 3.2/2.65 (dd, 2 H), 2.33 (m, 2 H), 2-1.5 (m, 6 H), 1.42 (s, 18 H), 1.4 (m, 2 H), 1.4 (s, 9 H), 1.25 (t, 3 H), 1.15/1 (2*m, 2 H)
EXAMPLE 260:3-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-phenylphenyl)methyl]-l,4azaphosphepane-3-carboxylic acid
Example 260 is obtained starting from intermediate 194 in accordance with procedure D described hereinbefore.
Ή NMR: (400 MHz, D2O) δ ppm 7.7-7.3 (m, 9 H), 4.45 (d, 1 H), 4.4 (d, 1 H), 3.25-3 (m, 4 H), 2.95 (q, 2 H), 1.95-1.5 (m, 5 H), 1.65 (m, 2 H), 1.35 (m, 1 H), 1.3-1.05 (m, 2 H) ESI/FIA/HR and MS/MS : [M+H]+ = 431.2094 (431.2094)
Elemental analysis : C=63.81(64.17);H=7.03(7.26);N=6.45(6.51)
Intermediate 67 : iert-Butyl 5-{4-[bis(ter/-butoxycarbonyl)amîno]butyl}-4-ethoxy-4oxo-l-[(2-phenylphenyl)methyl]-l,4-azaphosphepane-5-carboxylate
Intermediate 67 is obtained in accordance with procedure H described hereinbefore, replacing benzyl bromide b y 2-phenylbenzyl bromide.
EX AMPLE 261: 5-(4-Aminobutyl)-4-hydroxy-4-oxo-l-[(2-phenylphenyl)methyl]-l,4azaphosphepane-5-carboxylic acid
Example 261 is obtained starting from intermediate 67 in accordance with procedure D described hereinbefore.
NMR: (300/500 MHz, D2O) δ ppm 7.63/7.61 (m, 1 H), 7.54-7.45 (m, 4 H), 7.44 (m, 1 H),
7.38 (m, 1 H), 7.33/7.31 (m, 2 H), 4.38 (m, 2 H), 3.48-2.77 (m, 4 H), 2.94 (m, 2 H), 2.05/1.42 (m, 2 H), 2.03/1.43 (m, 2 H), 2.01/1.66 (m, 2 H), 1.6 (m, 2 H), 1.33/1.14 (m, 2 H) 13C NMR: (300/500 MHz, D2O) δ ppm 178.5, 143.3, 130.4, 129.4, 129.3, 129.2, 128.7, 127.7, 57.8, 55.1/51.6, 38.8, 31.7,28.9, 26.3,25.9, 20.5 31P NMR: (300/500 MHz, D2O) δ ppm 36.5
ESI/FIA/HR and MS/MS : [M+H]+ = 431.2095 (431.2094)
Elemental analysis : C=63.81(64.17);H=7.14(7.26);N=6.45(6.51)
-200p Préparation of Example 262:
Intermediate 195
Allyl alcohol (15.27 mL, 224 mmol, 8 eq), triethylborane (6.4 mL, 6.39 mmol, 0.23 eq) and 5 tributylphosphorus (1.17 mL, 5.6 mmol, 0.2 eq) are added in succession to a solution, degassed with argon for 30 minutes, of benzylamine (3 g, 28 mmol) and palladium acetate (0.31 g, 1.4 mmol) in THF (64 mL). The reaction mixture is degassed for 15 minutes with argon and heated at 70°C for 20 hours. The mixture is concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel using a DCM/AcOEt 10 gradient (from 100% to 95:5) as eluant. Intermediate 195 (3.45 g, 18.4 mmol) is obtained in the form of an oil with a yieid of 66 %.
jH NMR: (400 MHz, CDC13) δ ppm 7.3 (m, 5 H), 5.9 (m, 2 H), 5.15 (m, 4 H), 3.6 (s, 2 H), 3.1 (s, 4 H)
A solution of diisopropylamino-phosphorus dichloride (4.96 g, 24.6 mmol, 2 eq) in DCM (41.5 mL) is added to a suspension of aluminium chloride (3.27 g, 24.6 mmol, 2 eq) in DCM (41.5 mL) at -20°C and under an argon atmosphère. The mixture is stirred for 1 hour at ambient température and then cooled to -20°C, and intermediate 195 (2.3 g, 12.3 mmol) in solution in 10 mL of DCM is then added. The reaction mixture is stirred for 16 hours at ambient température and then heated for 1 hour at reflux. A solution (25 mL, 1:1) of EDTA
-201(0.2M in Η2Ο) and NaHCCh (10% in H2O) is then added 0°C, and the mixture is stirred for 16 hours at ambient température. The reaction mixture is then added to 100 mL of DCM cooled by an ice bath and rendered basic with a saturated Na2CO3 solution. The organic phase is separated off and washed with H2O (2 x 50 mL), dried over MgSCL and concentrated in vacuo. The residue obtained is purified by flash chromatography on a silica column using as eluant an AcOEt/THF gradient (from 100% to 95:5). Intermediate 196 (2,3 g, 6.8 mmol) is obtained in the form of an oil with a yield of 54%.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.3 (m, 5 H), 3.52 (2s, 2 H), 3.33 (m, 2 H), 2.78/2.6 (m, 2 H), 2.62 (m, 2 H), 2.3 (m, 2 H), 1.99/1.72 (m, 2 H), 1.4 (m, 2 H), 1.17 (2d, 12 H) 31P NMR: (400 MHz, DMSO-d6) δ ppm 69.2/66.9
Intermediate 197 :
N
A solution of 2N LDA in THF (4.81 mL, 9.6 mmol, 1.4 eq) is added to a solution of intermediate 196 (2.3 g, 6.87 mmol) in THF (16.5 mL) at -70°C and under an argon atmosphère. After stirring for 15 minutes at -70°C, a solution of (Boc)2O (2.1 g, 9.6 mmol,
1.4 eq) in THF (5 mL) is added dropwise, and stirring is maintained for 90 minutes at -70°C. A further 1.4 eq of 2N LDA in THF (4.81 mL, 9.6 mmol, 1.4 eq) is then added. When the addition is complété, the reaction mixture is maintained at -70°C for 90 minutes. A saturated NH4CI solution (30 mL) as well as AcOEt (60 mL) are then added, and the reaction mixture is slowly returned to ambient température. The mixture is extracted with AcOEt (2 x 100 mL). The organic phases are combined, dried and then concentrated under reduced pressure. The product obtained is purified by flash chromatography on silica gel using as eluant an AcOEt/THF gradient (50:50 to 20:80). Intermediate 197 (0.808 g, 1.86 mmol), a mixture of diastereoisomers, is obtained in the form of a yellow oil with a yield of 27%.
1H NMR: (400 MHz, dmso-d6) δ ppm 7.25 (m, 5 H), 3.55 (m, 2 H), 3.25 (m, 2 H), 2.91 (m, 1 H), 2.72 (m, 2 H), 2.6/2.3 (m, 4 H), 2.15/1.65 (m, 2 H), 1.39 (s, 9 H), 1.15 (m, 12 H) 31PNMR: (400 MHz, DMSO-d6) δ ppm 68.58
-202Intermediate 198 : tert-Butyi (3aR*, 4S*, 6aS*)-2-benzyl-4-{4-[bis(tert-butoxycarbonyl)amino]butyl}-5-[di(propan-2-yl)amino]-5-oxooctahydrophospholo[3,4-c]pyrrole-4-carboxylate
A solution of intermediate 204 (0.71 g, 2 mmol, 1,1 eq) in DMSO (1.5 mL) is added under argon to a 60% suspension of NaH (0.12 g, 2 mmol, 1.1 eq) in DMSO (6 mL). Intermediate 197 (0.8 g, 1.84 mmol) in solution in DMSO (2 mL) is then added and the mixture is stirred for 15 hours at ambient température. The reaction mixture is then hydrolysed at 0°C with an aqueous NH4CI solution (10 mL) and extracted with DCM (50 mL). The organic phase is washed with H2O (2 x 10 mL), dried over MgSO4 and concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel using as eluant an AcOEt/THF gradient (from 100% to 80:20). Intermediate 198 (0.232 g, 0.33 mmol), a mixture of diastereoisomers, is obtained in the form of an oil with a yield of 18%.
]H NMR: (400 MHz, dmso-d6) δ ppm 7.3 (m, 4 H), 7.22 (m, 1 H), 3.58/3.43 (d)+(d, 1+1 H), 3.42 (m, 2 H), 3.29 (m, 1 H), 3.1/2.09 (m)+(m, 1+1 H), 2.87 (m, 1 H), 2.82/2.59 (m)+(m, 1+1 H), 2.81 (m, 1 H), 2.05/1.46 (m)+(m, 1+1 H), 1.92/1.65 (m)+(m, 1+1 H), 1.45 (m, 2 H), 1.42 (2*(s, 27 H), 1.26/1.09 (m)+(m, 1+1 H), 1.17 (d, 12 H) 13C NMR: (400 MHz, DMSO-d6) δ ppm 128.1, 126.6, 60.8, 59.1, 55.7, 45.5, 45.4, 44.1, 34.3, 29.1, 27.7, 27.3, 26.6, 22.9, 22.3
EXAMPLE 262 : (3aR*,4S*,6aS*)-4-(4-Aminobutyl)-2-benzyl-5-hydroxy-5-oxo-octahydroPhospholo[3,4-c]pyrrole-4-carboxylic acid, trifluoroacetate
Intermediate 198 (0.232 g, 0.328 mmol) and 6N hydrochloric acid (5 mL, 30 mmol) are heated at reflux for 7 hours. The reaction mixture is concentrated under reduced pressure and then lyophilised. The residue is purified b y rever se-phase chromatography on RP 18 silica gel using as eluant an H2O/MeCN/TFA gradient. Example 262 (0.040 g, 0.109 mmol) is obtained in the form of a TFA sait after lyophilisation with a yield of 33%.
*H NMR: (500 MHz, D2O+NaOD) δ ppm 7.4-7.25 (m, 5 H), 3.59 (m, 2 H), 3.18/2.07 (m)+(m, 1+1 H), 2.9 (m, 1 H), 2.84/2.37 (m)+(m, 1+1 H), 2.7 (m, 1 H), 2.48 (m, 2 H), 1.85/1.31 (m)+(m, 1+1 H), 1.78/1.22 (m)+(m, 1+1 H), 1.31 (m, 2 H), 1.24/1.07 (m)+(m, 1+1 H)
-203p. 13C NMR: (500 MHz, D2O+NaOD) δ ppm 127-129, 60.9, 59.2, 55.5, 44.1, 40.1, 33.5, 32.2,
29.3, 28, 23
ESI/FIA/HR and MS/MS : [M+H]+ = 367.1789 (367.1786)
Préparation of Example 263
Intermediate 199 :
O OH P'
.HCl
Intermediate 196 (6.15 g, 18.4 mmol) and 6N hydrochloric acid (12.2 mL, 73.2 mmol) are heated at reflux for 6 hours. The reaction mixture is concentred in vacuo, taken up in éthanol (50 mL) and concentrated under reduced pressure. Intermediate 199 (7.57 g, 26.3 mmol) is 10 used without being purified further.
ΊΗ NMR: (400 MHz, dmso-d6) δ ppm 11.2 (si, 1 H), 7.6 (m, 2 H), 7.4 (m, 3 H), 4.3 (d, 2 H), 2.95;2.8 (m, 2*1H H), 3.6;3.3 (m, 2 H), 3.2;:2.95 (m, 2 H), 1.85;1.5 (m, 4 H)
Intermediate 199
Intermediate 200
Intermediate 201
Intermediates 200 and 201:
An oxalyl chloride solution (3.16 mL, 36.8 mmol, 2 eq) is added dropwise to a solution of intermediate 199 (5.29 g, 18.4 mmol) in solution in DCM (170 mL) at 0°C and under an argon atmosphère. The reaction mixture is stirred for 4 hours at ambient température, evaporated in vacuo and then dried under reduced pressure. The residue is taken up in
-204P anhydrous DCM (150 mL), and DMAP (0.0225 g, 0.18 mmol) is then added. The mixture is cooled to -70°C. TEA (3.1 mL, 22 mmol, 1.2 eq) and EtOH (1.3 mL, 22 mmol, 1.2 eq) are added in succession. The mixture is stirred for 2 hours at ambient température, poured onto an aqueous NH4C1 solution and then rendered basic with an aqueous NaHCO3 solution. The 5 solution is extracted with DCM (150 mL). The organic phase is washed with H2O (2 x 50 mL), dried over Na2SO4 and then concentrated in vacuo. The product obtained is purified by flash chromatography on silica gel using a DCM/EtOH gradient (from 95:5 to 85:15) as eluant. Intermediates 200 (0.291 g, 1.04 mmol) and 201 (2.95 g, 10.56 mmol) are obtained with a yield of 5% and 57%, respect!vely.
Intermediate 201
Intermediate 202
Intermediate 202:
A 2M LDA solution in THF (14.7 mmol, 7.39 mL, 1.4 eq) is added to a solution of intermediate 201 (2.95 g, 10.5 mmol) in THF (31 mL) at -70°C and under argon. After 15 minutes at -70°C, a solution of Boc2O (4.16 g, 14.7 mmol, 1.4 eq) in 10 mL of THF is then 15 added dropwise. Stirring is maintained for 90 minutes, and 1.4 eq of 2M LDA in THF (14.7 mmol, 7.39 mL) are then added dropwise. When the addition is complété, the reaction mixture is maintained at -70°C for 90 minutes. A saturated NH4C1 solution (30 mL) as well as AcOEt (60 mL) are added, and the reaction mixture is brought slowly to ambient température again. The product is then extracted with AcOEt (2 x 150 mL). The organic phases are 20 combined, washed with a saturated NaCl solution (2 x 150 mL), dried over MgSO4 and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel using an AcOEt/THF gradient (from 100% to 70:30) as eluant.
Intermediate 202 (2.52 g, 6.64 mmol) is obtained in the form of a yellowish oil with a yield of63 %.
-205Intermediate 203 : tert-Butyl (3aZÏ*,4/î*,6a5Î!!)-2-benzyl-4-{4-[bis(ieri-butoxycarbonyl)amino]butyl}-5-ethoxy-5-oxo-octahydrophosphoIo[3,4-c]pyrrole-4carboxylate
DMSO (5 mL) and 60% NaH (0.425 g, 10.6 mol, 1.6 eq) are introduced in succession, under an argon atmosphère, into a 250 mL three-necked flask. The flask is maintained at ambient température by means of a water bath. A solution of intermediate 204 (2,57 g, 7.3 mol, 1.1 eq) in DMSO (7.2 mL) is then added dropwise over a period of 5 minutes. A solution of intermediate 202 (2.52 g, 6.64 mmol) in DMSO (7.2 mL) is then added dropwise, the température being maintained below 20°C. After 7 hours, the reaction mixture is cooled by 10 means of an ice-water bath and hydrolysed by addition of 5 mL of a saturated NH4CI solution.
The mixture is then extracted with DCM (3 x 50 mL). The organic phases are then combined, washed with a saturated NaCl solution (2 x 50 mL) and dried over MgSCU, before being concentrated under reduced pressure. The residue so obtained is purified by chromatography on silica gel using an AcOEt/THF mixture (from 100% to 80:20) as eluant. Intermediate 203 15 (1.86 g, 2.86 mmol) is obtained with a yield of 43%.
‘H NMR: (500 MHz, CDCh) δ ppm 7.29 (m, 4 H), 7.23 (m, 1 H), 4.15 (m, 2 H), 3.66/3.58 (d)+(d, 1+1 H), 3.58 (m, 2 H), 3.06/2.49 (m)+(m, 1+1 H), 2.99/2.23 (m)+(m, 1+1 H), 2.73 (m, 1 H), 2.69 (m, 1 H), 2.07/1.63 (m)+(m, 1+1 H), 2.02/1.78 (m)+(m, 1+1 H), 1.65-1.5 (m, 2 H), 1.45/1.19 (s)+(s, 18+9 H), 1.4 (m, 2 H), 1.31 (t, 3 H) 13C NMR: (500 MHz, CDCh) δ ppm 128.1, 126.6, 61.2, 60.4, 59.4, 56.7, 45.8, 45.1, 33.8,
32.9, 29.2, 27.9, 26.9, 22.1, 16.5 31P NMR: (500 MHz, CDCh) δ ppm 74.9
EXAMPLE 263 : (3a/C\4R*,6aS*)-4-(4-Aniinobutyl)-2-benzyl-5-liydroxy-5-oxo-octahydrophospholo[3,4-c]pyrrole-4-carboxylic acid
Intermediate 203 (1.85 g, 2.84 mmol) and trimethylsilane bromide (4.5 mL, 34.11 mmol, 12 eq) in solution in DCM (20 mL) are stirred ovemight at ambient température and then concentrated in vacuo. The residue is taken up in MeOH (20 mL), stirred for 20 minutes and then concentrated in vacuo. The product is taken up in DCM (20 mL), and TFA (4.22 ml,,
56.8 mmol, 20 eq) is added. The mixture is stirred overnight at ambient température. The 30 reaction mixture is then concentrated under reduced pressure and purified by reverse-phase
-206chromatography using an H2O/CH3CN gradient as eluant. Example 263 (0.29 g, 0.79 mmol) is obtained in the form of a lyophilisate with a yield of 28%.
te NMR: (500 MHz, D2O+NaOD) δ ppm 7.4-7.25 (m, 5 H), 3.57 (m, 2 H), 3.08/2.38 (m, 1+1
H), 3.04/2.17 (m)+(m, 1+1 H), 2.52 (t, 2 H), 2.45 (m, 1 H), 2.42 (m, 1 H), 1.73/1.45 (m)+(m, 5 1+1 H), 1.67 (m, 2 H), 1.35 (m, 2 H), 1.28 (m, 2 H) 13C NMR: (500 MHz, D2O+NaOD) δ ppm 127-129, 60.5, 59.1, 57.4, 46.1, 40, 33.9, 33.2,
32.4, 28.3, 22.9
C=58.27(59.01);H=7.24(7.43);N=7.58(7.65)
ESI/FIA/HR and MS/MS : [M+H]+ = 367.1775 (367.1786)
PHARMACOLOGICAL STUDY
EXAMPLE 264 : Inhibition of TAFIa (hiyyuryl-Arg test)
Human TAFI (4nM) is incubated with human thrombin (lOnM) and human thrombomodulin (5nM) in the presence of calcium (lOmM). After incubation for 20 minutes, the activation reaction is stopped by addition of PPACK (ΙμΜ final), an irréversible thrombin inhibitor.
The reactions take place in Hepes buffer (25mM Hepes, 137mM NaCi, 3.5rnM KC1) + 0.1% bovine albumin, pH 7.4 at 28°C and with stirring.
The test compound is added to the solution of TAFIa (2nM) and incubated for 45 minutes in the presence of hippuryl-arginine (5mM). The reaction is stopped by addition of hydrochloric acid (IM) neutralised subsequently with sodium hydroxide (IM), and then the mixture is 20 buffered with disodium hydroxyphosphate (IM pH 7.4). The reaction product - hippuric acid
- is revealed b y addition of cyanuryl chloride (6%). The reaction mixture is stirred (vortex) and then centrifuged. The supernatant is transferred to a 96-well microplate, and the absorbance is measured using a spectrophotometer at 405 nm (Spectramax plus, Molecular Devices).
The OD value of a well containing the reagents without TAFI is subtracted from ail the OD values measured. The percentage inhibition of TAFIa at a given concentration of the test compound is determined by means of the following formula:
% inhibition = 100 - [(OD compound xl00)/OD carrier]
-207The compounds are evaluated at 10 nM and 20 nM under the experimental conditions described above and the results are expressed as the percentage inhibition relative to a control containing the carrier in the absence of compound.
| Ëxample | % inhibition at 10 nM | % inhibition at 20 nM |
| 48 | 45 (+/- 6) | 54 (+/- 9) |
| 49 | 60 (+/- 3) | 73 (+/- 3) |
| 50 | 53 (+/- 5) | 66 (+/- 6) |
| 104 | 37 (+/-13) | 68 (+/- 3) |
| 105 | 44 (+/- 10) | 66 (+/- 10) |
| 108 | 25 (+/- 1) | 29 (+/- 6) |
| 109 | 58 (+/- 10) | 71 (+/-9) |
| 113 | 68 (+/- 14) | 90 (+/- 9) |
| 114 | 42 (+/- 11) | 51 (+/- 1) |
| 164 | 66 (+/- 18) | 87 (+/-10) |
| 165 | 76 (+/- 8) | 91 (+/- 4) |
| 166 | 66 (+/- 11) | 93 (+/- 14) |
| 167 | 61 (+/- 3) | 67 (+/- 1) |
| 174 | 43 (+/-12) | 51 (+/- 2) |
| 175 | 55 (+/- 2) | 77 (+/- 1) |
| 179 | 74 | 83 (+/- 3) |
| 180 | 54 (+/- 8) | 73 (+/- 9) |
| 182 | 81 (+/- 1) | 95 (+/- 7) |
| 183 | 73 (+/- 8) | 88 (+/-14) |
| 184 | 67 (+/- 6) | 95 (+/- 1) |
| 185 | 69 (+/-1) | 85 (+/- 0) |
| 187 | 74 (+/-14) | 97 (+/- 2) |
| 188 | 64 (+/- 1) | 86 (+/- 14) |
| 189 | 71 (+/-8) | 78 (+/- 7) |
| 190 | 88 (+/-12) | 95 (+/- 6) |
| 191 | 66 (+/- 4) | 83 (+/- 4) |
| 192 | 77 (+/- 11) | 91 (+/- 6) |
-208-
| Example | % inhibition at 10 nM | % inhibition at 20 nM |
| 194 | 64 (+/- 2) | 80 (+/-0) |
| 195 | 74 (+/- 4) | 87 (+/- 3) |
| 196 | 77 (+/-1) | 91 (+/-1) |
| 197 | 60 (+/-1) | 78 (+/-1) |
| 198 | 72 (+/- 6) | 91 (+/- 5) |
| 199 | 54 (+/- 6) | 73 (+/- 2) |
| 200 | 28 (+/-11) | 46 (+/- 8) |
| 201 | 69 (+/- 5) | 84 (+/- 3) |
| 202 | 74 (+/- 3) | 87 (+/- 2) |
| 203 | 75 (+/- 4) | 89 (+/-1) |
| 204 | 70 (+/- 7) | 86 (+/- 2) |
| 206 | 67 (+/- 7) | 80 (+/- 5) |
| 207 | 71 (+/- 13) | 85 (+/- 10) |
| 208 | 35 (+/- 2) | 46 (+/- 7) |
| 209 | 76 (+/- 4) | 87 (+/- 2) |
| 210 | 71 | 79 (+/- 9) |
| 211 | 85 (+/- 2) | 95 (+/- 0) |
| 212 | 62 (+/- 6) | 86 (+/- 2) |
| 213 | 83 (+/- 4) | 92 (+/- 1) |
| . 214 | 79 (+/- 4) | 91 (+/- 1) |
| 215 | 82 (+/- 4) | 91 (+/-2) |
| 216 | 71 (+/- 4) | 85 (+/- 4) |
| 217 | 66 (+/- 10) | 83 (+/- 5) |
| 218 | 67 (+/- 6) | 83 (+/-6) |
| 219 | . 92 (+/- 9) | 98 (+/- 3) |
| 220 | 83 (+/- 3) | 97 (+/-1) |
| 221 | 75 (+/- 2) | 88 (+/- 3) |
| 222 | 73 (+/- 5) | 85 (+/- 4) |
| 223 | 71 (+/-2) | 83(+/-4) |
| 224 | 86 (+/- 3) | 93 (+/- 2) |
| 225 | 76 (+/- 2) | 85 (+/- 3) |
-209-
| Example | % inhibition at 10 nM | % inhibition at 20 nM |
| 226 | 71 (+/-3) | 88 (+/- 3) |
| 227 | 84 (+/- 7) | 91 (+/-13) |
| 228 | 63 (+/- 4) | 82 (+/- 1) |
| 229 | 81 | 89 |
| 232 | 80 (+/-10) | 89 (+/- 19) |
| 234 | 68 (+/- 8) | 79 (+/-1) |
| 235 | 60 (+/- 3) | 77 (+/- 5) |
| 236 | 81 (+/- 4) | 91 (+/-6) |
| 237 | 77 (+/- 5) | 84 (+/- 4) |
| 238 | 70 (+/- 7) | 87 (+/- 0) |
| 239 | 85 (+/- 3) | 96 (+/-4) |
| 240 | 66 (+/-1) | 80 (+/- 5) |
| 241 | 77 (+/- 11) | 91 (+/- 9) |
| 242 | 75 (+/- 2) | 88 (+/- 1) |
| 244 | 49 (+/- 1) | 68 (+/- 6) |
| 245 | 38 (+/- 2) | 52 (+/- 5) |
| 246 | 72 (+/- 4) | 86 (+/- 1) |
| 247 | 85 (+/- 16) | 89 (+/- 11) |
| 248 | 87 (+/- 14) | 95 (+/- 6) |
| 249 | 88 (+/- 6) | 94 (+/- 4) |
| 250 | 88 (+/- 1) | 97 (+/- 1) |
| 251 | 70 (+/- 14) | 90(+/- 11) |
| 252 | 76 (+/- 7) | 90 (+/- 2) |
EXAMPLE 265 : Pharmaceutical composition - tablet
Formulation for the préparation of 1000 tablets each containing 10 mg:
Compound of one of Examples 1 to 263.................... 10g
Hydroxypropylcellulose.........................................................................................................2g
Wheat starch........................... 10g
-210Lactose................................................................................................................................100g
Magnésium stéarate..................................................................................................................3g
Talc..........................................................................................................................................3g
EXAMPLE 266 : Pharmaceutical composition - tablet in association with warfarin
Formulation for the préparation of 1000 tablets each containing 10 mg:
Compound of one of Examples 1 to 263.............................................................................10g
Warfarin...................................................................................................................................2g
Hydroxypropylcellulose.........................................................................................................2g
Wheat starch................................... 10g
Lactose................................................................................................................................100g
Magnésium stéarate........................ 3g
Talc......................................................................... 3g
EXAMPLE 267 : Pharmaceutical composition - tablet in association with aspirin
Formulation for the préparation of 1000 tablets each containing 10 mg:
Compound of one of Examples 1 to 263.............................................................................. 10g
Aspirin.......................................... .............................................................100g
Hydroxypropylcellulose....................................................................................................... 2g
Wheat starch...........................................................................................................................10g
Lactose........................................ 100g
Magnésium stéarate............................................................................... 3g
Talc3 g
EXAMPLE 268 : Injectable solution
Formulation for the préparation of 10 ml of solution:
Compound of one of Examples 1 to 263.........................................................................200 mg
Injectable préparation of 0.9% NaCl..................................................................................10ml
Claims (20)
1. Compound of formula (I):
wherein:
Aki represents a Ci-Câ-alkyl chain,
X represents -(CH2)m-, -CH(R)-, -N(R)-, -CH2-N(R)~, -N(R)-CH2- or -CH2-N(R)-CH2-, m represents 0 or an integer from 1 to 4,
R represents a hydrogen atom or a group selected from Ci-Ce-alkyl, -Ak2-An, -Ak2-AriAr2 and -Ak2-Ari-O-Ar2, -Ak2-cycloalkyl or -Ak2-OH,
Ak2 represents a linear or branched Ci-Ce-alkyl chain,
An and Ar2, which may be identical or different, each represent an aryl or heteroaryl group,
Ri and R2 each represent a hydrogen atom when X represents -(CH2)m-, -CH(R)-, -N(R)-, -CH2-N(R)- or -N(R)-CH2-, or together form a bond when X represents -CH2-N(R)-CH2-,
R3 represents NH2, Cy-NH2, Cy-Ak3-NH2 or piperidin-4-yl,
Cy represents a group selected from cycloalkyl, aryl and heteroaryl,
Aks represents a Ci-C3-alkyl chain,
R4 and R5, which may be identical or different, each represent a hydrogen atom or a fluorine atom, its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
2. Compound of formula (I) according to claim 1, wherein Ri, R2, R4 and R5 each represent
-212a hydrogen atom, R3 represents NH2, X represents -N(R)-, -CH2-N(R)-, -N(R)-CH2or -CH2-N(R)-CH2-, and R represents a group selected from -Ak2-An, -Ak2-An-Ar2 and -Ak2-Ari-O-Ar2, wherein Ak2, An and Ar2 are as defined in claim 1.
3. -A.compound according ίο claim 1 having the formula (la):
wherein Ra represents a group selected from -CH2-An and -CH2-Ari-Ar2, wherein An and Ar2 are as defined in claim 1.
4. Compound of formula (I) according to claim 1, which is (3S)-3-(4-aminobutyl)-l-[[2(3,4-dimethoxyphenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3-
10 carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
5. Compound of formula (I) according to claim 1, which is (3S)-3-(4-aminobutyl)-l-[[4fluoro-2-(4-methylphenyl)phenyl]methyl]-4-hydroxy-4-oxo-l,4-azaphosphinane-3carboxylic acid, and its optical isomers, and addition salts thereof with a
15 pharmaceutically acceptable acid.
6. Compound of formula (I) according to claim 1, which is (35')-3-(4-aminobutyl)-l-[[4fluoro2“(4“methoxyphenyl)phenyl] methyl]-4-hydroxy-4-oxo-1,4-az apho sphinane-3carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
7. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-l-[[4fluoro-2-(4-fluorophenyl)phenyl]methyl] -4-hydroxy-4-oxo-1,4-azaphosphinane-3 -
-213Ç carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
8. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-4hydroxy- l-[(4-hydroxy-2-phenylphenyl)methyl] -4-oxo- l,4-azaphosphinane-3-carboxylic
5 acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
9. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-4hydroxy-1 -[2-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically
10 acceptable acid.
10. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-l-[[2-(4chlorophenyl)-4 -fluorophenyl] methyl] -4-hydroxy-4-oxo-1,4-azaphosphinane-3 carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
15
11. Compound of formula (Γ) according to claim 1, which is (35)-3-(4-aminobutyl)-l-[4fluoro-2-( 1-methyl-lH-imidazol-5-yl)benzyl]-4-hydroxy-4-oxo-1,4-azaphosphînane-3carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid. .
12. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-l-[2-(1,220 dimethyl- lÆ-imidazol-5-yl)-4-fluorobenzyl] -4-hydroxy-4-oxo-1,4-azaphosphinane-3- carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
13. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-4hydroxy-l-[[4-hydroxy-2-(4-methylphenyl)phenyl]methyl]-4-oxo-l,4-azaphosphinane-3-
25 carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
14. Compound of formula (I) according to claim 1, which is (35)-3-(4-aminobutyl)-4-
-214hydroxy-1 -[4-hydroxy-2-(imidazo [ 1,2-a]pyridin-3 -yl)benzyl] -4-oxo-1,4-azaphosphinane-
3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
15. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 14, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
16. Pharmaceutical composition according to claim 15, characterised in that it further comprises a fibrinolytic, an anticoagulant or an anti-platelet agent.
17. Compound according to any one of claims 1 to 14 for use as a TAFIa inhibitor.
18. Compound according to any one of claims 1 to 14 for use in the treatment, prévention or secondary prévention of cerebrovascular accidents, myocardial infarction, angina pectoris, arteritis of the lower limbs, thromboses, especially venous thromboses, pulmonary embolism, aortic aneurysms or dementias.
19. Compound according to any one of claims 1 to 14 for use according to claim 17 or 18, in association with a fibrinolytic, an anticoagulant or an anti-platelet agent.
20. Compound according to any one of claims 1 to 14 for use according to claim 19, in association with an injectable fibrinolytic selected from alteplase and tenecteplase.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR16/70004 | 2016-01-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA19047A true OA19047A (en) | 2019-12-27 |
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