NZ717223B2 - Aminoheteroaryl benzamides as kinase inhibitors - Google Patents
Aminoheteroaryl benzamides as kinase inhibitors Download PDFInfo
- Publication number
- NZ717223B2 NZ717223B2 NZ717223A NZ71722314A NZ717223B2 NZ 717223 B2 NZ717223 B2 NZ 717223B2 NZ 717223 A NZ717223 A NZ 717223A NZ 71722314 A NZ71722314 A NZ 71722314A NZ 717223 B2 NZ717223 B2 NZ 717223B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- mmol
- alkyl
- amino
- lcms
- compound
- Prior art date
Links
- -1 Aminoheteroaryl benzamides Chemical class 0.000 title claims description 243
- 229940054066 Benzamide antipsychotics Drugs 0.000 title description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 208
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 239000011780 sodium chloride Substances 0.000 claims abstract description 68
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 158
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 125000005843 halogen group Chemical group 0.000 claims description 69
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 42
- 125000005842 heteroatoms Chemical group 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 28
- 125000004043 oxo group Chemical group O=* 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 18
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- 201000002674 obstructive nephropathy Diseases 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 12
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 8
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- 229940113083 morpholine Drugs 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- RAOIDOHSFRTOEL-UHFFFAOYSA-N Tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 5
- 241001024304 Mino Species 0.000 claims description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N Thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- 150000004292 cyclic ethers Chemical class 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000006217 methyl sulfide group Chemical group [H]C([H])([H])S* 0.000 claims description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N 3,4-dihydro-2H-pyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 3
- AHHWIHXENZJRFG-UHFFFAOYSA-N Oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N Azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 126
- 239000003795 chemical substances by application Substances 0.000 abstract description 30
- 230000001225 therapeutic Effects 0.000 abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 357
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 207
- 239000011541 reaction mixture Substances 0.000 description 174
- 235000019439 ethyl acetate Nutrition 0.000 description 160
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 159
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 139
- 239000000243 solution Substances 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 238000006243 chemical reaction Methods 0.000 description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 98
- 239000012267 brine Substances 0.000 description 65
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 239000000047 product Substances 0.000 description 55
- 229910052938 sodium sulfate Inorganic materials 0.000 description 55
- 235000011152 sodium sulphate Nutrition 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000003814 drug Substances 0.000 description 49
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 47
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- 239000012043 crude product Substances 0.000 description 46
- 239000012044 organic layer Substances 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 42
- 201000010099 disease Diseases 0.000 description 42
- 238000003818 flash chromatography Methods 0.000 description 42
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 42
- 239000010410 layer Substances 0.000 description 41
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 40
- 238000000746 purification Methods 0.000 description 40
- 101700083887 MAPK1 Proteins 0.000 description 39
- 102100016823 MAPK1 Human genes 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- 239000002253 acid Substances 0.000 description 37
- 229940093499 ethyl acetate Drugs 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 34
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 34
- 101710024775 erkB Proteins 0.000 description 34
- 229910000029 sodium carbonate Inorganic materials 0.000 description 34
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 30
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 30
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Chemical compound [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 30
- 125000004429 atoms Chemical group 0.000 description 29
- 201000011510 cancer Diseases 0.000 description 28
- 125000003373 pyrazinyl group Chemical group 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- 125000003545 alkoxy group Chemical group 0.000 description 26
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
- 239000000463 material Substances 0.000 description 26
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Exidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 25
- 230000002401 inhibitory effect Effects 0.000 description 24
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical group NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 24
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 21
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 18
- 239000012458 free base Substances 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 108091007936 ERK family Proteins 0.000 description 17
- 125000001188 haloalkyl group Chemical group 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 229910052805 deuterium Inorganic materials 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 229910000033 sodium borohydride Inorganic materials 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 229960002949 Fluorouracil Drugs 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 230000001404 mediated Effects 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229960001866 silicon dioxide Drugs 0.000 description 14
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 238000007792 addition Methods 0.000 description 13
- 229960000485 methotrexate Drugs 0.000 description 13
- 230000002829 reduced Effects 0.000 description 13
- 125000004438 haloalkoxy group Chemical group 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 229960004316 cisplatin Drugs 0.000 description 11
- RCINICONZNJXQF-MZXODVADSA-N taxol derivatives Chemical class [H][C@]12[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C([C@@H](OC(C)=O)C(=O)[C@]1(C)[C@@H](O)C[C@H]1OC[C@@]21OC(C)=O)C3(C)C RCINICONZNJXQF-MZXODVADSA-N 0.000 description 11
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 10
- 229960001592 Paclitaxel Drugs 0.000 description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N Silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 150000002500 ions Chemical class 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 229930003347 taxol Natural products 0.000 description 10
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 9
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cells Anatomy 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 238000010348 incorporation Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 235000015424 sodium Nutrition 0.000 description 9
- 235000017550 sodium carbonate Nutrition 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- 108010022830 Cetuximab Proteins 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229960005395 cetuximab Drugs 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000001187 sodium carbonate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- 229960004562 Carboplatin Drugs 0.000 description 7
- ZADPBFCGQRWHPN-UHFFFAOYSA-N OBO Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 7
- UCFGDBYHRUNTLO-QHCPKHFHSA-N Topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- HSUIVCLOAAJSRE-UHFFFAOYSA-N bis(2-methoxyethyl) benzene-1,2-dicarboxylate Chemical compound COCCOC(=O)C1=CC=CC=C1C(=O)OCCOC HSUIVCLOAAJSRE-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-Hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 206010024324 Leukaemias Diseases 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- XIPFMBOWZXULIA-UHFFFAOYSA-N Pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 6
- JKEKMBGUVUKMQB-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JKEKMBGUVUKMQB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 201000010536 head and neck cancer Diseases 0.000 description 6
- 230000000155 isotopic Effects 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 230000003287 optical Effects 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 108010005144 Bevacizumab Proteins 0.000 description 5
- 229960002918 Doxorubicin Hydrochloride Drugs 0.000 description 5
- 229960001433 Erlotinib Drugs 0.000 description 5
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 5
- XGALLCVXEZPNRQ-UHFFFAOYSA-N Gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 5
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 5
- 239000005551 L01XE03 - Erlotinib Substances 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 206010025650 Malignant melanoma Diseases 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 229960004857 Mitomycin Drugs 0.000 description 5
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 108010061219 Panitumumab Proteins 0.000 description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 5
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N Trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N Tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 229960000397 bevacizumab Drugs 0.000 description 5
- 230000001808 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 229960002584 gefitinib Drugs 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 201000001441 melanoma Diseases 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 229960001972 panitumumab Drugs 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 5
- 229960005141 piperazine Drugs 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 229910001923 silver oxide Inorganic materials 0.000 description 5
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 229960004066 trametinib Drugs 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- ZROHGHOFXNOHSO-BNTLRKBRSA-L (1R,2R)-cyclohexane-1,2-diamine;oxalate;platinum(2+) Chemical compound [H][N]([C@@H]1CCCC[C@H]1[N]1([H])[H])([H])[Pt]11OC(=O)C(=O)O1 ZROHGHOFXNOHSO-BNTLRKBRSA-L 0.000 description 4
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 229960004397 Cyclophosphamide Drugs 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 4
- 229960005073 Erlotinib Hydrochloride Drugs 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 229960005144 Gemcitabine hydrochloride Drugs 0.000 description 4
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 4
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 4
- 102000038027 MAP kinase family Human genes 0.000 description 4
- 108091007472 MAP kinase family Proteins 0.000 description 4
- 108090000823 Mitogen-Activated Protein Kinases Proteins 0.000 description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 4
- 108091000081 Phosphotransferases Proteins 0.000 description 4
- 102000001253 Protein Kinases Human genes 0.000 description 4
- 210000003491 Skin Anatomy 0.000 description 4
- RMBAVIFYHOYIFM-UHFFFAOYSA-M Sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- UHTHHESEBZOYNR-UHFFFAOYSA-N Vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000005418 aryl aryl group Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- TZZXCFSNKBFOOG-UHFFFAOYSA-M cyclohexylmethanesulfonate Chemical compound [O-]S(=O)(=O)CC1CCCCC1 TZZXCFSNKBFOOG-UHFFFAOYSA-M 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 229940063519 doxorubicin hydrochloride liposome Drugs 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 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 4
- 239000000839 emulsion Substances 0.000 description 4
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 4
- 125000001207 fluorophenyl group Chemical group 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000002335 preservative Effects 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- 201000002510 thyroid cancer Diseases 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- 229960000303 topotecan Drugs 0.000 description 4
- 229960000241 vandetanib Drugs 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- OMJKFYKNWZZKTK-UXBLZVDNSA-N (5E)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1\N=CN=C1C(N)=O OMJKFYKNWZZKTK-UXBLZVDNSA-N 0.000 description 3
- WWQJIRVJWYMVDK-UHFFFAOYSA-N 4-(5-bromo-3-nitropyridin-2-yl)morpholine Chemical compound [O-][N+](=O)C1=CC(Br)=CN=C1N1CCOCC1 WWQJIRVJWYMVDK-UHFFFAOYSA-N 0.000 description 3
- CZDWJVSOQOMYGC-UHFFFAOYSA-N 4-borono-2-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C(F)=C1 CZDWJVSOQOMYGC-UHFFFAOYSA-N 0.000 description 3
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 3
- 229940064305 Adrucil Drugs 0.000 description 3
- 101700004551 BRAF Proteins 0.000 description 3
- 102100004328 BRAF Human genes 0.000 description 3
- IPWKHHSGDUIRAH-UHFFFAOYSA-N Bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 3
- 229960001561 Bleomycin Drugs 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- KXSZUHZMIFRFRW-NSHDSACASA-N CC(C)(C)OC(=O)NC[C@H](O)c1cccc(Cl)c1 Chemical compound CC(C)(C)OC(=O)NC[C@H](O)c1cccc(Cl)c1 KXSZUHZMIFRFRW-NSHDSACASA-N 0.000 description 3
- 229960005069 Calcium Drugs 0.000 description 3
- 229960004117 Capecitabine Drugs 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 206010008943 Chronic leukaemia Diseases 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N Crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N Cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 3
- FWFSEYBSWVRWGL-UHFFFAOYSA-N Cyclohexenone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 3
- 229960000684 Cytarabine Drugs 0.000 description 3
- BFSMGDJOXZAERB-UHFFFAOYSA-N Dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 3
- DIOQZVSQGTUSAI-UHFFFAOYSA-N Decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 3
- 229940099302 Efudex Drugs 0.000 description 3
- 229940064300 Fluoroplex Drugs 0.000 description 3
- 229940020967 Gemzar Drugs 0.000 description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 3
- 241000229754 Iva xanthiifolia Species 0.000 description 3
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- 101710009221 LD Proteins 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
- BCFGMOOMADDAQU-UHFFFAOYSA-N Lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N Nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 3
- YZFBWNIJEXIOAQ-RQJHMYQMSA-M O[C@@H]1C[C@@H](CC1)C=1N=CC(=NC=1)NC([O-])=O Chemical compound O[C@@H]1C[C@@H](CC1)C=1N=CC(=NC=1)NC([O-])=O YZFBWNIJEXIOAQ-RQJHMYQMSA-M 0.000 description 3
- 101710027499 Os03g0268000 Proteins 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 229910002666 PdCl2 Inorganic materials 0.000 description 3
- 229940063179 Platinol Drugs 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 3
- 108020004753 RAN Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229960002190 Topotecan Hydrochloride Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 3
- 150000001642 boronic acid derivatives Chemical class 0.000 description 3
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 3
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Inorganic materials [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229960002465 dabrafenib Drugs 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000011888 foil Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- DSLZVSRJTYRBFB-DUHBMQHGSA-L galactarate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C([O-])=O DSLZVSRJTYRBFB-DUHBMQHGSA-L 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 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
- 229960004891 lapatinib Drugs 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 229960001346 nilotinib Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 229960003931 peginterferon alfa-2b Drugs 0.000 description 3
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 3
- 239000000546 pharmaceutic aid Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 125000006684 polyhaloalkyl group Polymers 0.000 description 3
- 230000002285 radioactive Effects 0.000 description 3
- 229960004836 regorafenib Drugs 0.000 description 3
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 229960001367 tartaric acid Drugs 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 3
- 229960003862 vemurafenib Drugs 0.000 description 3
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 3
- 125000002348 vinylic group Chemical group 0.000 description 3
- STJIXOUDTUPEEL-QMMMGPOBSA-N (1R)-2-amino-1-(3-chlorophenyl)ethanol Chemical compound NC[C@H](O)C1=CC=CC(Cl)=C1 STJIXOUDTUPEEL-QMMMGPOBSA-N 0.000 description 2
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 2
- SBJSTQONOOUZKC-SECBINFHSA-N (4S)-4-phenyl-1,3-oxazolidine Chemical compound C1OCN[C@H]1C1=CC=CC=C1 SBJSTQONOOUZKC-SECBINFHSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- BVOBEKTUNHUKRO-UHFFFAOYSA-N 1,2-dimethoxyethane;methanol Chemical compound OC.COCCOC BVOBEKTUNHUKRO-UHFFFAOYSA-N 0.000 description 2
- LNETULKMXZVUST-UHFFFAOYSA-M 1-naphthoate Chemical compound C1=CC=C2C(C(=O)[O-])=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-M 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- BWTNNZPNKQIADY-UHFFFAOYSA-N 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide;hydrochloride Chemical compound Cl.C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 BWTNNZPNKQIADY-UHFFFAOYSA-N 0.000 description 2
- CGTGLMSBJLJNCL-UHFFFAOYSA-N 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(=O)CC1 CGTGLMSBJLJNCL-UHFFFAOYSA-N 0.000 description 2
- WUIABRMSWOKTOF-PATWWPTKSA-N 3-[[2-[2-[2-[[(2R,3R)-2-[[(2R,3R,4S)-4-[[(2S)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2R)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2S,3R,4R,5R,6R)-3-[(2R,3S,4S,5R,6R)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)oxan- Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@@H](C)[C@H](O)[C@@H](C)C(=O)N[C@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)C(O[C@@H]1[C@@H]([C@H](O)[C@@H](O)[C@@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-PATWWPTKSA-N 0.000 description 2
- YTEIHWVCQJZNEN-UHFFFAOYSA-N 3-pyridin-4-ylpyridine Chemical compound C1=CN=CC(C=2C=CN=CC=2)=C1 YTEIHWVCQJZNEN-UHFFFAOYSA-N 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 2
- 125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- QGPDJOYNWDQAHO-UHFFFAOYSA-N 5-cyclopropylpyrazin-2-amine Chemical compound C1=NC(N)=CN=C1C1CC1 QGPDJOYNWDQAHO-UHFFFAOYSA-N 0.000 description 2
- ACWZRVQXLIRSDF-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 2
- 229940035676 ANALGESICS Drugs 0.000 description 2
- 208000003200 Adenoma Diseases 0.000 description 2
- 206010001233 Adenoma benign Diseases 0.000 description 2
- 229940072107 Ascorbate Drugs 0.000 description 2
- 229940009098 Aspartate Drugs 0.000 description 2
- 229940120638 Avastin Drugs 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N BINAP Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- UBPYILGKFZZVDX-UHFFFAOYSA-N Bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 2
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- PTSRRDHYVOAEIG-UHFFFAOYSA-N COC(=O)C#Cc1cnc(N)cn1 Chemical compound COC(=O)C#Cc1cnc(N)cn1 PTSRRDHYVOAEIG-UHFFFAOYSA-N 0.000 description 2
- 229960003563 Calcium Carbonate Drugs 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N Chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- 108010070635 Edrecolomab Proteins 0.000 description 2
- 229940082789 Erbitux Drugs 0.000 description 2
- HKVAMNSJSFKALM-XJFKSLPYSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)C(C)=C[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-XJFKSLPYSA-N 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- BXKFZYRQRURBGE-UHFFFAOYSA-N FC1(C(C=CC=C1)C(C)N)F Chemical compound FC1(C(C=CC=C1)C(C)N)F BXKFZYRQRURBGE-UHFFFAOYSA-N 0.000 description 2
- 229960001731 GLUCEPTATE Drugs 0.000 description 2
- 208000005017 Glioblastoma Diseases 0.000 description 2
- 229940049906 Glutamate Drugs 0.000 description 2
- 229940093915 Gynecological Organic acids Drugs 0.000 description 2
- 102100004109 HEY1 Human genes 0.000 description 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 2
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 2
- 206010020243 Hodgkin's disease Diseases 0.000 description 2
- HYFHYPWGAURHIV-JFIAXGOJSA-N Homoharringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 2
- 229940088013 Hycamtin Drugs 0.000 description 2
- 229960003507 Interferon Alfa-2b Drugs 0.000 description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N Isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 2
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 2
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N LGX818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 description 2
- JYTUSYBCFIZPBE-AMTLMPIISA-N Lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 2
- 229960002293 Leucovorin Calcium Drugs 0.000 description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N Methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- DASWEROEPLKSEI-UIJRFTGLSA-N Monomethyl auristatin E Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 DASWEROEPLKSEI-UIJRFTGLSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-M N-benzoylglycinate Chemical compound [O-]C(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-M 0.000 description 2
- USINJNABHFLBMP-UHFFFAOYSA-N Nc1cnc(cn1)C1=CC(=O)CCC1 Chemical compound Nc1cnc(cn1)C1=CC(=O)CCC1 USINJNABHFLBMP-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 2
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 2
- 229940049964 Oleate Drugs 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N Phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M Potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010038038 Rectal cancer Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 101710019175 STATH Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N Sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940120982 Tarceva Drugs 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 229940035295 Ting Drugs 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical class [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 229960004528 Vincristine Drugs 0.000 description 2
- 229950000339 Xinafoate Drugs 0.000 description 2
- QBFAVXFPISPUNY-UHFFFAOYSA-N [4-(benzylcarbamoyl)-2-fluorophenyl]boronic acid Chemical compound C1=C(F)C(B(O)O)=CC=C1C(=O)NCC1=CC=CC=C1 QBFAVXFPISPUNY-UHFFFAOYSA-N 0.000 description 2
- XTSLGOGQMXSTRK-UHFFFAOYSA-N [4-(benzylcarbamoyl)-3-fluorophenyl]boronic acid Chemical compound FC1=CC(B(O)O)=CC=C1C(=O)NCC1=CC=CC=C1 XTSLGOGQMXSTRK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002730 additional Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229960002736 afatinib dimaleate Drugs 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000000202 analgesic Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229960003736 bosutinib Drugs 0.000 description 2
- 201000005216 brain cancer Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229960002865 cabozantinib s-malate Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 2
- 235000008207 calcium folinate Nutrition 0.000 description 2
- 239000011687 calcium folinate Substances 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical compound C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 201000009030 carcinoma Diseases 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 229940009662 edetate Drugs 0.000 description 2
- 229960001776 edrecolomab Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 108040009258 epidermal growth factor-activated receptor activity proteins Proteins 0.000 description 2
- 102000017256 epidermal growth factor-activated receptor activity proteins Human genes 0.000 description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethanedisulfonate group Chemical group C(CS(=O)(=O)[O-])S(=O)(=O)[O-] AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 201000005160 follicular thyroid carcinoma Diseases 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 229940097042 glucuronate Drugs 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229940099584 lactobionate Drugs 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002609 media Substances 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000006682 monohaloalkyl group Chemical group 0.000 description 2
- 201000009251 multiple myeloma Diseases 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 2
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- LKZAAHOOIJSWQR-UHFFFAOYSA-R palladium;triphenylphosphanium Chemical compound [Pd].[Pd].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 LKZAAHOOIJSWQR-UHFFFAOYSA-R 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 2
- 229960005184 panobinostat Drugs 0.000 description 2
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 2
- 229960003349 pemetrexed disodium Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229960002183 ponatinib hydrochloride Drugs 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 150000003216 pyrazines Chemical class 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- 229940116351 sebacate Drugs 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- BKBBTCORRZMASO-UHFFFAOYSA-M sodium;2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC([O-])=O)C(O)=O)C=C1 BKBBTCORRZMASO-UHFFFAOYSA-M 0.000 description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl N-[(3R)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cells Anatomy 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229960002760 ziv-aflibercept Drugs 0.000 description 2
- BFAQNLRAFSBFGU-QMMMGPOBSA-N (1S)-1-amino-1-phenylethanol Chemical compound C[C@](N)(O)C1=CC=CC=C1 BFAQNLRAFSBFGU-QMMMGPOBSA-N 0.000 description 1
- YVMKRPGFBQGEBF-QMMMGPOBSA-N (2R)-2-(3-chlorophenyl)oxirane Chemical compound ClC1=CC=CC([C@H]2OC2)=C1 YVMKRPGFBQGEBF-QMMMGPOBSA-N 0.000 description 1
- QNDVLZJODHBUFM-FCXWGWLASA-N (2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2'S,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hyd Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-FCXWGWLASA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2S)-2-[[(2R,3R)-3-methoxy-3-[(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-[methyl-[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 1
- DQFOSYRXEOWKOY-UHFFFAOYSA-N (3-methylsulfonylphenyl)methanamine Chemical compound CS(=O)(=O)C1=CC=CC(CN)=C1 DQFOSYRXEOWKOY-UHFFFAOYSA-N 0.000 description 1
- FHJYHLPYGBAQKI-UHFFFAOYSA-N (3-oxocyclohexen-1-yl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC(=O)CCC1 FHJYHLPYGBAQKI-UHFFFAOYSA-N 0.000 description 1
- NTUBEBXBDGKBTJ-LGAOZOLISA-N (4S,5R,6R)-6-[(1S)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;hydrate Chemical compound O.C=1([C@@H](C)[C@H]2[C@@H](C(N2C=1C(O)=O)=O)[C@@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 NTUBEBXBDGKBTJ-LGAOZOLISA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- ZVUKZMMMAIHDMQ-UHFFFAOYSA-N 1,2-dimethoxyethane;ethanol Chemical compound CCO.COCCOC ZVUKZMMMAIHDMQ-UHFFFAOYSA-N 0.000 description 1
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical compound B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3H-pyrrolo[3,2-e]indole-6-carbonyl]-1H-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- BJBMICJVJIETOV-UHFFFAOYSA-N 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1N1N=CC=C1 BJBMICJVJIETOV-UHFFFAOYSA-N 0.000 description 1
- PFQJVYVNOKTLLI-QMMMGPOBSA-N 1-O-tert-butyl 2-O-methyl (2S)-4-(trifluoromethylsulfonyloxy)-2,5-dihydropyrrole-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C PFQJVYVNOKTLLI-QMMMGPOBSA-N 0.000 description 1
- UPBHYYJZVWZCOZ-QMMMGPOBSA-N 1-O-tert-butyl 2-O-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C UPBHYYJZVWZCOZ-QMMMGPOBSA-N 0.000 description 1
- BFAQNLRAFSBFGU-UHFFFAOYSA-N 1-amino-1-phenylethanol Chemical compound CC(N)(O)C1=CC=CC=C1 BFAQNLRAFSBFGU-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- FLNMQGISZVYIIK-UHFFFAOYSA-N 1-ethylpyrazole Chemical compound CCN1C=CC=N1 FLNMQGISZVYIIK-UHFFFAOYSA-N 0.000 description 1
- BSXPDVKSFWQFRT-UHFFFAOYSA-N 1-hydroxytriazolo[4,5-b]pyridine Chemical compound C1=CC=C2N(O)N=NC2=N1 BSXPDVKSFWQFRT-UHFFFAOYSA-N 0.000 description 1
- BJMSXWLXFYZHIU-UHFFFAOYSA-N 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1C=CC(B2OC(C)(C)C(C)(C)O2)=N1 BJMSXWLXFYZHIU-UHFFFAOYSA-N 0.000 description 1
- ANMVTDVBEDVFRB-UHFFFAOYSA-N 1-propan-2-ylpyrazole Chemical compound CC(C)N1C=CC=N1 ANMVTDVBEDVFRB-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-M 2,2,2-triphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)[O-])C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-M 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-Dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- WLLTZJWJXOPFJH-UHFFFAOYSA-N 2-(1,4-dioxaspiro[4.5]dec-7-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1OC2(CC=CCC2)OC1 WLLTZJWJXOPFJH-UHFFFAOYSA-N 0.000 description 1
- XNIOWJUQPMKCIJ-UHFFFAOYSA-N 2-(benzylamino)ethanol Chemical compound OCCNCC1=CC=CC=C1 XNIOWJUQPMKCIJ-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N 2-Imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2S)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- BAMUAAIPBLVVHU-UHFFFAOYSA-N 2-acetyl-2-acetyloxy-3-hydroxybutanedioic acid Chemical compound CC(=O)OC(C(O)=O)(C(C)=O)C(O)C(O)=O BAMUAAIPBLVVHU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 150000003930 2-aminopyridines Chemical class 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- WGFCNCNTGOFBBF-UHFFFAOYSA-N 2-bromopyrazine Chemical compound BrC1=CN=CC=N1 WGFCNCNTGOFBBF-UHFFFAOYSA-N 0.000 description 1
- HKDVVTLISGIPFE-UHFFFAOYSA-N 2-bromopyridin-3-amine Chemical class NC1=CC=CN=C1Br HKDVVTLISGIPFE-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- PSSRGNDMEDQBOC-UHFFFAOYSA-N 2-cyclopropylpyrazine Chemical compound C1CC1C1=CN=CC=N1 PSSRGNDMEDQBOC-UHFFFAOYSA-N 0.000 description 1
- LIOLIMKSCNQPLV-UHFFFAOYSA-N 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1C1=NN2C(CC=3C=C4C=CC=NC4=CC=3)=CN=C2N=C1 LIOLIMKSCNQPLV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 description 1
- MQOPUXINXNVMKJ-UHFFFAOYSA-N 2-methyloxan-4-one Chemical compound CC1CC(=O)CCO1 MQOPUXINXNVMKJ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-M 2-sulfooxybenzoate Chemical compound OS(=O)(=O)OC1=CC=CC=C1C([O-])=O MOODSJOROWROTO-UHFFFAOYSA-M 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 108010024199 2C4 antibody Proteins 0.000 description 1
- GFYZIQQOKLUEAW-UHFFFAOYSA-N 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(=O)CCC1 GFYZIQQOKLUEAW-UHFFFAOYSA-N 0.000 description 1
- UNDZTSGXNXEERW-UHFFFAOYSA-N 3-(thiolan-2-yl)pyridine Chemical compound C1CCSC1C1=CC=CN=C1 UNDZTSGXNXEERW-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-M 3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GHOKWGTUZJEAQD-ZETCQYMHSA-M 0.000 description 1
- SLILNCISGMCZCQ-UHFFFAOYSA-N 3-bromocyclopent-2-en-1-one Chemical compound BrC1=CC(=O)CC1 SLILNCISGMCZCQ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- WZIYCIBURCPKAR-UHFFFAOYSA-N 4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1 WZIYCIBURCPKAR-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-STUHELBRSA-N 4-amino-1-[(3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-STUHELBRSA-N 0.000 description 1
- ZQQSRVPOAHYHEL-UHFFFAOYSA-N 4-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1F ZQQSRVPOAHYHEL-UHFFFAOYSA-N 0.000 description 1
- PCFIABOQFAFDAU-UHFFFAOYSA-N 4-bromo-2-fluorobenzoyl chloride Chemical compound FC1=CC(Br)=CC=C1C(Cl)=O PCFIABOQFAFDAU-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- WCCFLOQQACDOAX-UHFFFAOYSA-N 4-fluoropyridin-2-amine Chemical compound NC1=CC(F)=CC=N1 WCCFLOQQACDOAX-UHFFFAOYSA-N 0.000 description 1
- MQWCXKGKQLNYQG-UHFFFAOYSA-N 4-methylcyclohexan-1-ol Chemical compound CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- LMJXSOYPAOSIPZ-UHFFFAOYSA-N 4-sulfanylbenzoic acid Chemical compound OC(=O)C1=CC=C(S)C=C1 LMJXSOYPAOSIPZ-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CBNIRWXQQRNRJY-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)C=N1 CBNIRWXQQRNRJY-UHFFFAOYSA-N 0.000 description 1
- YFTAUNOLAHRUIE-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N)N=C1 YFTAUNOLAHRUIE-UHFFFAOYSA-N 0.000 description 1
- YCPXWRQRBFJBPZ-UHFFFAOYSA-N 5-Sulfosalicylic acid Chemical compound OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O YCPXWRQRBFJBPZ-UHFFFAOYSA-N 0.000 description 1
- JPLZLXLDDYKNPT-UHFFFAOYSA-N 5-[[3-[(3,3-dimethylpiperidin-1-ium-1-yl)methyl]-4-methoxyphenyl]-[6-hydroxy-1-(2-methylphenyl)-4-oxo-2-sulfanylidenepyrimidin-5-yl]methyl]-3-(2-methylphenyl)-6-oxo-2-sulfanylidenepyrimidin-4-olate Chemical compound COC1=CC=C(C(C=2C(NC(=S)N(C=3C(=CC=CC=3)C)C=2O)=O)C=2C(NC(=S)N(C=3C(=CC=CC=3)C)C=2[O-])=O)C=C1C[NH+]1CCCC(C)(C)C1 JPLZLXLDDYKNPT-UHFFFAOYSA-N 0.000 description 1
- QLXASFJHUCKEHU-UHFFFAOYSA-N 5-bromo-3-fluoropyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1F QLXASFJHUCKEHU-UHFFFAOYSA-N 0.000 description 1
- VVTVALQVXWRFAM-UHFFFAOYSA-N 5-iodopyrazin-2-amine Chemical compound NC1=CN=C(I)C=N1 VVTVALQVXWRFAM-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 229940100197 ANTIMETABOLITES Drugs 0.000 description 1
- 229950005186 Abagovomab Drugs 0.000 description 1
- 229940028652 Abraxane Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 229950009084 Adecatumumab Drugs 0.000 description 1
- 229950006790 Adenosine phosphate Drugs 0.000 description 1
- 229960001686 Afatinib Drugs 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010090838 Alemtuzumab Proteins 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 229940110282 Alimta Drugs 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229950003145 Apolizumab Drugs 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 229950006844 BIZELESIN Drugs 0.000 description 1
- 229950007843 Bavituximab Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N Benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N Benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 229940050390 Benzoate Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229940083476 Bosulif Drugs 0.000 description 1
- 229940098773 Bovine Serum Albumin Drugs 0.000 description 1
- 108091003117 Bovine Serum Albumin Proteins 0.000 description 1
- 108010013795 Brentuximab Vedotin Proteins 0.000 description 1
- 229960000455 Brentuximab vedotin Drugs 0.000 description 1
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 description 1
- MXKNSALOUZAATK-UHFFFAOYSA-N CC(=O)C1C=CC=CC1(F)F Chemical compound CC(=O)C1C=CC=CC1(F)F MXKNSALOUZAATK-UHFFFAOYSA-N 0.000 description 1
- QKCGCWHAYFTEKW-UHFFFAOYSA-N CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(CCOS(C)(=O)=O)cn1 Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(CCOS(C)(=O)=O)cn1 QKCGCWHAYFTEKW-UHFFFAOYSA-N 0.000 description 1
- NELDEGVZLJHLNJ-UHFFFAOYSA-N CC(C)(C)OC(=O)Nc1cnc(CCS(C)(=O)=O)cn1 Chemical compound CC(C)(C)OC(=O)Nc1cnc(CCS(C)(=O)=O)cn1 NELDEGVZLJHLNJ-UHFFFAOYSA-N 0.000 description 1
- VRJMBORAGSKUAL-UHFFFAOYSA-N CC1(C)OB(OC1(C)C)c1cc(cnc1N)N1CCOCC1 Chemical compound CC1(C)OB(OC1(C)C)c1cc(cnc1N)N1CCOCC1 VRJMBORAGSKUAL-UHFFFAOYSA-N 0.000 description 1
- 101700008359 CDK4 Proteins 0.000 description 1
- CAYHPTMRBMFMOC-UHFFFAOYSA-N COC(=O)CCc1cnc(N)cn1 Chemical compound COC(=O)CCc1cnc(N)cn1 CAYHPTMRBMFMOC-UHFFFAOYSA-N 0.000 description 1
- GWMONUOJKUOFCT-UHFFFAOYSA-N COCCc1cnc(N)cn1 Chemical compound COCCc1cnc(N)cn1 GWMONUOJKUOFCT-UHFFFAOYSA-N 0.000 description 1
- KSQFOQZVTOBEIO-UHFFFAOYSA-N CSCCc1cnc(NC(=O)OC(C)(C)C)cn1 Chemical compound CSCCc1cnc(NC(=O)OC(C)(C)C)cn1 KSQFOQZVTOBEIO-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940088954 Camptosar Drugs 0.000 description 1
- 229950007296 Cantuzumab mertansine Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229940056434 Caprelsa Drugs 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 229950001357 Celmoleukin Drugs 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 229960004630 Chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N Chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 Chloroprocaine Drugs 0.000 description 1
- 229950010905 Citatuzumab bogatox Drugs 0.000 description 1
- 229940001468 Citrate Drugs 0.000 description 1
- 229950006647 Cixutumumab Drugs 0.000 description 1
- 229950002595 Clivatuzumab tetraxetan Drugs 0.000 description 1
- 229940034568 Cometriq Drugs 0.000 description 1
- TUFGVZMNGTYAQD-UHFFFAOYSA-N Comins' reagent Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=C(Cl)C=N1 TUFGVZMNGTYAQD-UHFFFAOYSA-N 0.000 description 1
- 229950007276 Conatumumab Drugs 0.000 description 1
- LLLIKHLUUMWXPN-UHFFFAOYSA-N Conatumumab Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1.C1C(CC(C2)C3)CC3C12C1=NC(N(C(N(CCC)C2=O)=O)CCC)=C2N1 LLLIKHLUUMWXPN-UHFFFAOYSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L Copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N Cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N Cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N Cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N DCM Dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N DMSO dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- LHAPIGUPZIFFMA-XOGXUEEYSA-N Dacetuzumab Chemical compound O.Cl.O([C@@H]1[C@](C2=3)([C@]4(CC=5C6=CC=CC=C6NC=51)O)CC1)C=3C(O)=CC=C2CC4N1CC1CC1 LHAPIGUPZIFFMA-XOGXUEEYSA-N 0.000 description 1
- 229950007409 Dacetuzumab Drugs 0.000 description 1
- 108010084740 Daclizumab Proteins 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 229950008962 Detumomab Drugs 0.000 description 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N Dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- MUZIZEZCKKMZRT-UHFFFAOYSA-N Dithiolane Chemical compound C1CSSC1 MUZIZEZCKKMZRT-UHFFFAOYSA-N 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N Dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229940115080 Doxil Drugs 0.000 description 1
- 229960004679 Doxorubicin Drugs 0.000 description 1
- 229940112141 Dry Powder Inhaler Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N Duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 229960001904 EPIRUBICIN Drugs 0.000 description 1
- 229950000006 Ecromeximab Drugs 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N Eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- 229940120655 Eloxatin Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229950009760 Epratuzumab Drugs 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 229950008579 Ertumaxomab Drugs 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N EtOAc EtOAc Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 229950009569 Etaracizumab Drugs 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229960005420 Etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- LURDIXZBDNFWGU-UHFFFAOYSA-N Fc1cc(Br)ccc1C(=O)NCc1ncccn1 Chemical compound Fc1cc(Br)ccc1C(=O)NCc1ncccn1 LURDIXZBDNFWGU-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 240000003139 Ferula foetida Species 0.000 description 1
- 229950008085 Figitumumab Drugs 0.000 description 1
- 229950004003 Fresolimumab Drugs 0.000 description 1
- 229950001109 Galiximab Drugs 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 108010091266 Gemtuzumab Proteins 0.000 description 1
- 229940087158 Gilotrif Drugs 0.000 description 1
- 229940080856 Gleevec Drugs 0.000 description 1
- 229940074045 Glyceryl Distearate Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100007193 HDAC9 Human genes 0.000 description 1
- LJQLCJWAZJINEB-UHFFFAOYSA-N Hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F LJQLCJWAZJINEB-UHFFFAOYSA-N 0.000 description 1
- 108090000353 Histone deacetylases Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229960000908 Idarubicin Drugs 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 229960001101 Ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960003685 Imatinib mesylate Drugs 0.000 description 1
- 108010027059 Inotuzumab Ozogamicin Proteins 0.000 description 1
- 229950004101 Inotuzumab ozogamicin Drugs 0.000 description 1
- 229950001014 Intetumumab Drugs 0.000 description 1
- 229950010939 Iratumumab Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N Irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N Irinotecan hydrochloride Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 229960000779 Irinotecan hydrochloride Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N Isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 229950000518 Labetuzumab Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229950002884 Lexatumumab Drugs 0.000 description 1
- 229950002950 Lintuzumab Drugs 0.000 description 1
- 229940103064 LipoDox Drugs 0.000 description 1
- 229950004563 Lucatumumab Drugs 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101710028361 MARVELD2 Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229950001869 Mapatumumab Drugs 0.000 description 1
- 229950008001 Matuzumab Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N MeOH methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229960004961 Mechlorethamine Drugs 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229960003194 Meglumine Drugs 0.000 description 1
- 229940083118 Mekinist Drugs 0.000 description 1
- ANZJBCHSOXCCRQ-GCRZMMRQSA-N Mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)C1O[C@@]1(C)[C@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C/C=C(C)/CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-GCRZMMRQSA-N 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N Methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 108060004843 Mical Proteins 0.000 description 1
- 229950003734 Milatuzumab Drugs 0.000 description 1
- 229940042472 Mineral Oil Drugs 0.000 description 1
- 229950003063 Mitumomab Drugs 0.000 description 1
- WFCAUNYFSHIYTM-UHFFFAOYSA-N N,N,3-trimethylbut-2-en-1-amine Chemical compound CN(C)CC=C(C)C WFCAUNYFSHIYTM-UHFFFAOYSA-N 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N N,N-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- OJSPNJOHDAGGSO-UHFFFAOYSA-N N-benzyl-3-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide Chemical compound C=1C=CC(Br)=C(F)C=1C(=O)N(CCO)CC1=CC=CC=C1 OJSPNJOHDAGGSO-UHFFFAOYSA-N 0.000 description 1
- XVCDHVZMJKTVBL-UHFFFAOYSA-N N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide Chemical compound C=1C=C(Br)C=C(F)C=1C(=O)N(CCO)CC1=CC=CC=C1 XVCDHVZMJKTVBL-UHFFFAOYSA-N 0.000 description 1
- BUMCSIVWLOIKJT-UHFFFAOYSA-N N-bromopyridin-3-amine Chemical compound BrNC1=CC=CN=C1 BUMCSIVWLOIKJT-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- FRRHZGAJWLRVBF-UHFFFAOYSA-N N1OCC12CCC2 Chemical compound N1OCC12CCC2 FRRHZGAJWLRVBF-UHFFFAOYSA-N 0.000 description 1
- HBSOVEROGVCDPC-UHFFFAOYSA-M NC(CNC([O-])=O)C1=CC(=CC=C1)Cl Chemical compound NC(CNC([O-])=O)C1=CC(=CC=C1)Cl HBSOVEROGVCDPC-UHFFFAOYSA-M 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229950003027 Nacolomab tafenatox Drugs 0.000 description 1
- 229950009793 Naptumomab estafenatox Drugs 0.000 description 1
- VRUHFSYVDWAUFK-UHFFFAOYSA-N Nc1cnc(CCO)cn1 Chemical compound Nc1cnc(CCO)cn1 VRUHFSYVDWAUFK-UHFFFAOYSA-N 0.000 description 1
- ZRLJJOBBFFRVET-UHFFFAOYSA-N Nc1cnc(cn1)C1=CC(=O)CC1 Chemical compound Nc1cnc(cn1)C1=CC(=O)CC1 ZRLJJOBBFFRVET-UHFFFAOYSA-N 0.000 description 1
- MTLYMQNHOKQRMK-UHFFFAOYSA-N Nc1cnc(cn1)C1=CCOCC1 Chemical compound Nc1cnc(cn1)C1=CCOCC1 MTLYMQNHOKQRMK-UHFFFAOYSA-N 0.000 description 1
- YYUXCLBCYQNYLB-UHFFFAOYSA-N Nc1cnc(cn1)C1CCC(=O)CC1 Chemical compound Nc1cnc(cn1)C1CCC(=O)CC1 YYUXCLBCYQNYLB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 229950010203 Nimotuzumab Drugs 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- ZPVHAOCOFJKDLY-CQSZACIVSA-N OC[C@@H](NC(=O)c1ccc(Br)cc1)c1ccccc1 Chemical compound OC[C@@H](NC(=O)c1ccc(Br)cc1)c1ccccc1 ZPVHAOCOFJKDLY-CQSZACIVSA-N 0.000 description 1
- 229960002450 Ofatumumab Drugs 0.000 description 1
- LZMPYSIUWPEIRA-XFXZXTDPSA-N Ofatumumab Chemical compound N1=C2C=3COCCC=3N=CC2=N\C1=C1\NOC=C1 LZMPYSIUWPEIRA-XFXZXTDPSA-N 0.000 description 1
- 229950008516 Olaratumab Drugs 0.000 description 1
- 229950009057 Oportuzumab monatox Drugs 0.000 description 1
- 229950007283 Oregovomab Drugs 0.000 description 1
- 210000003463 Organelles Anatomy 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 101710018405 PTPN11 Proteins 0.000 description 1
- 102100017818 PTPN11 Human genes 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N Phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 229960003171 Plicamycin Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229950009904 Pritumumab Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229940087463 Proleukin Drugs 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 101700008447 RAB17 Proteins 0.000 description 1
- 102100016115 RAF1 Human genes 0.000 description 1
- 101700007719 RAF1 Proteins 0.000 description 1
- 229950003687 Ribociclib Drugs 0.000 description 1
- 229950003238 Rilotumumab Drugs 0.000 description 1
- 229950001808 Robatumumab Drugs 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229950008684 Sibrotuzumab Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 229920001891 Small hairpin RNA Polymers 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940068117 Sprycel Drugs 0.000 description 1
- 229940090374 Stivarga Drugs 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229940110546 Sylatron Drugs 0.000 description 1
- 229940022873 Synribo Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229940081616 Tafinlar Drugs 0.000 description 1
- 229950001603 Taplitumomab paptox Drugs 0.000 description 1
- 229940069905 Tasigna Drugs 0.000 description 1
- 229940063683 Taxotere Drugs 0.000 description 1
- 229950001289 Tenatumomab Drugs 0.000 description 1
- 229960001278 Teniposide Drugs 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229950004742 Tigatuzumab Drugs 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229940035504 Tromethamine Drugs 0.000 description 1
- 101710038834 U69 Proteins 0.000 description 1
- 229950000815 Veltuzumab Drugs 0.000 description 1
- 229960003048 Vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 229960004355 Vindesine Drugs 0.000 description 1
- 229950004393 Visilizumab Drugs 0.000 description 1
- 229950003511 Votumumab Drugs 0.000 description 1
- 229940049068 Xalkori Drugs 0.000 description 1
- 229940053867 Xeloda Drugs 0.000 description 1
- 229940055760 Yervoy Drugs 0.000 description 1
- 101700069422 ZHX2 Proteins 0.000 description 1
- 229940036061 Zaltrap Drugs 0.000 description 1
- 229950008250 Zalutumumab Drugs 0.000 description 1
- 229950009002 Zanolimumab Drugs 0.000 description 1
- 229940034727 Zelboraf Drugs 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N [(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]azanium;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N [4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-2,6-dimethoxyphenyl] dihydrogen phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- AMICKSOBTKELAE-YDHLFZDLSA-N [Si](C)(C)(C(C)(C)C)O[C@@H]1[C@H](C[C@H](CC1)C=1N=CC=NC=1)F Chemical compound [Si](C)(C)(C(C)(C)C)O[C@@H]1[C@H](C[C@H](CC1)C=1N=CC=NC=1)F AMICKSOBTKELAE-YDHLFZDLSA-N 0.000 description 1
- CTCBPRXHVPZNHB-VQFZJOCSSA-N [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate;(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O CTCBPRXHVPZNHB-VQFZJOCSSA-N 0.000 description 1
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 1
- 108010058250 abagovomab Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- RAFKCLFWELPONH-UHFFFAOYSA-N acetonitrile;dichloromethane Chemical compound CC#N.ClCCl RAFKCLFWELPONH-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 108091003858 adecatumumab Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045698 antineoplastic Taxanes Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 108010062611 apolizumab Proteins 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 108010001114 bavituximab Proteins 0.000 description 1
- 108010051561 belimumab Proteins 0.000 description 1
- 229960003270 belimumab Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- SIISYXWWQBUDOP-UHFFFAOYSA-N bis(1H-imidazol-2-yl)methanethione Chemical compound N=1C=CNC=1C(=S)C1=NC=CN1 SIISYXWWQBUDOP-UHFFFAOYSA-N 0.000 description 1
- 108010007057 bivatuzumab mertansine Proteins 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 108090000514 blinatumomab Proteins 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CYKRMWNZYOIJCH-UHFFFAOYSA-N bromo(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(Br)N1CCCC1 CYKRMWNZYOIJCH-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- LUEHNHVFDCZTGL-UHFFFAOYSA-M but-2-ynoate Chemical compound CC#CC([O-])=O LUEHNHVFDCZTGL-UHFFFAOYSA-M 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 108010016799 cantuzumab mertansine Proteins 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 108091005269 cixutumumab Proteins 0.000 description 1
- 108010050895 clivatuzumab Proteins 0.000 description 1
- 238000003181 co-melting Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 108010070304 conatumumab Proteins 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000004858 cycloalkoxyalkyl group Chemical group 0.000 description 1
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- LOGSONSNCYTHPS-UHFFFAOYSA-N cyclopentane-1,3-dione Chemical compound O=C1CCC(=O)C1 LOGSONSNCYTHPS-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 108010049391 dacetuzumab Proteins 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000036576 dermal application Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion media Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 108010069578 ecromeximab Proteins 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 108010007604 epratuzumab Proteins 0.000 description 1
- 108090000148 ertumaxomab Proteins 0.000 description 1
- 108010059577 etaracizumab Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical class OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 1
- SJKTUPAXGHJDEB-UHFFFAOYSA-N ethyl N-(5-bromopyridin-2-yl)carbamate Chemical compound CCOC(=O)NC1=CC=C(Br)C=N1 SJKTUPAXGHJDEB-UHFFFAOYSA-N 0.000 description 1
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 230000001747 exhibiting Effects 0.000 description 1
- 108010025050 figitumumab Proteins 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- OSTIHFXUTPZJQL-UHFFFAOYSA-N fluoro benzoate Chemical compound FOC(=O)C1=CC=CC=C1 OSTIHFXUTPZJQL-UHFFFAOYSA-N 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010073818 fresolimumab Proteins 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 108010012206 galiximab Proteins 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003463 hyperproliferative Effects 0.000 description 1
- 108010061572 ibritumomab tiuxetan Proteins 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 108010009550 intetumumab Proteins 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 108010093819 iratumumab Proteins 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 108010067624 labetuzumab Proteins 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 108010046731 lexatumumab Proteins 0.000 description 1
- 108010018575 lintuzumab Proteins 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 108010020744 lucatumumab Proteins 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108010021856 mapatumumab Proteins 0.000 description 1
- 108010029633 matuzumab Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 108010017913 milatuzumab Proteins 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 229960000060 monoclonal antibodies Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 108010071242 naptumomab estafenatox Proteins 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 108010033813 necitumumab Proteins 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- 108010043585 nimotuzumab Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 108010052070 ofatumumab Proteins 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 108010049284 olaratumab Proteins 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 108010060422 oregovomab Proteins 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QJVSMHJWAOSBMD-MYXYZBIASA-L pemetrexed disodium heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 QJVSMHJWAOSBMD-MYXYZBIASA-L 0.000 description 1
- 108010092042 pemtumomab Proteins 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 108010042024 pertuzumab Proteins 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229930001140 podophyllotoxin Natural products 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002250 progressing Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- ROSKZJGILXBSFM-UHFFFAOYSA-N pyrimidin-2-ylmethanamine Chemical compound NCC1=NC=CC=N1 ROSKZJGILXBSFM-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 108010026911 ramucirumab Proteins 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108010011457 rilotumumab Proteins 0.000 description 1
- 108091002741 robatumumab Proteins 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 108010043794 sibrotuzumab Proteins 0.000 description 1
- 230000001743 silencing Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005156 substituted alkylene group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QWUBZAZOZWCENL-UHFFFAOYSA-N tert-butyl 4-(6-aminopyridin-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=CC(N)=N1 QWUBZAZOZWCENL-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-M thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 1
- 108010092179 tigatuzumab Proteins 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 108091021661 tositumomab I-131 Proteins 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 108010063727 veltuzumab Proteins 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 108010010249 visilizumab Proteins 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 108010023055 zalutumumab Proteins 0.000 description 1
- 108010052251 zanolimumab Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
The present invention provides a compound of Formula (I) or a salt thereof; and therapeutic uses of these compounds. The present invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.
Description
AMINOHETEROARYL BENZAMIDES AS KINASE INHIBITORS
BACKGROUND
Protein s are involved in very x signaling cascades that regulate most
cellular ons, including survival and proliferation. These signaling pathways have
been heavily studied, particularly in the context of disorders caused by dysregulated
cellular function, such as cancer. The extracellular signal-regulated kinases (ERKs) are
one class of signaling kinases that are involved in ing extracellular signals into
cells and subcellular organelles. ERK1 and 2 (ERK1/2) are kinases in the mitogen
activated protein kinase (MAPK) pathway, and are also referred to as p42 and p44,
respectively. ERK1 and ERK2 are present in relatively large quantities in cells (~107
molecules per cell), and are involved in regulating a wide range of activities. lndeed,
dysregulation of the ERK1/2 e is known to cause a variety of pathologies including
neurodegenerative diseases, developmental es, diabetes and . Wortzel and
Seger, Genes & Cancer, 2:195-209 (2011), published online 9 May 2011.
The role of ERK1/2 in cancer is of special interest because activating mutations upstream
of ERK1/2 in its signaling cascade are believed to be responsible for more than half of all
s. Moreover, excessive ERK1/2 ty was also found in s where the
upstream components were not mutated, suggesting that ERK1/2 signaling plays a role in
carcinogenesis even in cancers without onal activations. The ERK pathway has
also been shown to control tumor cell migration and invasion, and thus may be
associated with metastasis. See A. von Thun, et al., ERK2 drives tumour cell migration in
3D microenvironments by suppressing expression of Rab17 and Liprin-,82, J. Cell
Sciences, online ation date 10 Feb. 2012. In addition, it has been reported that
silencing either ERK1 or ERK2 using shRNA killed melanoma cells in culture, and also
made ma cells more sensitive to inhibitors of BRAF. J. Qin, et al., J. Translational
m10:15 (2012). It is also reported that inhibitors of ERK1 and 2 are effective on tumor
cells resistant to MEK inhibitors, and that inhibition of MEK and ERK simultaneously
provides synergistic activity. Molec. Cancer eutics, vol. 11, 1143 (May 2012).
lndazole derivatives acting as ERK inhibitors have been reported as therapeutics for
treating cancers. WO2012/030685; WO2007/070398; WO2008/153858. Certain 2-amino
pyridine/pyrimidine compounds with a biaryl linkage to a pyridone or similar ring have also
been reported as inhibitors of ERK useful for treating cancer and hyperproliferative
disorders: W02013/130976. Other inhibitors of ERK have also been disclosed as
therapeutic agents, see e.g., /016597. Because of their therapeutic value, new
inhibitors of ERK1 and / or ERK2 are needed to treat disorders associated with undesired
levels of ERK1/2 activity. The current invention es novel compounds that inhibit
ERK1 or ERK2 or both, for use to treat diseases such as cancer that are associated with
excessive ty of ERK1 and/or ERK2.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a compound of the formula (I):
Y L\
\\ R
NI \ X
or a pharmaceutically acceptable salt thereof, wherein:
R1 is an optionally substituted group selected from C3_8 cycloalkyl, 5-8 ed
heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members,
, -SOg-phenyl, -C(O)—phenyl, -C(R8)2-phenyl, and 5-6 membered heteroaryl ring,
wherein said heterocyclyl and heteroaryl contain 1-2 heteroatoms ed from N, O and
S as ring members,
and n the optional substituents for R1 are 1-3 groups independently
selected from D, halo, hydroxy, amino, -N(R8)2, CN, C1_4 alkyl, C1_4 alkoxy, -S(C1_4 alkyl),
CM haloalkyl, CM haloalkoxy, C3_6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2
atoms selected from N, O and S, oxo t on aromatic rings), CN, COORB,
CON(R8)2, -NR8-C(O)R8, -NR8-C(O)OR8 -sozR8, -NR8802R8, and 802N(R8)2, where each
R8 is independently H or C1_4 alkyl;
L is a bond, or L can be a CM alkylene, C2_4 alkenylene, CM alkynylene, C3_6
cycloalkyl or a 4-7 membered heterocycloyl containing 1-2 heteroatoms selected from N,
O and S as ring members, wherein L is optionally substituted with 1-3 groups
ndently selected from R“, D, OH, NH2, -NHR“, -NHC(=O)R“, -NHC(=O)—OR“, -
NchoyNHz-NHcFoyNHR“,¢«R“h,CN,hadr%,CONG¥h,aijOOREnmem
each R11 is independently CM alkyl, which may be substituted with up to three groups
independently selected from D, halo, OH, NH2,-NHMe, -NMe2, -OP(O)(OH)2 and O-C1_4
alkyl;
X and Y are independently selected from H, D, halo, CN, amino, y, C1_4
alkyl, C1_4 haloalkyl, C1_4 alkoxy, and C1_4 haloalkoxy;
R2 is H, C1_4 alkyl, or aryl-C1_2-alkyl-, wherein the aryl and C1_4 alkyl are optionally
substituted with halo, CN, C1_4 alkyl, C1_4 haloalkyl, C3_6 cycloalkyl, C1_4 alkoxy, C1_4
koxy, or C1_4 alkylsulfonyl;
or R2 can cyclize with X to form a 5-7 membered heterocyclic ring
containing 1-2 heteroatoms selected from N, O and S fused to the phenyl
ring to which X is attached,
or R2 can cyclize with L to form a 5-7 ed cyclic ring
containing 1-2 heteroatoms selected from N, O and 8,
wherein the al heterocyclic ring formed by R2 cyclizing
with X, or by R2 cyclizing with L, can be optionally substituted with
one or two groups independently selected from CN, halo, CM alkyl,
CM alkoxy, CM haloalkyl, CM haloalkoxy, oxo, CN, COOR7,
CON(R7)2, and -SOZR7;
each R7 is independently H or CH alkyl;
ZSNMCW;
R4 is H, D, halo, C1_4 alkyl, C1_4 haloalkyl, or C1_4 alkoxy;
R5 is selected from —C(O)—R55’1 and R58; wherein R581 is an optionally tuted C3_8
cycloalkyl, C3_8 cycloalkenyl, saturated or unsaturated 3-8 membered heterocyclic ring
containing 1-2 atoms selected from N, O and S, phenyl, or 5-6 membered
heteroaryl ring containing 1-3 heteroatoms selected from N, O and 8, wherein the
al substituents for R5 are 1-4 groups independently selected from D, halo, hydroxy,
amino, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy, C3-6
cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and
S, oxo (except on aromatic rings), CN, -COOR9, -C(O)R9, CON(R9)2, -NR9C(O)R9, -
R9, -SO2R9, -NR9SO2R9, and -SO2N(R9)2, where each R9 is independently H or
C1-4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH,
NH2, NHMe and NMe2; and two tuents on the same or adjacent carbon atoms of R5
can optionally be taken together to form a 5-6 membered ring that can be saturated or
aromatic and contains 1-2 atoms selected from N, O and S and can optionally be
substituted with 1-2 groups ndently selected from D, Me, halo, OH, oxo, O(C1-4
alkyl), NH2, C1-4 alkylamino, di(C1-4 alkyl)amino; and
R6 is H, D, halo, C1-4 alkyl, or C1-4 haloalkyl;
including the ceutically acceptable salts of these compounds, for e a HCl
salt form, and isotopically enriched versions of the compounds and salts, especially
deuterated versions of the compounds, and salts thereof. These nds are
inhibitors of ERK1 and/or ERK2, and are accordingly useful to treat conditions associated
with excessive or undesired levels of activity of ERK1 and/or ERK2, particularly cancers
that respond to inhibitors of ERK1 and/or ERK2.
In a particular aspect, the present invention provides a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
[FOLLOWED BY PAGE 4a]
R1 is an optionally substituted group selected from C3-8 cycloalkyl, 5-8 ed
heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring s,
phenyl, -SO2-phenyl, -C(O)-phenyl, -C(R8)2-phenyl, and 5-6 membered heteroaryl ring,
wherein said heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from N, O and
S as ring members,
and wherein the optional tuents for R1 are 1-3 groups independently
selected from D, halo, hydroxy, amino, 2, CN, C1-4 alkyl, C1-4 alkoxy, -S(C1-4 alkyl),
C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2
heteroatoms selected from N, O and S, oxo (except on aromatic rings), COOR8,
CON(R8)2, -NR8-C(O)R8, -NR8-C(O)OR8 -SO2R8, -NR8SO2R8, and SO2N(R8)2, where each
R8 is independently H or C1-4 alkyl;
L is
wherein R” is methyl or ethyl, and is optionally substituted with fluoro, amino,
hydroxy, methylamino, ethylamino, ylamino, -OP(O)(OH)2, methoxy or ethoxy;
X and Y are independently selected from H, D, halo, CN, amino, hydroxy, C1-4
alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 koxy;
R2 is H, C1-4 alkyl, or 1alkyl-, wherein the aryl and C1-4 alkyl are optionally
substituted with halo, CN, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4
haloalkoxy, or C1-4 alkylsulfonyl; or
R2 and L are linked together to form a heterocyclic group selected from
morpholine, piperidine, thiomorpholine, piperazine, and pyrrolidine that is attached to R1
and is also optionally substituted with one or two groups independently selected from C1-4
alkyl, C1-4 alkoxy, oxo, CN, COOR7, CON(R7)2, and -SO2R7, where each R7 is
independently H or C1-4 alkyl;
Z is N or CR4;
R4 is H, D, halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy;
[FOLLOWED BY PAGE 4b]
R5 is selected from –C(O)-R5a and R5a ; wherein R5a is an optionally substituted C3-8
cycloalkyl, C3-8 cycloalkenyl, saturated or unsaturated 3-8 membered heterocyclic ring
containing 1-2 heteroatoms selected from N, O and S, phenyl, or 5-6 membered
heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the
al substituents for R5 are 1-4 groups independently selected from D, halo, hydroxy,
amino, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 yalkyl, C1-4 haloalkoxy, C3-6
cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and
S, oxo (except on aromatic rings), -COOR9, -C(O)R9, CON(R9)2, -NR9C(O)R 9, -
NR 9CO 9,
2R -SO2R9, -NR9SO 9,
2R and -SO2N(R 9)
2, where each R9 is independently H or
C1-4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH,
NH 5
2, NHMe and NMe2; and two tuents on the same or adjacent carbon atoms of R
can optionally be taken together to form a 5-6 membered ring that can be saturated or
aromatic and contains 1-2 heteroatoms selected from N, O and S and can optionally be
substituted with 1-2 groups independently selected from D, Me, halo, OH, oxo, O(C1-4
alkyl), NH2, C1-4 mino, di(C1-4 alkyl)amino; and
R6 is H, D, halo, C1-4 alkyl, or C1-4 haloalkyl.
In another , the invention es pharmaceutical compositions comprising a
compound of Formula (I), or any of the sub-classes thereof that are described herein,
d with at least one pharmaceutically acceptable r or excipient, ally
admixed with two or more pharmaceutically acceptable carriers or excipients. These
compositions are also useful to treat conditions associated with ive or undesired
levels of activity of ERK1 and/or ERK2, particularly cancers that respond to inhibitors of
ERK1 and/or ERK2. The compositions may also comprise one or more co-therapeutic
agents, such as those bed herein, to enhance treatment of the treated condition or
of associated symptoms of the condition.
In another aspect, the invention provides a method to treat a condition characterized by
excessive or undesired levels of activity of one or both of ERK1 and ERK2, wherein the
method comprises administering to a subject in need of such ent an effective
amount of a compound of Formula (I) or any subgenus thereof as described herein, or a
pharmaceutical composition comprising such compound. The subject can be a mammal,
[FOLLOWED BY PAGE 5]
and is preferably a human, and is typically a subject sed with a condition
associated with excessive activity of ERK1 and/or ERK2. Conditions treatable by the
compounds and s described herein include various forms of cancer that are
responsive to ERK1/2 tors, such as solid tumors, adenoma, bladder cancer, brain
cancer, breast cancer, al cancer, colorectal , colon cancer, epidermal
carcinoma, follicular carcinoma, genitourinary cancers, glioblastoma, head and neck
cancers, Hodgkin’s disease, dgkin’s lymphoma, hepatoma, kidney cancer , lung
cancers such as small cell or all cell lung , leukemias such as AML or CML,
multiple myeloma, lymphoid disorders, skin cancers including melanoma, neuroblastoma,
ovarian cancer, pancreatic , prostate cancer, rectal cancer, sarcoma, testicular
cancer, and thyroid cancer. The compounds are especially indicated for use to treat
melanoma, ovarian cancer, d , colon cancer, lung cancer, pancreatic cancer,
cervical cancer, head and neck cancer, and leukemias including chronic onocytic
leukemia (CMML), AML and CML. Indications of special interest for use of the
compounds of the invention include cancers where BRAF mutations like V600E are
present, e.g., melanoma, ovarian cancer, thyroid cancer, colorectal cancer and lung
cancer; breast cancer where the MAPK and/or P|3K pathway is dysregulated; cancers
associated with KRAS mutations such as lung cancer, pancreatic cancer, and colorectal
; cancers having ERK2 mutations such as cervical or head and neck cancers;
leukemia, especially when exhibiting NF-1 mutations; and non-small cell lung cancer
wherein EGFR is mutated.
In one aspect, the invention provides nds of Formula (I) and the subgenera of
Formula (I) described herein, as well as pharmaceutically acceptable salts of these
compounds, and all stereoisomers (including diastereoisomers and enantiomers),
tautomers and isotopically enriched versions thereof (including deuterium substitutions).
Compounds of the present ion also comprise polymorphs of compounds of Formula
| (or subformulae thereof) and salts thereof. These compounds can be for use to treat
conditions responsive to an ERK1/2 inhibitor, such as those described herein, and for use
in the preparation of a medicament for treating these ers, and can be used in
ation with co-therapeutic agents for treating these disorders. The pharmaceutical
compositions and methods described herein can also be used with orformulated with a
co-therapeutic agent; for example, compounds of Formula | and sub-formulae thereof can
be used with or formulated with inhibitors of B-RAF and other therapeutic agents as
further described herein.
In r aspect, the invention provides methods of making the nds of Formula I
as well as key intermediate compounds useful for making the compounds of the
invention.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the X—ray powder diffraction pattern of the free base of 4-(3-amino
((1S,38,48)f|uorohydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromo
fluorophenyl)(methylamino)ethyl)fluorobenzamide.
Figure 2 is a DSC/TGA thermograph of the free base of 4-(3-amino((1S,38,4S)—3-
fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromofluorophenyl)
(methylamino)ethyl)fluorobenzamide.
Figure 3 shows the X—ray powder ction pattern of the HCI salt form of 4-(3-amino
((1S,38,48)f|uorohydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromo
fluorophenyl)(methylamino)ethyl)fluorobenzamide.
Figure 4 is a DSC/TGA thermograph of the HCI salt form of 4-(3-amino((1S,38,4S)—3-
fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromofluorophenyl)
(methylamino)ethyl)fluorobenzamide.
DETAILED DESCRIPTION
The following definitions apply unless otherwise provided or apparent from t:
As used herein, the term “halogen” (or halo) refers to fluorine, bromine, chlorine or iodine.
Halogen-substituted groups and moieties, such as alkyI substituted by halogen (haloaIkyI)
can be mono-, pon- or per-halogenated. Chloro and quoro are preferred halo
substituents on alkyl or IkyI groups, unless ise specified; quoro, chIoro, and
bromo are often preferred on aryl or heteroaryl , unless otherwise specified.
As used , the term “hetero atoms” refers to nitrogen (N), oxygen (0) or sulfur (S)
atoms, in particular nitrogen or oxygen, unless otherwise provided.
WO 66188 2014/062913
As used herein the term “optionally substituted” indicates that a group being described
can be unsubstituted or it can be tuted. Substituted groups are not intended to
encompass numbers, ent or selections of substituent groups that would result in a
nd that is not expected to be stable in water at room temperature for at least long
enough to be administered as a pharmaceutical agent. When multiple substituents are
present, the substituents are selected independently unless otherwise indicated, so where
2 or 3 substituents are present, for example, those tuents may be the same or
different.
As used herein, the term “alkyl” refers to a fully saturated branched or unbranched
hydrocarbon moiety having up to 10 carbon atoms. Unless otherwise provided, alkyl
refers to hydrocarbon moieties having 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
Representative examples of alkyl include, but are not limited to, , ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, tyl, n-hexyl,
3-methylhexyl, 2,2— dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl
and the like.
A substituted alkyl is an alkyl group containing one or more substituents in place of
hydrogen atoms of the unsubstituted alkyl, such as one, two or three substituents, or 1-4
tuents, up to the number of hydrogens present on the unsubstituted alkyl group.
Suitable substituents for alkyl groups, if not otherwise specified, may be selected from
halogen, D, CN, oxo, hydroxy, substituted or unsubstituted C1_4alkoxy, substituted or
unsubstituted C3_6 cycloalkyl, tuted or unsubstituted 3-7 membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from N, O and S as ring members, substituted or
unsubstituted phenyl, amino, lkyl)amino, di(C1_4 alkyl)amino, C1_4 alkylthio, C1_4
alkylsulfonyl, -C(=O)— CM alkyl, COOH, COO(C1_4 , -O(C=O)— CM alkyl, —
NHC(=O)C1_4 alkyl and —NHC(=O)OC1_4 alkyl groups; wherein the substituents for
substituted C1_4alkoxy, substituted C3_6 cycloalkyl, 3-7 membered heterocycloalkyl, and
substituted phenyl are up to three groups independently selected from halo, C1_4alkyl, CM
kyl, D, C1_4 alkoxy, amino, C1_4 alkylamino, di(C1_4 alkyl)amino, hydroxy, and ON.
Preferred substituents for alkyl groups, unless otherwise specified, include halogen, CN,
oxo, hydroxy, C1_4 alkoxy, C3_6 cycloalkyl, phenyl, amino, (CM alkyl)amino, 4
alkyl)amino, C1_4 alkylthio, C1_4 alkylsulfonyl, — C1.4 alkyl, COOH, -COO(C1.4 alkyl), -
O(C=O)—C1_4 alkyl, —NHC(=O)C1_4 alkyl and —NHC(=O)O CM alkyl groups.
As used herein, the term ene” refers to a divalent alkyl group having 1 to 10 carbon
atoms, and two open valences to attach to other molecular components. The two
molecular components attached to an alkylene can be on the same carbon atom or on
different carbon atoms; thus for example propylene is a 3-carbon ne that can be
1,1-disubstituted, substituted or 1,3-disubstituted. Unless otherwise provided,
alkylene refers to moieties having 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
Representative examples of alkylene include, but are not limited to, methylene, ne,
ylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-
pentylene, isopentylene, tylene, n-hexylene, 3-methylhexylene, 2,2-
dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, ndecylene
and the like. A tuted ne is an ne group containing one or
more, such as one, two or three tuents; unless otherwise specified, suitable and
preferred substituents are selected from the substituents described as suitable and
preferred for alkyl groups.
Similarly, “alkenylene” and “alkynylene” refer to alkylene groups having a double bond or
a triple bond, respectively; they are typically 2-6 and often 2-4 carbon atoms in length,
and can be substituted as explained for alkylene groups generally.
As used herein, the term “haloalkyl” refers to an alkyl as defined herein, which is
substituted by one or more halo groups as defined herein. Unless otherwise specified,
the alkyl portion of the haloalkyl has 1-4 carbon atoms. The kyl can be
monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl including perhaloalkyl. A
monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a
combination of different halo groups within the alkyl. Typically the polyhaloalkyl contains
up to 6, or 4, or 3, or 2 halo groups. miting examples of haloalkyl include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, romethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo—alkyl refers to an
alkyl having all hydrogen atoms replaced with halo atoms, e.g., trifluoromethyl. Preferred
haloalkyl groups, unless specified otherwise, include monofluoro-, difluoro- and trifluoro-
substituted methyl and ethyl groups, e.g. CF3, CF2H, CFH2, and CH2CF3.
WO 66188
As used herein, the term “alkoxy” refers to alkyl-O-, wherein alkyl is as defined above.
Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy,
propoxy, 2—propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. lly,
alkoxy groups have 1-6 carbons, more commonly 1-4 carbon atoms.
A “substituted alkoxy” is an alkoxy group containing one or more, such as one, two or
three substituents on the alkyl portion of the alkoxy. Unless otherwise specified, suitable
and red substituents are selected from the substituents listed above for alkyl
groups, except that hydroxyl and amino are not normally present on the carbon that is
directly attached to the oxygen of the substituted ‘alkyl-O’ group.
As used herein, the term “haloalkoxy” refers to haloalkyl-O-, n haloalkyl is defined
above. Representative es of haloalkoxy include, but are not limited to,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2—chloroethoxy, 2,2,2-
oroethoxy, 1,1,1,3,3,3-hexafluoro-2—propoxy, and the like. Typically, haloalkyloxy
groups have 1-4 carbon atoms, and up to three halogens, e.g., monofluoro, difluoro and
trifluoro substituted methoxy groups and ethoxy groups.
Similarly, each alkyl part of other groups like “alkylaminocarbony , alkoxyalkyl”,
“alkoxycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”,
“haloalkyl” shall have the same meaning as described in the above-mentioned definition
of “alkyl”. When used in this way, unless otherwise indicated, the alkyl group is often a 1-
4 carbon alkyl and is not further substituted by groups other than the component named.
When such alkyl groups are substituted, suitable substituents are selected from the
le or preferred substituents named above for alkyl groups unless otherwise
specified.
As used herein, the term "cycloalkyl" refers to saturated or rated non-aromatic
monocyclic, bicyclic, tricyclic or spirocyclic hydrocarbon groups of 3-12 carbon atoms: the
lkyl group may be unsaturated, and may be fused to another ring that can be
saturated, unsaturated or aromatic, provided the ring atom of the lkyl group that is
connected to the molecular a of interest is not an ic ring atom. Unless
otherwise provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and
9 ring carbon atoms or between 3 and 7 ring carbon atoms. ably, cycloalkyl groups,
unless otherwise specified, are saturated monocyclic rings having 3-7 ring atoms, e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A tuted cycloalkyl is a lkyl group substituted by 1-3 (one, two, three), or more
than three substituents, up to the number of hydrogens on the tituted group.
lly, a substituted lkyl will have 1-4 or 1-2 substituents. le substituents,
unless otherwise specified, are independently selected from the group consisting of
halogen, hydroxyl, thiol, cyano, nitro, oxo, C1_4 -alkylimino, C1_4 -alkoximino, hydroxyimino,
C1_4 -alkyl, C2_4-alkenyl, C2_4-alkynyl, C1_4 -alkoxy, C1_4 -thioalkyl, C2_4-alkenyloxy, C24-
alkynyloxy, C1_4 -alkylcarbonyl, y, C1_4 -alkoxycarbonyl, amino, C1_4 -alkylamino, di-
C1_4 -alkylamino, C1_4 -alkylaminocarbonyl, C1_4 -alkylaminocarbonyl, C1_4 -
alkylcarbonylamino, C1_4 -alkylcarbonyl(C1_4 -alkyl)amino, C1_4 -alkylsulfonyl, C1_4 -
alkylsulfamoyl, and C1_4 -alkylaminosulfonyl, where each of the aforementioned
hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further
substituted by one or more groups independently selected at each occurrence from the
list of substituents for ‘alkyl’ groups herein. Preferred substituents for a cycloalkyl, unless
otherwise specified, include CM alkyl and the tuent groups listed above as red
substituents for alkyl groups.
Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, exyl and cyclohexenyl and the like.
Similarly, each cycloalkyl part of other groups like “cycloalkyloxy , cycloalkoxyalkyl”,
“cycloalkoxycarbonyl”, alkoxy-carbonylalkyl”, “cycloalkylsulfonyl”, “halocycloalkyl”
shall have the same meaning as bed in the above definition of “cycloalkyl”. When
used in these terms, the lkyl is typically a monocyclic 3-7 carbon ring that is
unsubstituted or is substituted with 1-4 groups, commonly 1-2 groups. When (optionally)
substituted, the substituents are typically selected from CM alkyl and those groups set
forth above as suitable or preferred substituents for alkyl groups, unless otherwise
specified.
As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-14
carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl
having 6-14 carbon atoms, often 6-10 carbon atoms, e.g., phenyl or naphthyl. Phenyl is
sometimes preferred. Furthermore, the term "aryl” as used herein, refers to an aromatic
substituent which can be a single aromatic ring, or multiple ic rings that are fused
together. Non-limiting examples e phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl,
provided the tetrahydronaphthyl is connected to the formula being described h a
carbon of the aromatic ring of the tetrahydronaphthyl group.
A substituted aryl is an aryl group substituted by 1-5 (such as one, or two, or three)
substituents independently selected from the group consisting of hydroxyl, thiol, cyano,
nitro, C1_4 -alkyl, C2_4-alkenyl, C2_4-alkynyl, C1_4 -a|koxy, C1_4 |kyl, C2_4-alkenyloxy, C24-
alkynyloxy, halogen, C1_4-alkylcarbonyl, carboxy, C1_4-alkoxycarbonyl, amino, CM-
alkylamino, di- C1_4 -a|kylamino, C1_4 -a|kylaminocarbonyl, di- C1_4 -alkylaminocarbonyl, C1_4
-a|kylcarbonylamino, C1_4 -alkylcarbonyl(C1_4 )amino, C1_4 -a|kylsulfonyl, sulfamoyl, C1.
lsulfamoyl, and C1_4 -alkylaminosulfonyl where each of the afore-mentioned
arbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy es) may be further
substituted by one or more groups independently selected at each occurrence from the
groups listed above as le substituents for alkyl groups. Preferred tuents for a
substituted aryl group, unless otherwise specified, are C1_4alkyl, halogen, CN, y,
substituted or unsubstituted CM alkyl, substituted or unsubstituted CM alkoxy, tuted
or unsubstituted C3_6 cycloalkyl, substituted or unsubstituted 3-6 membered
heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S as ring members,
amino, (C1_4alkyl)amino, di(C1_4 alkyl)amino, C1_4 alkylthio, C1_4 alkylsulfonyl, -C(=O)— C1_4
alkyl, COOH, COO(C1_4 alkyl), -O(C=O)— CM alkyl,—NHC(=O)C1_4 alkyl and —NHC(=O)O
CM alkyl groups; wherein the substituents for substituted C1-4 alkoxy, substituted C3_6
cycloalkyl, 3-6 membered heterocycloalkyl, and substituted alkyl are up to three groups
independently selected from halo, oxo, C1_4alkyl, CM haloalkyl, CM alkoxy, amino,
hydroxy, and ON.
Similarly, each aryl part of other groups like “aryloxy , aryloxyalky , aryloxycarbonyl”,
“aryloxy-carbonylalkyl” shall have the same meaning as described in the above-
mentioned definition of “aryl”.
As used herein, the term “heterocyclyl” or “heterocycloalkyl” refers to a heterocyclic radi-
cal that is saturated or partially unsaturated but not aromatic, and can be a monocyclic or
a polycyclic ring, ing a fused or bridged bicyclic, lic or spirocyclic ring system.
A heterocycle or heterocyclyl contains at least one non-carbon atom as a ring member,
typically N, O or 8 unless otherwise ied. Unless otherwise specified, a heterocyclyl
group has 3 to 10, and preferably 4 to 7 ring atoms; wherein one or more, preferably one
to four, especially one or two ring atoms are heteroatoms independently selected from O,
S and N (the remaining ring atoms ore being carbon). An unsaturated heterocyclyl
can have one or two double bonds, but is not aromatic. ably, unless described as
unsaturated, the heterocyclyl groups in the compounds of the invention are saturated
single rings. Even though described at times as, e.g., a C54; atom group, a cycle
contains at least one heteroatom as a ring atom and has the total number of ring atoms
stated, e.g. 5 or 6 in this example; so a C54; heterocyclyl group refers to a 5-6 membered
heterocyclic ring wherein at least one ring member is a heteroatom. Preferably, a
heterocyclyl group has one or two atoms as ring atoms, and preferably the
heteroatoms are not directly connected to each other. The bonding ring (i.e. the ring
connecting to the Formula of interest) preferably has 4 to 7 ring atoms. The heterocyclic
group can be fused to an ic ring, provided the atom of the heterocyclic group
attached to the Formula of interest is not aromatic. The heterocyclic group can be
attached to the Formula of interest via a heteroatom ally nitrogen) or a carbon atom
of the heterocyclic group. The cyclyl can comprise fused or bridged rings as well
as spirocyclic ring systems (e.g., 2-oxaazaspiro[3.3]heptane), and only one ring of a
polycyclic heterocyclic group needs to contain a atom as a ring atom. Examples of
heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-
dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,
pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-
dithiane, ane, thiomorpholine, and the like.
A substituted heterocyclyl is a heterocyclyl group independently substituted by 1-5 (such
as one, or two, or three) substituents selected from the substituents described above as
suitable or preferred for a lkyl group, unless otherwise specified.
Similarly, each heterocyclyl part of other groups like “heterocyclyloxy”,
ocyclyloxyalkyl”, “heterocyclyloxycarbonyl” shall have the same meaning as
described in the above-mentioned definition of “heterocyclyl”.
A “cyclic ether” as used herein refers to a heterocyclic ring containing 0 as a ring atom,
typically a 4-8 membered ring, e.g., oxetane, tetrahydrofuran or tetrahydropyran. A cyclic
ether of 5-8 members can contain two non-adjacent oxygen atoms as ring members, e.g.,
dioxane and dioxolane. These rings can be substituted as for heterocyclic rings;
2014/062913
preferred substituents if not otherwise ied include CM alkyl (e.g., methyl, ethyl), CN,
OH, NH2, NHR, NR2, COOH, COOR, CONRZ, and OR, where each R is independently C1.
4alkyl. Typically, for stability reasons, OH, NH2, NHR, and NR2 substituents are not
attached at a ring carbon directly bonded to an oxygen atom in the ring.
As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic-
or tricyclic-aromatic ring system, having 1 to 8 heteroatoms as ring members; the
atoms are selected from N, O and 8. Typically, the heteroaryl is a 5-10 membered
ring system, e.g., a 5-6 membered monocyclic or an 8-10 membered bicyclic group.
Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-
imidazolyl, 1-, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or
olyl, 3-, 4-, or azolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2, 3-triazolyl), 1- or 2-
or 3-tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4-, or 5-
pyrimidinyl.
The term oaryl” also refers to a group in which a heteroaromatic ring is fused to one
or more aryl, cycloalkyl, or heterocyclyl rings, where the radical or point of attachment to
the Formula of interest is on a heteroaromatic ring. Nonlimiting examples include 1-, 2-,
3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl,
and 2-, 3-, 4-, 5-, 6-, or 7-indazolyl.
A substituted heteroaryl is a heteroaryl group having one or more substituents on the
heteroaryl ring replacing a hydrogen atom that would be on the unsubstituted heteroaryl,
typically 1, 2 or 3 substituents, selected from the tuents described above as suitable
or preferred for an aryl group, unless otherwise ied.
Similarly, each heteroaryl part of other groups like “heteroaryloxy”, “heteroaryloxyalkyl”,
“heteroaryloxycarbonyl” shall have the same meaning as described in the above-
ned definition of “heteroaryl”.
Various embodiments of the invention are described herein. It will be recognized that
es specified in each embodiment may be combined with other specified features to
e further ments of the present invention. The following enumerated
embodiments are representative of the invention.
Embodiment 1. A compound of formula (I):
Y L\
\\ R
Nl \ X
R6J\(Z
or a pharmaceutically acceptable salt thereof, wherein:
R1 is an optionally substituted group selected from C3_8 cycloalkyl, 5-8 ed
heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members,
phenyl, -SOg-phenyl, phenyl, 2-phenyl, and 5-6 membered heteroaryl ring,
wherein said heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from N, O and
S as ring members,
and wherein the al substituents for R1 are 1-3 groups independently
selected from D, halo, hydroxy, amino, -N(R8)2, CN, C1_4 alkyl, C1_4 alkoxy, -S(C1_4 alkyl),
CM haloalkyl, CM haloalkoxy, C3_6 cycloalkyl, 3-6 ed heterocyclyl containing 1-2
heteroatoms selected from N, O and S, oxo (except on aromatic rings), CN, COORB,
CON(R8)2, -NR8-C(O)R8, (O)OR8 -802R8, -NR8802R8, and 802N(R8)2, where each
R8 is independently H or C1_4 alkyl;
L is a bond, or L can be a CM alkylene, C2.4 alkenylene, CM alkynylene, C34;
cycloalkyl or a 4-7 membered heterocycloyl containing 1-2 heteroatoms selected from N,
O and S as ring members, n L is optionally substituted with 1-3 groups
independently selected from R“, D, OH, NH2, -NHR“, O)R“, O)—OR“, -
NHC(=O)—NH2, -NHC(=O)—NHR“, -N(R“)2, CN, halo, N3, CON(R7)2, and COOR7; where
each R11 is independently CM alkyl, which may be substituted with up to three groups
independently selected from D, halo, OH, NH2,-NHMe, -NMe2, -OP(O)(OH)2 and O-C1_4
alkyl;
X and Y are independently selected from H, D, halo, CN, amino, hydroxy, C1_4
alkyl, C1_4 haloalkyl, C1_4 alkoxy, and C1_4 haloalkoxy;
R2 is H, C1_4 alkyl, or 1_2-alkyl-, wherein the aryl and C1_4 alkyl are ally
substituted with halo, CN, C1_4 alkyl, C1_4 kyl, C3_6 cycloalkyl, C1_4 alkoxy, C1_4
haloalkoxy, or C1_4 alkylsulfonyl;
or R2 can cyclize with X to form a 5-7 membered heterocyclic ring
containing 1-2 heteroatoms selected from N, O and S fused to the phenyl
ring to which X is ed,
or R2 can cyclize with L to form a 5-7 membered heterocyclic ring
containing 1-2 heteroatoms selected from N, O and 8,
wherein the optional heterocyclic ring formed by R2 cyclizing
with X, or by R2 cyclizing with L, can be optionally substituted with
one or two groups independently selected from CN, halo, C1.4 alkyl,
CM , CM haloalkyl, CM haloalkoxy, oxo, CN, COOR7,
CON(R7)2, and -802R7;
each R7 is independently H or CH alkyl;
ZSNMCW;
R4 is H, D, halo, C1_4 alkyl, C1_4 haloalkyl, or C1_4 alkoxy;
R5 is selected from —C(O)—R55’1 and R58; wherein R581 is an ally substituted C3_8
cycloalkyl, C3_8 cycloalkenyl, saturated or unsaturated 3-8 ed heterocyclic ring
containing 1-2 heteroatoms selected from N, O and S, phenyl, or 5-6 membered
heteroaryl ring containing 1-3 heteroatoms selected from N, O and 8, wherein the
optional substituents for R5 are 1-4 groups independently selected from D, halo, hydroxy,
amino, CN, C1_4 alkyl, C1_4 alkoxy, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1_4 haloalkoxy, C3_6
cycloalkyl, 3-6 ed heterocyclyl containing 1-2 heteroatoms selected from N, O and
s, oxo (except on aromatic rings), CN, -COOR9, -C(O)R9, CON(R9)2, -NR9C(O)R9, -
NR9cozR9, -802R9, -NR9802R9, and -SOZN(R9)2, where each R9 is independently H or
C1_4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH,
NH2, NHMe and NMe2; and two tuents on the same or adjacent carbon atoms of R5
can optionally be taken together to form a 5-6 membered ring that can be saturated or
aromatic and contains 1-2 heteroatoms selected from N, O and S and can ally be
substituted with 1-2 groups independently selected from D, Me, halo, OH, oxo, O(C1_4
alkyl), NH2, C1_4 alkylamino, di(C1_4 alkyl)amino; and
R6 is H, D, halo, C1_4 alkyl, or C1_4 haloalkyl.
Embodiment 2. The compound ing to embodiment 1 or a pharmaceutically
acceptable salt thereof, wherein Z is N.
Embodiment 3. The compound of embodiment 1 or a pharmaceutically acceptable
salt thereof, wherein Z is CH.
Embodiment 4. The compound according to any of embodiments 1-3 or a
ceutically acceptable salt thereof, wherein R2 is H or Me.
Embodiment 5. The compound according to any one of embodiments 1 to 4 or a
pharmaceutically acceptable salt thereof, wherein R6 is H.
Embodiment 6. The nd according to any one of embodiments 1 to 5 or a
pharmaceutically acceptable salt thereof, wherein R5 is selected from —C(O)—R55’1 and R58;
wherein R581 is selected from C3_8 cycloalkyl, 5-8 membered cyc|y| containing 1-2
heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl, and is
optionally substituted with 1-3 groups independently selected from D, halo, CN, hydroxy,
C1_4 , C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1_4 haloalkoxy, -802R’, -N(R’)2, -
O)—R’, and —SOZNR’2, where each R’ is independently H or C1_4 alkyl.
Embodiment 7. The compound according to any of embodiments 1-6, wherein R5 is
selected from R52’1 and R58; wherein R581 is selected from , pyridine, pyridone,
pyrazine, pyridazine, pyrazole, triazole, tetrazole, thiazole, oxazole, imidazole, azole,
isoxazole, furan, and thiophene, each of which is optionally substituted with one or two
groups independently selected from halo, D, CN, CM alkyl, C1_4alkoxy, CM haloalkyl, CM
hydroxyalkyl, c1.4 haloalkoxy, CN, COORQ, CON(R9)2, and -802R9, where each R9 is
independently H or CH alkyl.
Embodiment 8. The compound of embodiment 3 or a ceutically able
salt thereof, wherein R5 is selected from —C(O)—R5a and R521; wherein R581 is C5_6 heteroaryl
containing at least one N as a ring member, which is optionally substituted with 1-2
groups independently selected from halo, CN, CM alkyl, CM haloalkyl, CM hydroxyalkyl,
CM alkoxy, and CM haloalkoxy.
WO 66188
Embodiment 9. The compound of embodiment 8 or a pharmaceutically acceptable
salt thereof, wherein R5 is selected from R55’1 and R5a; n R581 is le or
triazole and is optionally substituted with 1-2 groups independently selected from halo,
CN, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1_4 alkoxy, and C1_4 haloalkoxy.
Embodiment 10. The compound according to any of embodiments 1-6, wherein R5 is
selected from —C(O)—R55’1 and R58; wherein R581 is selected from cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl, tetrahydropyran, dihydropyran, tetrahydrofuran, oxetane,
azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrothiopyran
(thiacyclohexane), and tetrahydrothiofuran (thiacyclopentane), each of which is optionally
substituted with 1-3 groups independently selected from halo, D, CN, N(R9)2, hydroxy, C1.
4alkyl, C1_4 alkoxy, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1_4 haloalkoxy, oxo, CN, COORQ,
CON(R9)2, )R9, R9, -NH802R9, and -802R9, where each R9 is
independently H or CH alkyl.
Embodiment 11. The compound of any of embodiments 1-10, n R1 is phenyl
and is optionally substituted with up to three groups independently selected from halo, D,
CN, 01.4 alkoxy, 01.4 alkyl, 01.4 haloalkyl, 01.4 haloalkoxy, SR’, -SOZR’, -N(R’)2, -NR’-C(O)—
R’, and —SOZNR’2, where each R’ is independently H, C1_4 alkyl or C1_4 haloalkyl.
Embodiment 12. The compound of any of embodiments 1-10, wherein R1 is
thiophene, thiazole, pyridine, pyrimidine, pyrazine or pyridazine, and is optionally
tuted with up to three groups independently ed from halo, CN, C1_4alkoxy, CM
alkyl, CM haloalkyl, C1_4 haloalkoxy, , -N(R’)2, -NR’-C(O)—R’, and —802NR’2, where
each R’ is independently H or C1-4 alkyl.
Embodiment 13. The compound according to any of embodiments 1 to 12 or a
pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting
of: cyclopropane-1,1-diyl; ropane-1,2-diyl; and , wherein R” is H, D, or C1-2
alkyl optionally substituted with up to three groups independently selected from D,
hydroxy, halo, amino, C12 alkylamino, 2 alkyl)amino, and C12 alkoxy.
Embodiment 14. The compound of embodiment 13, wherein L is:
WO 66188
wherein R” is methyl or ethyl, and is optionally substituted with fluoro,
amino, hydroxy, methylamino, ethylamino, dimethylamino, -OP(O)(OH)2, methoxy
or ethoxy.
Embodiment 15. The compound according to any of ments 1 to 14 or a
pharmaceutically acceptable salt thereof, wherein R2 and L are linked together to form a
heterocyclic group selected from morpholine, piperidine, thiomorpholine, piperazine, and
pyrrolidine that is attached to R1 and is also optionally substituted with one or two groups
independently selected from C1_4 alkyl, C1_4alkoxy, oxo, CN, COOR7, CON(R7)2,
and -SOZR7, where each R7 is independently H or CM alkyl.
Embodiment 16. The compound of any of ments 1-15, wherein Y is H,
methyl, or halo.
Embodiment 17. The compound of any of embodiments 1-16, n X is H, or R2
cyclizes with X to form a 5-7 ed cyclic ring fused to the phenyl ring to which
X is attached, wherein the 5-7 membered ring is optionally substituted as described in
Embodiment 1.
Embodiment 18. The compound of ment 1, which is of the Formula IA:
Y 0 §
NH2 N\/\
(IA)
wherein R5 is pyrazole, imidazole, isoxazole, isothiazole, oxazole, triazole, or
thiazole, which can be substituted with up to two groups independently selected from D,
F, Cl, CN, Me, OMe, Et, iPr, OEt, and CF3;
Y is H, F, Cl, or Me;
R10 is H or—CHz-R*, where R* is H, -OH, F, -NH2, -NHMe, -NMe2, -OP(O)(OH)2 or
—OMe; and
R1 is phenyl or thienyl, optionally substituted with 1-2 groups independently
selected from halo, CN, C1_4alkyl, C1_4alkoxy, CM haloalkyl, CM haloalkoxy, CN, COORB,
)2, -SMe, and , where each R8 is ndently H or CH alkyl;
or a pharmaceutically acceptable salt thereof.
Embodiment 19. The compound of embodiment 1, which is of the Formula IB:
Y 0 E10
NH2 N\/\
('3)
n R5 is a 4-7 membered cyclic ether or C54; cycloalkyl, and R5 can be substituted
with up to four groups independently selected from D, F, Cl, CN, amino, NHMe, NMe2, -
CHZOH, -NHC(O)Me, -NHCOOMe, -NHSOzMe, Me, OMe, OH, oxo, Et, iPr, OEt, CN, and
CF3;
Y is H, F, Cl, or Me;
R10 is H or—CHz-R*, where R* is H, -OH, F, -NH2, -NHMe, -NMe2, -OP(O)(OH)2 or
—OMe; and
R1 is phenyl, optionally substituted with 1-2 groups independently selected from
halo, CN, C1_4alkyl, C1_4alkoxy, c1.4 haloalkyl, 01.4 haloalkoxy, CN, COORB, CON(R8)2,
and -802R8, where each R8 is independently H or C1.4 alkyl;
or a pharmaceutically acceptable salt thereof.
Embodiment 20. The compound of any one of embodiments 1-6 or 19, wherein R5 is
cyclohexyl substituted with 1-3 groups groups independently selected from D, F, Cl, CN,
amino, NHMe, NMe2, Me, NHSOZMe, NHCOMe, OMe, OH, Et, CN, , and CF3.
In an alternative to embodiment 20, the compound of any one of embodiments 1-6
or 19 wherein R5 is tetrahydropyranyl, especially 4-tetryahdropyranyl.
In another ative, the compound of any of embodiments 1-6 or 19, wherein
R5 is selected from:
QHIF © QF
OH OH
ment 21. The compound of any one of ments 1-20, wherein R1 is
phenyl substituted with 0, 1 or 2 groups ndently selected from F, Cl, Br, I, SMe,
SOzMe, and CH3.
Embodiment 22. The compound of embodiment 1, which is selected from the group
consisting of the compounds of Examples 1-452 and pharmaceutically acceptable salts
thereof.
ment 23. A pharmaceutical composition comprising a compound according
to any one of embodiments 1-22 admixed with at least one pharmaceutically acceptable
excipient.
Embodiment 24. The pharmaceutical composition of embodiment 23, further
comprising a therapeutic co-agent.
Embodiment 25. The pharmaceutical composition of embodiment 24, wherein the
therapeutic co-agent is selected from anticancer compounds, analgesics, and antiinflammatory
compounds.
Embodiment 26. A method to treat , sing administering to a subject in
need of such treatment a eutically effective amount of a nd according to
any of ments 1-20 or a pharmaceutical composition of any of embodiments 23-25.
Embodiment 27. The method of embodiment 26, wherein the cancer is selected from
adenoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal ,
colon cancer, epidermal carcinoma, follicular carcinoma, genitourinary cancers,
glioblastoma, head and neck cancers, Hodgkin’s disease, non-Hodgkin’s lymphoma,
hepatoma, head and neck cancers, kidney cancer, lung s such as small cell or
non-small cell lung cancer, leukemias such as AML or CML, multiple myeloma, id
disorders, skin cancers including melanoma, neuroblastoma, ovarian cancer, pancreatic
cancer, prostate cancer, rectal cancer, sarcoma, testicular cancer, and thyroid cancer.
Embodiment 28. A compound according to any one of embodiments 1-22 for use as
a medicament.
Embodiment 29. Use of a compound according to any one of embodiments 1 to 22
or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of ; or use of a compound according to any one of embodiments 1 to 22
or a pharmaceutically acceptable salt thereof in medicine, ally for treatment of a
cancer such as those named in embodiment 27.
Embodiment 30. A method of sythesizing a compound of the invention. For
example, a method for synthesizing 4-(3-amino((1S,38,4S)—3-fluoro
hydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide comprising:
(a). reacting 5-((1S,3S,4S)—4-((tert-butyldimethylsilyl)oxy)—3-fluorocyclohexyl)pyrazin
amine with utyl 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate in
the presence of Pd(dppf)C|2, DCM, Na2C03 and DME to form tert-butyl 4-(3-amino
((18,38,48)((tert-butyldimethylsilyl)oxy)fluorocyclohexyl)pyrazinyl)—2-
fluorobenzoate;
(b). reacting tert-butyl 4-(3-amino((1S,38,48)((tert-butyldimethylsilyl)oxy)
fluorocyclohexyl)pyrazinyl)fluorobenzoate in the presence of HCI, ETOH and NaOH
to form 4-(3-amino((1S,38,4S)—3-fluorohydroxycyclohexyl)pyrazinyl)
fluorobenzoic acid;
(c). reacting 4-(3-amino((18,38,4S)fluorohydroxycyclohexyl)pyrazinyl)
fluorobenzoic acid with (S)—N-(2—amino(3-bromofluorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide hydrochloride in the presence of EDCI and HOAT to give 4-(3-
amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromo
fluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)—2—fluorobenzamide; and
(d). reacting 4-(3-amino((18,38,4S)fluorohydroxycyclohexyl)pyrazinyl)-N-((S)-
1-(3-bromofluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)
fluorobenzamide in the presence of LiOH, DMF and 4-mercaptobenzoic acid to give 4-
(3-amino((18,38,4S)fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromo
fluorophenyl)(methylamino)ethyl)fluorobenzamide.
Embodiment 31. The invention provides a high crystallinity HCI salt of mino
((1S,38,48)fluorohydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromo
fluorophenyl)(methylamino)ethyl)fluorobenzamide in that said form has at least one
of the following characteristics:
a) A X-ray powder ction pattern with two or more peaks (preferably three peaks,
able all peaks) at s 2—theta (wherein the angle variation is +/- 0.3, 0.2
or 0.1 degrees) as shown in Example 184;
b) A X-ray powder diffraction pattern with peaks substantially the same as depicted
in the Figure 3; or
c) A thermal gravimetric analysis curve substantially in ance with that shown
in Figure 4.
In some embodiments of Formula | or lA or IB, Y is H or halo, particularly F or Cl. Halo,
especially F, is preferred. Y may be positioned ‘ortho’ to the yl depicted in these
Formulas.
In many ments of the compounds described above, X is H. In other embodiments,
X is a group ortho to the carbonyl shown in Formula I, such as F, Me or Cl, and in some
such embodiments, X is a group that, taken together with R2 as described herein, forms a
ring fused to the phenyl ring shown in Formula |. This fused ring is typically a 5, 6 or 7
atom ring, and may contain, in addition to the N to which R2 is attached, an additional N,
O or S as a ring . The fused ring can be substituted or unsubstituted; when
substituted, it can have one or two substituents as described for Formula (I), with halo, C1.
4 alkyl, 0x0, and hydroxy as preferred tuents unless otherwise specified.
In some embodiments of the compounds of Formula I and other ments described
above, R2 is H or Me, and is preferably H. In alternative embodiments, R2 and X taken
togetherform a 5-7 membered heterocyclic ring as described for Formula I above, in
which case X is attached to the phenyl ring at a position ortho to the carbonyl group
depicted in Formula I.
In certain of the foregoing embodiments, L is a C1_4 alkylene, which may be straight chain
or branched, and can be unsubstituted or substituted with 1-3 groups as described for
Formula I. In some embodiments, L is a group of the formula -CH(RL)- where RL is a C1.
3 alkyl or a C12 alkyl and is optionally substituted with 1-3 groups as described for Formula
I. Preferably, L is C12 alkyl and is substituted by 1 or 2 groups independently selected
from hydroxy, halo, amino, OMe, -NHMe, (OH)2 and —NMe2. In some
ments, particularly where R1 is an aryl or heteroaryl group, L is -CH2- or a
substituted alkylene of the formula —CH(CH2R*)- where R* is H, Me, OH, F, NH2, NHMe, -
OP(O)(OH)2 or OMe. In other embodiments, L is -CH2CH2—. When L is substituted, it is
often substituted with methyl, hydroxymethyl, aminomethyl, methylamino,
methylaminomethyl, fluoromethyl, or ymethyl.
In embodiments where L is substituted ne (e.g., a group of formula —CHR”- as
described herein), L contains a chiral center; in certain of these embodiments, L has this
stereochemistry:
>-u|:u
[N1 [R11
where [N] and [R1] indicate the ons where -CH(R”)— is connected to NR2 and
R1, respectively. ably, R” is -CH3, -CH20H, -CH2NH2, -CH2NHMe, -CH2NMe2, -
CH2F, -CH20Me, -CH(OH)Me, (O)(OH)2 or -CH(OH)CH20H. In some
ments, the compound of Formula (I) comprises L having the chiral configuration
shown in excess over its enantiomer, so the compound is optically active. Preferably,
such compounds of the invention are substantially free of the opposite enantiomer, i.e., at
least 95% of the compound has the chirality shown above.
In some embodiments of the foregoing compounds, R1 is aryl or heteroaryl, optionally
substituted as described below, and commonly R1 is an optionally substituted group
ed from phenyl, thienyl, thiazolyl, nyl, pyridazinyl, pyrazinyl, and pyrimidinyl.
Substituted phenyl is preferred for R1.
R1 is often substituted with at least one group selected from those described for the
embodiments described above. In some ments, R1 is phenyl, 3-thienyl, 2-
thiazolyl, 2-pyridinyl, or 3-pyridinyl that is unsubstituted or is substituted with 1-2 groups
independently selected from halo (F, Cl, Br or I), , methoxy, -SMe, methylsulfonyl,
cyano, and cyclopropyl. In some ments, R1 is phenyl and is substituted in at least
one position ‘meta’ to [L] (the position of R1 that is attached to L) with F, Cl, Br, I, SMe,
CH2F, CHF2, or methylsulfonyl.
In some ments, the -C(=O)—NR2-L-R1 portion of the structure in Formula (I) has the
following formula, where W1 and W2 are selected independently:
o gHzR" R* = H, OH, NH2, NHMe,
i NMeg, OMe, F, (OH)2
EL NH \
I 22 = CH
w1,w2 = H, F, Cl, CN,
w2 -SOZMe, Me, OMe, Br,
I, CH2F, CF2H, SMe
In these embodiments, at least one of W1 and W2 is typically other than H, and preferably
at least one of W1 and W2 is halo, particularly Cl, Br or I.
In some embodiments of the compounds of the invention, R6 is H or Me; often R6 is H.
In some embodiments of any of the compounds bed above, Z is N. In alternative
embodiments of any of the compounds described above, Z is CR4, preferably CH.
WO 66188
In some embodiments, R5 is a 5-6 membered heteroaryl ring or phenyl, and may be
substituted as described for a | above. In such embodiments, R5 can be phenyl,
pyridyl, pyridazinyl, or pyrimidinyl, optionally substituted as bed above. In other
such embodiments, R5 is a nitrogen-containing 5-membered heteroaryl ring, such as
pyrazole, ole, isoxazole, oxazole, thiazole, triazole, tetrazole, isothiazole, e,
and the like, optionally substituted as described above; in these embodiments, Z is
preferably CH. Pyrazoles, triazoles, and oles are sometimes preferred options for
In the embodiments wherein R5 is heteroaryl, R5 may be unsubstituted or it may be
substituted with 1-3 groups independently selected from Me, Et, isopropyl, propyl, butyl, t-
butyl, sec-butyl, isobutyl, CF3, CN, Cl and F.
Some preferred embodiments of these R5 groups include:
JV'V M M
5A 5A 5A 5A 5A
/ \ \ /
N—N N_ N
RSA/ R5A RSA/ R5A
I I I
JVV Mn. WV
R5A R5A\ R5A A R5A
N)E/ N)E/ N N/
>\ N )_N >_(
R5A \R5A R5A RSA R5A
where each R5A is independently selected from H, Me, Et, propyl, and isopropyl.
Preferably, no more than one or two of the R581 groups on R5 are other than H, and in most
embodiments, R5A on N in these groups is methyl, ethyl, or isopropyl. Specific suitable
groups include 1-methylpyrazole, 1-ethylpyrazole, 1-isopropylpyrazole, and 3-
pyrazole and its tautomer; ylimidazolyl, 1-methylimidazolyl, 1-methylimidazol-
-yl; and methyl-substituted versions of these.
2014/062913
In other embodiments, R5 is a non-aromatic cycloalkyl or heterocyclic group such as
cyclohexyl, cyclopentyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), 3-oxetanyl, 3- or 4-
piperidinyl, 4- or 3- piperidinonyl, 3- or 4-thiacyclopentane, 3-thiacyclohexane, 3-
tetrahydrofuran, and the like. In these embodiments, a ring sulfur can be oxidized to
sulfoxide or sulfone oxidation state, and each of these rings may be substituted with 1-3
groups, typically 1-2 groups, selected from oxo, Me, Et, isopropyl, CF3, CN, Cl and F.
Some preferred examples of these ments include:
NH2 NHMe NM62 NH2
The 1,4-disubstituted cyclohexyl embodiments can have either a cis or trans relative
stereochemistry n the groups attached at positions 1 and 4; in some
embodiments, a trans relative ation between these groups is preferred. Suitable
cycloalkyl and heterocyclyl embodiments of R5 include:
0 (1, Q, Q, 0,
0H 6H OH OH OH
OMe CHZF CHF2 CHZOH
Preferred embodiments of R5 include these:
Where R5 is heterocyclic or cycloalkyl and is substituted, it frequently will contain at least
one chiral center. In these chiral compounds, both R and S isomers can be used
dually, as well as mixtures of R and 8, including a racemic mixture. The compounds
of the invention can also include somers where rotation about an heteroaryl-
aryl(heteroaryl) bond is hindered by the presence of substituent groups; in these
situations, each atropisomer is ed. Where one isomer (enantiomer, diastereomer,
atropisomer, or geometric isomer) has higher intrinsic activity as an inhibitor of ERK1 or
ERK2 than its opposite isomer, the more active isomer is lly preferred.
As used herein, the term “optical isomer” or “stereoisomer” refers to any of the various
stereo isomeric configurations which may exist for a given nd of the present
invention and includes geometric isomers. It is understood that a substituent may be
attached at a chiral center of a carbon atom. The term "chiral" refers to molecules which
have the property of non-superimposability on their mirror image partner, while the term
"achiral" refers to les which are superimposable on their mirror image partner. The
invention includes enantiomers, diastereomers or racemates of the compounds.
“Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of
each other. A 1:1 mixture of a pair of enantiomers is a "racemic” e. The term is
used to designate a racemic e where appropriate. "Diastereoisomers” are
stereoisomers that have at least two asymmetric atoms, but which are not mirror-images
of each other. The absolute stereochemistry is specified according to the Cahn-lngold-
Prelog ‘R-S’ . When a compound is a pure enantiomer, the chemistry at
each chiral carbon may be specified by either R or 8. Resolved compounds whose
absolute uration is unknown can be designated (+) or (-) depending on the direction
o- or levorotatory) which they rotate plane polarized light at the wavelength of the
sodium D line. Certain compounds described herein contain one or more asymmetric
centers or axes and may thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute chemistry, as (R)— or
(S)--
Depending on the choice of the ng materials and synthesis procedures, the
compounds can be present in the form of one of the possible isomers or as mixtures
thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates
and diastereoisomer mixtures, depending on the number of tric carbon atoms.
The t invention is meant to include all such possible isomers, including racemic
mixtures, riomeric mixtures and optically pure forms. Optically active (R)— and (S)-
isomers may be prepared using chiral synthons or chiral reagents, or resolved using
conventional techniques. If the compound contains a double bond, the substituent may
be E or Z configuration unless specified. If the compound contains a di-substituted
cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration, unless
otherwise specified. All eric forms are also intended to be ed.
In many cases, the compounds of the present invention are capable of forming acid
and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups
similar o. As used herein, the terms “salt” or “salts” refers to an acid addition or
base addition salt of a compound of the invention. “Salts” include in particular
aceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to
salts that retain the biological effectiveness and ties of the nds of this
invention and, which typically are not biologically or otherwise undesirable.
Pharmaceutically acceptable acid addition salts can be formed with nic acids and
organic acids, e.g., acetate, adipate, aluminum, ascorbate, aspartate, benzoate, besylate,
bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,
caproate, chloride/hydrochloride, chloroprocaine, chlortheophyllonate, citrate, edetate,
calcium edetate, ethandisulfonate, ethylsulfonate, ethylene e, fumarate, galactarate
(mucate), gluceptate, gluconate, glucuronate, glutamate, glycolate, hexyl resorcinate,
hippurate, hydroiodide/iodide, hydroxynapthoate (xinafoate), isethionate, e,
lactobionate, laurylsulfate, lithium, malate, maleate, malonate, mandelate, mesylate,
methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate,
palmitate, pamoate, pantothenate, phosphate/hydrogen phosphate/dihydrogen
phosphate, polygalacturonate, procaine, propionate, salicylate, sebacate, stearate,
subacetate, ate, sulfate, sulfosalicylate, e, te, bitartrate, tosylate,
triphenylacetate, and trifluoroacetate salts. Lists of additional suitable salts can be found,
e.g., in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th ed., Mack hing Company,
, Pa., (1985); and in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES,
SELECTION, AND USE, by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
In one embodiment, the present invention provides 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2—fluorobenzamide in acetate, ascorbate, adipate, aspartate, benzoate, besylate,
bromide/hydrobromide, onate/carbonate, bisulfate/sulfate, camphorsulfonate,
e, chloride/hydrochloride, heophyllonate, citrate, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate,
hydroiodide/iodide, isethionate, e, lactobionate, laurylsulfate, malate,
maleate, malonate, ate, mesylate, methylsulphate, mucate, naphthoate,
napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate,
sebacate, stearate, succinate, alicylate, sulfate, tartrate, te
trifenatate,trifluoroacetate or xinafoate salt form.
In another embodiment, the present invention provides 4-(3-amino((1S,38,4S)—3-
fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromofluorophenyl)
(methylamino)ethyl)fluorobenzamide in hydrochloride salt form.
Inorganic acids from which salts can be derived include, for e, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic
acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, ic acid, methanesulfonic acid, ethanesulfonic
acid, esulfonic acid, trifluoroacetic, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic or organic
bases and can have inorganic or organic counterions.
Inorganic counterions for such base salts include, for example, ammonium salts and
metals from columns | to XII of the periodic table. In certain embodiments, the counterion
is selected from sodium, ium, ammonium, alkylammonium having one to four C1-
C4 alkyl groups, calcium, magnesium, iron, silver, zinc, and ; particularly suitable
salts e ammonium, potassium, sodium, calcium and ium salts.
Organic bases from which salts can be derived include, for example, primary, secondary,
and tertiary amines, substituted amines including naturally ing substituted amines,
cyclic amines, basic ion exchange , and the like. Suitable organic amines e
isopropylamine, benzathine, ate, diethanolamine, diethylamine, lysine, meglumine,
piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a
basic or acidic moiety, by conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a stoichiometric amount of
the appropriate base (such as Na, Ca, Mg, or K ide, carbonate, bicarbonate or the
like), or by ng free base forms of these compounds with a stoichiometric amount of
the appropriate acid. Such reactions are typically d out in water or in an organic
solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl
e, tetrahydrofuran, toluene, chloroform, dichloromethane, methanol, ethanol,
isopropanol, or acetonitrile is desirable, where practicable.
Any formula given herein is intended to represent unlabeled forms (i.e., compounds
n all atoms are present at natural isotopic abundances, and not isotopically
enriched) as well as isotopically enriched or labeled forms of the compounds. lsotopically
enriched or labeled compounds have structures depicted by the formulas given herein
except that at least one atom of the compound is replaced by an atom of the same
element but having an atomic mass or mass number different from the atomic mass or
the atomic mass distribution that occurs naturally. Examples of isotopes that can be
incorporated into enriched or labeled compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H,
11C, 13C, 14C, 15N, 18F 31P, 32P, 358, 36Cl, 125| respectively. The ion includes various
isotopically labeled compounds as defined herein, for example those in which radioactive
isotopes, such as 3H and 14C, or those in which non-radioactive isotopes, such as 2H and
13C, are present at levels icantly above the natural abundance for these isotopes.
These isotopically labeled compounds are useful in lic studies (with 14C), reaction
kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as
positron emission tomography (PET) or single-photon emission computed tomography
(SPECT) including drug or substrate tissue bution assays, or in radioactive treatment
of patients. In particular, an 18F or labeled compound may be particularly desirable for
PET or SPECT studies. lsotopically-labeled compounds of formula (I) can generally be
prepared by conventional techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and Preparations using an
appropriate isotopically-labeled ts in place of the non-labeled t previously
employed.
Further, tution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford
certain therapeutic advantages resulting from greater lic stability, for example
increased in vivo ife or reduced dosage requirements or an improvement in
therapeutic index. It is tood that deuterium in this context is regarded as a
substituent of a compound of the formula (I) if it is incorporated at substantially above the
level of natural isotopic abundance. The invention includes isotopically enriched versions
of the compounds, e.g., deuterated versions as well as non-deuterated versions.
Deuterated versions may be deuterated at a single site, or at multiple sites.
The degree of incorporation of such an isotope in an isotopically-enriched compound,
particularly deuterium, may be defined by the isotopic enrichment . The term
"isotopic enrichment factor" as used herein means the ratio n the isotopic
abundance of a specified isotope in a sample, and the natural abundance of the isotope
in a non-enriched sample. If a substituent in a compound of this invention is d
deuterium, such compound has an isotopic enrichment factor for each designated
deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated
deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500
(82.5% deuterium incorporation), at least 6000 (90% ium oration), at least
6333.3 (95% deuterium oration), at least 6466.7 (97% deuterium oration), at
least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those
wherein the t of crystallization may be isotopically substituted, e.g. D20, d6-
acetone, d6-DMSO, as well as solvates with non-enriched solvents.
Compounds of the invention, e.g., compounds of a (I) that contain groups capable
of acting as donors and/or acceptors for hydrogen bonds, may be capable of forming co-
crystals with suitable co-crystal formers. These co-crystals may be prepared from
compounds of formula (I) by known co-crystal g procedures. Such procedures
include ng, heating, co-subliming, co-melting, or contacting in solution compounds
of formula (I) with the co-crystal former under crystallization conditions and isolating co-
crystals thereby formed. Suitable co-crystal formers include those described in WO
2004/078163. Hence the invention further provides stals comprising a compound
of formula (I).
As used herein, the term "pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g.,
antibacterial agents, antifungal ), isotonic agents, absorption delaying agents,
salts, preservatives, drug stabilizers, s, excipients, disintegration , lubricants,
sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as
would be known to those skilled in the art (see, for example, REMINGTON'S
PHARMACEUTICAL SCIENCES, 18th Ed. Mack Printing y, 1990, pp. 1289-1329).
Except r as any conventional r is incompatible with the active ingredient, its
use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a nd of the present ion
refers to an amount of the compound of the present invention that will elicit the biological
or medical response of a subject, for example, reduction or inhibition of an enzyme or a
protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease
progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a
therapeutically effective amount” refers to the amount of the nd of the present
invention that, when administered to a subject, is ive to (1) at least partially alleviate,
inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by a
kinase such as ERK1/2 or (ii) associated with activity of a kinase such as ERK1/2, or (iii)
characterized by activity (normal or abnormal) of ERK1/2; or (2) reduce or inhibit the
activity of ERK1/2 or (3) reduce or inhibit the expression of ERK1/2.
In another non-limiting embodiment, the term “a therapeutically effective ” refers to
the amount of the compound of the present invention that, when administered to a cell, or
a , or a non-cellular biological material, or a medium, is effective to at least partially
reduce or inhibit the activity of ERK1/2, or at least partially reduce or inhibit the
expression of ERK1/2.
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal.
A t also refers to for e, primates (e.g., humans, male or female), cows,
sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain
embodiments, the subject is a e. In specific embodiments, the subject is a human.
As used herein, the term “inhibit”, "inhibition" or iting” refers to the reduction or
suppression of a given condition, activity, effect, symptom, or disorder, or disease, or a
significant decrease in the baseline activity of a biological activity or process.
As used herein, the term “treat
, treating" or "treatment" of any disease or er refers
in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the clinical symptoms thereof).
In another embodiment “treat”, ing" or "treatment" refers to alleviating or
ameliorating at least one physical parameter including those which may not be discernible
by the patient. In yet r embodiment, “treat”, "treating" or "treatment" refers to
ting the disease or disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., ization of a physical parameter), or both. In yet
another embodiment, “treat”, "treating" or "treatment" refers to delaying the development
or progression of the disease or disorder.
As used herein, a subject is “in need of” a treatment if such subject would be expected to
benefit biologically, medically or in quality of life from such treatment.
As used , the term "a,” "an,” "the” and similar terms used in the context of the
present invention (especially in the context of the claims) are to be construed to cover
both the singular and plural unless otherwise indicated herein or clearly contradicted by
the t.
All methods described herein can be performed in any suitable order unless otherwise
indicated herein or ise clearly contradicted by context. The use of any and all
examples, or exemplary language (e.g. "such as”) provided herein is intended merely to
better illuminate the invention and does not pose a limitation on the scope of the invention
otherwise claimed.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present
invention can be present in racemic or enantiomerically enriched, for example the (R)—,
(S)— or (R,S)— configuration. In certain embodiments, each asymmetric atom has at least
50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric
excess, at least 80 % omeric excess, at least 90 % enantiomeric excess, at least 95
% enantiomeric excess, or at least 99 % enantiomeric excess of either the (R)— or (8)-
configuration; i.e., for optically active compounds, it is often preferred to use one
enantiomer to the substantial exclusion of the other omer. Substituents at atoms
with carbon-carbon double bonds may, where possible, be present in cis- (Z)- or trans-
(E)— form, and both are included in the invention unless otherwise indicated.
Accordingly, as used herein a compound of the present invention can be in the form of
one of the possible isomers, rotamers, atropisomers, or tautomers or as a mixture thereof,
for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical
isomers (antipodes), racemates or mixtures thereof. ‘Substantially pure’ or ‘substantially
free of other isomers’ as used herein means the product contains less than 5%, and
preferably less than 2%, of other s relative to the amount of the preferred isomer,
by weight.
Any resulting es of isomers can be separated on the basis of the physicochemical
differences of the constituents, into the pure or substantially pure geometric or optical
isomers, reomers, racemates, for e, by chromatography and/or fractional
crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical
des by known methods, e.g., by separation of the diastereomeric salts f,
obtained with an optically active acid or base, and liberating the optically active acidic or
basic compound. In particular, a basic moiety may thus be employed to resolve the
compounds of the present ion into their optical antipodes, e.g., by fractional
llization of a salt formed with an lly active acid, e.g., tartaric acid, dibenzoyl
ic acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid
or camphorsulfonic acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral
adsorbent.
Furthermore, the compounds of the present invention, including their salts, can also be
obtained in the form of their hydrates, or e other ts used for their
crystallization. The compounds of the present invention may inherently or by design form
solvates with pharmaceutically acceptable solvents (including water); therefore, it is
intended that the invention embrace both solvated and unsolvated forms. The term
te" refers to a molecular complex of a nd of the present invention (including
pharmaceutically acceptable salts thereof) with one or more t molecules. Such
solvent molecules are those ly used in the pharmaceutical art, which are known
to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate"
refers to the complex where the solvent molecule is water.
The compounds of the present invention, including salts, hydrates and solvates thereof,
may inherently or by design form polymorphs.
The compounds of a (I) can be ed according to the Schemes and examples
provided herein. The Schemes in some instances illustrate preparation of compounds
wherein L is methylene or a substituted alkylene group, but methods for preparing
suitable benzamides where L is a bond or other options encompassed by Formula (I) are
readily nt to the skilled person in view of the many known methods for making the
ite benzamide intermediates, so these methods are equally applicable to
preparation of compounds with other embodiments of L.
Scheme A.
0 R10
Y 0 R10 Y A
\ A PyBrop, HOBt \\ N R1
L: OH + HZN R1 L} H
/\XI DIEA, THF /
Br x
A B C
NH2 NH2 NH2 NH2 oR
N)\ N/S NJ\/Br | —’ N)\(B\OR
R6 Reyz| —> RekfzI —> R6J\¢ZI
Br R5 R5 R5
F G
B\ NH2 06H\ N R1
BrNummfi/x R
Precursors A and B can be coupled using known peptide bond formation conditions to
provide intermediate C. Intermediate C can be coupled with a heteroaryl boronic acid
such as intermediate G under well-known palladium-assisted conditions to form products
of formula H, which are compounds of Formula (I). The requisite yridine/pyrazine
compounds (G) for coupling with Compound C can be prepared from
yridine/pyrazines by introducing a desired R5 group using palladium chemistry
(see intermediate E above), then brominating adjacent to the amino group and converting
to the boronic acid or ester (G). Scheme C illustrates application of this sequence,
including hydrogenation of an olefin to arrive at a compound of formula G, where R5 is a
ydropyran.
Alternatively, as shown in Scheme B, compound C can be converted to an ronic
acid or ester, and can be coupled to heteroaryl bromide F, again using known palladium
zed coupling conditions, to provide compounds of the invention.
Scheme B.
Intermediate F can be prepared by methods known in the art and s disclosed
herein. Numerous compounds of Formula F can be synthesized from known amino-
bromo-pyridines and -pyrazines as illustrated in Scheme C. Various aryl, heteroaryl, and
vinyl boronic acid esters can be coupled to the bromopyridine or bromopyrazine using
ium sts as is known in the art, to introduce a desired R5 group. This method
WO 66188
is especially useful to introduce aryl or heteroaryl groups as R5 in Formula (I). Where the
initial coupling product introduces a partially unsaturated group at the R5 position, as
illustrated in Scheme C, the unsaturation can be reduced by conventional methods to
provide compounds having a ted group (e.g., heterocyclyl or cycloalkyl) as R5. This
option is illustrated in Scheme C, where preparation of a compound having 4-
tetrahydropyranyl as R5 is shown.
Scheme C.
N)\ N \
0‘ /0 Pdd(MD)fCl-DCM
B 2 |
RfikfzI + #R6
NH2 NH2
N \ NJYBF
H2, Pd/C I NBS I
/ Z / Z flR6 —> R6
MeOH
O 0
Scheme D rates another synthesis route, where the group ponding to R5 in
a (I) is attached after the ne or pyrimidine is coupled to the benzamide
portion. The method allows incorporation of a wide array of aryl, heteroaryl or vinylic
(unsaturated) R5 groups, and as illustrated herein, a vinylic R5 group can be reduced after
the coupling reaction to provide a saturated R5 group. Again, the route is depicted with a
benzylic group on the amide nitrogen, corresponding to L = optionally substituted
alkylene, and R1 = optionally substituted , but due to the wide availability of starting
materials and methods for making the amide intermediates, it is equally applicable for
synthesis of compounds with other L and R1 groups. Once the heteroaryl group is
coupled to the benzamide phenyl ring, R5 can be attached by palladium coupling, where
the c acid / ester can be on R5 or on the aminopyridine / aminopyrazine ring. R“ in
this scheme represents optional substituents on the phenyl group, selected to correspond
to substituents on R1 in Formula (I).
WO 66188
Scheme D.
0 R10
NJ\(Br
Pd<dppn)Clz
+ kagY
Rekz jig; ’\X, R2 /
Na2003DME
R5-B(OR)2
Pd catalyst
hi5: R1* O R10
Y\ RR
R5-Br NHz \
l u X
Pd<dppf)CI2 32(PIN)2 “(ka l
, R2 /
KOAC dioxane R6)\( f)CI2 NI \ \X
B ReJYZ
O, ‘o Na2003,DME
Scheme E illustrates a method to make compounds of Formula (I) starting from a 3-
bromoaminopyridine or a corresponding pyrazine, and a benzoate ester substituted
with a boronic acid or ester. After coupling to form a biaryl group, the aminopyridine can
be ated readily under mild conditions, and the desired amide group can be
prepared. R5 can be introduced by palladium-catalyzed replacement of Br from the
pyridine ring. Here again, the boronic acid ester can be on either the aminopyridine ring,
or on the aryl, heteroaryl or vinylic R5 group.
Scheme E.
Y O
Pd(dppf)Cl2- Y O
NQYBr + /
o DCM
NH2 0/ NBS
—’ —’
K/zI Hos
E? Na2003, DME N/ CH3CN
OH \/2I
Y O
Y O H2N
NH2 0/
LiOH (1 M) NH2 OH R“
N / —>
I _
Krz N /
THF, MeOH KrI EDC HOAt
\ Z '
V Y 0 R10
NH2 Sb 0‘ NHz N
B’ H
N/ +
Pd(dppf)C|2—DCM N/
RV \/$ |
NI \ _. R1 * \ Z
N , DME
Br \
Pd (B(OR)2)2
Y 0 R10
Y 0 R10
R5-Br NH2 N
NH2 N
H —>
N / Pd |
$2 1*
R“ Krz R
B(OR)2
The invention further includes any variant of the present processes in which an
intermediate obtainable at any stage thereof is used as starting material and the
ing steps are carried out, or in which the starting materials are formed in situ under
the reaction conditions, or in which the reaction components are used in the form of their
salts or lly pure material. Compounds of the invention and intermediates can be
interconverted ing to methods generally known to those skilled in the art.
In another aspect, the invention provides intermediates useful for the synthesis of the
compounds of Formula (I), including compounds of Formula (II):
wherein Z2 is CH or N;
G is Br or—B(OR21)2;
where each R21 is H or C1_4 alkyl, or two R21 taken er with the linkage
—O-B-O- to which they are attached form a cyclic borate ester;
J is H, F, Cl or Me; and
R20 is H or C1_6alkyl.
In some embodiments, J is advantageously fluoro (F), and in other embodiments J is Cl.
In some embodiments G is a cyclic borate ester group such as 4,4,5,5-tetramethyl-1,3,2—
dioxaborolanyl or 1,3,2—dioxaborolan-2—yl.
In another aspect, the present invention provides a pharmaceutical composition
comprising a compound of the t invention, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable carrier or excipient. The
pharmaceutical composition can be formulated for particular routes of administration such
as oral administration, eral administration, and rectal administration, and the like.
In addition, the pharmaceutical compositions of the present invention can be made up in a
solid form (including without limitation capsules, s, pills, es, powders or
suppositories), or in a liquid form (including without limitation solutions, suspensions or
emulsions). Pills or tablets may be either film coated or c coated according to
methods known in the art. The pharmaceutical compositions can be subjected to
conventional pharmaceutical operations such as sterilization and/or can contain
conventional inert diluents, lubricating agents, or buffering agents, as well as nts,
such as preservatives, stabilizers, g agents, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions comprising compounds of the invention are
tablets or gelatin es comprising a compound of Formula (I) as an active ingredient
together with one or more of the following excipients:
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; for s also
c) binders, e.g., magnesium aluminum te, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired
d) disintegrants, e.g., starches, agar, c acid or its sodium salt, or effervescent
mixtures; and/or
e) absorbents, colorants, flavors and sweeteners.
Selection of suitable capsules for encapsulation and of suitable excipients for formulating
the compound of Formula | to make oral dosage forms is within the ordinary level of skill.
Tablets may be either film coated or enteric coated using s known in the art.
Suitable compositions for oral administration include an effective amount of a compound
of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible
powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. itions
intended for oral use are prepared according to any method known in the art for the
cture of ceutical compositions and such compositions can contain one or
more agents selected from the group consisting of sweetening agents, flavoring agents,
coloring agents and preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient in admixture with
nontoxic ceutically acceptable excipients which are suitable for the manufacture of
tablets, ing the ones listed above. These excipients are, for example, inert diluents,
such as calcium carbonate, sodium carbonate, lactose, m phosphate or sodium
phosphate; granulating and disintegrating agents, for e, corn starch, or alginic
acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for
example magnesium stearate, stearic acid or talc. The s are uncoated or coated by
known techniques to delay disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate can be ed.
Formulations for oral use can be presented as hard gelatin es wherein the active
ingredient is mixed with an inert solid diluent, for e, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed
with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil, to form a
solution, emulsion or dispersion inside the soft capsule.
Certain injectable compositions are s ic solutions or suspensions, and
suppositories are advantageously prepared from fatty emulsions or suspensions. Said
itions may be sterilized and/or contain adjuvants, such as preserving, stabilizing,
wetting or emulsifying agents, solution promoters, salts for regulating the osmotic
pressure and/or buffers. In addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to conventional mixing,
granulating or coating methods, respectively, and n about 0.1-75%, or contain
about 1-50%, of the active ingredient.
Suitable compositions for transdermal ation include an effective amount of a
nd of the invention with a suitable r. Carriers suitable for transdermal
delivery include absorbable pharmacologically acceptable solvents to assist passage
through the skin of the host. For example, transdermal devices are in the form of a
bandage comprising a backing member, a reservoir containing the compound optionally
with rs, optionally a rate controlling r to deliver the compound of the skin of the
host at a controlled and predetermined rate over a prolonged period of time, and means
to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous
solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for
delivery by aerosol or the like. Such topical delivery s will in particular be
appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for
prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly
suited for use in topical, ing cosmetic, ations well-known in the art. Such may
contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal
ation. They may be conveniently delivered in the form of a dry powder (either
alone, as a mixture, for example a dry blend with lactose, or a mixed component particle,
for example with phospholipids) from a dry powder inhaler or an aerosol spray
presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or
without the use of a le propellant.
The t invention further provides anhydrous pharmaceutical compositions and
dosage forms comprising the compounds of the present invention as active ingredients,
where it is desirable to minimize exposure of the compound to water prior to
administration. Anhydrous ceutical compositions and dosage forms of the
invention can be prepared using anhydrous or low moisture containing ingredients and
low moisture or low humidity ions. An anhydrous pharmaceutical ition may
be prepared and stored such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are packaged using materials known to prevent exposure to
water such that they can be included in suitable formulary kits. Examples of suitable
packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose
containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical itions and dosage forms that
comprise one or more agents that reduce the rate by which the compound of the present
invention as an active ingredient will ose. Such agents, which are referred to
herein as "stabilizers,” e, but are not limited to, antioxidants such as ascorbic acid,
pH buffers, or salt buffers, etc.
The compounds of formula I in free form or in salt form, exhibit valuable pharmacological
properties, e.g. they modulate or inhibit activity of ERK1 and/or ERK2, as indicated by test
data provided in the following sections, and are ore indicated for therapy as
described herein, or for use as research chemicals, e.g. as tool compounds to further the
understanding of the effects of EKR1/2 inhibition or inhibition of a mical pathway
(MAPK).
Thus, as a r embodiment, the present invention provides the use of a compound of
a (I) or any of the embodiments within the scope of Formula (I) as described herein,
in therapy, or for the manufacture of a medicament. In a further embodiment, the therapy
or medicament is for a disease which may be treated by tion of ERK1 and/or ERK2.
In another embodiment, the compounds of the invention are useful to treat cancers,
including but not d to those mentioned herein.
In another embodiment, the invention provides a method of ng a disease which is
ble by inhibition of ERK1 and/or ERK2, comprising administration of a
therapeutically effective amount of a compound of formula (I) or (IA) or any of the
embodiments of the invention as described . In a further embodiment, the disease
is selected from the afore-mentioned lists of suitable conditions. The method typically
comprises administering an effective amount of a compound as described herein or a
pharmaceutical composition comprising such compound to a subject in need of such
treatment. The compound may be administered by any suitable method such as those
described herein, and the administration may be repeated at intervals ed by a
treating physician. The ion thus provides a compound of Formula | and IA or any
subgenus thereof as described herein for use to treat a condition ed by or
associated with excessive or undesired levels of ERK1/2 activity, ing those
mentioned above.
Thus, as a further embodiment, the present invention provides the use of a compound of
formula (I), or any of the embodiments of such compounds described herein, for the
manufacture of a medicament. In a further embodiment, the medicament is for treatment
of a disease which may be treated by inhibition of ERK1 and/or ERK2. In another
embodiment, the disease is a cancer, e.g., a cancer selected from the aforementioned
list, suitably.
In some embodiments, the compounds are used in combination with one or more co-
therapeutic agents. Suitable co-therapeutic agents include anticancer agents, analgesics,
nflammatory agents, and the like. In some embodiments, the compositions include a
co-therapeutic agent that acts on the RAF pathway, such as a B-RAF inhibitor or a C-Raf
inhibitor.
In one embodiment, the invention provides a kit comprising two or more separate
pharmaceutical compositions, at least one of which contains a compound of formula (I). In
one ment, the kit comprises means for tely retaining said compositions,
such as a container, divided bottle, or divided foil . An example of such a kit is a
blister pack, as lly used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering ent dosage forms, for
example, oral and parenteral, for administering the separate compositions at different
dosage intervals, or for titrating the separate compositions against one another. To assist
compliance, the kit of the invention typically comprises directions for administration.
In the ation therapies of the invention, the compound of the invention and the other
eutic co-agent may be manufactured and/or formulated by the same or different
manufacturers. Moreover, the compound of the invention and the other therapeutic may
be brought together into a combination therapy: (i) prior to release of the combination
product to physicians (e.g. in the case of a kit sing the compound of the invention
and the other eutic agent); (ii) by the physician themselves (or under the guidance
of the ian) shortly before administration; (iii) in the patient themselves, e.g. during
sequential administration of the compound of the invention and the other therapeutic
agent
Accordingly, the invention provides the use of a compound of formula (I) for treating a
disease or condition mediated by ERK1 and/or ERK2, n the medicament is
prepared for administration with another therapeutic agent. The invention also provides
the use of another co-therapeutic agent for ng a disease or condition, wherein the
co-agent is administered with a compound of formula (I).
The invention also es a compound of formula (I) for use in a method of treating a
disease or ion mediated by ERK1 and/or ERK2, wherein the compound of formula
(I) is ed for stration with another therapeutic agent. The invention also
provides another therapeutic co-agent for use in a method of treating a disease or
condition mediated by ERK1 and/or ERK2, wherein the other therapeutic co-agent is
prepared for administration with a compound of formula (I). The invention also provides a
compound of a (I) for use in a method of ng a e or condition mediated
by ERK1 and/or ERK2, wherein the compound of formula (I) is administered with another
therapeutic co-agent. The invention also provides another co-therapeutic agent for use in
a method of treating a disease or condition mediated by ERK1 and/or ERK2, n the
other therapeutic co-agent is administered with a compound of formula (I).
The invention also provides the use of a compound of formula (I) for treating a disease or
condition mediated by ERK1 and/or ERK2, wherein the patient is one treated previously
or subsequently (e.g. within 24 hours) with another therapeutic agent. The invention also
provides the use of a co-therapeutic agent for treating a disease or condition mediated by
ERK1 and/or ERK2, wherein the patient has previously (e.g. within 24 hours) been
treated with a compound of formula (I).
In one embodiment, the other therapeutic agent (co-therapeutic agent orjust co-agent) is
a compound useful for treating a cancer, and is typically an FDA approved drug approved
for ng at least one type of cancer. le co-therapeutic agents include erlotinib,
bortezomib, trant, sunitib imatinib mesylate, letrozole, finasunate, platins such as
oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin,
lapatinib, lonafamib, sorafenib, gefitinib,capmtothecin, topotecan, bryostatin, adezelesin,
anthracyclin, esin, bizelesin, dolastatin, auristatins, duocarmycin, eleutherobin,
taxols such as paclitaxel or docetaxel, cyclophasphamide, doxorubicin, vincristine,
prednisone or prednisolone, other ting agents such as mechlorethamine,
chlorambucil, and ifosfamide, antimetabolites such as oprine or mercaptopurine,
other ubule inhibitors (vinca alkaloids like vincristine, vinblastine, vinorelbine and
vindesine, as well as taxanes), podophyllotoxins (etoposide, teniposide, etoposide
phosphate, and epipodophyllotoxins), topoisomerase inhibitors, other cytotoxins such as
mycin, ubicin, icin, idarubicin, edrecolomab, epirubicin, cin,
plicamycin, mitomycin, as well as other ncer antibodies (cetuximab, bevacizumab,
ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab,
anatumomab, apolizumab, bavituximab, belimumab, bivatuzumab mertansine,
blinatumomab, brentuximab vedotin, cantuzumab mertansine, catumazomab, cetuximab,
citatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab,
dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, umab,
epratuzumab, ertumaxomab, etaracizumab, uzumab, figitumumab, fresolimumab,
galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan, inotuzumab
ozogamicin, intetumumab, umab, iratumumab, labetuzumab, lexatumumab,
lintuzumab, lucatumumab, lumilisimab, mapatumumab, matuzumab, milatuzumab,
mitumomab, nacolomab tafenatox, naptumomab estafenatox, necitumumab,
nimotuzumab, ofatumumab, olaratumab, oportuzumab monatox, oregovomab,
panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab,
rilotumumab, robatumumab, mab, sibrotuzumab, tacatuzumab etan,
taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab or 131I-
tositumomab, trastuzumab, imumab, tuocotuzumab celmoleukin, veltuzumab,
visilizumab, volocixumab, votumumab, zalutumumab, zanolimumab, lGN-101, MDX-
010,ABX-EGR, EMD72000, , MDX—220, MRA, H-11 scFv, huJ591, TriGem, TriAb,
R3, MT-201, G-250, ACA—125, Onyvax-105, CD:—960,Cea-Vac, BrevaRex AR54, IMC-
1C11, GlioMab-H, lNG-1, anti-LCG MAbs, MT-103, KSB-303, Therex, KW2871, anti-
, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, Prostate Cancer dy,
H22xKi-r, ABX-Mai, lmuteran, Monopharm-C), and antibody-drug ates comprising
any of the above agents (especially auristatins MMAE and MMAF, maytansinoids like
DM-1, calicheamycins, or various cytotoxins). Preferred rapeutics, unless otherwise
specified, include finib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-
0332991, panobinostat, stat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib,
panitumumab, vandetanib, |NC280, everolimus, simolimus, , BYL719, and
CLR457.
The pharmaceutical composition or combination of the present invention can be in unit
dosage of about 1-2000 mg of active ingredient(s) for a subject of about 50-70 kg, or
about 1-500 mg or about 1-250 mg or about 1-150 mg or about 05-100 mg, or about 1-50
mg of active ingredients. The therapeutically effective dosage of a compound, the
pharmaceutical composition, or the combinations thereof, is dependent on the species of
the subject, the body weight, age and individual condition, the er or disease being
treated and the severity thereof. A physician, clinician or veterinarian of ordinary skill can
readily determine the ive amount of each of the active ingredients necessary to
prevent, treat or inhibit the ss of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using
advantageously s, e.g., mice, rats, dogs, monkeys or isolated organs, tissues
and preparations thereof. The compounds of the present invention can be applied in vitro
in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally,
advantageously intravenously, e.g., as a sion or in aqueous solution. The dosage
in vitro may range between about 10-3 molar and 10-9 molar concentrations. A
therapeutically effective amount in vivo may range depending on the route of
administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
The compound of the present invention may be administered either simultaneously with,
or before or after, one or more co-therapeutic agents, also referred to herein as co-
agent(s). The compound of the present invention may be administered separately, by the
same or different route of administration, or together in the same ceutical
composition as the co-agent(s).
In one ment, the invention es a product comprising a compound of formula
(I) and at least one other therapeutic co-agent as a combined preparation for
simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is
the treatment of a disease or condition mediated by ERK1 and/or ERK2, such as cancer.
Products provided as a combined preparation include a composition comprising the
compound of formula (I) and the other therapeutic co-agent(s) together in the same
pharmaceutical ition, or the compound of formula (I) and the other eutic coagent
(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising a
compound of formula (I) and another therapeutic co-agent(s). ally, the
pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as
described above.
In one embodiment, the ion provides a kit comprising two or more separate
ceutical compositions, at least one of which ns a compound of formula (I). In
one embodiment, the kit comprises means for separately retaining said compositions,
such as a container, divided bottle, or divided foil packet. An example of such a kit is a
r pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering ent dosage forms, for
example, oral and parenteral, for administering the te compositions at different
dosage intervals, or for titrating the separate compositions against one another. To assist
compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the invention and the other
eutic nt may be ctured and/or formulated by the same or different
manufacturers. Moreover, the compound of the invention and the other therapeutic may
be brought together into a combination therapy: (i) prior to release of the combination
product to physicians (e.g. in the case of a kit comprising the compound of the invention
and the other therapeutic agent); (ii) by the physician themselves (or under the guidance
of the physician) shortly before administration; (iii) in the patient themselves, e.g. during
sequential administration of the compound of the invention and the other therapeutic
agent
Accordingly, the invention provides the use of a nd of formula (I) for treating a
disease or condition mediated by ERK1 and/or ERK2, wherein the medicament is
ed for administration with another therapeutic agent. The invention also provides
the use of another therapeutic co-agent for ng a disease or condition, wherein the
medicament is administered with a compound of formula (I). Suitable co-therapeutic
agents for use with the nds of the invention are typically selected based on the
condition for treatment. For example, in the ent of ma, the co-therapeutic
agent may be selected from Aldesleukin, Dabrafenib, Dacarbazine, DTIC-Dome
(Dacarbazine), lntron A (Recombinant Interferon Alfa-2b), lpilimumab, Mekinist
(Trametinib), Peginterferon Alfa-2b, PEG-lntron (Peginterferon Alfa-2b) Proleukin
(Aldesleukin), inant Interferon Alfa-2b, Sylatron (Peginterferon Alfa-2b), Tafinlar
(Dabrafenib), Trametinib, Vemurafenib, Yervoy (lpilimumab), and Zelboraf (Vemurafenib).
For the treatment of ovarian cancer, the co-therapeutic agent may be selected from
Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin
Hydrochloride), Carboplatin, Clafen (Cyclophosphamide), Cisplatin, Cyclophosphamide,
Cytoxan phosphamide), bicin Hydrochloride, Dox-SL (Doxorubicin
Hydrochloride Liposome), DOXIL (Doxorubicin Hydrochloride Liposome), Doxorubicin
Hydrochloride Liposome, Evacet (Doxorubicin Hydrochloride Liposome), abine
Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Hycamtin (Topotecan
hloride), LipoDox ubicin Hydrochloride Liposome), Neosar
(Cyclophosphamide), Paclitaxel, Paraplat (Carboplatin), Paraplatin (Carboplatin), Platinol
(Cisplatin), Platinol-AQ (Cisplatin), Taxol (Paclitaxel), and Topotecan Hydrochloride. For
the treatment of thyroid cancer, the co-therapeutic agent may be selected from
Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin
Hydrochloride), Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-
S-Malate), Doxorubicin Hydrochloride, and anib. For the treatment of colon
cancer, the co-therapeutic may be selected from Adrucil (Fluorouracil), Avastin
(Bevacizumab), Bevacizumab ,Camptosar (Irinotecan Hydrochloride), Capecitabine,
Cetuximab, Efudex ouracil), Eloxatin (Oxaliplatin), Erbitux (Cetuximab) ,Fluoroplex
(Fluorouracil), Fluorouracil ecan hloride, Leucovorin Calcium, Oxaliplatin,
Panitumumab, Regorafenib, Stivarga (Regorafenib), ix (Panitumumab), Wellcovorin
(Leucovorin Calcium), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-
Aflibercept. For the treatment of lung cancer, the rapeutic may be selected from
Abitrexate trexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle
Formulation), Afatinib Dimaleate, Alimta (Pemetrexed Disodium), Avastin (Bevacizumab),
Bevacizumab, Carboplatin, Cisplatin, Crizotinib, Erlotinib Hydrochloride, Folex
(Methotrexate), Folex PFS (Methotrexate), Gefitinib, Gilotrif (Afatinib Dimaleate),
Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochlorde), lressa (Gefitinib),
Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ
(Methotrexate), Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation,
at (Carboplatin), Paraplatin (Carboplatin), Pemetrexed Disodium, Platinol
(Cisplatin), Platinol-AQ (Cisplatin), Tarceva (Erlotinib Hydrochloride), Taxol (Paclitaxel),
and ,Xalkori (Crizotinib). For the treatment of pancreatic cancer, the co-therapeutic agent
can be selected from Adrucil (Fluorouracil), Efudex (Fluorouracil), Erlotinib Hydrochloride,
Fluoroplex (Fluorouracil), Fluorouracil, Gemcitabine Hydrochloride, Gemzar (Gemcitabine
Hydrochloride), Mitomycin C, Mitozytrex (Mitomycin C), Mutamycin (Mitomycin) and
Tarceva (Erlotinib Hydrochloride. For the treatment of al cancer, the co-therapeutic
agent may be selected from Blenoxane (Bleomycin), Bleomycin, Cisplatin, Hycamtin
(Topotecan Hydrochloride), ol (Cisplatin), Platinol-AQ atin), and Topotecan
Hydrochloride. For the ent of head and neck cancer, the rapeutic agent may
be ed from Abitrexate (Methotrexate), Adrucil (Fluorouracil), Blenoxane
ycin), Bleomycin, Cetuximab, Cisplatin, Docetaxel, Efudex ouracil), Erbitux
(Cetuximab), Fluoroplex (Fluorouracil), Fluorouracil, Folex (Methotrexate), Folex PFS
(Methotrexate), Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate),
-AQ (Methotrexate), Platinol atin), Platinol-AQ (Cisplatin), and Taxotere
(Docetaxel). For the treatment of leukemia, including CMML, the co-therapeutic agent
can be selected from Bosulif inib), Bosutinib ,Clafen (Cyclophosphamide),
hosphamide, Cytarabine, Cytosar—U (Cytarabine), Cytoxan (Cyclophosphamide),
Dasatinib, Gleevec (lmatinib Mesylate), lclusig (Ponatinib Hydrochloride) ,lmatinib
Mesylate, Neosar (Cyclophosphamide), Nilotinib, Omacetaxine Mepesuccinate, Ponatinib
Hydrochloride, Sprycel inib), Synribo taxine Mepesuccinate), Tarabine PFS
(Cytarabine), and Tasigna (Nilotinib).
The invention also provides a compound of formula (I) for use in a method of ng a
e or condition mediated by ERK1 and/or ERK2, wherein the compound of formula
(I) is prepared for administration with another therapeutic agent. The invention also
provides another therapeutic co-agent for use in a method of treating a disease or
condition mediated by ERK1 and/or ERK2, wherein the other therapeutic co-agent is
prepared for administration with a compound of formula (I). The invention also provides a
nd of formula (I) for use in a method of treating a e or condition ed
by ERK1 and/or ERK2, wherein the compound of formula (I) is administered with another
therapeutic co-agent. The invention also provides another therapeutic co-agent for use in
a method of treating a disease or condition mediated by ERK1 and/or ERK2, wherein the
other eutic co-agent is administered with a compound of formula (I).
The invention also provides the use of a compound of formula (I) for treating a disease or
condition ed by ERK1 and/or ERK2, wherein the patient has previously (e.g. within
24 hours) been treated with another therapeutic agent. The invention also provides the
use of another therapeutic agent for treating a disease or condition mediated by ERK1
and/or ERK2, wherein the patient has previously (e.g. within 24 hours) been d with
a compound of formula (I).
Specific individual ations which may e particular treatment benefits e a
compound of the invention with at least one compound selected from inhibitors of BRAF,
MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, Pl3K, and AKT. Examples of thes
inhibitors include vemurafinib, debrafinib, LGX818, trametinib, MEK162, , PD-
0332991, panobinostat, stat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib,
panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719, and
CLR457.
The following examples are intended to illustrate the invention and are not to be
construed as being limitations thereon. Temperatures are given in degrees Celsius. If
not mentioned otherwise, all evaporations are performed under reduced pressure,
lly between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of
final products, intermediates and starting materials is confirmed by standard analytical
methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.
All starting materials, building blocks, reagents, acids, bases, dehydrating ,
solvents, and sts ed to synthesize the compounds of the present invention are
either commercially available or can be produced by organic synthesis methods known to
one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, METHODS OF ORGANIC
SYNTHESIS, THIEME, Volume 21). Further, the compounds of the present invention can be
produced by organic synthesis s known to one of ry skill in the art in view of
the following examples.
The compounds and/or intermediates were characterized by high performance liquid
chromatography (HPLC) using a Waters Millennium tography system with a
2695 Separation Module rd, MA). The analytical columns were reversed phase
Phenomenex Luna C18 -5 u, 4.6 x 50 mm, from Alltech (Deerfield, IL). A gradient elution
was used (flow 2.5 mL/min), starting with 5% acetonitrile/95% water and progressing to
100% acetonitrile over a period of 10 minutes. All solvents contained 0.1% trifluoroacetic
acid (TFA). nds were ed by ultraviolet light (UV) absorption at either 220 or
254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Ml), or Fisher
Scientific (Pittsburgh, PA).
Mass spectrometric analysis was performed on a Waters System (Waters Acquity UPLC
and a Waters SQD mass spectrometer detector; Column: Phenomenex Kinetex 2.6 um
C18, column size 4.6 x 50 mm; column temperature 50°C. gradient: 2-98% acetonitrile in
water with 0.1% TFA over a 1.5min period; flow rate 1.2 mL/min (or Polar gradient 1-30%
over 1.3 min, NonPolar gradient 55-98% over 1.3min); Mass Spectrometer molecular
weight scan range 0; or 150-1900. cone Voltage 20 V. All masses were reported
as those of the protonated parent ions, unless ise ted. Nuclear magnetic
resonance (NMR) analysis was performed on selected compounds, using a
Varian 400 MHz NMR (Palo Alto, CA). The spectral reference was either TMS or the
known chemical shift of the solvent.
X-ray Powder Diffraction (XRPD) was performed as follows:
X-ray powder diffraction patterns were determined under the following
conditions:
ment: Bruker D8 Discovery
Irradiation: CuK1oc (40 kV, 40 mA)
CuK1 = 1.540598 A
Scan range 3° — 40O (2—theta value)
Scan type: 2—theta scan / detector scan (HI-STAR detector)
Step time 60 seconds per frame
Step size 0.02 s
As will be iated by the skilled , the relative intensities of the various peaks
within the “Table for figure 3” may vary due to a number of factors such as orientation
effects of ls in the X-ray beam or the purity of the material being analysed or the
degree of crystallinity of the sample. The peak positions may also shift for variations in
sample height but the peak positions will remain substntially as defined in the “table for
figure 3”. The skilled person will aslo appreciate that measurements using a different
wavelength will result in different shifts according to the Bragg equation — nk = 2d sin 6.
Such alternative XRPD patterns generated by use of alternative wavelengths are
heless representations of the same material.
Differential Scanning Calorimetry/Thermogravimetric Analysis (DSC/TGA) was performed
as follows:
Instrument: TA DSC QZOOO/TGA Q5000
ature Range: room temperature to 300°C
Scan Rate: 10°/min
Nitrogen Flow: 50 ml/min
As will be tood by persons skilled in the art, slight variantions in observed peaks
are expected based on the specific spectrometer employed and the anlyst’s sample
preparation technique. Some margin of error is present in each of the peak assignments
(+/- cm'1).
Abbreviations used herein have their ordinary meaning in the art unless otherwise
indicated or defined in the following list:
ATP adenosine phosphate
BINAP racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
BOC tertiary butoxycarbonyl
br broad
BSA bovine serum albumin
d doublet
dd doublet of doublets
DCM dichloromethane
DIEA diethylisopropylamine
DME 1,4-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DTT dithiothreitol
EDTA ethylenediamine tetraacetic acid
ESI electrospray ionization
EtOAc ethyl acetate
FCC flash column tography
h )
HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-) 3-
oxide
HOBt 1-hydroxyazabenzotriazole
HPLC high pressure liquid chromatography
IR infrared spectroscopy
LCMS liquid chromatography and mass spectrometry
MeOH methanol
MS mass spectrometry
MW microwave
m multiplet
min s
mL milliliter(s)
m/z mass to charge ratio
NMR nuclear ic resonance
ppm parts per million
PyBOP riazolyloxytripyrro|idinophosphonium hexafluorophosphate
rac racemic
rt room temperature
s singlet
t triplet
TFA trifluoroacetic acid
THF tetrahydrofuran
Tris-HCI aminotris(hydroxymethyl)methane hydrochloride
EXAMPLES
The following examples illustrate certain embodiments of the invention and how to make
and use them, they are not intended to limit the scope of the invention.
Method 1
Example 1
S s of S 3-amino tetrah dro-2H- ran l razin l-N- 2-h drox
phenylethyl )benzamide
Scheme 1
$211112 $2; NH2 mg
NHZ W
\ N)\ N\
NJ\ Pd(dppf)C|2-DCM I H2,Pd/C I I NHzB
/N /N N_BS. /N
I o/GJLN/\©
/N god Na2C03 DMEE MeOH
Br quantitative fig
crude crude mg
V szdba3, PCy3, KOAc
BZ(P|N)2, dioxane
0 (OH
Step 6 5—2—
H O
Pd(dppf)C|2-DCM N \ N/\© {OH
I : PyBrop HOBt
N OH + 1:”N:o
Ste 1. 5- 3 6-dih dro-2H- ran l razinamine
To a solution of boronic ester (6.64 g, 31.6 mmol), 5-bromopyrazinamine (5 g, 28.7
mmol), and PdCl2(dppf) (2.1 g, 2.87 mmol) was added DME (71.8 mL) and 2 M Na2C03
solution (24 mL). The reaction e was heated at 90 °C for 15 h. The on mixture
was worked up with EtOAc. The organic layer was washed with water and brine, dried
over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude t
was purified by flash chromatography (gradient EtOAc in heptanes) yielding 5-(3,6-
dihydro-2H-pyran-4—yl)pyrazin-2—amine in 57% yield. LCMS (m/z): 178.1 (MH+), 0.34 min;
1H NMR (400MHz, CDCI3) 6 ppm 8.17 - 8.03 (m, 1 H), 8.04 - 7.88 (m, 1 H), 6.57 - 6.41
(m, 1 H), 4.68 - 4.42 (m, 2 H), 4.42 - 4.29 (m, 2 H), 4.06 - 3.84 (m, 2 H), 2.68 - 2.47 (m, 2
Ste 2. 5- tetrah dro-2H- ran l razinamine
A solution of 5-(3,6-dihydro-2H-pyranyl)pyrazinamine (2.7 g, 15.24 mmol) and Pd-C
(10%, a type) (1.6 g, 1.5 mmol) in MeOH (50 mL) was degassed by N2 stream for
min. After equipped with hydrogen gas balloon, the reaction mixture was stirred for 15
h at room temperature. The crude t was filtered off through celite pad and washed
with EtOAc. The volatile material was concentrated in vacuo yielding 5-(tetrahydro-2H-
4-yl)pyrazinamine and was used for the next step. LCMS (m/z): 180.3 (MH+),
0.28 min.
Ste 3. 3-bromo tetrah dro-2H- ran l razinamine
To an ice cold solution of 5-(tetrahydro-2H-pyrany|)pyrazinamine (2.8 g, 15.6 mmol)
in CH3CN (52 mL) was added NBS (2.78 g, 15.62 mmol) in two portions at 0 °C. The
reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl
acetate and was washed with saturated sodium carbonate solution, water, brine, dried
and concentrated. The crude 3-bromo(tetrahydro-2H-pyranyl)pyrazinamine (3.9
g, 97%) was used for the next step without r purification. LCMS (m/z): 258/260
(MH+), 0.52 min; 1H NMR (400MHz, CDCI3) 6 ppm 7.83 (s, 1H), 4.90 (br. s., 2H), 4.14 -
4.02 (m, 2H), 3.59 - 3.43 (m, 2H), 2.83 (d, J=5.5 Hz, 1H), 1.91 — 1.77 (m, 4H).
Step 4. (S)—4-bromo-N-(2-hydroxy-1phenylethyl)benzamide
To a solution of 4-bromobenzoic acid (892 mg, 4.44 mmol) in THF (9.9 mL) was added
(S)aminophenylethanol (609 mg, 4.44 mmol), DIEA (1.9 mL, 11.1 mmol), PyBroP
(2.5 g, 5.32 mmol), and HOBT (815 mg, 5.32 mmol). The reaction mixture was stirred at
room temperature for 20 h. The reaction mixture was extracted with EtOAc. The organic
layer was washed with water and brine. After dried over anhydrous sodium sulfate,
ed and concentrated in vacuo, the crude product was purified by flash
chromatography (gradient EtOAc in DCM) yielding (S)—4-bromo-N-(2-hydroxy
phenylethyl)benzamide (850 mg, 60%). LCMS (m/z): 338.1 (MH+), 0.61 min.
Ste 5. S -N- 2-h drox hen leth l 4 4 5 5-tetrameth H 3 2-dioxaborolan
y|)benzamide
To a solution of (S)bromo-N-(2-hydroxyphenylethyl)benzamide, 4,4,4',4',5,5,5',5'-
thyl-2,2'-bi(1,3,2-dioxaborolane (B2(P|N)2) (238 mg, 0.937 mmol), Pd2(dba)3 (21.45
mg, 0.023 mmol), tricyclohexylphosphine (19.71 mg, 0.070 mmol) in dioxane (1.562 mL)
was added potassium acetate (138 mg, 1.405 mmol). The reaction mixture was degassed
by N2 stream for 15 min. The on mixture was heated at 100 OC overnight. After
diluted with EtOAc, the reaction mixture was filtered through Celite. After concentrated,
(S)—N-(2-hydroxyphenylethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
was used for the next step without further purification. LCMS (m/z): 368.3 (MH+), 0.88
min (for c ester) and 286.1 (MH+), 0.49 min (for the corresponding boronic acid).
Ste 6. S 3-amino tetrah dro-2H- ran l razin l-N- 2-h drox
ethyl)benzamide
To a solution of 3-bromo(tetrahydro-2H-pyranyl)pyrazinamine (154 mg, 0.418
mmol), (S)—N-(2-hydroxyphenylethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
y|)benzamide (90 mg, 0.349 mmol), and PdC|2(dppf) (25.5 mg, 0.035 mmol) was added
dioxane (2.3 mL) and 2 M Na2C03 solution (1.163 mL). The reaction mixture was heated
at the microwave synthesizer (120 °C, 10 min). The reaction mixture was worked up with
EtOAc. The c layer was washed with water and brine, dried over anhydrous sodium
sulfate, filtered off, and concentrated in vacuo. The crude product was purified by prep
HPLC. The pure fractions were combined, free-based with sodium carbonate solution,
and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate,
filtered off, and dried in vacuo. The pure solid was ved in MeCN/water (1:1, 6 mL)
and lized yielding (S)—4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)-N-(2-
hydroxyphenylethyl)benzamide as free base (46%). LCMS (m/z): 419.2 (MH+), 0.58
min; 1H NMR (400MHz, DMSO-d6) 8 ppm 8.74 (d, J =12 Hz, 1 H), 7.99 (d, J = 8 Hz, 2
H), 7.88 (s, 1 H), 7.79 (d, J =12 Hz, 2 H), 7.37 (d, J = 8 Hz, 2 H), 7.29 (m, 2 H), 7.22 (m,
1 H), 5.99 (bs, 1 H), 5.07 (m, 1 H), 3.91 (m, 2 H), 3.67 (m, 2 H), 3.41 (m, 2 H), 2.82 (m, 1
H), 1.72 (m, 4 H).
S nthesis of 3-fluoro 3- meth lsulfon lbenz lcarbamo l hen lboronic acid
Scheme 2
O O
o\ ,o
O\\ 00 \S’
+ H2N
Ho~ H
i|3 F US\ —> HO‘EI;
F N/\©/ \
OH OH
A mixture of nofluorobenzoic acid (218 mg, 1.2 mmol), (3-
(methylsulfonyl)phenyl)-methanamine (200 mg, 1.08 mmol), DIEA (0.754 mL, 4.32 mmol)
and TBTU (381 mg, 1.2 mmol) in DMF (2 mL) was stirred at room temperature for 2 days,
then the reaction mixture was diluted with water (10 mL), and t precipitated out as
gum, and the supernatant was separated via centrifugation, and the gummy residue was
sonicated with water (3 mL), and the gummy residue was further dried under high vacuum
yielding 3-fluoro(3-(methylsulfonyl)benzylcarbamoyl)-phenylboronic acid (335 mg,
88%) as white foam. LCMS (m/z): 352.1 (MH+), 0.51 min.
8 s of +/- - 3-fluoro 222-trifluoro hen |eth lcarbamo | hen Iboronic acid
Scheme 3
COOH —.TEA
+ + jl: N
NHz \N Cl H
HO\B | HO
(5H OH
(”9 (+/-)
A mixture of 4-boronofluorobenzoic acid (54 mg, 0.294 mmol) in DCM (1468 uL) was
cooled to 0 °C. Then ghosez reagent N,N,3-trimethylbut—2-enamine (65.8 uL, 0.587
mmol) was added and the whole mixture was stirred at rt for 20 min. The e was
added into a mixture of TEA (246 uL, 1.762 mmol), 2,2,2-trifluorophenylethanamine
(59.1 mg, 0.338 mmol) and DCM (1468 uL). The reaction was stirred at room temperature
for 2 h. To the reaction mixture was added EtOAc, and washed with sat. sodium
bicarbonate, water, and dried over Na2804. Filtered and concentrated to provide the
crude product which was taken to the next step without further purification. LCMS (m/z):
342.2 (MH+), 0.84 min.
S nthesis of R 2-fluoro hen n l i amine
HZN,“
(R)—3-Boc—aminopiperidine (1.05 g, 5.25 mmol) was dissolved in DCM (10 mL) and then
triethylamine (1.10 mL, 7.89 mmol) was added. To this solution at room temperature was
added 2-f|uorobenzenesu|fony|ch|oride (1.127 g, 5.79 mmol). After 2h, reaction was
deemed complete by LCMS and d with water and extracted with DCM (30 mL), and
the organic layer was separated and dried over magnesium sulfate, filtered and
concentrated and taken to the next step as such. The crude product from above was
dissolved in DCM (25 mL) and TFA (10 mL) added in one portion. Reaction mixture
followed by LCMS. After 1 h, TFA was stripped in vacuo and then the e suspended
in 3N HCI and washed with ether. The aq. layer was basified and extracted with DCM
and the DCM |ayer separated and dried over magnesium sulfate, filtered and
concentrated in vacuo to give 873 mg of (R)—1-((2-f|uoropheny|)su|fony|)piperidinamine
as the desired product as free base. LCMS (m/z): 255.5 (MH+), 0.49 min.
8 s of R hen lsulfon l i eridinamine
HZN,“
cm:0
(R)—3-Boc—aminopiperidine g, 4.21 mmol) was dissolved in DCM (10 mL) and then
triethylamine (0.88 mL, 6.31 mmol) was added. To this solution at room temperature was
added benzenesulfonylchloride (0.818g, 4.63 mmol). After 2 h, reaction was deemed
complete by LCMS and diluted with water and extracted with DCM (30 mL), and the
organic layer was separated and dried over magnesium sulfate, filtered and concentrated
and taken to the next step as such. The crude product from above was dissolved in DCM
(25 mL) and TFA (10 mL) added in one portion. on mixture followed by LCMS.
After 3 h, complete Boc—deprotection was observed. At this stage, TFA was stripped in
vacuo and then the residue suspended in 3N HCI and washed with ether. The aq. layer
was basified and extracted with DCM and the DCM layer separated and dried over
magnesium sulfate, filtered and trated in vacuo to give 850 mg of (R)—1-
(phenylsulfonyl)piperidinamine as the desired product as free base. LCMS (m/z):
241.4 (MH+), 0.43 min.
8 s of R fluoro1- 2-fluoro hen lsulfon l i eridin
lcarbamo l hen lboronic acid
Scheme 4
HN,2
F O "
F 0
..(R) N
OH N N‘ ‘302
HO so HO H F
‘B ‘B
To a solution of 4-boronofluorobenzoic acid (160 mg, 0.870 mmol), (R)—1-(2-
fluorophenylsulfonyl)piperidinamine (225 mg, 0.870 mmol), and DIEA (456 uL, 2.61
mmol) in THF (1450 uL) and DMF (1450 uL) was added HOAt (237 mg, 1.740 mmol) and
EDC (417 mg, 2.175 mmol). After 3 h stirring at room temperature, the on mixture
was extracted with EtOAc. The organic layer was washed with NaHC03, water and brine,
dried over anhydrous sodium sulfate, filtered off, and trated in vacuo yielding (R)-
3-fluoro(1-(2-f|uorophenylsulfonyl)piperidinylcarbamoyl)phenylboronic acid, which
was used in next step reaction without purification. LCMS (m/z): 425.2 (MH+), 0.72 min.
S nthesis of 4- 22-difluoro hen leth Icarbamo lfluoro hen ic acid
Scheme 5
m_1 Sfig_2 F F
F o
(>)‘\(F_>LiHMDS ©2YI= HOBdOH EDCI, HOAt
Ho. db]H
F BH3-DMS DIEA El;
% 90%
(+/_) (44.)
Ste 1. 22-difluoro hen lethanamine
To a solution of 2,2-difluorophenylethanone (1 g, 6.4 mmol) in toluene (32 mL) at room
temperature was added LiHMDS (1M in THF) (7.05 mL, 7.05 mmol). The reaction mixture
was stirred for 30 min, followed by addition of BH3-DMS (1.216 mL, 12.81 mmol). The
reaction mixture was stirred for 1 h. After g at 0 °C, s 2 N NaOH solution
was lly added over 5 min (Caution! gas ion). The reaction was d for 1 h.
The layer was separated and washed with water and brine. After dried over sodium
sulfate, HCI in MeOH (7.17 mL, 8.97 mmol) was added to form a white precipitate. The
precipitate was filtered off, washed with ether, and dried in vacuo yielding 2,2-difluoro
phenylethanamine (21%). 1H NMR (400MHz, CDCI3) 6 ppm 7.49 (s, 5 H), 6.52 - 6.07 (m
1 H), 4.78 - 4.69 (m, 2 H).
Ste 2. 4difluoro hen leth Icarbamo lfluoro hen Iboronic acid
To a solution of 4-boronofluorobenzoic acid (200 mg, 1.087 mmol), 2,2-difluoro
phenylethanamine (232 mg, 1.196 mmol), and DIEA (0.570 mL, 3.26 mmol) in THF
(3.866 mL) and DMF (0.483 mL) was added HOAt (296 mg, 2.175 mmol) and EDC (521
mg, 2.72 mmol). After 3 h stirring at room temperature, 10% citric acid solution was added
(pH ~3) and extracted with 2-methyl THF and EtOAc (1:1). The organic layers were dried
over anhydrous Na2804, filtered, and concentrated. The crude 4-(2,2-difluoro
phenylethylcarbamoyl)fluorophenylboronic acid was obtained (90%) and used for the
next step without purification. LCMS (m/z): 375.3 (MH+), 0.48 min.
Synthesis of 4-benzyl(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2—yl )—3,4-
dih drobenzo 1 4 oxaze in-5 2H -one
Scheme 6
0 m1 Step;
dCI “MWQ —> —>
+ H
Br F
0 Step g
cm 9 N
N /
O\ ,B\OJ? _.
+ r 0 0312
Br 0 O (I)
Ste 1. N-benz lbromofluoro-N- 2-h drox eth | benzamide
To a solution of 4-bromofluorobenzoyl chloride (1 g, 4.21 mmol) in THF (14.04 mL)
was added DIEA (1.103 mL, 6.32 mmol) and 2-(benzylamino)ethanol (0.764 g, 5.05
mmol) at room temperature. The reaction mixture was stirred for overnight. The reaction
mixture was ted with EtOAc. The organic layer was washed with water and brine.
After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude
N-benzyl-4—bromofluoro-N-(2-hydroxyethyl)benzamide was used for the next step
(83%). LCMS (m/z): 352/354 (MH+), 0.83 min.
Ste 2. 4-benz lbromo-3 4-dih drobenzo 1 4 oxaze in-5 2H -one
To a solution of N-benzylbromofluoro-N-(2-hydroxyethyl)benzamide (494 mg, 1.403
mmol) in DMF (14.00 mL) was added NaH (60% in oil) (61.7 mg, 1.543 mmol) .
After H2 gas evolved, the reaction mixture was heated at 90 °C for 24 h. After quenched
with water, the reaction e was extracted with EtOAc. The organic layer was washed
with water and brine. After drying over anhydrous sodium sulfate and filtration, the organic
layer was ated in vacuo. The oily crude 4-benzylbromo-3,4-
dihydrobenzo[f][1,4]oxazepin-5(2H)—one was purified by flash chromatography (gradient
EtOAc in heptane) in 84% yield. LCMS (m/z): 332.1/334.1 (MH+), 0.94 min.
Step 3. 4-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—3,4-
dih drobenzo 1 4 oxaze in-5 2H -one
2014/062913
To a on of 4-benzylbromo-3,4-dihydrobenzo[f][1 ,4]oxazepin-5(2H)—one (111.3 mg,
0.335 mmol), B2(P|N)2 (170 mg, 0.670 mmol), Pd2(dba)3 (15.34 mg, 0.017 mmol),
tricyclohexylphosphine (14.09 mg, 0.050 mmol) in dioxane (3.35 mL) was added
ium acetate (99 mg, 1.005 mmol)just right after degassing. The reaction mixture
was heated at 100 °C overnight. After diluted with EtOAc, the reaction mixture was filtered
through Celite. After concentrated, the crude 4-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolany|)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)—one was obtained (>99%) and
used for the next step without r purification. LCMS (m/z): 298.1 (MH+for boronic
acid), 0.63 min and 380.2 (MH+), 1.05 min.
8 nthesis of S meth lamino hen lethanol
Scheme 7
To a suspension of LiAlH4 (0.689 g, 18.16 mmol) in THF (20.18 mL) was added (S)—2-
(methylamino)pheny|acetic acid (1 g, 6.05 mmol) in THF (20mL) slowly over 10 min at
0 °C. The reaction mixture was stirred at room temperature for overnight. After
quenched with water (0.7 mL), NaOH (2.1 mL), water (0.7 mL). The reaction mixture was
filtered off. The filtrate was extracted with EtOAc 3 times. The combined organic layer
was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and
concentrated in vacuo. The crude product was purified by flash tography (10%
methanol in DCM) yielding (S)(methy|amino)pheny|ethanol as a colorless oil in 55%
yield. LCMS (m/z): 152.1 (MH+), 0.31 min; 1H NMR z ,CDCI3) 87.40 - 7.33 (m, 2
H), 7.32 - 7.27 (m, 3 H), 3.77 - 3.69 (m, 1 H), 3.69 - 3.63 (m, 1 H), 3.58 (d, J= 9.8 Hz, 1
H), 2.36 (s, 3 H).
sis of (S)—4-phenyloxazolidine
Scheme 8
©Y\OH + HYO —> HN
NH2 H MeOH L
To a solution of aminophenylethanol (1.5 g, 10.93 mmol) in methanol (36.4 mL)
was added dehyde (1.065 g, 13.12 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 2 days . The reaction mixture was
concentrated to dryness. The crude material was purified by flash chromatography (0-
50% EtOAc/heptanes) to give (S)—4-phenyloxazolidine in 40% yield. LCMS (m/z): 150.1
(MH+), 0.31 min.
8 nthesis of S -tert-but l 2—amino 3-chloro hen leth lcarbamate
Scheme 9
Step 1 Step 2 Step 3
OH OH O
o NaHMDS 1 Boczo ! NHBOc ©:: DTBAD
—> —> + NH —>
I 0
CI CI CI
Ste fl
NHBoc
oR o
N g/
HZNNHZ
Q/K/NHBOC —> H2N/\©
Ste 1. R amino 3-chloro hen lethanol
To a solution of (R)—2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added
NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0 °C. The reaction mixture was
warmed up to room temperature and stirred for overnight. To the reaction e, water
(33 mL, 2.5 mL/g) added. After ng for 5 h at room temperature, solvent was removed
in vacuo to about 1/4 and partitioned by DCM. The bottom layer is a little cloudy and the
top layer was a brown solution. Both layers were concentrated, which contained the
desired (R)—2-amino(3-chlorophenyl)ethanol (14 g, 97%). The combined ts were
used in next step without further cation. LCMS (m/z): 172.1 (MH+), 0.37 min.
Step 2. (R)—tert—butyl (2—(3-chlorophenyl)—2-hydroxyethyl)carbamate
To a solution of (R)—2-amino(3-chlorophenyl)ethanol (14 g, 82 mmol) in THF (272 mL)
was added di-tert-butyl dicarbonate (24.92 g, 114 mmol). The mixture was stirred at room
temperature for overnight. The reaction mixture was diluted with DCM and then washed
with saturated sodium bicarbonate solution. The separated organic layer was then dried
over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product
was purified by flash chromatography (0 to 50% ethyl e in heptane) yielding (R)-
tert-butyl (2-(3-chlorophenyl)hydroxyethyl)carbamate (49.2%). LCMS (m/z): 216 (MH-
tBu), 0.85 min; 1H NMR (400 MHz, CD3OD) 6 ppm 1.40 (s, 9 H) 3.18 (s, 1 H) 3.26 (d,
J=4.70 Hz, 1 H) 4.69 (br. s., 1 H) 7.20 - 7.34 (m, 3 H) 7.35 - 7.41 (m, 1 H).
Ste 3. S -tert-but l 2- 3-chloro hen l 1 oisoindolin leth lcarbamate
To a solution of (R)—tert-butyl (2-(3-chlorophenyl)hydroxyethyl)carbamate (8.12 g, 29.9
mmol) in THF (100 mL) was added phthalimide (6.16 g, 41.8 mmol) and polymer-bound
triphenylphosphine (3 mmol of PPh3/1 g of resin, 9.8 g). DTBAD (7.09 g, 30.8 mmol) in
THF (20 mL) was added slowly at room ature to the reaction mixture, which was
then stirred at room temperature overnight. The reaction mixture was filtered through
Celite and washed with EtOAc. The resulting filtrate was washed with Na2C03 solution,
water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in
vacuo. The crude material was purified by flash chromatography (0-30% EtOAc/heptane)
ng (S)—tert-butyl chlorophenyl)(1,3-dioxoisoindolinyl)ethyl)carbamate
(58.4%). LCMS (m/z): 301.1 (MH+-Boc), 1.06 min.
Step 4. (S)—tert—butyl no(3-chlorophenyl)ethyl)carbamate
To a solution of (S)—tert-butyl (2-(3-chlorophenyl)(1,3-dioxoisoindolin
y|)ethyl)carbamate (5.0 g, 12.47 mmol) in ethanol (41.6 mL) was added hydrazine hydrate
(6.06 mL, 125 mmol). The reaction mixture was heated at 60 °C for 2 h. The reaction
mixture was filtered through Celite pad. The filtrate was concentrated and the residue was
diluted with DCM and filtered off through Celite. The same process was repeated until no
white precipitate was shown. To remove the white side product tely, the product
was dissolved in 1N HCI (30 mL), washed with EtOAc, and the s phase was
neutralized to pH 7 then xtracted by EtOAc. The organic was dried over anhydrous
sodium sulfate, filtered off, and concentrated in vacuo ng (S)—tert-buty| (2-amino
(3-chlorophenyl)ethyl)carbamate (89%). LCMS (m/z): 271.1 (MH+), 0.58 min.
Table 1. Aryl halides or the corresponding boronic esters/acids obtained from amide bond
formation and/or boronic ester formation
Structure Name MH+
F O _/OH (S)—4-bromof|uoro-
flaw' ydroxy—1 -
338 0'76
phenylethyl)benzamid
Br e
OH (S)—2-f|uoro-N-(2—
F O =/
fiflfihydroxy phenylethylH' 32%;: 051
(LB (4,4,5,5-tetramethy|— '
>§Vé acid)
1,3,2-dioxaborolan-2—
y|)benzamide
1H NMR (400 MHz, CDCI3) 6
ppm 7.70 (d, J=8.2 Hz, 2 H)
0” (S)'4'br°m°'N'(2'
7.56 — 7.62 (m, 2 H) 7.30 — 7.44
fim/fi hyd roxy-1 - 321.9 0.75 (m, 5 H) 6.82 (d, J=5.9 Hz,1
. H,
:henylethyl)benzamld NH?) 5.27 (dt, J=7_0, 4.7Hz, 1
Br H) 4.03 (t, J=5.1 Hz, 2 H) 2.38
(t, J=5.9 Hz, 1 H)
Structure Name MH+ ("ii”) NMR
0 N-(3-
QXN (methylsulfonyl)benzy
0‘? : ')4(4’4’5’5_ _ _
416.2 0.86
o 802Me tetramethyI-1,3,2- N/A
dioxaborolan-Z-
y|)benzamide
F 0 ;/ (S)—4-bromo-N-(1-(3-
N chlorophenyl)—2—
4 0 89 '
H hydroxyethyl)—2— N/A
fluorobenzamide
(S)-(4-((1-(3-
F O =/ chlorophenyl)—2—
N hydroxyethyl)carbamo
420/422
HO‘B W3—
1 fluorophenyl)boronic
OH CI
acnd.
O {OH (S)—4-bromo-N-(2—
‘ hydroxy'1'
N 334 0.76
ethyl)—2—
H N/A
Br methylbenzamide
0 {OH (S)—N-(2-hydroxy
' phenylethyl)—2—
o methyl(4,4,5,5-
‘3 H/\©N 382.2
ethyI-1,3,2- N/A
dioxaborolan-Z-
y|)benzamide
1H NMR (400 MHz, DMSO-d6)
NH2 0 (S)—2—amino-4—bromo- . ppm 8.51 (d, J=7.8 Hz,1 H)
N-(2-hydroxy 7.60 (d, J=8.2, 2 H) 7.15 — 7.45
337.0 0.71
phenylethyl)benzamid (m, 5H) 6.90 (d, J=2.0 Hz, 1 H)
e ..70 (dd, J=8.2, 2.0 Hz, 1 H)
..56 (bs, 2 H, NH2) 4.83 — 5.01
(m, 1 H)4.92 (m, 1H, OH) 3.53
Structure Name
3.76 (m, 2 H)
(S)—3-f|uoro(1-(2—
fluorobenzyl)piperidin-
ylcarbamoyl)pheny|bo
ronic acid
(R)—3-f|uoro(1-(2—
fluorobenzyl)piperidin-
ylcarbamoyl)pheny|bo
ronic acid
(S)-(4-((2-((tert-
0 /NHBoc .
; butoxycarbonyl)amino
- N/A
N )—1-(3-
HO pheny|)ethy|)car 437.1 0.86
‘B F
I bamoyl)—3-
HO CI
fluorophenyl)boronic
acid
Example 2
S s of S 2—amino i eridin | ridin Ifluoro-N- 2—h drox
phenylethyl )benzamide
Scheme 10
Step 1 NH2 Stag g NH2 mg NH2
NH2 W Br
NI \ NI \ \
0‘ ,o Pd(dppf)C|2-DCM H2, Pd/C NBS ”I
N \ B
. / /
_, _. /
' +
/ / N22003,DME MeOH MeCN
quantitative. .
0A0J< OAOJ<N Dick 010k
F O
Ste 4 :/
_r;_ NH2 9 Step; =
B /OH NH2
Pd(dppf)Cl2-DCM H
| ?
/ 1.Pd(dppf)CI2-DCM
HA© N \ N/\©
—> + N —> |
B2(P|N)2, KOAc /
N32003, DME
dioxane
2. 30%TFA in DCM
To a solution of 5-bromopyridinamine (0.84 g, 4.85 mmol) in DME (10 mL) was added
N-Boc—5,6-dihydropyridine-1(2H)-carboxy|ate (1 g, 3.23 mmol), and sodium carbonate
(4.85 mL, 9.70 mmol). The mixture was purged with nitrogen for 5 min, and followed by
the addition of dppf)-CH2C|2 (0.26 g, 0.32 mmol). The resulting mixture was heated
to 120 °C in an oil bath for 2 h. The reaction mixture was diluted with ethyl acetate,
washed with water, brine, dried and was concentrated. The residue was purified by flash
column chromatography on silica gel (ISCO) eluting with 0-90% ethyl acetate in heptane
to give tert-butyl 6-amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxy|ate (560 mg, 63 %)
as brown color solid. LCMS (m/z): 276 (MH+), 0.59 min.
Ste 2. tert-But l4- 6-amino ridin l i eridinecarbox late
A suspension of tert-butyl 6-amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxy|ate (560
mg, 2.03 mmol), 5% Pd/C (1082 mg, 0.5 mmol) in methanol (30 mL) was purged with
nitrogen for 2 min. The reaction e was stirred under hydrogen at ambient
temperature for 16 h. The reaction mixture was diluted with romethane (50 mL) and
was filtered h Celite pad. The te was concentrated and the e was purified
by flash column chromatography on silica gel (ISCO) eluting with 0-90% ethyl acetate in
heptane to give tert-butyl 4-(6-aminopyridinyl)piperidinecarboxylate (180 mg, 31.9
%) as yellow color solid. LCMS (m/z): 278 (MH+), 0.57 min.
Ste 3. tert-but l4- 6-aminobromo ridin l i eridinecarbox late
To an ice cold on of tert-butyl 4-(6-aminobromopyridiny|)piperidine
carboxylate(180 mg, 0.65 mmol) in DCM (18 mL) was added NBS (116 mg, 0.65 mmol) in
two portions. The reaction mixture was stirred at 0 °C in an ice bath for 30 min. The
reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous
sodium bicarbonate, brine, dried over sodium sulfate and trated. The resulting
residue was purified by flash column chromatography on silica gel (ISCO) eluting with 0-
100% ethyl e in heptane to give tert-butyl 4-(6-aminobromopyridin
yl)piperidinecarboxylate (180 mg, 78%) as yellow color 0“. LCMS (m/z): 300/302 (MH+),
0.67 min.
Ste 4. tert-but l 4- 6-amino 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridin
yl)piperidinecarboxy|ate
To a suspension of tert-butyl 4-(6-aminobromopyridiny|)piperidinecarboxy|ate
(180 mg, 0.50 mmol) in oxane (8 mL) was added bis(pinaco|ato)diboron (385 mg,
1.51 mmol) and potassium acetate (248 mg, 2.53 mmol). The mixture was purged with
nitrogen for 3 min, then dppf)-CH2C|2Adduct (49.5 mg, 0.061 mmol) was added.
The reaction mixture was heated to 110 °C in an oil bath for 20 h and ed through
neutral alumina (1 g). The filtrate was concentrated to give crude tert-butyl 4-(6-amino
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)piperidinecarboxylate, which
was used directly in next step without any purification. LCMS (m/z): 322 (MH+ for c
acid), 0.60 min.
Ste 5. S 2-Amino i eridin l ridin lfluoro-N- 2-h drox
phenylethyl)benzamide
To a suspension of (S)bromof|uoro-N-(2-hydroxypheny|ethy|)benzamide (67.1
mg, 0.20 mmol) in DME (5 mL) was added tert-butyl 4-(6-amino(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)pyridinyl)piperidinecarboxylate (40 mg, 0.099 mmol) and
sodium carbonate (0.24 mL, 0.49 mmol). The mixture was purged with nitrogen for 10
min, then PdC|2(dppf)-CH2C|2Adduct (12.15 mg, 0.015 mmol) was added. The reaction
mixture was heated to 120 °C in an oil bath for 3 h. The on mixture was diluted with
ethyl acetate. The organic on was washed with water, brine, dried over sodium
sulfate and concentrated. The resulting residue was treated with 30% TFA in DCM (20
mL) for 15 min. The reaction mixture was concentrated and the crude product was
purified by HPLC to give (2-amino(piperidinyl)pyridinyl)—2-fluoro-N-(2-
hydroxyphenylethyl)benzamide (9 mg, 20.8 %) as TFA salt. LCMS (m/z): 435 (MH+),
0.44 min; 1H NMR (300 MHz, CD3OD) 6 ppm 8.63 (br. s., 1 H) 7.90 (t, J=7.77 Hz, 1 H)
7.84 (s, 2 H) 7.47 -7.24 (m, 7 H), 5.27 -5.17 (m, 1 H) 3.93- 3.79 (m, 2 H) 3.52 (d, J=12.60
Hz, 2 H) 3.21- 3.05 (m, 2 H) 2.96 (t, J=12.31 Hz, 1 H) 2.15 (d, J=14.07 Hz, 2 H) 1.96 -
1.78 (m, 2 H).
S nthesis of 3-bromo 1- meth Isulfon l i eridin l razinamine and meth l4- 5-
aminobromo razin l i eridinecarbox late
Scheme 11
Stegz Ngfirm
| \ N
DIEA/DCM
NAYBI‘ $21 46%
\ IN TFA/DCM o”?“o
Stegg
N Bl’
Boc Nfi/
MeC02C| \ N
DIEA/DCM
02‘0/
Following Step 1 to 3 in Scheme 10, using 5-bromopyrazinamine and N-Boc—5,6-
dihydropyridine-1(2H)-carboxylate, tert-butyl 4-(5-aminobromopyrazinyl)piperidine
carboxylate was ed. LCMS (m/z): 301 .0/303.0 (MH+-tBu), 0.875 min.
Ste 1.3-bromo ieridinl razinamine
To a on of tert-butyl 4-(5-aminobromopyrazinyl)piperidinecarboxylate (70
mg, 0.196 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction
mixture was stirred at room temperature for 45 min. After toluene was added, the volatile
materials were evaporated yielding 3-bromo(piperidinyl)pyrazinamine. The crude
product was used directly for the next reaction (99%). LCMS (m/z): 259.0 (MH+),
0.329 min.
Ste 2. 3-bromo 1- meth lsulfon | i eridin | razinamine
To 3-bromo(piperidinyl)pyrazinamine (50 mg, 0.194 mmol) in DCM (2 mL) in ice
bath was added DIEA (340 pl, 1.945 mmol) and methanesulfonyl chloride (16.67 ul,
0.214 mmol). The reaction mixture was stirred for 60 min. The reaction mixture was
extracted with DCM. The c layer was washed with brine, dried over sodium sulfate,
filtered and ated in vacuo. (30mg, 46%). LCMS (m/z): 335.2/3372 (MH+), 0.572
min.
Ste 3. meth l4- obromo razin | i eridinecarbox late
To a solution of 3-bromo(piperidinyl)pyrazinamine (60 mg, 0.233 mmol) in DCM
(2 mL) in ice bath was added DIEA (408 pl, 2.333 mmol) and methyl chloroformate (18.07
ul, 0.233 mmol). The reaction mixture was stirred under ice bath for 30 min. The reaction
mixture was partitioned between DCM and water. The organic layer was separated and
washed with brine, dried over sodium sulfate, filtered off, and evaporated in vacuo. The
crude methyl 4-(5-aminobromopyrazinyl)piperidinecarboxy|ate was used for next
step. LCMS (m/z): 315.0/317.0 (MH+), 0.647 min.
Example 3
S nthesis of 4- 2-amino tetrah - ran | ridin lfluoro-N-meth l-N-
(pyrimidinylmethyl)benzamide
Scheme 12
Stepl Br Step; NH2 0
NH2 N \ E's \ F o
I O
N \ QB/O / szdba3,PCy3,KOAc N
+ :: NI \
I —. / + N/\f \
/ 6] B2(P|N)2,dioxane I N /
o Stegfl
F 0 I Mel, NaH
Stepé NH2 ll“ NIJ F o —Qs‘e Q
F o
/ N
N \ H N / PyBOP N
I 2W
_. / | _.
N\ New \
Br DIEA N /
Ste 1. 3-bromo tetrah dro-2H- ran | 2-amine
Following Step 1 to 3 in Scheme 10, using 5-bromopyridinamine, 3-bromo
(tetrahydro-2H-pyranyl)pyridinamine was obtained. LCMS (m/z): 257/259 (MH+),
0.38 min.
Ste 2. 5- tetrah dro-2H- ran | 4 4 5 5-tetrameth H 3 aborolan
yl inamine
Following Step 4 in Scheme 10, using 3-bromo(tetrahydro-2H-pyranyl)pyridin
amine was ed, 5-(tetrahydro-2H-pyranyl)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridinamine was obtained. LCMS (m/z): 233 (MH+), 0.36 min.
Ste 3. 4-bromofluoro-N- rimidin-2— lmeth lbenzamide
To a flask was charged with 4-bromofluorobenzoic acid (180 mg, 0.821 mmol),
pyrimidinylmethanamine (89.6 mg, 0.821 mmol), DIEA (0.358 mL, 2.05 mmol) in DMF
(3 mL), and to the resulting solution was added PyBOP (513 mg, 0.915 mmol) and the
resulting mixture was stirred at room temperature overnight, then was concentrated under
reduced pressure and the residue was diluted with EtOAc (20 mL), washed with water (3
x 10 mL), brine (10 mL) and dried (NazSO4), concentrated and the residue was purified by
flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-100%) and 4-
bromofluoro-N-(pyrimidinylmethyl)benzamide (74.5 mg, 29.3%) was obtained as
light color solid. LCMS (m/z): 310.0/312.0 (MH+), 0.64 min.
Ste 4. 4-bromofluoro-N-meth l-N- n lmeth Ibenzamide
To a flask was charged with ofluoro-N-(pyrimidinylmethyl)benzamide (74.5
mg, 0.24 mmol), NaH (60% dispersion in mineral oil, 11.5 mg, 0.288 mmol) in DMF(2
mL), to the slurry was added iodomethane (20 ul, mol) and to the resulting e
was stirred at room temperature for 10min, then was quenched by water (20 ul),
concentrated and the crude residue was dissolved in EtOAc, washed with water, and
brine, dried (Na2804), trated and 4-bromofluoro-N-methyl-N-(pyrimidin
y|methy|)benzamide was obtained as oil (55.3mg, 71% ). LCMS (m/z): 324.1/326.1 (MH+),
0.66 min.
Ste 5. 4- 2-amino tetrah dro-2H- ran | ridin |f|uoro-N-meth l-N-
(pyrimidinylmethyl)benzamide
To a microwave reactor vial was charged with 5-(tetrahydro-2H-pyrany|)(4,4,5,5-
ethyl-1,3,2-dioxaborolanyl)pyridinamine (39.4 mg, 0.13 mmol), 4-bromo
fluoro-N-methyl-N-(pyrimidinylmethyl)benzamide (28 mg, 0.086 mmol), aqueous
Na2C03 (2 M, 0.26 mL) in DME (1.5 mL), and the mixture was purged with Argon followed
by addition of tetrakis(triphenylphosphin) palladium (10 mg, 8.6 mmol), and final purge,
then sealed and heated at 115 °C for 15 min in microwave synthesizer. The DME layer
was collected, concentrated and the residue was subjected to prep HPLC purification and
fractions containing final product were combined, frozen, lyophilized and TFA salt of 4-(2-
amino(tetrahydro-2H-pyranyl)pyridinyl)f|uoro-N-methyl-N-(pyrimidin
y|methy|)benzamid was obtained as white powder. LCMS (m/z): 422.2 (MH+), 0.49 min;
1H NMR (400 MHz, CD3OD) 6 8.81 (d, J = 4.9 Hz, 1H), 8.77 (d, J = 4.9 Hz, 1H), 7.95 (d, J
= 2.2 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 2.2, 0.6 Hz, 1H), 7.76 (dd, J = 2.2,
0.6 Hz, 1H), 7.62 - 7.70 (m, 1H), 7.51 - 7.58 (m, 1H), 7.45 (s, 1H), 7.38 - 7.43 (m, 1H),
7.35 (dd, J = 10.0, 1.5 Hz, 1H), 7.28 (dd, J = 7.8, 1.6 Hz, 1H), 4.99 (s, 1H), 4.74 (s, 1H),
3.98 - 4.10 (m, 2H), 3.54 (tdd, J = 11.5, 8.8, 2.7 Hz, 2H), 3.15 - 3.24 (m, 3H), 2.78 - 2.93
(m, 1H), 1.65 - 1.89 (m, 4H).
S nthesis of 4- 6-Aminobromo ridin Itetrah dro-2H-thio ran 1 1-dioxide and 4-
o 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridin l tetrah dro-2H-
thiogyran 1,1-dioxide
Scheme 13
Stegl NH2 m2 NH2
NH2 W N \ N \
0‘ ,o Pd(dppf)C|2-DCM I H2, Pd/C I
N \ B —, / /
l +
/ / ,DME MeOH
/ . .
Br quantitative
s s
Stegg NH2 Stegfl NH2 St 95 NH2 (ID/g
N \ N \ N \ B‘O
mCPBA I NBs I Pd(dppf)Cl2-DCM I
/ / /
_, _, —,
DCM MeCN BZ(P|N)2, KOAc
dioxane
0”“ d’s‘b d’s‘b
Ste 1. 5- 3 6-Dih dro-2H-thio ran l ridinamine
To a solution of 5-bromopyridin-2—amine (344 mg, 1.99 mmol) in DME (6mL) was added
2-(3,6-dihydro-2H-thiopyrany|)-4,4,5,5-tetramethy|-1,3,2—dioxaborolane (300 mg, 1.33
mmol), and sodium carbonate (1.99 mL, 3.98 mmol). The mixture was purged with
nitrogen for 5 min, and followed by the addition of PdCI2(dppf)-CH2C|2 (108 mg, 0.13
mmol). The resulting mixture was heated to 115°C in an oil bath for 5 h. The reaction
mixture was diluted with ethyl acetate, washed with water, brine, dried and was
trated. The residue was purified by flash column chromatography on silica gel
(ISCO) eluting with 0-90% ethyl acetate in heptane to give Fractions were combined and
concentrated to give 5-(3,6-dihydro-2H-thiopyranyl)pyridinamine (120 mg, 47%) as
brown color solid. LCMS (m/z): 193 (MW), 0.44 min.
Ste 2. 5- Tetrah dro-2H-thio ran l ridinamine
A suspension of 5-(3,6-dihydro-2H-thiopyranyl)pyridinamine (260 mg, 1.35 mmol),
Pd/C (36 mg, 0.33 mmol) in methanol (16 mL) was stirred under en at ambient
temperature for 16 h. The reaction mixture was diluted with DCM (80 mL), and was
filtered through Celite. The filtrate was trated to give 5-(tetrahydro-2H-thiopyran
y|)pyridinamine (240 mg, 91% yield) as yellow color solid. LCMS (m/z): 195 (MW),
0.46 min.
Ste 3. 4- 6-Amino 3- ltetrah dro-2H-thio ran1 1-dioxide
To an ice cooled solution of 5-(tetrahydro-2H-thiopyranyl)pyridinamine (290 mg,
1.49 mmol) in DCM (15 mL) was added 3-chlorobenzoperoxoic acid (592 mg, 3.43
mmol). The resulting solution was stirred at ambient temperature for 4 h. The reaction
mixture was diluted with ethyl acetate. The resulting solution was washed with water,
saturated aqueous sodium bicarbonate, dried over sodium sulfate and trated. The
residue was purified by flash column chromatography on silica gel (ISCO) eluting with 0-
100% ethyl acetate in heptane to give minopyridinyl)tetrahydro-2H-thiopyran 1,1-
dioxide (140 mg, 41.4 %) as white color solid. LCMS (m/z): 227 (MH+), 0.25 min.
Ste 4. 4- 6-Aminobromo ridin ltetrah dro-2H-thio ran1 ide
To an ice cold solution of 4-(6-aminopyridinyl)tetrahydro-2H-thiopyran 1,1-dioxide (140
mg, 0.62 mmol) in DCM (15 mL) was added NBS (110 mg, 0.62 mmol) in two portions.
The reaction mixture was stirred at 0°C for 20 min. The reaction solution was diluted with
ethyl acetate, washed with water, saturated aqueous sodium onate solution, brine,
dried over sodium sulfate and concentrated to give 4-(6-aminobromopyridin
y|)tetrahydro-2H-thiopyran 1,1-dioxide (190 mg, 0.62 mmol). LCMS (m/z): 305/307 (MH+),
0.33 min.
Ste 5. 4- o 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridin l tetrah dro-
2H-thiopyran 1,1-dioxide
To a suspension of 4-(6-aminobromopyridiny|)tetrahydro-2H-thiopyran 1,1-dioxide
(190 mg, 0.62 mmol) in 1,4-dioxane (7 mL) was added naco|ato)diboron (474 mg,
1.86 mmol) and potassium acetate (305 mg, 3.11 mmol), and followed by the addition of
dppf)-CH2C|2 (61.0 mg, 0.075 mmol) was added. The reaction mixture was heated
to 100 °C in an oil bath for 16 h. The reaction mixture was diluted with ethyl acetate and
was filtered through neutral a (5 g). The filtrate was refiltered again through Celite.
The filtrate was concentrated and the residue was triturated with heptane, and filtered to
give 4-(6-amino(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl)pyridinyl)tetrahydro-2H-
thiopyran oxide (140 mg, 64% . LCMS (m/z): 271 (MW), 0.15 min.
8 nthesis of meth l3- 6-aminobromo ridin l rrolidinecarbox late
Scheme 14
Steal cr=3 ,9 Stag; Stegg
0 i0 N \
Cg CF3SOZ‘N ’302CF3 I
Pd PPhs / co /
arms #3
+ w,
ON)" )4 THF THF water / RT/ON
o )4 71/00
Ste N / Ste if g
\ I
NBS / ACN TFA/ DCM MeOCOCI / DCM
—> —> —>
83% N
m1 NH2
MeSOZCI / DCM Ni
Ste 1. tert-but l3- trifluorometh lsulfon lox -2 5-dih dro-1H- rrolecarbox late
To an oven dried flask under N2 was added tert-butyl 3-oxopyrrolidinecarboxy|ate (2 g,
.8 mmol) and THF (16 mL). The solution was cooled in acetone ice bath (-78 °C). To
that was added lithium bis(trimethylsilyl)amide (12.96 mL, 12.96 mmol) (1 M solution in
THF). The reaction e was stirred at -78 °C for 15min then added dropwise a
solution of 1,1 ,1-trif|uoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (4.05
g, 11.34 mmol) in THF (16 mL). The reaction mixture was stirred for 30 min then warmed
to 0 °C and stirred for 1.5 h. The on mixture was quenched with satd. sodium
bicarbonate solution and then extracted with ethyl acetate. The combined extracts were
washed with brine, dried over sodium sulfate, filtered and evaporated. The crude t
was purified by ISCO column (0-30%EtOAc/heptane) providing tert-butyl 3-
(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrolecarboxylate (1.9 g, 55.5%).
Ste 2. tert-but l3- 6-amino ridin l-2 5-dih dro-1H- rrolecarbox late
A solution of tert-butyl rifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole
carboxylate (400 mg, 0.882 mmol) in THF (10 mL) was purged with N2 for 5 min and then
was added potassium carbonate (610 mg, 4.41 mmol), ,5,5-tetramethyl-1,3,2-
orolanyl)pyridinamine (233 mg, 1.059 mmol), Pd(PPh3)4 (10.20 mg, 8.82
umol) and water ( 0.1 mL). The reaction mixture was heated and stirred at 70 °C
overnight. The reaction mixture was poured to saturated sodium bicarbonate solution and
extracted with ethyl ether. The organic layer was separated, washed with brine, dried over
sodium sulfate, filtered and evaporated. The crude product was ed by flash
chromatography (0-10%MeOH / DCM) to yield the desired product (180 mg, 54.6%).
LCMS (m/z): 262.2 (MH+), 0.598 min.
Ste 3. tert-but l3- 6-amino ridin l rrolidinecarbox late
To tert-butyl 3-(6-aminopyridinyl)—2,5-dihydro-1H-pyrrolecarboxylate (180 mg, 0.482
mmol) in MeOH (10 mL) under N2 here was added Pd-C (103 mg, 0.096 mmol).
The reaction mixture was stirred at room temperature under H2 balloon. After 2 h, the
reaction mixture was filtered through Celite pad, washed with methanol and evaporated to
provide desired product, which ded for next step without purification (150 mg,
71%). LCMS (m/z): 264.2 (MH+), 0.565 min.
Ste 4. tert-but l3- 6-aminobromo ridin l rrolidinecarbox late
To tert-butyl 3-(6-aminopyridinyl)pyrrolidinecarboxy|ate(60 mg, 0.228 mmol) in
Acetonitrile (4 mL) in ice bath was added NBS (36.5 mg, 0.205 mmol) and stirred. LCMS
after 30 min showed ~1:1 mixture of starting material and desired product. To this added
12mg (0.3 equiv.) of NBS and stirred 30 min. LCMS shows complete reaction. To the
reaction mixture was added aqueous saturated NaHC03 d 10 min and extracted with
ethyl e. The combined extracts were dried over sodium sulfate, filtered off, and
WO 66188
evaporated. The crude product was used for next step without purification (65 mg, 83%).
LCMS (m/z): 342.1/344.1 (MH+), 0.624 min.
Ste 5. 3-bromo rrolidinl ridinamine
To tert-butyl 3-(6-aminobromopyridinyl)pyrrolidinecarboxylate (65 mg, 0.171
mmol) in DCM ( 2.4 mL) was added TFA (0.6 mL, 7.79 mmol). The reaction mixture was
stirred at room temperature for 45 min. The on mixture was evaporated in vacuo
after dilution with toluene. The crude product was used for next step without purification.
The crude yield was quantitative. LCMS (m/z): 242.1/244.1 (MH+), 0.214 min.
Ste 6. meth l3- 6-aminobromo ridin l rrolidinecarbox late
To 3-bromo(pyrrolidinyl)pyridinamine,(20 mg, 0.083 mmol) in DCM in ice bath
was added DIEA (43.3 ul, 0.248 mmol) and methyl chloroformate (6.40 ul, 0.083 mmol).
The on mixture was stirred in ice bath for 30 min. The reaction mixture was
ioned between DCM and water. The DCM layer was separated and washed with
brine, dried over sodium sulfate, filtered off, and evaporated. The crude product was used
for next step without purification. LCMS (m/z): 300.0, 302.0 (MH+), 0.421 min.
Ste 7. 3-bromo 1- meth lsulfon l rrolidin l 2-amine
To 3-bromo(pyrrolidinyl)pyridinamine (20 mg, 0.083 mmol) in DCM in ice bath
was added DIEA (57.7 ul, 0.330 mmol) and methanesulfonyl chloride (7.08 ul, 0.091
mmol). The reaction mixture was d in ice bath 30 min. The reaction mixture was
partitioned between DCM and water. The DCM layer was separated and washed with
brine, dried over sodium sulfate, filtered and evaporated. The crude product was used for
next step without purification. LCMS (m/z): 320.0/322.0 (MH+), 0.363 min.
Examples 4, 5, and 6
S nthesis of 4- 2-amino 1 idotetrah drothio hen l ridin l-N-benz l
fluorobenzamide S 2-amino 1 1-dioxidotetrah drothio hen l ridin l-N-
benz lfluorobenzamide and R 2-amino 1 1-dioxidotetrah drothio hen
yl )pyridinyl)-N-benzylfluorobenzamide
Scheme 15
St 1 F ””2
_e2_ Ste NH
0 F 2 2 m;
0 \\S)<F N \
N(8020Fs)2 N \
\ LDA o’ “o I
' / I C
i _’ /
fl 6 * —’
s /N \
CI ,B\
s O O \
/)—(\ 5
NH NH
2 2 NH2
mg m5 0 Stegfi
NI \ N \ N \
I I N Pd(PPh3)4
/ mCPBA / NBS / _,
HO H
—’ +
—’ ‘ila F Na2C03
8 I§=o §=o
o o
O O
s—w—
N \ F mm
N \ N \ F no
I chiral separation | |
/ —.
+ _/
S: O
, O H I: ‘0
0' O o
Ste 1. 4 5-dih drothio hen ltrifluoromethanesulfonate
To freshly prepared LDA (10.5 mmol in 40 mL THF) between -75 to -65 °C was dropwise
added dihydrothiophene(2H)—one/THF solution (1.02 g/2 mL THF, 10 mmol) over 3
min, then the resulting reaction mixture was d at -75 °C for 3 h, followed by dropwise
addition of N-(5-chloropyridinyl)-1,1,1-trifluoro-N-
(trifluoromethylsulfonyl)methanesulfonamide/THF (4.12 g, 10.5 mmol in 5 mL THF) over
min, then the reaction e was stirred at -75 °C for at least 1 h, then with
temperature gradually warm up to room temperature overnight. The reaction mixture was
concentrated, and the e was partitioned between EtZO/HZO (100 mL/50 mL); the
ether layer was sequentially washed with water (2 x 50 mL), 3 M sodium e pH 4.8
buffer (2 x 50 mL), 3M NaOH (2 x 50 mL), and dried over magnesium sulfate,
concentrated and a brown 0” was obtained as crude product (2.05 g) which was further
purified by flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-
%) and desired product (0.9 g, 38.5% yield) was obtained as colorless oil.
2014/062913
Ste 2. 5- 4 5-dih drothio hen l ridinamine
To a vial was charged with all reagents: 4,5-dihydrothiophenyl
oromethanesulfonate (900 mg, 3.84 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-
orolanyl)pyridinamine(1.69 g, 7.69 mmol), K3PO4 (2.45 g, 11.5 mmol), and
PdC|2(dppf)-CH2C|2 adduct (314 mg, 0.384 mmol) and DME(16 mL), and the mixture was
purged with Argon, then sealed and heated at 90 °C via external oil bath overnight. The
reaction mixture was cooled down to room temperature, and the precipitates in the
on mixture was removed by filtration, and the filtrate was concentrated under
reduced pressure and a black residue was obtained as crude product. The crude product
was dissolved in EtOAc (30 mL), washed with water (20 mL), and the slug between the
two layers was removed by filtration. The EtOAc layer was collected, stripped with 1N
HCI (2 x 20 mL) and the s layers were combined, scrubbed with EtOAc (20 mL),
basified with aqueous NaOH (3 g in 10 mL water), ted with EtOAc (2 x 30 mL), and
the obtained EtOAc extracts were combined, washed with brine (30 mL), dried (Na2804),
concentrated and desired t was obtained as light color solid. LCMS (m/z): 179.0
(MH+), 0.41, 0.43 min (for regioisomers).
Ste 3. 5-tetrah drothio hen l ridinamine
-(4,5-dihydrothiophenyl)pyridinamine(0.78g, 4.38 mmol) was dissolved in
ethanol(30 mL), to it was added Pd-C (Deggussa, 10%, 0.233 g) and the mixture was
stirred under H2 balloon overnight. The on was not complete by LCMS. The Pd-C
catalyst was removed by filtering through a Celite pad, and to the filtrate was added new
Pd-C catalyst (0.24 g), and the mixture was stirred under H2 balloon under same condition
for another 6 h. The reaction mixture was filtered off through Celite pad, and the filtrate
was concentrated under reduced pressure yielding 5-(tetrahydrothiophenyl)pyridin
amine (0.661 g, 84%) as colorless oil. LCMS (m/z): 181.2 (MH+), 0.39 min.
Ste 4. 3- 6-amino ridin ltetrah drothio hene1 1-dioxide
-(tetrahydrothiophenyl)pyridinamine (0.33 g, 1.831 mmol) was dissolved in CH2C|2
(15 mL), to it was added mCPBA (70%, 0.903 g, 3.66 mmol) and the e was stirred
at room temperature for 10 min and the reaction mixture was concentrated under reduced
pressure and the residue was partitioned between EtOAc/sat. NaHC03 (30 mL/20 mL),
the EtOAc layer was washed with sat. Na2C03 (20 mL), brine (20 mL), dried (Na2804),
filtered off, and concentrated in vacuo yielding 3-(6-aminopyridinyl)tetrahydrothiophene
1,1-dioxide as light brown oil (96 mg, 25%). LCMS (m/z): 197.1 (MH+), 0.21 min.
Ste 5. 3- 6-aminobromo ridin h drothio hene1 1-dioxide
3-(6-aminopyridinyl)tetrahydrothiophene 1,1-dioxide (96 mg, 0.452 mmol) was
dissolved in acetonitrile (5 mL) and the solution was cooled to 0 °C, to it was added NBS
(80 mg, 0.452 mmol) and the mixture was stirred at 0 °C for 40 min. The on mixture
was concentrated under reduced pressure and the residue was partitioned between
sat. NaHC03 (30 mL/20 mL), the EtOAc layer was washed with sat. Na2C03 (20
mL), brine (20 mL), dried (Na2804), filtered off and concentrated in vacuo yielding 3-(6-
aminobromopyridinyl)tetrahydrothiophene oxide as light brown oil (50 mg, 38%
yield). LCMS (m/z): 291.0 (MH+), 0.29 min.
Ste 6. 4- 2-amino 1 1-dioxidotetrah drothio hen | ridin l-N-benz l
fluorobenzamide
To a microwave reactor was d with 3-(6-aminobromopyridin
yl)tetrahydrothiophene 1,1-dioxide (50 mg, 0.172 mmol), 4-(benzylcarbamoyl)—3-
phenylboronic acid (94 mg, 0.343 mmol), 2 M aqueous Na2C03 (0.34 mL) and
PdC|2(dppf)-DCM adduct (14 mg) and DME (3 mL) were charged in a microwave vial and
the mixture was purged with Argon, sealed and heated at 105 0C for 20 min. The DME
layer of the reaction mixture was collected, concentrated under reduced pressure and the
residue was redissolved in EtOAc (5 mL). The EtOAc solution was stripped with 1N HCI
(4 x 1 mL) and the s layers were ed, scrubbed with EtOAc (2 x 1 mL), then
concentrated under reduced pressure and the residue was partitioned between
EtOAc/sat. Na2C03 (5 mL/1 mL), and the EtOAc extract was washed with sat. Na2C03 (2
x 1 mL), brine (1 mL), dried (Na2804), concentrated and the residue was redissolved in
acetonitrile/water (6 mL/6 mL), frozen and lyophilized yielding racemic 4-(2-amino(1,1-
dioxidotetrahydrothiophenyl)pyridinyl)-N-benzy|fluorobenzamidein as light yellow
powder. LCMS (m/z): 440.2 (MH+), 0.60 min; 1H NMR (CDSOD) 8 ppm 7.97 (d, J = 2.0 Hz,
1H), 7.84 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.31 - 7.44 (m, 6H), 7.22 - 7.30 (m,
1H), 4.61 (s, 2H), 3.55 - 3.70 (m, 1H), 3.47 (dd, J = 13.3, 7.0 Hz, 1H), 3.33 - 3.39 (m, 1H),
3.08 - 3.25 (m, 2H), 2.53 (ddd, J = 13.1, 7.4, 5.7 Hz, 1H), 2.18 - 2.40 (m, 1H). The
racemic product was further resolved by chiral SFC (ChiralPak 5mic OJ column, 4.6x100
(mm), 5mL/min, MeOH+0.1% DEA= 50%) to afford (S)—4-(2-amino(1,1-
dioxidotetrahydrothiophenyl)pyridinyl)-N-benzylfluorobenzamide (Rt = 1.7 min)
and (R)—4-(2-amino(1,1-dioxidotetrahydrothiophenyl)pyridinyl)—N-benzyl
fluorobenzamide (Rt = 2.22 min). The absolute stereochemistry was arbitrarily assigned.
Example 7
S nthesis of 4- 2-amino BR 58 h drox meth l rrolidin l ridin l-N- S
orophenyl )—2-hyd roxyethyl )—2-fluorobenzamide
Scheme 16
NH2 NH2
NH2 N \
OH O N \
Steal Stepg OTf
Stegé I |
N \ / Stegfl /
I g
’ ' @ + / —’ —’
N N /
‘ N
01~ Boc 0‘~ Boc ~
0% Boc O’B\O N oN
/O /O :
/O fl 03‘ Boc O=~\‘ Boo
0 o
/ /
F o /
NH2 NH2 _
“ii Br {OH m1 NH2
M; Stegg NI \ F 0 3
_/ .
| _/ N _, +
E NI \
H / CI
0 0 H0
w: ,
Ni N, HO CI
\ Boc i Boc 0NH
OH OH N
Ste 1. S tert-but l2-meth l4-oxo rrolidine-1 2-dicarbox late
A solution of (2S,4R)—1-tert-butyl 2-methyl oxypyrrolidine-1,2-dicarboxylate (10 g,
40.8 mmol) in DCM (100 mL) was cooled to 0 °C, then treated portion wise with Dess-
Martin inane (17.29 g, 40.8 mmol) over 20 min. The reaction was ined at 0
°C for 1 h, and then the cold bath was removed. After another 3 h at room temperature,
the reaction was treated with 300 mL of 1:1 sat. aq. Na2803:sat. aq. NaHC03. The
reaction was stirred vigorously overnight at room temperature, then the layers were
separated. The organics were washed with water and brine, then dried over magnesium
sulfate and concentrated. The ing mixture was slurried in DCM (20 mL) then filtered
over Celite. The cs were concentrated. The crude oil was further purified by direct
filtration from grained solids to provide (S)—1-tert-butyl yl 4-oxopyrrolidine-1,2-
oxylate (8.53 g, 87% yield). LCMS (m/z): 244.3 (MH+), 0.42 min.
Ste 2. 1-tert-but |2-meth |4- trifluorometh lsulfon lox -1H- rrole-1 2 2H 5H -
dicarboxylate
A solution of (S)—1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.9 g, 11.92
mmol) in THF (30 mL) was cooled to -78 °C, then treated with 1.0 M LiHMDS in THF
(14.31 mL, 14.31 mmol). The reaction was maintained at -78 °C for 1h, then treated with
a on of N-(5-chloropyridinyl)-1,1,1-trifluoro-N-
luoromethyl)sulfonyl)methanesulfonamide (5.62 g, 14.31 mmol) in THF (15 mL). The
reaction was maintained at -78 °C for 1 h, and then placed in a -30 °C refrigerator
overnight. At completion, the reaction was quenched with water, and diluted with ether.
The organics were washed with 1N aqueous solution. NaOH (40 mL), then dried over
magnesium sulfate and concentrated. The residue was dissolved in chloroform (40 mL)
and cooled to 0 °C for 30 min. The resulting slurry was concentrated to ~8 mL total
volume, then the viscous material was filtered and concentrated to provide (S)—1-tert—
butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)—dicarboxylate (4.4
g, 98% . LCMS (m/z): 376.4 (MH+), 0.64 min.
Ste 3. S tert-but |2-meth |4- 6-amino 3- l -1H- rrole-1 2 2H 5H -
dicarboxylate
A mixture of (S)—1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-
,5H)—dicarboxylate (1.55 g, 4.13 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridinamine (1.00 g, 4.54 mmol), Pd(PPh3)4 (0.239 g, 0.21 mmol) and Cs2C03
(3.36 g, 10.32 mmol) in THF (10 mL) and water (2 mL) was microwave heated to 100 °C
for 10 min. The reaction was then diluted with ethyl acetate (50 mL) and water (25 mL).
The layers were separated and the cs were washed with water (25 mL) and brine
(25 mL), dried over magnesium sulfate and concentrated, then purified by flash
chromatography [0-8% methanol/DCM eluent] to provide (S)—1-tert-butyl 2-methyl 4-(6-
aminopyridinyl)—1H-pyrrole-1,2(2H,5H)—dicarboxylate (0.955g, 72% yield). LCMS (m/z):
320.4 (MH+), 0.50 min.
WO 66188
Ste 4. 28 4R tert-but l2-meth l4- 6-amino ridin l rrolidine-1 2-dicarbox late
A ed solution of (S)tert-butyl 2-methyl 4-(6-aminopyridinyl)—1H-pyrrole-
1,2(2H,5H)—dicarboxylate (0.955 g, 2.99 mmol) in methanol (30 mL) was treated with 10%
Pd/C (0.183 g, 0.172 mmol), then maintained under an atmosphere of hydrogen for 3 h.
At completion, the reaction then filtered over a pad of Celite and concentrated to provide
(2S,4R)tert-butyl yl 4-(6-aminopyridinyl)pyrrolidine-1,2-dicarboxylate (0.95 g.
99% yield). LCMS (m/z): 322.5 (MH+), 0.52 min.
Ste 5. 2S 4R -tert-but l4- 6-amino ridin l h drox meth l ine
carboxylate
To a solution of (2S,4R)tert-butyl 2-methyl 4-(6-aminopyridinyl)pyrrolidine-1,2-
dicarboxylate (250 mg, 0.778 mmol) in 2-methyl THF (18 mL) was added LiAlH4 (59 mg,
1.56 mmol). After 15 min, the reaction was quenched by the sequential addition of water
(60 uL), 1 N NaOH aqueous solution (60 uL) and water (60 uL). The mixture was stirred
vigorously for 5 min, and then filtered over Celite, rinsing with 2-methyl THF. The
organics were concentrated to provide (2S,4R)—tert-butyl 4-(6-aminopyridinyl)—2-
(hydroxymethyl)pyrrolidinecarboxylate (230 mg, 100% yield). LCMS (m/z): 294.1
(MH+), 0.49 min.
Ste 6. 2S 4R but l4- 6-aminobromo ridin l h drox meth l rrolidine
carboxylate
A solution of )-tert-butyl 4-(6-aminopyridinyl)(hydroxymethyl)pyrrolidine
carboxylate (230 mg, 0.784 mmol) in MeCN (10 mL) was treated with NBS (147 mg,
0.823 mmol). After 10 min, the reaction was complete. The reaction was treated with 10
mL 1:1 sat. aq. NaHC03:sat.aq. Na28203 and the mixture was d vigorously for 10
min. The mixture was d with ethyl acetate (30 mL) and the layers were ted.
The organics were washed with brine, dried over magnesium sulfate and concentrated to
provide (2S,4R)-tert-butyl 4-(6-aminobromopyridinyl)—2-(hydroxymethyl)pyrrolidine-
1-carboxylate (290 mg, 100% yield). LCMS (m/z): 372.1/374.0 (MH+), 0.55 min.
Ste 7. 4- 2-amino 3R 58 h drox meth l rrolidin l 3- l-N- S 3-
chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide
Following Step 5 in Scheme 10, using (28, 4R)—tert—butyl 4-(6-aminobromopyridinyl)—
2-(hydroxymethyl)pyrrolidinecarboxylate and (S)—(4-((1-(3-chlorophenyl)
hydroxyethyl)carbamoyl)fluorophenyl)boronic acid, (2S,4R)—tert—butyl 4-(6-amino(4-
(((S)—1-(3-chlorophenyl)hydroxyethyl)carbamoyl)—3-fluorophenyl)pyridinyl)—2-
(hydroxymethy|)pyrro|idinecarboxy|ate was obtained as TFA salt (30 mg, 35% yield.
LCMS (m/z): 585.3 587.3 (MH+), 0.74 min. Then, a on of (2S,4R)—tert—buty| 4-(6-
amino(4-(((S)—1-(3-chlorophenyl)hydroxyethyl)carbamoyl)—3-fluorophenyl)pyridin
y|)(hydroxymethyl)pyrrolidinecarboxylate-TFA was dissolved in DCM (2 mL) and
treated with TFA (2.0 mL). After 30 min, the reaction was concentrated, and then purified
by reverse phase prep HPLC yielding mino((3R,5S)(hydroxymethy|)pyrro|idin-
3-yl)pyridinyl)—N-((S)—1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide as the bis-
TFA salt (15.0 mg, 54% yield). LCMS (m/z): 485.2, 487.2 (MH+), 0.51 min; 1H NMR (400
MHz, CD3OD) 6 ppm 8.59 (dd, J = 4.50, 7.24 Hz, 1H), 7.87 - 7.77 (m, 4H), 7.39 - 7.31 (m,
3H), 7.29 - 7.24 (m, 2H), 7.24 -7.16 (m, 1H), 5.15 - 5.05 (m, 1H), 3.87 - 3.71 (m, 5H), 3.70
- 3.60 (m, 2H), 3.59 - 3.46 (m, 1H), 2.41 (td, J = 6.46, 12.91 Hz, 1H), 1.98 - 1.82 (m, 1H),
1.29 - 1.16 (m, 1H).
Example 8
Scheme 17
F 0 :/OH F o Z/OH
”I \ HQ 1. chloroacetic acid, HATU NI \ “Q
/ CI / CI
G 2' NaH 0
. NH N
A solution of 4-(2-amino((3R,5S)(hydroxymethyl)pyrrolidinyl)pyridinyl)-N-((S)-
1-(3-ch|oropheny|)hydroxyethy|)f|uorobenzamide (45 mg, 0.063 mmol) (see
Example 7) and chloroacetic acid (7.2 mg, 0.076 mmol) in THF (2.5 mL) was treated with
HATU (36 mg, 0.095 mmol) and DIEA (55 uL, 0.316 mmol). The reaction was maintained
at room temperature for 1 h. The reaction mixture was then treated directly with NaH
(15.2 mg, 0.631 mmol). After 15 min, the reaction was quenched with water (2 mL) and
the reaction mixture was extracted with ethyl e (10 mL). The organics were washed
with brine, then dried over Na2804, trated, then purified by reverse phase prep
HPLC yielding 4-(2-amino((7R,8aS)—4-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin
yl)pyridinyl)—N-((S)—1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide (13.0 mg,
39% . LCMS (m/z): 525.2, 527.2 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) 6
ppm 8.61 (dd, J = 4.30, 7.04 Hz, 1H), 7.91 (d, J = 1.96 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.40 -
7.31 (m, 3H), 7.30 - 7.24 (m, 2H), 7.24 - 7.16 (m, 1H), 5.16 - 5.05 (m, 1H), 4.18 - 4.08 (m,
2H), 3.99 - 3.85 (m, 2H), 3.85 - 3.70 (m, 3H), 3.53 - 3.42 (m, 2H), 3.39 - 3.29 (m, 1H),
2.34 - 2.19 (m, 1H), 1.67 (q, J = 11.48 Hz, 1H).
Example 9
S nthesis of 4- 2-amino 6R 7aS oxohexah dro rrolo 1 2-c oxazol l ridin
l-N- S 3-chloro hen lh drox eth lfluorobenzamide
Scheme 18
F o {0
NH2 N NH2 N
H H
N \ N \
I CDI, DIEA I
/ c | _/ CI
\Ofio5
A solution of 4-(2-amino((3R,5S)(hydroxymethyl)pyrrolidinyl)pyridinyl)-N-((S)-
1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide (20 mg, 0.041 mmol) (Example 7)
and DIEA (72 uL, 0.412 mmol) in itrile (0.5 mL) was treated with
carbonyldiimidazole (8.0 mg, 0.049 mmol). After 1 h, the starting material was completely
ed. The reaction mixture was quenched with 1.0 N aqueous NaOH solution (1.0
mL) and the mixture was stirred vigorously for 5 min, then, diluted with DCM (10 mL). The
organics were washed with brine (2 mL) and dried over Na2804 and concentrated. The
crude al was purified by reverse phase prep HPLC yielding 4-(2-amino
((6R,7aS)—3-oxohexahydropyrrolo[1,2-c]oxazolyl)pyridinyl)-N-((S)(3-
chlorophenyl)hydroxyethyl)f|uorobenzamide (2.0 mg, 7% yield). LCMS (m/z): 511.3,
513.3 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) 6 ppm 7.92 - 7.84 (m, 2H), 7.46 (s,
1H), 7.44 - 7.40 (m, 1H), 7.38 - 7.35 (m, 1H), 7.34 - 7.28 (m, 1H), 5.19 (t, J = 5.87 Hz,
1H), 4.61 - 4.56 (m, 1H), 4.34 (dd, J = 3.52, 9.00 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.92 - 3.80
(m, 1H), 3.74 - 3.62 (m, 1H), 2.41 (td, J = 5.72,11.64 Hz, 1H), 1.84 - 1.71 (m, 1H).
Example 10
S nthesis of 4- 2-amino 6R 7aS iminohexah dro rrolo 1 2-c oxazol l 3-
l-N- S 3—chloro hen lh drox eth lfluorobenzamide
Scheme 19
F O {OH
NH2 3 NH2 3
N \ N \
| B ON Cr
v S2CO3 I
/ CI / CI
:\O\A\NH
A room temperature mixture of 4-(2-amino((3R,5S)—5-(hydroxymethyl)pyrrolidin
yl)pyridinyl)—N-((S)(3-chlorophenyl)hydroxyethyl)f|uorobenzamide (12.5 mg,
0.026 mmol) le 7) and cesium carbonate (33.6 mg, 0.103 mmol) in ethanol (0.75
mL) was treated with cyanogen bromide (6.2 uL, 0.031 mmol). After 1 h, the reaction was
diluted with water (1.0 mL) and extracted into ethyl acetate (10 mL). The organics were
washed with brine (2 mL), then dried over Na2804 and concentrate and purified by
reverse phase prep HPLC ng 4-(2-amino((6R,7aS)—3-iminohexahydropyrrolo[1,2-
c]oxazolyl)pyridinyl)—N-((S)—1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide.
LCMS (m/z): 510.1, 512.1 (MH+), 0.52 min. 1H NMR (400 MHz, CD3OD) 6 ppm 8.63 -
8.54 (m, 1H), 7.92 - 7.85 (m, 2H), 7.80 (t, J = 7.83 Hz, 1H), 7.40 - 7.31 (m, 3H), 7.29 -
7.24 (m, 2H), 7.24 - 7.16 (m, 1H), 5.14 - 5.06 (m, 1H), 4.97 - 4.88 (m, 1H), 4.61 - 4.49 (m,
2H), 3.88 - 3.70 (m, 4H), 3.32 (s, 1H), 2.41- 2.31 (m, 1H), 2.02 -1.89 (m, 1H).
Example 11
4- 2-amino 6R 7aS thioxohexah dro rrolo 1 2-c l ridin l -N- S
ro hen lh drox eth lfluorobenzamide
Scheme 20
F O :/OH
NH2 N NH2 N
H H
N \ N \
| tIoCh' - DI DIEA
/ Cl
/ CI
\Oks:.
To a solution of (2S,4R)—tert-butyl 4-(6-amino(4-(((S)—1-(3-chlorophenyl)
hyd hyl)carbamoyl)fluorophenyl)pyridinyl)—2-(hyd roxymethyl)pyrro|idine-1 -
carboxylate (45 mg, 0.063 mmol) (see e 7) in acetonitrile (0.75 mL) and DMF (0.5
mL) was added DIEA (42 ML, 0.240 mmol) and thiocarbonyl diimidazole (15.6 mg, 0.088
mmol). After 2 h, the reaction was quenched with 1 N aqueous solution. NaOH (1 mL)
and stirred vigorously to effect decomposition of a mixed thiocarbamate byproduct. The
reaction was then diluted with ethyl acetate (10 mL), washed with water (5 mL) and brine
(5 mL), then dried over sodium sulfate and concentrated. The crude material was purified
by reverse phase prep HPLC yielding 4-(2-amino((6R,7aS)—3-
thioxohexahydropyrrolo[1,2-c]oxazolyl)pyridinyl)—N-((S)—1-(3-chlorophenyl)
hydroxyethyl)fluorobenzamide (3.2 mg, 11% yield). LCMS (m/z): 527.3, 529.3 (MH+),
0.67 min; 1H NMR (400 MHz, CD30D) 6 ppm 8.64 (dd, J = 3.91, 7.04 Hz, 1H), 7.85 (d, J =
1.96 Hz, 2H), 7.83 - 7.77 (m, 3H), 7.39 - 7.32 (m, 5H), 7.30 - 7.26 (m, 3H), 7.25 - 7.19
(m, 2H), 5.15 - 5.07 (m, 2H), 4.73 - 4.69 (m, 2H), 4.45 - 4.35 (m, 3H), 3.85 - 3.65 (m, 8H),
2.38 (td, J = 5.58, 11.54 Hz, 2H), 1.80 - 1.70 (m, 1H).
8 nthesis of 5-mor holino 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridinamine
Scheme 21
m1 Br Step 2 Br Step g
\ \
Br N N Br
\N | | \N
| / / |
/ —> —> N02 —> /
0 NH 0 NH NO
V 2
NH2 ‘n’ V\n’
0 0
m4. No2 m; No2 mg NH2 m1
NH2 0
NH2 Br Br 53
N \ N \ N \ N/ ‘o
I I I
/ / / I
a _. \
, _,
EN] EN] [NJ ”
o o 0 EO1
Ste 1. Eth | 5-bromo ridin lcarbamate
-bromopyridinamine (20 g, 116 mmol) was dissolved in DCM (500 mL) and pyridine
(28.0 mL, 347 mmol) was added, followed by ethyl chloroformate (11.44 mL, 119 mmol)
dropwise. The reaction mixture was stirred for 1.5 h at room temperature. The reaction
mixture was diluted with DCM. The two phases were separated and the organic phase
was washed with 10% CuSO4 solution (2x) sat. NaHC03 solution (1x) Brine (1x) dried
(Na2804) and evaporated. The residue was triturated with diethyl ether filtered and dried
ing ethyl (5-bromopyridinyl)carbamate (21.58 g, 76 %) as a white solid. LCMS
(m/z): 247.0 (MH+), 0.58 min; 1H NMR (400 MHz, CDCI3 )6 2 - 8.15 (m, 3 H) 7.00
(br. s., 1 H) 4.27 (q, J=7.0 Hz, 2 H) 1.34 (t, J=7.0 Hz, 3 H).
Ste 2. Eth l 5-bromonitro ridin lcarbamate
To a mixture of concentrated H2804 (60 mL, 1126 mmol) and fuming HN03 (40 mL, 895
mmol), ethyl mopyridinyl)carbamate (21.5 g, 88 mmol) was added portionwise at
0 °C. After stirring at 0 °C for 5 min, the mixture was stirred at rt ght and poured
onto ice water. A crash out formed and was filtered off and washed thoroughly with water
and dried. Ethyl (5-bromonitropyridinyl)carbamate (21.26 g, 84%) was thus obtained
as a white solid. LCMS (m/z): 290.1 (MH+), 0.76 min. 1H NMR (400 MHz, CDCI3) 6 ppm
9.63 (br. s., 1 H) 9.33 (d, J=2.0 Hz, 1 H) 8.28 (d, J=2.0 Hz, 1 H) 4.32 (q, J=7.3 Hz, 3 H)
1.68 (br. s., 2 H) 1.38 (t, J=7.0 Hz, 4 H).
Step 3. 5-Bromonitropyridinamine
Ethyl (5-bromopyridinyl)carbamate (8 g, 27.6 mmol) was dissolved in EtOH (250 mL)
and the solution was cooled down to 5 °C with an ice bath. Cold 1M KOH (130 mL, 130
mmol) was added dropwise, maintaining below 5 °C. The reaction mixture was stirred at
room temperature ght, concentrated under d pressure. Upon concentration a
crash out forms, which was filtered off washed with water and dried affording 5-bromo
yridinamine (5.02 g, 83%). LCMS (m/z): 220.1 (MH+), 0.46 min; 1H NMR (400
MHz, CDCI3) 6 ppm7.97 (d, J=1.6 Hz, 1 H) 7.50 (d, J=2.0 Hz, 1 H) 6.03 (br. s., 2 H).
Step 4. 5-morpholinonitropyridinamine
-Bromonitropyridinamine (2.32 g, 10.6 mmol) was suspended in morpholine (5 mL,
57.4 mmol) and the solution was heated at 140 °C for 1h. The reaction mixture was
cooled to room ature and the solid crash out was triturated with water and filtered.
The solid this obtained was washed with water, EtOH, and dried, obtaining 5-morpholino-
2-nitropyridinamine (2.0 g, 8.92 mmol, 84%) as a bright yellow powder. Depending on
the outcome of the previous step, this solid may still contain the ethoxy derivative from the
previous step, and the two compounds can be separated by column chromatography on
silica gel (analogix, 20% EtOAc in heptane for 2 min, to 100% EtOAc to 15 min, then
100% EtOAc to 20 min). LCMS (m/z): MH+), 0.43 min; 1H NMR (400 MHz, CDCI3)
6 ppm 10.54 (s, 1 H) 8.57 (d, J=2.7 Hz, 1 H) 7.85 (d, J=2.7 Hz, 1 H) 7.70 (d, J=2.3 Hz, 1
H) 6.32 (d, J=2.3 Hz, 1 H) 6.00 (br. s., 1 H) 3.93 - 3.83 (m, 7 H) 3.83 - 3.74 (m, 3 H) 3.63 -
3.55 (m, 3 H) 3.51 - 3.43 (m, 3 H) 3.41- 3.31 (m, 4 H).
Ste 5. 4- onitro ridin lmor holine
A three neck round bottom flask equipped with a magnetic stir bar, a dropping funnel and
a thermometer, was charged with CuBr (629 mg, 4.4 mmol) and HBr (25 mL). The
solution was cooled to -5 °C (ice salt bath). Solid 5-morpholinonitropyridinamine
(983 mg, 4.4 mmol) was slowly added, followed by the slow addition of a NaNOz (333 mg,
4.8 mmol) solution in H20 (25 mL) via the dropping funnel, ensuring that the temperature
did not rise above 0 °C. The reaction mixture was stirred at -5 °C for 1 h, warmed to room
temperature and stirred an additional 1.5 h. The reaction was deemed complete by LCMS
and the mixture was cooled again to 0 °C, quenched with 6 N NaOH to pH 12, diluted with
water and extracted with EtOAc. EtOAc was washed with water (x2), brine (x1) dried and
concentrated. The residue was azeotroped with EtOH dried under high vacuum, obtaining
4-(5-bromonitropyridinyl)morpholine (1.21 g, 4.20 mmol, 96 % yield) as a light yellow
solid. LCMS (m/z): 288.2 (MH+), 0.65 min. 1H NMR (400 MHz, CDCI3) 6 ppm 8.08 - 7.99
(d, J=2.3 Hz, 1 H) 7.41 (d, J=2.3 Hz, 1 H) 3.98 - 3.81 (m, 4 H) 3.45 - 3.30 (m, 4 H).
Step 6. omorpholinopyridinamine
4-(5-Bromonitropyridinyl)morpholine (95 mg, 0.33 mmol) was dissolved in EtOH (12
mL) and water (3.0 mL) was added, followed by SnCIz (313 mg, 1.65 mmol). The reaction
mixture was heated to 80 °C for 2 h, cooled to room temperature and d with DCM.
The two phases were separated, the organic phase was washed with water. The water
phase was back extracted with DCM. The pH was adjusted to 12 with 6N NaOH and the
mixture was further extracted with DCM. The organic extracts were combined, dried
(Na2804) and evaporated under reduced pressure ing the d 3-bromo
linopyridinamine (71.5 mg, 84%). LCMS (m/z): 260.0 (MH+), 0.37 min.
Alternate Method
To a solution of 4-(5-Bromonitropyridinyl)morpholine (2 g, 6.9 mmol) in MeOH (150
mL) in a round bottom flask was added Zn dust (4.54 g, 69.4 mmol). The reaction mixture
was cooled to 0 °C. Solid NH4C| (3.71 g, 69.4 mmol) was added in portions, over 5 min.
The heterogeneous reaction e was stirred at room temperature for 2 h, filtered
through a plug of Celite washing the filter cake with methanol and ethanol. The te
was concentrated to a brownish solid which was purified by flash column chromatography
on silica gel (ISCO, 80 g column, 0-70% EtOAc/heptane in 15 min and 70% EtOAc to 25
min), obtaining 3-bromomorpholinopyridinamine (936 mg, 52.2 %) as a slightly off
white solid. LCMS (m/z): 258.2 (MH+), 0.35 min; 1H NMR (400 MHz, CDCI3) 6 ppm 7.75
(d, J=2.3 Hz, 1 H) 7.40 - 7.30 (m, 1 H) 4.66 (br. s., 2 H) 3.91- 3.74 (m, 4 H) 3.07 - 2.90 (m,
4 H).
Ste 7. 5-Mor holino 4 4 5 5-tetrameth H 3 aborolan l ridinamine
3-bromomorpholinopyridinamine (36 mg, 0.14 mmol), bis(pinacolato)diboron (70.8
mg, 0.28 mmol), potassium e (41.1 mg, 0.42 mmol) and tricyclohexylphosphine
(5.9 mg, 0.021 mmol) were dissolved in 1,4-dioxane (1.5 mL) in a pressure vessel. The
mixture was sparged with N2 for 5 min and palladium diacetate (3.1 mg, 0.014 mmol) was
added. The reaction mixture was heated to 110 °C for 16 h, cooled to room ature
and diluted with ethyl acetate. SyliaBondDMT was added, the mixture was stirred for 1h,
filtered over a Celite pad and concentrated, obtaining 21.3 mg of a solid which contains
the desired 5-morpholino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine.
This solid was used in the next step without further purification. LCMS (m/z): 224.0 (MH+),
0.33 min (for boronic acid).
Scheme 22
CF so3 2 so CF
2N 2 3 Ste
O/SOZCF3
\N LiHMDS
THF 78 OC —ESte §
0 N \
f)Cl2_DCM I
_9_Ste 2 Na co2 3, DME
NH2 \
”HEN N \
O O
\ KCO
lB—B: —>\
Pd(dPPf)C|2, 2 3 0
O Kg”| / O dioxane B
NH2 NH2 NH2 NH2
$94 N)\ N)\ Br
fieé N \
I I N)\(BrI
1.Pd/C,MeOH /N /N k/N /N
2. chiral separation
N"O \\\"O O O O
Step 1. 2-methyl-3,6-dihydro-2H-pyranyl trifluoromethanesulfonate
To a solution of 2-methyldihydro-2H-pyran-4(3H)—one (2g, 17.52 mmol) in THF (8.76 mL)
was added LiHMDS (18.40 mL, 18.40 mmol) dropwise at -78 °C. The reaction mixture
was stirred at -78 °C for 1.5 h, then N-(5-chloropyridiny|)-1,1,1-trifluoro-N-
((trifluoromethyl)sulfonyl)methanesulfonamide (7.22 g, 18.40 mmol) in THF (17 mL) was
added at -78 °C. The e was stirred at -78 °C for 1h, and then allowed to warm up
to room temperature, and stirred overnight. The reaction was monitored by TLC. After
quenched with sat NaHC03, The reaction mixture was ted with EtOAc 3 times. The
combined c layers were washed with water, brine, and dried over anhydrous
sodium sulfate. Filtered and concentrated in vacuo. The desire compound (4.2 g, 17.06
mmol) was obtained as a brown oil by flash column chromatography eluting with 30%
EtOAc in heptane.
Ste 2. 5- 4 4 5 5-tetrameth H 3 2-dioxaborolan l razinamine
To a solution of 5-bromopyrazinamine (1 g, 5.75 mmol), bis(pinacolato)diboron (2.92 g,
11.49 mmol), and PdC|2(dppf)CH2C|2 adduct (0.469 g, 0.575 mmol) in dioxane (16.42 mL)
was added ium acetate (1.692 g, 17.24 mmol) just right after degassing. The
reaction mixture was heated in microwave at 120 °C for 20 min. Diluted with EtOAc, and
the reaction mixture was filtered through Celite. trated, and the crude product was
used for next step without further purification. LCMS (m/z): 140 (MH+ for c acid),
0.12 min.
Ste 3. 5- 2-meth l-3 6-dih dro-2H- ran l razinamine
To a on of 2-methyl-3,6-dihydro-2H-pyranyl trifluoromethanesulfonate (0.637 g,
2.88 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrazinamine (0.914 g, 3.74
mmol), and dppf)-CH2C|2 adduct (0.235 g, 0.288 mmol) in DME (9.82 mL) was
added 2M Na2C03 (3.27 mL). The reaction mixture was heated at microwave synthesizer
(120 0C, 10 min). Ethyl acetated was added, and washed with sat NaHC03, and water.
Then the desired compound was extracted to 1N HCI aqueous layer, and washed with
EtOAc. Basified with 2N NaOH, and the product was extracted to EtOAc layer. EtOAc
organic layer was washed with water and dried over Na2804. Filtered and concentrated to
provide 250 mg of desired compound. LCMS (m/z): 192.2 (MH+), 0.40 min.
Ste 4. 5- 2R 4R meth ltetrah dro-2H- ran l razinamine
To a on of 5-(2-methyl-3,6-dihydro-2H-pyranyl)pyrazinamine (250 mg, 1.307
mmol) in MeOH (13.100 mL) was added Pd/C (278 mg, 0.261 mmol). The solution was
degassed by N2 stream for 10 min. After flushed by H2 gas, hydrogen balloon was
equipped. The reaction mixture was stirred for 25 h. After filtered through Celite, the
volatile material was removed to give the crude product, which was purified with flash
chromatography eluting with 0-10% of MeOH in DCM to provide 180 mg of
diastereomers. Then chiral separation (ChiraIPak 5mic AD column, 4.6x100 (mm),
5mL/min, EtOH+0.1% DEA = 15%) provided 40 mg of 5-((2R,4R)—2—methyltetrahydro-2H-
pyranyl)pyrazinamine (Rt = 1.32 min; LCMS (m/z): 194.2 (MH+), 0.44 min) in 22%
yield and 30 mg of desired 5-((2S,4S)—2-methy|tetrahydro-2H-pyranyl)pyrazinamine
(Rt = 1.83 min; LCMS (m/z): 194.2 (MH+), 0.44 min) in 16% yield.
Ste 5. 3-bromo 2R 4R meth h dro-2H- ran l razinamine and 3-
bromo 28 4S meth ltetrah dro-2H- ran l razinamine
To a solution of 5-((2R,4R)—2-methyltetrahydro-2H-pyranyl)pyrazinamine (40 mg,
0.207 mmol) in acetonitrile (3 mL) was added NBS (35.0 mg, 0.197 mmol) at 0 °C. The
reaction mixture was stirred at 0 °C for 15 min. After ed with NaHC03, the
reaction e was extracted with EtOAc three times. The c layers were
combined and washed with water, and brine. Dried over Na2804, filtered and
concentrated to afford 47 mg of 3-bromo—5-((2R,4R)—2-methy|tetrahydro-2H-pyran
yl)pyrazinamine, which was used as it was. LCMS (m/z): 274 (MH+), 0.64 min. For 5-
((2S,4S)methyltetrahydro-2H-pyranyl)pyrazinamine, following the above method,
3-bromo((2S,4S)—2-methyltetrahydro-2H-pyranyl)pyrazinamine was obtained.
LCMS (m/z): 274 (MH+), 0.65 min. The absolute stereochemistry of the products were
ed arbitrarily.
S nthesis of 3-bromoc clo ro | razinamine
Scheme 23
NH2 NH2 NH2
N \ Y KOt—Bu, Pd(PPh)4 NBS
Rf %| + / \ —> Nl)\ —> Nl)\(Br
N O O / N / N
dioxane/water, 160 °C
Ste 1.5-c clo ro l razinamine
To a microwave vial was charged with 5-bromopyrazinamine (400 mg. 2.3 mmol), 2-
cyclopropyI-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g, 6.9 mmol), KOt—Bu (1 M in t-
BuOH, 9.2 mL), 1,4-dioxane (10 mL), and water (0.10 mL), and the mixture was purged
with Argon, followed by addition of Palladium tetrakis (266 mg, 0.23 mmol) and final
Argon purge, then the mixture was sealed and heated at 150 °C via microwave reactor for
min. To the reaction mixture was added 2nd portion of PalladiumTetrakis (266 mg)
and the reaction was heated at 160 °C via microwave reactorfor 20 min. The on
mixture was ed through a thin layer of Celite, and the filtrate was concentrated. The
residue was triturated with EtOAc (6 mL), and the itates were removed via
centrifugation and filtration. The EtOAc supernatant was back extracted with aqueous
TFA solution (3 x 3 mL, ter- 1 mL/10 mL). The TFA solutions were combined,
diluted with acetonitrile (10 mL), frozen and lyophilized to afford 5-cyclopropylpyrazin
amine in a yellow . The product after lyophilization was transferred to a vial,
basified to pH > 12 with sat. Na2C03 (3mL), extracted with EtOAc(4 x 6 mL), and the
EtOAc extracts were combined, and concentrated and further dried under high vacuum,
and final 5-cyclopropylpyrazinamine free base was obtained (79 mg, 25.4% yield).
LCMS (m/z): 136.1 (MH+), 0.30 min. 1H NMR (CD3OD) 6 ppm 8.29 (d, J = 1.2 Hz, 1H),
7.70 (d, J = 1.6 Hz, 1H), 2.00 - 2.08 (m, 1H), 0.94 - 1.00 (m, 2H), 0.87 - 0.93 (m, 2H).
Step 2. 3-bromocyclopropylpyrazinamine
A solution of 5-cyclopropylpyrazinamine (79 mg, 0.584 mmol) in acetonitrile (10 mL)
was cooled down to 0 °C, and treated with l on of NBS (140 mg, 1.46 mmol)
over the course of 1 hour while closely monitoring reaction progress by LCMS. The
reaction e was concentrated and the residue was triturated with EtOAc (2 x 5 mL)
and the EtOAc supernatants were separated via fugation, combined and washed
with 1N NaOH (3 x 1 mL) and the EtOAc layer was dried (over Na2804), concentrated
and a crude brown reside was obtained. The crude product was further purified by flash
chromatography on silica gel eluted with gradient EtOAc/CHZCIZ (0-30%) to afford 3-
bromocyclopropylpyrazinamine in colorless solid (38.2 mg, 38.5% yield). LCMS
(m/z): 216.0 (MH+), 0.64 min.
8 nthesis of 3'-meth l 4 4 5 5-tetrameth H 3 2-dioxaborolan | - 3 4'-bi ridin
amine
Scheme 24
NH2 NH2
NH2 NH2 9J§<
Ste 2 Br
43‘s 1 J- 4‘Ste 3
N \ N \
C. 1 \ N. \
I / / I
/ Pd(dPPf)C|2 NBS Pd(dPPf)CI2.Bz(P|N)2 /
+ \ —> —> —>
,B\ I NaZCO3, DME \ / KOAc, dioxane /
o o /
N | |
/ \ I
+4 ~ N \N
Ste 1. 3'-meth l-3 4'-bi ridinamine
To a solution of (2 g, 9.09 mmol) in DME (45.4 mL) was added 4-chloromethylpyridine
(1.739 g, 13.63 mmol), and PdCl2(dppf)-CH2Cl2Adduct (0.742 g, 0.909 mmol) and 2 M
Na2C03 (15.15 mL), mixture was purged with nitrogen for 5min, The reaction mixture in
sealed glass bomb was heated to 120 °C overnight. The reaction mixture was extracted
by EtOAc, the organic layers and washed with brine water The organic was dried by
Na2804 anhydrous, filtered and concentrated to yield crude t. The crude material
was purified by flash chromatography (0-100% EtOAc/heptane) to yield 3'-methyl-3,4'-
bipyridinamine (255 mg, 1.377 mmol, 15.15 % yield). LCMS (m/z): 406.3 (MH+), 0.47
Step 2. o-3'-methyl-3,4'-bipyridinamine
To an ice cold solution of 3'-methyl-3,4'-bipyridinamine (250 mg, 1.350 mmol) in DCM
(4499 uL) was added NBS (264 mg, 1.485 mmol) in two portions. The reaction mixture
was stirred at 0 °C for 2 h. Reaction mixture was diluted with ethyl acetate, and was
washed with water, brine, dried and trated. Residue was treated heptane, the solid
filtered to give 5-bromo-3'-methyl-3,4'-bipyridinamine (350 mg, 1.325 mmol, 98 %
yield) as brown color solid, used in next step reaction without purification. LCMS (m/z):
264.4/266.4 (MH+), 0.32 min; 1H NMR z, CDCI3) 6 ppm 8.51 (s, 1 H), 8.47 (d, J:
.1 Hz, 1 H), 8.04 (d, J: 2.0 Hz, 1 H), 7.69 (d, J: 2.0 Hz, 1 H), 7.12 (d, J: 5.1 Hz, 1 H),
.06 (br. s., 2 H), 2.32 (s, 3 H).
Ste 3. 3'-meth l 4 4 5 5-tetrameth H 3 2-dioxaborolan l -3 4'-bi ridinamine
To a suspension of (5-bromo-3'-methyl-3,4'-bipyridinamine (100 mg, 0.379 mmol) in
1,4-dioxane (947 uL) was added bispinB (288 mg, 1.136 mmol) and potassium acetate,
(186 mg, 1.893 mmol). Mixture was purged with nitrogen for 3min, then
dppf)CH2C|2 adduct (30.9 mg, 0.038 mmol) was added. The reaction mixture was
heated to 120 °C in microwave for 10 min, Formation of desired t was confirmed.
still some starting material left, resubmitted for microwave 120 °C for 10 min. The reaction
mixture was filtered h filter and rinsed with dioxane (0.7 mL), the filtrate solution
was used in next step reaction without purification. LCMS (m/z): 230.1 (MH+for boronic
acid), 0.22 min.
8 nthesis of 1- 4- 5-aminobromo 2- l i eridin lethanone
Scheme 25
NH2 ““2
NAKBr| MeCOCl N&Brl
\ N \ N
DIEA/DCM
To 3-bromo(piperidinyl)pyrazinamine (50 mg, 0.194 mmol) in DCM (4 mL) in ice
bath was added DIEA (0.136 mL, 0.778 mmol) and acetyl chloride (0.017 mL, 0.233
mmol) . The reaction mixture was stirred at in ice bath 30min. The on mixture was
partitioned between DCM and water. The DCM layer was separated and washed with
brine. Dried over sodium sulfate, filtered and evaporated. Proceed for next step. LCMS
(m/z): 299.1/301.1 (MH+), 0.508 min. 1H NMR (400 MHz, CD3OD) 6 ppm 7.81-7.69 (m, 2
H), 7.62-7.45 (m, 2 H), 7.37-7.09 (m, 6 H), 6.5 (dd, J=8.61, 2.35 Hz, 1 H), 6.50 (dd,
J=13.50, 2.15 Hz, 1 H), 5.17—5.01 (m, 1 H), 4.55 (d, J=13.30 Hz, 1 H), 3.94 (d, J=13.69
Hz, 1 H), 3.63-3.63 (m, 2 H), 2.88 (tt, J=11.84, 3.62Hz, 1 H), 2.67 (td, J=12.91, 2.35 Hz, 1
H), 2.03 (s, 3 H), 1.96-1.79 (m, 2 H), 1.78-1.50 (m, 2 H).
S nthesis of 3-bromo 1-meth l-1H- razol l ridinamine
Scheme 26
Ste e2
0 Pd(dDP)f)C|
\ 2 Nl \
“1 +
/ NyiO
/N NagCO3 DME
Br Z\
Ste 1. 5- 1-meth l-1H- razol l ridinamine
To a microwave vial was charged opyridinamine (500 mg, 2.89 mmol), 1-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole (1.2 g, 5.78 mmol),
aqueous Na2C03 (2 M, 5.78 mL), PdC|2(dppf) CH2C|2 (0.236 g) and DME (15 mL), and
the reaction e was purged with Argon for 5min, sealed and heated with microwave
reactor at 115 °C for 20min. The DME layer of reaction mixture was collected,
trated and the residue was subjected to flash column chromatography on silica gel
eluted with gradient Methanol/CH2CI2 and 5-(1-methyl-1H-pyrazolyl)pyridinamine
was obtained as light brown solid (383 mg, 76% yield). LCMS (m/z): 175.2 (MH+), 0.34
min.
Ste 2. 3-bromo 1-meth l-1H- razol l ridinamine
To 5-(1-methyl-1H-pyrazolyl)pyridinamine(380 mg, 2.18mmol) acetonitrile(30 mL)
on at 0 °C was added NBS (388 mg, 2.18 mmol) and the reaction mixture was
stirred at 0 °C for 30 min, then at room temperature for additional 40 min. The reaction
mixture was then concentrated, redissolved in methanol, to it was added solid LiOH (80
mg), sonicated and concentrated, the residue was triturated with water (2 x 5 mL), and
the supernatants were ded. the residue was dried under high vacuum, then
triturated with EtOAc (2 x 8 mL), and the supernatants were collected, ed, and
concentrated and the light brown residue was obtained as crude o(1-methyl-1H-
pyrazolyl)pyridinamine. LCMS (m/z): 253.0/255.0 (MH+), 0.38 min.
8 nthesis of S 2-aminofluoro 1-meth l-1H- razol l ridin lfluoro-N-
2-h drox hen |eth Ibenzamide
Scheme 27
“”2 ””2
St 91 St 92 _er g
NH2 NHZ Br
N / N /
NBS f)C'2 | NBS |
N/ N/ O\B,o \ \
l —> | —>
+ F —> F
\ \ Na co DME
Br NxN / /
\ N—N N—N
/ /
Ste 1.5-bromofluoro 2-amine
To a solution of 4-fluoropyridinamine (400 mg, 3.57 mmol) in acetonitrile (35. 7 mL)
was added NBS (648 mg, 3.64 mmol) in three portions at 0 °C . The reaction mixture was
stirred at 0 °C for 20 min. LCMS showed the reaction complete. After quenched with sat
Na28203 and NaHC03, stirred for 30 min. The reaction mixture was extracted with
EtOAc 3 times. Washed by sat NaHC03, water and brine. Dried and concentrated. The
crude material was ated with ether and taken to the next step without further
purification. LCMS (m/z): 192.9 (MH+), 0.32 min.
Ste 2. 4-fluoro 1-meth l-1H- razol l ridinamine
To the reaction mixture of 5-bromofluoropyridinamine (369 mg, 1.932 mmol), 1-
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (603 mg, 2.90 mmol),
PdCl2(dppf)DCM (141 mg, 0.193 mmol) and DME (9.660 uL), 2M Na2C03 (3.220 mL) was
added. The reaction mixture was heated at microwave synthesizer (120 °C 12 min). To
the reaction e, anhydrous sodium sulfate was added, filtered, and concentrated.
The crude product was purified by flash chromatography eluting with 0-100% EtOAc
ining 10% of MeOH/heptane to provide 280 mg of desired product in 75 % yield.
LCMS (m/z): 193.1 (MH+), 0.35 min.
Ste 3. 3-bromofluoro 1-meth l-1H- razol l ridinamine
To a solution of 4-fluoro(1-methyl-1H-pyrazolyl)pyridinamine (150 mg, 0.780
mmol) in acetonitrile (7. 805 mL) was added NBS (142 mg, 0.796 mmol) in three ns
at 0 °C . The reaction mixture was stirred at 0 °C for 20 min. LCMS showed the reaction
complete. After quenched with sat Na2803 and NaHC03, stirred for 30 min. The reaction
mixture was ted with EtOAc 3 times. Filtered out solid. The solid was not the
desired product. The EtOAc layers were washed by sat NaHC03, water and brine. Dried
and concentrated. The crude material was purified with flash chromatography g with
0-100% EtOAc (containing 10% MeOH/heptane to provide 30 mg of desired product.
LCMS (m/z): 273.1 (MH+), 0.46 min.
8 nthesis of +/- - 18 BR 5-aminobromo razin l c clo entanol +/- - 1R 3R
-aminobromo 2- lc clo entanol and +/- bromo 1R 3R
methox c clo ent l razinamine
Scheme 28
SteL Steg g m;
0 NH2
Brz, PPh3 Pd(dppf)C|2, BZ(P|N)2 ['3 Pd(dppf)CI2
—. ‘0 + NI \ —.
TEA benzene KOAc, dioxane / N NaZCO3, dioxane
85 OC. 5 h
0 Br 100 ”C, o/n
NH2 m-4 NBoq Steg g NBoc2 Step 6 NBocQ NBOCz
N)\ 80020 N)\| H2 N)\ NJN
| NaBH4 I NJNI
I / N / N
/ N / N
/ N —> —> +
DMAP Pd/C MeOH
OH OH
(+/_)
Ste NH2
1 NHZ
Br St 97e
N \ NJ\(Br NJYBr _ NI \
1. HCI, e I | I
/N / N /N 1. HCI, dioxane /N
—, + ‘—
2. NBS 2. NBS
OH OH OMe OMe
(+/_) (+/_)
Ste 1. 3-bromoc c|o entenone
To a solution of PPh3 (44.1 g, 168 mmol) in benzene (510 mL), Br2 (8.67 mL, 168 mmol)
was added dropwise at 0 °C, the solution turned to yellow suspension, then TEA (23.44
mL, 168 mmol) was added . To the e was added cyclopentane-1,3-dione (15
g, 153 mmol) in benzene (100 mL). The reaction mixture was stirred at room temperature
for overnight. Ether 200 mL was added, the reaction mixture was then filtered. The filtrate
was concentrated, the residue was treated with EtZO, the solid was filtered one
, repeated
more time. The crude product was used in next step reaction. LCMS (m/z): 160.9 (MH+),
0.35 min.
Ste 2. 3- 4 4 5 5-tetrameth H 3 2-dioxaborolan l c clo entenone
To a solution of 3-bromocyclopent—2-enone (13 g, 81 mmol) in dioxane ( 161 mL) was
added B2(P|N)2 (41.0 g, 161 mmol) and PdC|2(dppf)CH2C|2 (2.95 g, 4.04 mmol). The
reaction mixture was degassed for 15 min by N2 bubbling. Then KOAc (23.77 g, 242
mmol) was added. The reaction mixture was heated at 90 °C overnight. After cooling
down, the reaction mixture was filtered off through a frit glass filter and rinsed with
dioxane (160 mL), the filtrate was concentrated in vacuo ng crude 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)cyclopentenone, which was used for the next step
without purification. LCMS (m/z): 126.9 (MH+), 0.17 min.
Ste 3. 3- 5-amino razin lc clo entenone
To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclopent—2-enone (2.99 g, 14.37 mmol)
(the te from last step) was added 2-amino-5 bromopyrazine (2.5 g, 14.37 mmol),
PdCI2(dppf)-CH2C|2 (1.173 g, 1.437 mmol), Na2C03 (7.61 g, 71.8 mmol) and water (17.96
mL) the reaction mixture was stirred at 100 0C oil bath for overnight, filtered through
. The reaction mixture was then extracted by EtOAc. The organic was then used 3N
HCI (20mL) washed 2 times, and water 50mL once, the AQ was then neutralized by
NaOH to pH= 8, the reaction mixture was then extracted by IPA (7:3) 3 times, the
organic was dried and concentrated and used as it. LCMS (m/z): 176.1 (MH+), 0.32 min.
Ste 4. N N- di-tert-but l 5- 3-oxoc clo enten l razin |carbamate
To a solution of 3-(5-aminopyrazinyl)cyclopentenone (500 mg, 2.85 mmol) in DCM
(9.5mL) was added Boc20 (1988 ul, 8.56 mmol) and DMAP (523 mg, 4.28 mmol), the
reaction mixture is dark solution, the reaction mixture was stirred at room temperature for
h. The reaction mixture was concentrated and purified by flash chromatography (0-40%
heptane) to give N,N- di-tert-butyl oxocyclopent—1-enyl)pyrazin
y|)carbamate in 47% yield. LCMS (m/z): 376.2 (MH+) 0.96 min. 1H NMR (400MHz CDCI3)
6 ppm 8.77 (d, J = 1.2 Hz, 1 H), 8.72 (d, J :12 Hz, 1 H), 6.89 (s, 1 H), 3.15 (td, J = 2.3,
4.7 Hz, 2 H), 2.64 (td, J = 2450 Hz, 2 H), 1.45 - 1.37 (m, 18H).
Ste 5. +/- -N N-Di-tert-but l 5- 3-oxoc clo ent l razin |carbamate
N,N- di-tert-butyl (5-(3-oxocyclopenteny|)pyraziny|)carbamate (600 mg, 1.598
mmol) in methanol was purged by N2 for 10 min, the Pd/C (170 mg, 0.160 mmol) was
added, the reaction mixture was purged by N2 for another 5 min, the reaction mixture was
then charged with en balloon and stirred at room temperature for 2 h. Filtered
through Celite, the filtrated was concentrated, the crude material was used in next step
reaction without purification. LCMS (m/z): 378.1 (MH+), 0.83 min.
Ste 6. +/- -N N-Di-tert-but l 5- 1R 3R h drox c clo ent l razin |carbamate
and (+/—)—N,N-Di-tert—butyl R,3S)—3-hydroxycyclopentyl)pyrazinyl)carbamate
(+/-)-N,N-Di-tert-butyl oxocyclopentyl)pyrazinyl)carbamate (600 mg, 1.590 mmol)
was dissolved in methanol (5299 ul), then NaBH4 (90 mg, 2.385 mmol) was added, the
reaction mixture was stirred at room temperature for 30 min, sat. NH4C| added, the
on mixture was then concentrated to remove methanol. Extracted by EtOAc, the
c was washed by sat.NaHC03 solution, water and brine, dried over anhydrous
N32804, concentrated to yield the crude product. The crude product was purified by flash
chromatography to give (+/-)-N,N-Di-tert-butyl (5-((1R,3R)—3-hydroxycyclopentyl)pyrazin-
2-y|)carbamate (24.9%). LCMS (m/z): 280.1 (MH+), 0.86 min. 1H NMR z ,CDCI3) 6
ppm 8.50 - 8.43 (m, 1 H), 8.43 - 8.33 (m, 1 H), 4.40 (br. s., 1 H), 3.58 - 3.45 (m, 1 H), 2.36
- 2.17 (m, 2 H), 2.02 - 1.75 (m, 5 H), 1.50 - 1.39 (m, 18 H). (+/-)-N,N-Di-tert-buty| (5-
((1R,3S)—3-hydroxycyclopentyl)pyrazinyl)carbamate (4%), LCMS (m/z): 380.1 (MH+),
0.85 min. 1H NMR (400MHz ,CDCI3) 6 ppm 8.43 (d, J = 1.2 Hz, 1 H), 8.36 - 8.32 (m, 1 H),
4.59 (d, J = 2.7 Hz, 1 H), 3.69 - 3.57 (m, 1 H), 2.37 - 2.13 (m, 2 H), 2.13 - 2.01 (m, 2 H),
1.93 - 1.68 (m, 2 H), 1.49 - 1.39 (m, 18 H).
Ste 7. +/- - 1S 3R 5-aminobromo razin l c clo entanol
N,N-Di-tert-buty| (5-((1R,3S)—3-hydroxycyclopentyl)pyrazinyl)carbamate (35 mg, 0.092
mmol) in DCM (461 pl) was added HCI (922 pl, 3.69 mmol), the reaction e was
stirred at room temperature overnight and concentrated to dryness yielding HCI salt. The
crude product was used in next step reaction without purification. LCMS (m/z): 180.1
(MH+), 0.22 min. (+/-)-(1S,3R)—3-(5-aminopyrazinyl)cyclopentanol (15 mg, 0.084 mmol)
was dissolved in acetonitrile (2 mL), then NBS (16.39 mg, 0.092 mmol) was added, the
reaction mixture was stirred at room ature for 30 min, water was added, the
reaction mixture was then extracted by EtOAc, the organic was dried and concentrated,
the crude material was used in next step reaction. LCMS (m/z): 258.1/260.2 (MH+), 0.45
min. Following the above method, using N,N-Di-tert-buty| (5-((1R,3S)—3-
hydroxycyclopentyl)pyrazinyl)carbamate, (1R,3R)—3-(5-aminobromopyrazin
y|)cyc|opentano| was obtained. LCMS (m/z): 260.1 (MH+), 0.50 min.
Ste 8. N N-Di-tert—but l 5- 3-methox c clo ent l razin lcarbamate
To a solution of diastereomeric mixture of -tert—butyl (5-(3-
hydroxycyclopentyl)pyrazinyl)carbamate (50 mg, 0.132 mmol) in Mel (2.635 mL) was
added silver oxide (305 mg, 1.318 mmol), the reaction mixture was capped in a reaction
vial and stirred at room temperature overnight. 10 equiv. of silver oxide and 2 mL of Mel
was added, the reaction mixture was stirred at room temperature for another day. The
reaction mixture was filtered through Celite pad and washed with EtOAc and methanol.
After the filtrate was concentrated, the crude product was purified by flash
chromatography (0-40% EtOAc/heptane) yielding N,N-Di-tert-butyl R,3R)—3-
methoxycyclopentyl)pyrazinyl)carbamate (25 mg). LCMS (m/z): 394.1 (MH+), 1.06 min.
Example 12
S nthesis of +/- 3-amino 18 BR h drox c clohex | razin I-N-benz I
fluorobenzamide
Scheme 29
Step
Step 1 0
PM fg)C| O O DP 2 NH2
’BZ(P'N)2
NaZCO3 szo’
—’ —. +
B NI \
KOAc, ’ \ /N
O DCM OTf O 0
dioxane ?—$ Br
Ste g J“: Step4_ NH2
f)C|2 | NaBH4, CeCI3
/ N NI)\
é —. /N
Na2003, DME EtOH
Step
Step; NH2 § NH2
Pd/C,
_ _ N)\ H
TBDMSCI, Imldazole 2 N/S
| |
—> /N —> 9N
DMF :
: "’OTBDMS(+/_)
OTBDMS
NJYBr|
NBS /N HOB/©ij/\© Pd((dppf)C|2
—> 5 + HO\
O (+/-) N82C03, DME
HQ 4%— 2
N \ GHQ
6N HCI, MeOH, THF
9N /N
o"’OTBDMS <3"’OH
Ste 1. 3-oxoc clohex—1-en |trifluoromethanesulfonate
Cyclohexane-1,3-dione (8 g, 71.3 mmol) was weighed into a 500 mL round bottom flask
and CH2C|2 (160 mL) was added resulting in clear colorless slurry at 0 °C under N2.
Sodium carbonate (8.32 g, 78 mmol) was added and the suspension was stirred for
15min. Trifluoromethanesulfonic anhydride (13.26 mL, 78 mmol) ved in DCM (16
mL) was added se over 1.2 h g internal temperature less than 1.9 °C to
avoid bis-triflate ion. The mixture was left stirring at 0 °C for 45 min then allowed to
p to 10 °C during 20 min. ed through fritted glass funnel to get rid of Na2C03
and sat NaHC03 was added. c layer was separated and washed with brine. Dried
over NazSO4, filtered, concentrated and dried under reduced pressure to provide 9.18 g of
desired product. LCMS (m/z): 245.1 (MH+), 0.81 min.
Step 2. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohexenone
To a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (19.09 g, 75
mmol) and potassium acetate (11.07 g, 113 mmol) was added 3-oxocyclohexenyl
trifluoromethanesulfonate (9.18 g, 37.6 mmol) as a solution in dioxane (44.6 mL). Argon
was bubbled through for 15min, then Pd(dppf)C|2-DCM (0.824 g, 1.128 mmol) was
added. The whole reaction mixture was heated at 100 °C overnight. Filtered the solution
through Celite and all the solvent was evaporated. Dried under high vacuum to provide
quantitative product which was used as it was. LCMS (m/z): 141 (MH+ for boronic acid),
0.43 min.
Ste 3. 3- 5-amino razin lc clohexenone
Into a 500mL glass weighed 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohex
enone (4.1 g, 18.46 mmol), 5-bromopyridinamine (4.15 g, 24.00 mmol) was added as a
solution in dioxane (69.2 mL), followed by sat Na2C03 (23.08 mL) and Pd(dppf)C|2-DCM
(1.350 g, 1.846 mmol). The whole mixture was then degassed by bubbling Ar through for
15min and refluxed overnight. EtOAc and water was added, and stirred for 30 min.
Organic was ted and the aqueous layer was ted with EtOAc three times.
Organic layers were combined and dried over NazSO4, filtered and concentrated. Purified
with flash chromatography eluting with 0-100% EtOAc (containing 10% of
MeOH)/heptane to provide 2 g of desired product. LCMS (m/z): 190 (MH+), 0.42 min.
Ste 4. 3- 5-amino razin lc clohexenol
WO 66188
To a solution of 3-(5-aminopyrazinyl)cyclohexenone (150 mg, 0.793 mmol) in
ethanol (2643 uL) was added cerium (lll) chloride (293 mg, 1.189 mmol) at room
ature. The reaction mixture was stirred at room temperature for 1 h until all the
materials were dissolved. The reaction mixture was then cooled to 0 °C and sodium
borohydride (45.0 mg, 1.189 mmol) was added in ns. The reaction mixture was
stirred upon warming up to room temperature for 2 h. The reaction mixture was cooled to
0 °C and 2 mL of water was slowly added until the bubbles clearly showed up and then
disappeared, Continued to stir for 30 min. Then, sodium sulfate was added and stirred for
min. Filtered and dried under high vacuum to provide 149 mg of desired product.
LCMS (m/z): 192.1 (MH+), 0.46 min.
Ste 5. 5- 3- ut ldimeth lsil lox c clohexen | razinamine
To a solution of 3-(5-aminopyrazinyl)cyclohexenol (149 mg, 0.779 mmol) in DMF
(5.5 mL) at 0 °C were added tert-butylchlorodimethylsilane (294 mg, 1.95 mmol) ) and 1H-
imidazole (212 mg, 3.12 mmol).The reaction mixture was stirred at room temperature
ght. After quenched with sat NaHC03, the reaction mixture was extracted with
EtOAc 3 times. The ed organic layers were dried over anhydrous sodium sulfate.
Filtered and concentrated in vacuo. The crude product was purified with flash
chromatography eluting with 0-100% of EtOAc/heptane to provide 238 mg of crude
product which was used as it was. LCMS (m/z): 306.9 (MH+), 1.04 min.
Ste 6. 5- 1R 3S tert-but ldimeth lsil lox c clohex | razinamine
A mixture of 5-(3-((tert-butyldimethylsi|y|)oxy)cyclohexeny|)pyrazinamine (238
mg, 0.779 mmol) and Pd/C (10%) (50 mg, 0.779 mmol) in MeOH (7.79 mL) was stirred
under H2 atmosphere for 3 h . LCMS indicated about 60% conversion. More Pd/C (20 mg)
was added, and stirred about r 4 h. LCMS indicated still little amount of starting
material left. More Pd/C (20 mg) was added and stirred overnight. Catalyst was filtered
out and solvent was evaporated. The residue was purified with flash chromatography
g with 0-100% of EtOAc/heptane to provide 110 mg of desired cis racemate
compound. LCMS (m/z): 308.4 (MH+), 1.01 min.
Ste 7. 3-bromo 3- tert-but ldimeth lsil lox c clohex | razinamine
To a solution of 5-((1R,3S)—3-((tert—butyldimethylsi|y|)oxy)cyc|ohexy|)pyrazinamine (110
mg, 0.358 mmol) in acetonitrile (5.50 mL) was added NBS (66.9 mg, 0.376 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 15 min. After quenched with sat sodium
thiosulfate and sat NaHC03, extracted with EtOAc three times. The organic layers were
combined and washed with brine, dried over , filtered and concentrated to afford
138 mg of desired cis racemate compound, which was used as it was. LCMS (m/z): 388
(MH+), 0.72 min.
Ste 8. 4- 3-amino 3- tert-but |dimeth lsil lox c c|ohex | razin nz l
fluorobenzamide
To 3-bromo(3-((tert-butyldimethylsilyl)oxy)cyc|ohexyl)pyrazinamine (68 mg, 0.176
mmol) in 2 mL MW vial was added (4-(benzylcarbamoyl)—3-fluorophenyl)boronic acid
(72.1 mg, 0.264 mmol), PdC|2(dppf)-DCM (12.88 mg, 0.018 mmol), DME (1.32 mL) and
2M Na2C03 solution (0.44 mL). The reaction mixture was heated at microwave
synthesizer (12 min, 120 °C). The reaction mixture was diluted with EtOAc and washed
with water three times, dried over NaZSO4, filtered and concentrated. The crude product
was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of
MeOH)/heptane to provide 60 mg of crude cis racemate compound which was taken to
the next reaction without r purification. LCMS (m/z): 535.4 (MH+), 1.31 min.
Ste 9. 4- o 1R 3S h drox c c|ohex | razin l-N-benz l
fluorobenzamide
A mixture of 4-(3-amino(3-((tert-butyldimethylsilyl)oxy)cyc|ohexy|)pyrazinyl)—N-
benzylfluorobenzamide (61 mg, 0.114 mmol) in 6N HCI (0.29 mL),THF (0. 57 mL) and
MeOH (0.285 mL) was stirred for 2 h. Solid sodium bicarbonate was added to neutralize
the reaction mixture. t was evaporated and 25 % of the residue was dissolved in
DMSO, and purified with rep to provide 15 mg of desired cis racemate compound
as a TFA salt. LCMS (m/z): 421.3 (MH+), 0.74 min. 1H NMR (400 MHz, MeOD-d4) 6 ppm
7.82 - 7.69 (m, 2 H) 7. 62 - 7. 45 (m, 2 H) 7.37 - 7.12 (m, 5 H) 4.52 (s, 2 H) 3.66 -3.52 (m,
1 H) 2.75 - 2.60 (m, 1 H) 2.11 - 2.01 (m, 1 H) 1.97 - 1.70 (m, 3 H) 1.52 - 1.29 (m, 3 H)
1.24 - 1.08 (m, 1 H).
S nthesis of +/- bromo 1R 3S methox c clohex l razinamine
Scheme 30
NH2 Steg l N(Boc)2 Steg; N(Boc)2 m; N(Boc)2
N)\ N)\
I H2 N)\
/N 30620 I N)\
/N I NaBH4 I
/ N / N
. —,
DMAP Pd/C. MeOH
o o OH
Step 4 N(Boc)2 mi NHz
N§ N)\(Br A92O MeI
, | 1. HCI, dioxane. I
/N /N
(+/_) (+/—)
2. NBS
o/ O/
Ste 1. +/- -N N-di-Boc o razin lc clohex—2-enone
To 3-(5-aminopyrazinyl)cyclohex—2-enone (1.3 g, 6.87 mmol) in DCM (34.0 mL) was
added di-tert-butyl dicarbonate (4.50 g, 20.61 mmol) and N,N-dimethylpyridinamine
(0.084 g, 0.69 mmol) and the mixture was stirred at room temperature overnight. The
reaction mixture was diluted with DCM and then washed with sat sodium bicarbonate
solution. The separated organic layer was then dried with sodium sulfate and
concentrated. The crude product was purified by flash chromatography (0 to 50% ethyl
e in heptane) yielding 1.3 g of (+/-)-N,N-di-Boc(5-aminopyrazinyl)cyclohex
enone. LCMS (m/z): 390.3 (MH+), 1.02 min.
Ste 2. +/- -N N-di-Boc 5-amino razin lc clohexanone
A mixture of N,N-di-Boc—3-(5-aminopyrazinyl)cyclohexenone (1.3 g, 3.34
mmol) and Pd/C (10%) (400 mg, 10.57 mmol) in MeOH (33.4 mL) was stirred under H2
atmosphere ght. The on mixture was filtered through Celite, and washed well
with MeOH and EtOAc. The filtrate was evaporated yielding (+/-)-N,N-di-Boc(5-
aminopyrazinyl)cyclohexanone which was used for the next step without r
purification. LCMS (m/z): 392.9 (MH+), 0.97 min.
2014/062913
Ste 3. +/- -N N-di-Boc— 1S 3R 5-amino razin l c clohexanol
(+/-)-N,N-di-Boc—3-(5-aminopyrazinyl)cyclohexanone (600 mg, 1.533 mmol) was
ved in EtOH (17.2 mL), then NaBH4 (87 mg, 2.299 mmol) was added. The reaction
mixture was stirred at room temperature for 30 min. After water added to quench the
reaction, the reaction mixture was concentrated to remove ol and extracted by
EtOAc, and the organic layer was washed by NaHC03 solution, water and brine, dried
over anhydrous Na2804, and concentrated ng the crude (+/-)-N,N-di-Boc-(1S,3R)—3-
(5-aminopyrazinyl)cyclohexanol (containing 5% trans isomer) which was taken to the
next step without further purification. LCMS (m/z): 394.2 (MH+), 0.89 min.
Ste 4. +/- -N N-di-Boc 1R 3S methox c clohex l razinamine
A mixture of (+/-)-N,N-di-Boc-(1S,3R)—3-(5-aminopyrazinyl)cyclohexanol (350 mg, 0.89
mmol), silver oxide (2.06 g, 8.9 mmol), acetonitrile (2. 224 mL) and methyl iodide (55.6
uL, 0.890 mmol) was stirred overnight. After EtOAc was added, the reaction e was
filtered off. After volatile material was evaporated, the crude product was purified by flash
chromatography (0-100% EtOAc in heptane) yielding 184 mg of (+/-)-N,N-di-Boc
((1R,3S)—3-methoxycyclohexyl)pyrazinamine (184 mg, 0.452 mmol). LCMS (m/z):
408.3 (MH+), 1.10 min.
Ste 5. +/- bromo 1R 3S methox c clohex l razinamine
(+/-)-N,N-di-Boc((1R,3S)methoxycyclohexyl)pyrazinamine (184 mg, 0.452 mmol)
in DCM (4. 515 mL) was added HCI (4M in dioxane) (4.515 mL, 18.06 mmol). The
reaction mixture was stirred at room temperature overnight. After the volatile material
was removed in vacuo, the residue was dissolved in EtOAc. The organic layer was
washed by NaHC03 solution, water and brine, dried over ous Na2804, and
concentrated affording (+/-)((1R,3S)methoxycyclohexyl)pyrazinamine in
quantitative yield. LCMS (m/z): 208 (MW), 0.43 min. To a solution of (+/-)((1R,3S)—3-
methoxycyclohexyl)pyrazinamine (54 mg, 0.261 mmol) in acetonitrile (4. 008 uL) was
added NBS (48.7 mg, 0.274 mmol) at 0 °C. The on mixture was stirred at 0 °C for 15
min. After quenched with NaHC03, extracted with EtOAc three times. The organic layer
was washed by water and brine, dried over ous Na2804, and concentrated to
afford 75 mg of (+/-)bromo((1R,3S)methoxycyclohexyl)pyrazinamine in
quantitative yield. LCMS (m/z): 286 (MW), 0.73 min.
Example 13
S nthesis of +/- 3-amino 3- meth n lc clohex l razin l-N-benz l
benzamide
Scheme 31
Ste Stegg o _28te é o
NH NH
N \Kr?” TEA D MC
/N :1th TBAF N \ MsCI, TEA NJYBF
I I
/N —> I
(+/-)
(+/') (+/—) (+/.)
OTBDMS
OTBDMS OH OSOZMe
o F o
o F o
OSOzMe
o F o
w AM no ._.,
H WooH Oxone NI \ K2003,MeOH NI \
—— /N —> /N
(+1.) (+H
"’s< . /
Ste 1. +/- -N- 3-bromo 3- tert-but Idimeth lsil lox c clohex l razin
yl)pivalamide
Pivaloyl chloride (71.5 uL, 0.569 mmol) was added se to a stirred, cooled (0 °C)
mixture of (+/-)bromo((1R,38)((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin
amine (110 mg, 0.285 mmol) and TEA (159 uL, 1.139 mmol) in CH2C|2 (949 uL). The red
mixture was stirred at 0 °C for 1 h, then at room temperature for 2 h. EtOAc and Sat
NaHC03 was added and stirred well. Organic layer was separated and the aqueous layer
was extracted well with EtOAc. Combined EtOAc layers were washed with brine, dried
over Na2804, filtered and concentrated. The residue was purified by flash
chromatography on silica gel eluting with EtOAc/heptane to give (+/-)-N-(3-bromo(3-
((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazinyl)pivalamide 97 mg in 72.4% yield.
LCMS (m/z): 472.3 (MH+), 1.19 min.
Ste 2. +/- -N- 3-bromo 1R 3S tert-but ldimeth lsil lox c c|ohex l razin
yl)pivalamide
A mixture of (+/-)-N-(3-bromo(3-((tert—butyldimethylsilyl)oxy)cyclohexyl)pyrazin
yl)pivalamide (97 mg, 0.206 mmol) in 6N HCI (687 uL), THF (687 uL) MeOH (687 uL)
was stirred for 2h. LCMS indicated that the reaction was completed. Solid sodium
onate was added to neutralize the HCI. Dissolved in EtOAc and water. Organic
layer was separated and washed with brine, dried over , filtered and concentrated
to provide 72 mg of crude (+/-)-N-(3-bromo((1R,3S)—3-((tert—
butyldimethylsilyl)oxy)cyclohexyl)pyrazinyl)pivalamide in 98% yield. LCMS (m/z): 358.6
(MH+), 0.70 min.
Ste 3. +/- - 1S 3R 6-bromo ido 2- l c c|ohex l methanesulfonate
To a mixture of (+/-)-N-(3-bromo((1R,3S)—3-((tert—
butyldimethylsilyl)oxy)cyclohexyl)pyrazinyl)pivalamide (72 mg, 0.202 mmol) in CH2C|2
(2021 uL) at 0 °C was added TEA (56.3 uL, 0.404 mmol) and methanesulfonyl chloride
(18.90 uL, 0.243 mmol). The resulting mixture was stirred at room temperature for 3h.
Another TEA (56.3 uL, 0.404 mmol) and Methanesulfonyl chloride (18.90 uL, 0.243 mmol)
was added, and stirred for 6h. Worked up the reaction by adding water. The organic
phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The
crude product was purified with flash chromatography eluting with 0-100% EtOAc/heptane
to provide 54 mg of (+/-)-(1S,3R)—3-(6-bromopivalamidopyrazinyl)cyclohexyl
methanesulfonate in 61.5% yield. LCMS (m/z): 436.1 (MH+), 0.75 min.
Ste 4. +/- - 1S 3R 6- 4- benz lcarbamo lfluoro hen l ivalamido razin
lohexyl methanesulfonate
To cis racemate (+/-)(6-bromopivalamidopyrazinyl)cyclohexyl methanesulfonate
(54 mg, 0.124 mmol) in 2.0 mL MW vial was added (4-(benzylcarbamoyl)—3-
fluorophenyl)boronic acid (50.9 mg, 0.186 mmol), dppf) (9.10 mg, 0.012 mmol),
DME (1166 uL) and 2M Na2C03 solution (389 uL). The reaction mixture was heated at
microwave synthesizer (12 min, 80 °C).The reaction mixture was diluted with EtOAc and
washed with water three times, dried over NazSO4, filtered and trated. The crude
product was purified by flash chromatography eluting with 0-100% of EtOAc (containing
% of MeOH) to provide 73 mg of (1S,3R)—3-(6-(4-(benzylcarbamoyl)—3-
fluorophenyl)pivalamidopyrazinyl)cyclohexyl methanesulfonate which was taken to
the next reaction t further purification. LCMS (m/z): 583.4 (MH+), 0.87 min.
Ste 5. +/- -N-benz lfluoro 6- 1R 3R meth lthio c c|ohex l
pivalamidopyrazinyl )benzamide
A mixture of (+/-)-(1S,3R)—3-(6-(4-(benzylcarbamoyl)—3-fluorophenyl)pivalamidopyrazin-
2-yl)cyclohexy| methanesulfonate (25 mg, 0.043 mmol) and sodium methanethiolate
(24.09 mg, 0.344 mmol) in MeOH (430 uL) was heated at 80 °C for 2 h. Solvent was
d and the residue was purified with flash chromatography g with EtOAc
(containing 10% of MeOH)/heptane to provide 25 mg of crude (+/-)-N-benzylfluoro
(6-((1R,3R)—3-(methylthio)cyclohexy|)pivalamidopyrazinyl)benzamide which was
taken to the next step without r purification. LCMS (m/z): 535.3 (MH+), 1.09 min.
Ste 6. +/- -N-benz lfluoro 6- 1R 3R meth lsulfon lc c|ohex l
pivalamidopyrazinyl )benzamide
To trans racemate N-benzylfluoro(6-((1R,3R)—3-(methylthio)cyclohexyl)
pivalamidopyrazinyl)benzamide (35 mg, 0.065 mmol) in MeOH (327 uL) at 0 °C was
added oxone (52.3 mg, 0.085 mmol) in water (327 uL). The reaction mixture was stirred
at 0 °C and room temperature thereafter for 3 h. The reaction mixture was quenched by 2
equiv. of sodium thiosu|fate (20.70 mg, 0.131 mmol) in 2 mL water at 0 °C. Stirred for 30
min, and then basified by adding 6N NaOH at 0 °C. Diluted with EtOAc, and dried over
sodium sulfate three times. Then filtered and concentrated to afford 25 mg of (+/-)-N-
benzylfluoro(6-((1R,3R)—3-(methylsulfonyl)cyclohexyl)pivalamidopyrazin
yl)benzamide in 67.4% yield which was taken to the next step without further purification.
LCMS (m/z): 567.4 (MH+), 0.90 min.
Ste 7. +/- 3-amino 1R 3R meth lsulfon lc c|ohex l razin l-N-benz l
fluorobenzamide
To (+/-)-N-benzylfluoro(6-((1R,3R)—3-(methylsulfony|)cyclohexyl)
pivalamidopyrazinyl)benzamide (25 mg, 0.044 mmol) in MeOH (221 uL) was added
potassium carbonate (61.0 mg, 0.441 mmol). The ing mixture was heated at 80 °C
for 4 h. The reaction mixture was filtered and concentrated. Purified with auto-prep to
provide 5.4 mg of (+/-)(3-amino((1R,3R)—3-(methylsulfonyl)cyclohexyl)pyrazinyl)—
N-benzyIfluorobenzamide in 20.11% yield. LCMS (m/z): 483.1 (MH+), 0.78 min. 1H
NMR (400MHz, 4) 6 ppm 8.00 — 7.81 (m, 2 H) 7.76 - 7.56 (m, 2 H) 7.43 - 7.16
(m, 5 H) 4.65 - 4.55 (m, 2 H) 3.61 - 3.51 (m, 1 H), 3.46 - 3.36 (m, 2 H) 2.87 - 2.97 (m, 3 H)
2.61 - 2.48 (m, 1 H) 2.19 — 1.95 (m, 3 H) 1.92 - 1.78 (m, 3 H).
Example 14
S nthesis of 4- 3—amino 1r4r h drox c clohex l razin l-N-benz l
fluorobenzamide
Scheme 32
NHz NH2
m1 m; m;
NH2 0. [0 N/ N/
NJ} l
B \ N Pd(dppf)CI2.CHzCl2 \ N NBSiACN
+ —. —2> —>
DME/2 M NaZCO3 Pd—c MeOH 79% yield
0 0 56% yield 98% yield
\ / o o o o
F o
NJYBr F 0 Step_ N/\© $25
N P)d(dppfC|20H20|2 HCI 3M aq
+ H
H0\ —> —>
)3 DME/2 M Na2CO3 ACN/water
47% yield
O O
\_/ O O
F 0 F o
NH2 N
NH2 N
H Stepfi H
| N/
\ N NaBH4,MeOH \ N
32% (two steps)
0 SH
Ste 1. 5- 1 4-dioxas iro 4.5 decen | 2-amine
To 5-bromopyrazinamine (225 mg, 1.293 mmol) was added 4,4,5,5-tetramethyl(1,4-
dioxaspiro[4.5]dec—7-enyl)—1,3,2-dioxaborolane (482 mg, 1.810 mmol), PdCl2(dppf)-
CH2C|2 adduct (84 mg, 0.103 mmol), DME (3.5 mL) and then last sodium carbonate 2M
(1.616 mL, 3.23 mmol). The reaction was microwaved at 120 °C for 15 min. To the
reaction was added 80 mL of DCM, washed with water (1x), dried sodium sulfate, filtered
and concentrated to residue. The crude was purified by silica gel tography using
12 gram column (solid load) eluting with 10-90% ethyl acetate and heptane. The desired
fractions were trated to constant mass to give 173 mg of the d product as
free base used as is (56% yield). LCMS (m/z): 234.2 (MH+), 0.43 min; 1H NMR (400 MHz,
DMSO-d6) 6 ppm 8.01 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 6.33 (s, 2H), 6.27 (t,
J=3.9 Hz, 1H), 3.89 (s, 4H), 2.52 (d, J=1.6 Hz, 2H), 2.33 (br. s., 2H), 1.76 (t, J=6.7 Hz,
2H).
Ste 2. 5- 1 4-dioxas iro 4.5 decan | razinamine
To 5-(1,4-dioxaspiro[4.5]decenyl)pyrazinamine (645 mg, 2.77 mmol) in a round
bottom flask that was flushed with argon was added Pd-C 10% degaussa (294 mg, 0.277
mmol). Then under argon with syringe was added MeOH ( 10 mL) and then last a
hydrogen balloon was added. The flask was evacuated and refilled with hydrogen (6 X).
The reaction was stirred at room ature for total of 16 h, under the hydrogen
balloon, ed by LCMS. The reaction was flushed with argon and 25 mL of DCM was
added. The crude mixture was filtered through a Celite plug, and concentrated to
constant mass to give 635 mg of the d product as free base, used as is (98% yield).
LCMS (m/z): 236.2 (MH+), 0.41 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.78 (d, J=1.2
Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 6.09 (s, 2H), 3.85 (s, 4H), 2.52-2.60 (m, 1H), 1.65-1.78
(m, 6H), 1.49-1.61 (m, 2H).
Ste 3. 3-bromo14-dioxas iro 4.5 decan l razinamine
To 5-(1,4-dioxaspiro[4.5]decanyl)pyrazinamine (620 mg, 2.64 mmol) was added
Acetonitrile (20 mL) and then was added NBS (469 mg, 2.64 mmol) in ns over 2
min. The reaction was stirred at room temperature for 20 min and quenched with
saturated sodium bicarbonate solution, and 250 mL of ethyl acetate was added. The
aqueous was extracted and the organic layer was washed with saturated sodium
bicarbonate, water (2x), saturated salt solution, then dried with sodium sulfate, filtered
and concentrated to residue to give 650 mg of the desired product, used as is, (79%
yield). LCMS (m/z): 316.1 (MH+), 0.61 min.
Ste 4. 4- 3-amino 1 4-dioxas iro 4.5 decan l razin l-N-benz l
fluorobenzamide
To 3-bromo(1,4-dioxaspiro[4.5]decanyl)pyrazinamine (630 mg, 2.005 mmol) was
added (4-(benzylcarbamoyl)fluorophenyl)boronic acid (767 mg, 2.81 mmol),
PdC|2(dppf)CH2C|2 adduct (164 mg, 0.201 mmol), DME (9 mL) and then last sodium
carbonate 2M (3.01 mL, 6.02 mmol) . The reaction was microwaved at 115 °C for 12 min
.To the on was added 400 mL of ethyl acetate washed with water (2x), dried with
sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel
chromatography using 40 gram column g with 20-100% ethyl acetate and heptane.
The desired fractions were concentrated to constant mass to give 432 mg of the d
t as free base used as is, (47% yield). LCMS (m/z): 463.2 (MH+), 0.82 min; 1H
NMR (400 MHz, DMSO-d6) 6 ppm 8.94 - 8.81 (m, 1H), 7.89 (s, 1H), 7.80 - 7.69 (m, 1H),
7.67 - 7.52 (m, 2H), 7.33 (d, J=4.3 Hz, 4H), 7.27 -7.18 (m, 1H), 6.09 (s, 2H), 4.49 (d,
J=5.9 Hz, 2H), 3.85 (s, 4H), 2.70 - 2.61 (m, 1H), 1.84 -1.67 (m, 6H), 1.65 -1.48 (m, 2H).
Ste 5. 4- 3-amino 4-oxoc clohex l razin l-N-benz lfluorobenzamide
To 4-(3-amino(1,4-dioxaspiro[4.5]decan-8—yl)pyrazinyl)-N-benzylfluorobenzamide
(170 mg, 0.368 mmol) was added acetonitrile (3 mL), water (2 mL) and then HCI 3M
aqueous solution (0.613 mL, 1.838 mmol). The on was stirred at room temperature
for 30 min followed by LCMS. To the reaction was added 200 mL of ethyl acetate,
basified with excess 1M NaOH. The aqueous layer was ted and the organic layer
was washed with water (3x), filtered and concentrated to residue to give the desired
product as free base. Assume quantitative yield (0.368 mmol). LCMS (m/z): 419.3
(MH+), 0.75 min.
Ste 6. 4- 3-amino 1r4r h drox c clohex l razin l-N-benz l
fluorobenzamide
To 4-(3-amino(4-oxocyclohexyl)pyrazinyl)-N-benzylfluorobenzamide (77 mg,
0.184 mmol) was added MeOH (3 mL), cooled to 0 °C. Then sodium borohydride (6.96
mg, 0.184 mmol) was added. The reaction was stirred for 20 min while allowing it to warm
to room temperature, followed by LCMS. Crude LCMS shows about a 9:1 \cis)
isomers as expected. The reaction was quenched with excess saturated sodium de
and stirred at room temperature for 1 hour. Then 150 mL of ethyl acetate was added and
washed with saturated sodium bicarbonate, water (2x), saturated salt solution, dried with
sodium sulfate, filtered and concentrated to residue to give 73 mg of crude product. To
half (36.5 mg) of the crude product was dissolved in 2.0 mL of DMSO, filtered, purified by
prep HPLC, and lyophilized to give 16.3 mg of the d t 4-(3-amino((1r,4r)-
4-hydroxycyclohexyl)pyrazinyl)-N-benzylfluorobenzamide as TFA salt, in (32 %
. LCMS (m/z): 421.3 (MH+), 0.69 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.82
(br. s., 1H), 7.83 (s, 1H), 7.64-7.73 (m, 1H), 7.45-7.61 (m, 2H), 7.25-7.31 (m, 4H), 7.14-
7.23 (m, 1H), 4.43 (d, J=5.9 Hz, 2H), 1.66-1.91 (m, 3H), 1.38-1.57 (m, 2H), 1.11-1.31 (m,
2H).
e 15
S nthesis of 4- 3-amino 1s 4s h drox c clohex l razin l-N-benz l
fluorobenzamide
Scheme 33
F o F O
NH2 N/\© NH2
H N/\©H
\ 'N L—Selectride,THF \ N
0 OH
To 4-(3-amino(4-oxocyclohexyl)pyrazinyl)-N-benzylfluorobenzamide (77 mg,
0.184 mmol) was added THF (3 mL), cooled to 0 °C. Then ctride 1M THF (0.460
mL, 0.460 mmol) was added. The reaction was stirred for 20 min while allowing to warm
to room temperature, followed by LCMS. The crude LCMS show about greater than 9:1
(cis/trans) isomers as expected. The reaction was basified with excess 5M NaOH and
stirred at room temperature for 1 hour. Then 150 mL of ethyl acetate was added and
washed with water (3x), saturated salt solution, dried with sodium sulfate, filtered and
WO 66188
concentrated to residue to give 75 mg of product, used as is. To half (36.5 mg) of the
crude product was dissolved in 2.0 mL of DMSO, filtered, ed by prep HPLC, and
lyophilized to give 23 mg of the desired product 4-(3-amino((1s,4s)—4—
hydroxycyclohexyl)pyrazinyl)—N-benzylfluorobenzamide as TFA salt, in (45% yield).
LCMS (m/z): 421.3 (MH+), 0.72 min; 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.87 (br. s.,
1H), 7.89 (s, 1H), 7.79 - 7.70 (m, 1H), 7.67 - 7.45 (m, 2H), 7.33 (d, J=4.3 Hz, 4H), 7.28 -
7.21 (m, 1H), 6.06 (s, 2H), 4.49 (d, J=5.9 Hz, 2H), 4.30 (br. s., 1H), 3.84 (br. s., 1H), 2.01
-1.84(m,2H), 1.75 - 1.64 (m, 2H), 1.60 - 1.43 (m, 4H).
Example 16
S nthesis of 4- 3-amino 1s 4s meth lsulfon lc clohex l razin l-N-benz l
fluorobenzamide
Scheme 34
F o o F 0
NH2 ”AK; NH N
$21 A» H/\@ mg
N/ N
I \ IN
\ O
YKCI \
—s—CI
—> g —>
OH OH
DCM, TEA DCM, TEA
o F o
*LNH o F o
H NH
| N/\©H
\ N S_gte 2 N/
IN Stegfl
sodium thiomethoxide,
tert—butanol mCPBA, DCM
—> —>
6‘ 0
48”\ S
O \
o F o F o
YLNH Stegg NH2
N’ ”AK;
I I
\ N HClconc., \ N
ACN,Water
6% overall yield
o=s=o
| O=?=O
Ste 1. N-benz lfluoro 6- 1r4r h drox c clohex l ivalamido 2-
yl)benzamide
To 4-(3-amino((1r,4r)hydroxycyclohexyl)pyrazinyl)-N-benzylfluorobenzamide
(0.105 g, 0.25 mmol) was added DCM (2.5 mL), TEA (0.105 mL, 0.750 mmol) and then
pivaloyl chloride (0.045 g, 0.375 mmol). The reaction was stirred at room temperature for
3 h ed by LCMS. To the reaction was added 150 mL of ethyl acetate, basified with
excess saturated bicarbonate. The organic layer was washed with water (3x), saturated
salt solution, dried sodium sulfate, filtered and concentrated to residue to give the t
as free base, used as is. Assume quantitative yield (0.25 mmol). LCMS (m/z): 505.4
(MH+), 0.82 min.
Ste 2. 1r4r 6- 4- benz lcarbamo lfluoro hen l ivalamido razin
yl)cyclohexyl methanesulfonate
To N-benzylfluoro(6-((1r,4r)hydroxycyclohexyl)pivalamidopyrazin
yl)benzamide (125 mg, 0.248 mmol) was added DCM (2.5 mL), TEA (0.104 mL, 0.743
mmol) and cooled to 0 °C then methanesulfonyl de (42.6 mg, 0.372 mmol) was
added. The reaction was allowed to warm to room ature and stirred for 2 h,
followed by LCMS. Then additional TEA (0.104 mL, 0.743 mmol) and methanesulfonyl
chloride (42.6 mg, 0.372 mmol) was added and stirred at room temperature for 3 h more,
for total of 5 h. To the reaction was added 150 mL of ethyl acetate, basified with excess
saturated bicarbonate. The organic layer was washed water (3x), saturated salt solution,
dried sodium sulfate, filtered and concentrated to residue to give product as free base,
used as is. Assume quantitative yield (0.248 mmol). LCMS (m/z): 583.3 (MH+), 0.90 min.
Ste 3. N-benz lfluoro 6- 1s 4s meth lthio c clohex l ivalamido 2-
yl)benzamide
To (1 r,4r)(6-(4-(benzylcarbamoyl)fluorophenyl)pivalamidopyrazinyl)cyclohexyl
methanesulfonate (130 mg, 0.223 mmol) was added t-butanol ( 3.5 mL), sodium
thiomethoxide (235 mg, 3.35 mmol). The reaction was heated at 80 °C for 1 h followed by
LCMS. The reaction was let cool. Then 75 mL of ethyl e was added, washed with
saturated sodium bicarbonate, water (2x), saturated salt on, dried sodium sulfate,
filtered and concentrated to residue to give product as free base, used as is. Assume
quantitative yield (0.223 mmol). LCMS (m/z): 535.3 (MH+), 1.06 min.
Step 4. ylfluoro(6-((1s,4s)—4-(methylsulfonyl)cyclohexyl)—3-
pivalamidopyrazinyl )benzamide
To N-benzylfluoro(6-((1s,4s)(methylthio)cyclohexyl)pivalamidopyrazin
y|)benzamide (118 mg, 0.221 mmol) was added DCM (4 mL). Then with stirring at room
temperature a solution ofmCPBA (118 mg, 0.527 mmol) in DCM (1 mL) was slowly
titrated in until on was done, followed by LCMS. Then 75 mL of ethyl e was
added, washed with saturated sodium bicarbonate, water (2x), saturated salt on,
dried sodium sulfate, filtered and concentrated to residue. The crude was dissolved in 5
mL of DMSO, filtered and purified by prep HPLC. The desired fractions were combined.
The product as a 100 mL solution in itrile/water with 0.1% TFA, was used as is in
next step. Assume quantitative yield (0.221 mmol). LCMS (m/z): 567.4 (MH+), 0.85 min.
Ste 5. 4- 3-amino 1s 4s meth lsulfon lc clohex l 2- l-N-benz l
fluorobenzamide
To N-benzylfluoro(6-((1s,4s)(methylsulfonyl)cyclohexyl)—3-pivalamidopyrazin
y|)benzamide (120 mg, 0.212 mmol) in a solution of water (60 mL) and Acetonitrile (40
mL) with 0.1% TFA was added HCI conc. (2 mL, 65.8 mmol). The reaction was stirred at
60 °C for 12 h, followed by LCMS. The crude was |yophi|ized to residue. The residue
was dissolved in DMSO, purified by prep HPLC, and |yophi|ized to give 10.2 mg of the
desired product 4-(3-amino((1s,4s)(methy|su|fony|)cyc|ohexy|)pyraziny|)-N-
benzyIfluorobenzamide as TFA salt, in 6% overall yield. LCMS (m/z): 483.2 (MH+),
0.72 min; 1H NMR (CD3OD) 8 ppm 7.80 (s, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.63 (dd, J=8.2,
1.6 Hz, 1H), 7.55 (dd, J=11.7, 1.2 Hz, 1H), 7.22-7.34 (m, 4H), 7.10-7.20 (m, 1H), 4.52 (s,
2H), 3.12 (dt, J=8.9, 4.4 Hz, 1H), 2.96 (t, J=4.9 Hz, 1H), 2.81 (s, 3H), 2.16-2.30 (m, 2H),
1.99-2.13 (m, 2H), .96 (m, 2H), 1.70-1.85 (m, 2H).
Example 17
S nthesis of 4- 3-amino 1r4r meth lsulfon lc clohex l razin l-N-benz l
fluorobenzamide
Scheme 35
F 0
F o
NH2 N/\©H an/
0|| _w| ||0
Following Scheme 35, using 4-(3-amino((1s,4s)hydroxycyclohexyl)pyrazinyl)—N-
benzylfluorobenzamide (Example 15), 4.5 mg of the desired product 4-(3-amino—6-
((1r,4r)(methylsulfonyl)cyclohexyl)pyrazinyl)-N-benzylfluorobenzamide was
obtained as TFA salt in 3% overall yield. LCMS (m/z): 483.2 (MH+), 0.71 min; 1H NMR
) 6 ppm .89 (m, 2H), 7.68 (dd, J=8.0, 1.4 Hz, 1H), 7.60 (dd, J=11.7, 1.6 Hz,
1H), 7.31-7.42 (m, 4H), 7.19-7.30 (m, 1H), 4.61 (s, 2H), 3.05-3.15 (m, 1H), 2.92 (s, 3H),
2.67-2.78 (m, 1H), 2.34 (br. s., 2H), 2.11 (br. s., 2H), 1.60-1.82 (m, 4H).
Example 18
S nthesis of N- S amino 3-chloro hen | eth | 3-amino 1r 4S
methox c clohex | razin lfluorobenzamide
Scheme 36
NH2 NH2 N(Boc)2 N(BOC)2
Stegfl
N \ m1 NJ§ Steg; N)\ Stegg N)\
| l
N | |
/ N / N
B0020 NaBH4 f A920, Mel
—> 3 —>
MeCN/water DMAP EtOH Q
O\ (O 0 OH
N(Boc)2 ””2 NH2
NHB0C
Stag;
N \ “1&0 Stegfi NJ\(Br O _
St 91 NH2 N Step NH2 N
H g H
N \ N \
EDC,HOAt _, k?” TFA I
CI _. 9N Cl
DMF, DIEA ? :
O\ 0\
Ste 1. 4- 5-amino razin lc clohexanone
To -dioxaspiro[4.5]decanyl)pyrazinamine (8.68 g, 45.4 mmol) was added
acetonitrile (368 mL), water (245 mL) and 3M HCI (76 mL). The reaction was stirred at
room temperature for 30 min. The reaction was basified with excess 1M NaOH, and then
diluted with of ethyl acetate. The organic layer was separated. The aqueous layer was
ted well with EtOAc/2-methyl THF (1:1) three times. Organic layers were combined
and dried over Na2804, filtered and concentrated to give 6.91 g of product as free base.
LCMS (m/z): 192.12 (MH+), 0.30 min.
Ste 2. lmidodicarbonic acid 2- 5- 4-oxoc clohex l razin l- 1 3-bis 1 1-
dimethylethyl) ester
To 4-(5-aminopyrazinyl)cyclohexanone (3.0 g, 15.69 mmol) in DCM ( 105 mL) was
added di-tert-butyl dicarbonate (10.27 g, 47.1 mmol) and N,N-dimethylpyridinamine
(0.192 g, 1.569 mmol). The mixture was stirred at room temperature ght. The
reaction mixture was diluted with DCM and then washed with sat sodium bicarbonate
solution. The separated organic layer was dried over sodium sulfate and trated.
Purified on the flash chromatography and eluting with 0 to 50% ethyl e in heptane
to provide 2.2 g of desired product. LCMS (m/z): 392.7 (MH+), 0.91 min.
Ste 3. lmidodicarbonic acid 2- 5- 4-h drox c clohex l razin l- 1 3-bis 1 1-
dimethylethyl) ester
lmidodicarbonic acid, 2-(5-(4-oxocyclohexyl)pyrazinyl)-, s(1,1-dimethylethyl) ester
(350 mg, 0.894 mmol) was dissolved in EtOH (10 mL), then NaBH4 (50.7 mg, 1.341
mmol) was added. The reaction mixture was d at room temperature for 30 min. The
trans and cis ratio is around 85:15 from TLC. Saturated NaHC03 solution was added to
quench the reaction. The reaction mixture was then extracted by EtOAc/2-methyl THF
(1:1). The organic layers were combined and dried over anhydrous NazSO4, and
concentrated to yield the crude product, which was taken to the next step without further
cation. LCMS (m/z): 394.3 (MH+), 0.89 min.
Ste 4. lmidodicarbonic acid 2- 5- 4-methox c clohex l razin l- 1 3-bis 1 1-
dimethylethyl) ester
A mixture of imidodicarbonic acid, 2-(5-(4-hydroxycyclohexyl)pyrazinyl)-, 1,3-bis(1,1-
dimethylethyl) ester (350 mg, 0.890 mmol), silver oxide (1.649 g, 7.12 mmol), acetonitrile
(2.22 mL) and methyl iodide (1.112 mL, 17.79 mmol) was stirred overnight. EtOAc was
added, and the solid was filtered out. Solvent was evaporated and the residue was
purified via flash chromatography g with 0-100% EtOAc/heptane to provide 168 mg
of desired trans compound in 46.3% yield. LCMS (m/z): 408.3 (MH+), 1.10 min.
Ste 5. 5- 1r4r hox c clohex l razinamine
lmidodicarbonic acid, 2-( 5-(4-methoxycyclohexyl)pyrazinyl)-, 1,3-bis(1,1-dimethylethyl)
ester (168 mg, 0.412 mmol) in DCM (4.123 mL) was added HCI (4M in e) (4.123
mL, 16.49 mmol), the reaction mixture was stirred at room temperature overnight.
Concentrated, and EtOAc was added. Washed with sat NaHC03, and water. The
aqueous layer was extracted with EtOAc and 2-methyl THF (1:1) three times. Dried over
NazSO4, filtered and trated to afford the desired trans product. LCMS (m/z): 208
(MH+), 0.42 min.
Ste 6. 3-bromo 1r4r methox c clohex l razinamine
To a solution of ,4r)methoxycyclohexyl)pyrazinamine (92 mg, 0.444 mmol) in
itrile (8.877 mL) was added NBS (83 mg, 0.466 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 15 min. After quenched with sat Na2803 and NaHC03,
extracted with EtOAc and 2-methyl THF (1:1) three times. The organic layers were
combined dried over NaZSO4, filtered and concentrated to afford 127 mg of desired trans
compound in quantitative yield. LCMS (m/z): 288 (MW), 0.72 min.
Ste 7. tert-but | S 4- 3-amino 1r4S methox c clohex | razin l
benzamido)—2-(3-chlorophenyl )ethyl )carbamate
To 3-bromo((1r,4r)methoxycyclohexyl)pyrazinamine (35 mg, 0.122 mmol) in 2 mL
MW vial was added (S)-(4-((2-((tert-butoxycarbonyl)amino)(3-
phenyl)ethyl)carbamoyl)fluorophenyl)boronic acid (64.1 mg, 0.147 mmol),
PdC|2(dppf) (8.95 mg, 0.012 mmol), DME (917 uL) and 2M Na2C03 solution (306 uL) .
The on mixture was heated at microwave synthesizer (12 min, 120 °C). The reaction
mixture was diluted with EtOAc and washed with water three times, dried over Na2804,
filtered and concentrated. The crude product was purified by flash chromatography to
provide 28 mg of desired trans product in 38.3% yield.
Ste 8. N- S no 3-chloro hen | eth | 3-amino—6- 1r4S
methoxycyclohexyl )pyrazinyl )—2-fluorobenzamide
A mixture of tert-butyl ((S)—2-(4-(3-amino((1r,4S)methoxycyclohexyl)pyraziny|)
fluorobenzamido)—2-(3-chlorophenyl)ethyl)carbamate (28 mg, 0.047 mmol), TFA (0.4 mL,
0.047 mmol) and CH2C|2 (1 mL) was stirred at room temperature for 30 min. Solvent was
evaporated and the residue was dissolved in DMSO, purified with auto-prep to provide 15
mg of desired trans product as a TFA salt in 51.3% yield. LCMS (m/z): 498.2 (MH+), 0.76
min; 1H NMR (400 MHz, CD3OD) 6 ppm 7.94 - 7.85 (m, 2 H) 7.70 (dd, J=8.22, 1.56 Hz, 1
H) 7.62 (dd, J=11.93, 1.37 Hz, 1 H) 7.55 (s, 1 H) 7.49 - 7.34 (m, 3 H) 5.49 (dd, J=9.00,
.87 Hz, 1 H) 3.53 - 3.41 (m, 2 H) 3.38 (s, 3 H) 2.70- 2.59 (m, 2 H) 2.20 (d, J=9.78 Hz, 2
H) 1.98 (d, J=12.91 Hz, 2 H) 1.65 (qd, J=13.04, 3.13 Hz, 2 H) 1.41 - 1.27 (m, 2 H).
S nthesis of 1s 4s obromo razin | meth lc clohexanol and 1r 4r -
4- 5-aminobromo razin lmeth lc clohexanol
Scheme 37
NHBoc NHN NHN
g Q:12 lb)
_f W | Arm
ZW0eN
Z / 9(D IA ESQ/S
' I," O I ~‘ 0H s OH
/ N MeLi
—> + + +
NHBoc NH2 NH2
NJ\ Stegg Stegfi Br
N \ N \
0 I I I
/ N / N / N
—> —>
H6 ; HO: HO:
Ste 1. tert-but l 5- 1s 4s h drox meth lc clohex l razin lcarbamate and
tert-butyl (5-((1r,4r)—4-hydroxymethylcyclohexyl)pyrazinyl)carbamate
N,N-di-Boc—4-(5-aminopyrazinyl)cyclohexanone (657 mg, 1.678 mmol) in THF (11.8
mL) was treated with methyllithium (1.469 mL, 2.350 mmol) at -78 °C. The reaction was
stirred at -78 °C for 2 h. After methyllithium (1.469 mL, 2.350 mmol) was added more, the
reaction mixture was stirred at -78 °C for another 2 h. This process repeated once more.
Then, the reaction e was ed with methanol and water. The resulting mixture
was concentrated and the residue was suspended in ethyl acetate. The organic layer was
washed with water and brine, dried over anhydrous Na2804, filtered off, and
concentrated. The crude diastereomeric mixture was purified by chromatography (0-100%
ethyl acetate in ). For tert-butyl s,4s)hydroxymethylcyclohexyl)pyrazin-
2-yl)carbamate (26.7% yield). LCMS (m/z): 308.7 (MH+), 0.79 min. For tert-butyl (5-
((1r,4r)hydroxymethylcyclohexyl)pyrazinyl)carbamate (23.3% yield), LCMS (m/z):
308.7 (MH+), 0.75 min.
Ste 2. 1s 4s 5-amino razin lmeth lc clohexanol
Tert-butyl (5-((1s,4s)hydroxymethylcyclohexyl)pyrazinyl)carbamate (138 mg,
0.449 mmol) in DCM was added HCI (4 M in dioxane) (4489 uL, 17.96 mmol). The
on mixture was stirred at room temperature overnight. Diluted with EtOAc and
washed with sat NaHC03. No separation, and dried with Na2804. Filtered and washed
with EtOAc. Concentrated to provide 93 mg of desired product in quantitative yield. LCMS
(m/z): 208 NH), 0.41 min.
Ste 3. 1s 4s 5-aminobromo razin lmeth lc clohexanol
To a solution of (1s,4s)(5-aminopyrazinyl)—1-methylcyclohexanol (93 mg, 0.449
mmol) in acetonitrile (8974 uL) was added NBS (80 mg, 0.449 mmol) at 0 °C. The
reaction mixture was stirred at 0 °C for 15 min. After ed with NaHC03. extracted
with EtOAc three times. The organic layers were combined and washed with water, and
brine. Dried over NaZSO4, filtered and concentrated to afford 100 mg of (1s,4s)—4-(5-
6-bromopyraziny|)methylcyclohexano| in 78 % yield. LCMS (m/z): 288 (MW),
0.60 min.
Ste 4. 1r 4r 5-amino razin l meth lc clohexanol and Ste 5. 1r 4r 5-
aminobromo razin th lc clohexanol
Following Steps 2 and 3, using )(5-aminopyrazinyl)—1-methylcyclohexanol,
(1r,4r)(5-aminobromopyraziny|)methylcyclohexanol was obtained. LCMS (m/z):
288 NH), 0.57 min.
Examples 19 and 20
S nthesis of meth |3- 5-amino 4- benz lcarbamo lfluoro hen l razin
| ro anoate and 4- 3-amino 3- meth lamino oxo ro | razin I-N-benz |
fluorobenzamide
Scheme 38
m1 NH2 mg NH2 m;
NH2 NJW NJWI
NJW o PdCI2(PPh3)2,Cu| NBS
\ N pd/C \ N
IN + %0/ —~
\ ¢ chog, THF l l MeOH
37% 81% \
\O O O
F O
Step4_
NA/Br F O NHz
| f)C|2 HA©
N N \
+ mg —» I
”0‘3 / N
DME, NaZCO3
o o
\o o
Stepfi l LIOH
F o
NHZ $9§ NHZ Stegz NHZ
NArBr ArBr F O H
N N/\©
' MeNH30| | Pd(dppf)C|2 NI \ \ N \ N N
—> N
—. /
+ H0 H
TBTU, DIEA ‘ll3 DME, Na2003
74% 24%
o N o
H H
Ste 1. meth l3- 5-amino razin l ro iolate
To a 5 mL of microwave vial was added 5-iodopyrazinamine (100 mg, 0.452 mmol),
methyl propiolate (161 uL, 1.810 mmol), potassium carbonate (125 mg, 0.905 mmol),
copper (I) iodide (3.45 mg, 0.018 mmol), and THF (1508 uL). The on mixture was
heated at 65 0C for 2 h. The reaction mixture was diluted with water and extracted with
EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and
evaporated in vacuo. The crude product was ed by flash chromatography
OAc in DCM) yielding methyl 3-(5-aminopyrazinyl)propiolate (38%). LCMS
(m/z): 178.4 (MH+), 0.48 min.
Ste 2. meth l3- 5-amino razin l ro anoate
To a solution of methyl 3-(5-aminopyrazinyl)propiolate (30 mg, 0.169 mmol) in MeOH
(847 uL) was added Pd-C (36.0 mg, 0.034 mmol). The solution was degassed by N2
stream for 15 min. After flushed with hydrogen gas and equipped with a hydrogen
balloon, the reaction mixture was stirred for 16 h. The reaction mixture was ed
through Celite. The volatile materials were removed in vacuo. The crude methyl 3-(5-
aminopyrazinyl)propanoate was obtained (81%) and used for the next step without
further purification. LCMS (m/z): 182.1 (MH+), 0.31 min.
Ste 3. meth l3- 5-aminobromo razin l ro anoate
To a solution of methyl minopyrazinyl)propanoate (25 mg, 0.138 mmol) in
CH3CN (690 uL) was added NBS (24.56 mg, 0.138 mmol). The reaction mixture was
d for 1 h at room temperature. After quenched with Na28203 solution, the reaction
mixture was d with NaHC03 solution for 20 min and extracted with EtOAc. The
organic layer was washed with water and brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude methyl 3-(5-aminobromopyrazinyl)propanoate
was obtained (28%). LCMS (m/z): 260.2/262.2 (MH+), 0.54 min.
Ste 4. meth l3- 5-amino 4- benz lcarbamo lfluoro hen l razin l ro anoate
To a solution of methyl 3-(5-aminobromopyrazinyl)propanoate (10 mg, 0.038 mmol),
4-(benzylcarbamoyl)f|uoropheny|boronic acid (13.65 mg, 0.050 mmol) and PdCI2(dppf)
(2.81 mg, 3.84 umol) in DME (256 uL) was added 2M Na2C03 (3.87 mL). The reaction
mixture was heated at microwave synthesizer (120 °C, 10 min). LCMS (m/z): 409.2 (MH+
for ester), 0.75 min; 395.2 (MH+ for very small amount of acid, but mixed with boronic
ester), 0.66 min. To the on e, anhydrous sodium sulfate was added, filtered,
and concentrated. The crude t was ed by prep HPLC, lyophilized yielding
methyl 3-(5-amino(4-(benzylcarbamoyl)f|uoropheny|)pyraziny|)propanoate as a
TFA salt (12%). LCMS (m/z): 409.1 (MH+), 0.73 min; 1H NMR (400MHz, MeOH-d4) 8 ppm
7.89 - 7.76 (m, 2 H), 7.69 - 7.61 (m, 1 H), 7.60 - 7.51 (m, 1 H), 7.42 - 7.28 (m, 5 H), 7.28 -
7.20 (m, 1 H), 4.64 - 4.55 (m, 2 H), 3.62 (s, 3 H), 3.06 - 2.93 (m, 2 H), 2.79 - 2.67 (m, 2
Ste 5. 3- 5-aminobromo razin | ro anoic acid
To a solution of methyl 3-(5-aminobromopyrazinyl)propanoate (55 mg, 0.211 mmol)
in MeOH (961 uL) and H20 (96 uL) was added potassium carbonate (170 mg, 1.230
mmol). The reaction mixture was stirred for overnight. To the reaction mixture, anhydrous
NazSO4 was added. After diluted with EtOAc (3 mL) and filtered, the volatile materials
were removed in vacuo. The crude 3-(5-aminobromopyrazinyl)propanoic acid was
obtained and used for the next step without further purification. LCMS (m/z): 246.0/248.0
(MH+, major), 0.26 min.
Ste 6. 3- obromo razin l-N-meth l ro e
To a solution of 3-(5-aminobromopyrazinyl)propanoic acid (32 mg, 0.130 mmol) in
DMF (1300 uL) was added TBTU (62.6 mg, 0.195 mmol), DIEA (68.1 uL, 0.390 mmol),
and methanamine hydrochloride (9.66 mg, 0.143 mmol). The reaction mixture was stirred
for 3 h. The reaction mixture was extracted with EtOAc. The organic layer was washed
with water and brine, dried over NaZSO4, filtered and concentrated in vacuo. The crude 3-
(5-aminobromopyrazinyl)-N-methylpropanamide (74%) was obtained and was used
for the next step without further purification. LCMS (m/z): 259/261 (MH+), 0.35 min.
Ste 7. 4- 3-amino 3- meth lamino oxo ro l razin l-N-benz l
fluorobenzamide
Following Step 4 in Scheme 38, using 3-(5-aminobromopyrazinyl)-N-
methylpropanamide, 4-(3-amino(3-(methylamino)oxopropyl)pyrazinyl)-N-benzyl-
2-fluorobenzamide was obtained (24%). LCMS (m/z): 408.1 (MH+), 0.51 min; 1H NMR
(400MHz, MeOH-d4) 6 ppm 7.89 - 7.78 (m, 2 H), 7.68 - 7.51 (m, 2 H), 7.41 - 7.29 (m, 4 H),
7.26 (d, J = 7.1 Hz, 1 H), 4.60 (s, 2 H), 2.98 (t, J = 7.3 Hz, 2 H), 2.66 (s, 3 H), 2.57 (t, J =
7.3 Hz, 2 H).
S s of 2- 5-aminobromo razin l ethanol
Scheme 39
NH2 Step 1 NH2 Step 2 NH2 NH2
Steg g
CsF, f)Cl2 N \
N \ o 03 I NBS NJYBrI
KfI + I
\B / N
I _> / N
N / N
0’ A NaBH4
I OH OH
Ste 1.5-alll razinamine
2014/062913
To a solution of 5-bromopyrazinamine (1.3 g, 7.47 mmol) in was added 2-allyl-,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1.883 g, 11.21 mmol), PdC|2(dppf)CH2C|2 adduct (0.610
g, 0.747 mmol) and CsF (3.40 g, 22.41 mmol), the on mixture was purge though
Nitrogen. The reaction mixture was then heated at 100 0C in oil bath for 3h.The on
mixture was filtered through Celite, washed by EtOAc, the filtrated was ioned
between EtOAc and water. The organic was dried over anhydrous sodium sulfate and
concentrated in vacuo, The crude material was purified by flash chromatography column
to yield 5-allylpyrazinamine in 37% yield. LCMS (m/z): 136.0 (MH+), 0.30 min.
Ste 2. 2- o razin l ethanol
-allylpyrazinamine (180 mg, 1.332 mmol) in DCM (26.6 mL) was cooled down to -78
0C, then Ozone was bubbled through for 10 min until the solution turned to blue color.
Then Nitrogen was purged through for 5 min. NaBH4 (151 mg, 4.00 mmol) in ethanol (10
mL) was added slowly, The reaction e was allowed to return to room temperature.
After 1h, Sat. NH4C| was added slowly, the reaction mixture was then extracted by
CHCI3/IPA(7:3) (3 times), the organic was dried and concentrated to yield the crude
product. The crude product is used in next step reaction without purification. LCMS (m/z):
140.0 (MH+), 0.21 min.
Ste 3. 2- 5-aminobromo razin l ethanol
To a solution of 2-(5-aminopyrazinyl)ethanol (30 mg, 0.216 mmol) in CH3CN (719 uL)
was added NBS (38.4 mg, 0.216 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 30 min. The reaction mixture was quenched by sat. NaHC03, then extracted by
EtOAc, The combined organic layer was washed with water and brine, dried over
anhydrous sodium sulfate. Filtered and concentrated in vacuo yielding crude mino-
6-bromopyrazinyl)ethanol which was used in next step reaction without purification.
LCMS (m/z): 218.0/220.0 (MH+), 0.33 min.
S nthesis of 3-bromo 2-methox eth l razinamine
Scheme 40
m1 m2 $2 §
NH2 NBocz NBocZ NBocZ
N)\ BOCZO \
N \ ozone A920
I ' I ng
/ N / / N
DMAP NaBH4 Mel
I 40% 95% N 80%
I OH 0\
Step 5 NHZ
N \ NJ\/Br
Ste 1. N N-di-tert-but l 5-all l razin lcarbamate
To a on of 5-allylpyrazinamine (1.2 g, 8.88 mmol) in CH2C|2 (29.6 mL) was added
Boc20 (4.07 g, 18.64 mmol) and DMAP (1.627 g, 13.32 mmol) at room temperature. The
reaction mixture was stirred at room temperature for overnight. After quenched with sat
NaHC03, the reaction mixture was extracted with CH2C|2 3 times. The combined organic
layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and
concentrated in vacuo. The desire was ed as a white solid (1.1 g, 37% yield) by
flash column chromatography. Rf (TLC) = 0.3 (20% EtOAc in hexanes). LCMS (m/z):
336.2 (MH+), 1.04 min.
Ste 2. N N-di-tert-but l 5- 2-h drox eth l razin lcarbamate
A solution of -tert—butyl (5-allylpyrazinyl)carbamate (1.1 g, 3.28 mmol) in DCM
(32.8 mL) was cooled down to -78 OC, ozone was bubbled through until blue color
appears, then Nitrogen was purged through for 5 min. NaBH4 (0.74 g, 19.6 mmol) in
methanol (20 mL) was added slowly, The reaction mixture was allowed to return to room
temperature. After 2 h, saturated NH4CI solution was added, the reaction mixture was
partitioned n EtOAc and water. The organic was washed with NaHC03,water and
brine, dried over anhydrous , filtered and concentrated. The crude product was
used in next step reaction without purification. LCMS (m/z): 340.3 (MH+), 0.77 min.
Ste 3. N N-di-tert-but l 5- 2-methox eth l razin lcarbamate
To a solution of -tert-butyl (5-(2-hydroxyethyl)pyrazinyl)carbamate (240 mg,
0.707 mmol) in Mel (7.7 mL) was added silver oxide (983 mg, 4.24 mmol). The reaction
mixture was stirred at room temperature for overnight. The on mixture was filtered
through Celite and washed with EtOAc and methanol, the organic was washed by sat.
NaHC03, water and brine, dried and concentrated. The crude material was used in next
step reaction without purification. LCMS (m/z): 354.2 (MH+), 0.92 min.
Ste 4. 5- 2-methox eth l razinamine
N,N-Di-tert—butyl (5-(2-methoxyethyl)pyrazinyl)carbamate (200 mg, 0.566 mmol) in
DCM (1.9 mL) was added TFA (872 uL, 11.32 mmol) the on mixture was stirred at
room ature for 1h, the reaction e was added 5 mL toluene and concentrated
to dryness. The crude material was used in next step reaction without purification. LCMS
(m/z): 154.1 (MH+), 0.27 min.
Ste 5. 3-bromo 2-methox eth | razin-2—amine
To a solution of 5-(2-methoxyethyl)pyrazinamine (80 mg, 0.522 mmol) in DCM (1.7 mL)
was added NBS (93 mg, 0.522 mmol) at room temperature. The reaction e was
stirred at room temperature for 1 h. After quenched with NaHC03, the reaction mixture
was extracted with DCM 3 times. The combined c layer was washed with water and
brine, dried over anhydrous sodium sulfate. The crude material was used in next step
reaction without purification. LCMS (m/z): 232.1/234.1 (MH+), 0.49 min.
Example 21
S nthesis of 4- 3-amino 2- meth lsulfon l eth l razin l -N-benz l
fluorobenzamide
Scheme 41
Step 1 Step_2 Step_3 Step 1
NB002 NBoc2 NHBoc NHBoc
NI \ MsCl NI \ NaSMe NI \ mCPBA “RN TFA
py, DCM DCM
98% 84% 98%
OH OMS o=,,3\
Step 5‘ Ste
NH2 NH2
N| \ NBS N]JV Pd(dppf)C|2 CHZCIZ Ol\l/\©
/ N —. / N —>
MeCN “QB DME/2 M Na2003
71% (2 SteP5 ) °
O=§\ o=,5\ 34A; KRF
O O 0’" \
Ste 1. 2- 5- bis utox carbon l amino razin l eth Imethanesulfonate
To N,N-di-tert-butyl (5-(2-hydroxyethyl)pyrazinyl)carbamate (450 mg, 1.326 mmol) in
DCM (10 mL) was added ne (0.429 mL, 5.30 mmol) and cooled to 0 °C using ice
bath. Then Mesyl-Cl (0.382 mL, 4.91 mmol) was added and the reaction was allowed to
warm to room temperature and stirred for 16 h. To the reaction was added 150 mL of
ethyl acetate and saturated sodium bicarbonate. The organic layer was extracted and
washed again with saturated sodium bicarbonate, water (3x), filtered, dried with sodium
sulfate and concentrated to constant mass to give 540 mg of desired product, used as is,
(98% yield). LCMS (m/z): 418.3 (MH+), 0.89 min; 1H NMR (400 MHz, CDCI3) 5 ppm 8.50
(s, 1H), 8.38 (s, 1H), 4.67 (t, J=6.3 Hz, 2H), 3.28 (t, J=6.3 Hz, 2H), 2.94 (s, 3H), 1.45 (s,
18H).
Ste 2. tert-but l5- 2- meth lthio eth l razin lcarbamate
To 2-(5-(bis(tert-butoxycarbonyl)amino)pyrazinyl)ethyl methanesulfonate (540 mg,
1.293 mmol) in DMF (7 mL) was added sodium thiomethoxide (408 mg, 5.82 mmol) and
was stirred at 85 °C for 3 h, followed by LCMS. The on was let cool, 200 mL of ethyl
e and saturated sodium bicarbonate was added. The organic layer was ted
and washed water (3x), saturated salt solution, dried sodium sulfate, filtered through 2 cm
silica gel plug and flushed with ethyl acetate. The solvent was concentrated off to
constant mass to give 294 mg of the desired product as free base used as is, (84% yield).
LCMS (m/z): 270.4 (MH+), 0.84 min. 1H NMR (400 MHz, cocks) 6 ppm 9.19 (s, 1H), 8.08
WO 66188
(d, J=1.2 Hz, 1H), 7.20 (br. s., 1H), 2.99-3.08 (m, 2H), 2.79-2.94 (m, 2H), 2.12 (s, 3H),
1.54 (s, 9H).
Ste 3. tert-but l5- 2- meth Isulfon leth | razin mate
To tert-butyl 5-(2-(methylthio)ethyl)pyrazinylcarbamate (292 mg, 1.084 mmol) in DCM
(10 mL) was added 40% (3.5 mL) of a freshly made solution of mCPBA (972 mg, 4.34
mmol) in DCM (8.7 mL) with stirring at room ature, followed by LCMS. After 30
min another 15% (1.3 mL of the above mCPBA solution) was added and stirred for 30
min, followed by LCMS. Then another 5% (0.044 mL of the above mCPBA solution) was
added and stirred for 30 min more. The reaction was followed by LCMS. To the reaction
was added 200 mL of ethyl acetate and excess saturated sodium bicarbonate. The
organic layer was extracted and washed again with saturate sodium onate, water
(3x), filtered and concentrated to constant mass to give 320 mg of the desired product
used as is, (98% yield). LCMS (m/z): 302.1 (MH+), 0.62 min; 1H NMR (400 MHz, CDCI3) 6
ppm 9.20 (s, 1H), 8.14 (s, 1H), 7.23 (br. s., 1H), 3.47-3.57 (m, 2H), 3.26-3.36 (m, 2H),
2.86-2.93 (m, 3H), 1.55 (s, 9H).
Ste 4. 5- 2- meth Isulfon leth | razinamine
To tert-butyl 5-(2-(methylsulfonyl)ethyl)pyrazinylcarbamate (320 mg, 1.062 mmol) in
DCM (6 mL) was added TFA (2.5 mL, 32.4 mmol) and stirred at room temperature for 1
hour. The solvent was trated off to constant mass. The product was free based by
using solid supported carbonate 2.5 grams at 0.8 mmol/gram with 6 mL of acetonitrile and
stirred for 5 min. The solid support was filtered off and flush with acetonitrile. The product
was concentrated to constant mass to give the desired product used as is, assume
quantitative yield (1.062 mmol). LCMS (m/z): 202.1 (MH+), 0.20 min.
Ste 5. o 2- meth Isulfon leth | razinamine
To 5-(2-(methylsu|fony|)ethy|)pyrazinamine (213 mg, 1.06 mmol) in acetonitrile (6 mL)
was added NBS (179 mg, 1.007 mmol) and was stirred at room temperature for 1 h. The
t was concentrated off to residue. To the crude was added ethyl acetate, washed
with saturated sodium carbonate, water (2x), dried sodium sulfate, filtered and
concentrated to constant mass to give 210 mg of the desired product as free base used
as is, (71% yield). LCMS (m/z): 280.0/282.0 (MH+), 0.38 min.
Ste 6. 4- 3-amino 2- meth lsulfon leth l razin l-N-benz lfluorobenzamide
To 3-bromo(2-(methylsulfonyl)ethy|)pyrazinamine (126 mg, 0.405 mmol) was added
N-benzylfluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (144 mg,
0.405 mmol), PdC|2(dppf)-CH2C|2adduct (33.1 mg, 0.040 mmol), DME (1.5 mL) and then
sodium ate 2 M aqueous solution (0.607 mL, 1.214 mmol). The reaction was
microwave at 125 °C for 12 min followed by LCMS. To the reaction was added 5 mL of
DME and 5mL of MeOH, filtered and concentrated to residue. The crude was dissolved in
2.5 mL of DMSO, filtered, purified by prep HPLC and lyophilized to TFA salt. To the TFA
salt was added 200 mL of ethyl acetate, washed with saturated sodium carbonate (3x),
water (3x), dried sodium sulfate, filtered and concentrated to constant mass to give 59 mg
of the desired product 4-(3-amino(2-(methylsulfonyl)ethyl)pyrazinyl)-N-benzyl
benzamide as free base in 34% yield. LCMS (m/z): 429.2 (MH+), 0.65 min; 1H NMR
(400 MHz, CD3OD) 6 ppm 7.95 (s, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.67 (dd, J=8.0, 1.4 Hz,
1H), 7.59 (dd, J=11.7, 1.2 Hz, 1H), 7.29-7.42 (m, 4H), 7.20-7.28 (m, 1H), 4.59 (s, 2H),
3.48-3.57 (m, 2H), 3.18 (dd, J=9.0, 6.7 Hz, 2H), 2.96 (s, 3H).
es 22, 23, and 24
fluorobenzamide
WO 66188
Scheme 42
Steal _p_>Ste 2
NH2 NH2
Br\/K ,0 Mg 0 NJ\ Pd(dppf)C|2 NI \
+ H8 —> [évg + | # / N
‘o / N
THF 0
C5,:
m§ N8002 8&2 é NB002 $2 § mg
80020 NJ\ 03 NJ\ TFA
I NI NBS
—> / N —>
—> / N
DMAP NaBH4
(+/-) (+l')
OH OH
NH2 F o
NJ\( F o Stegz
NH2 N
| N Pd(dppf)C|2
/N H
+ HO\B H —> N \
(5H DME,NaZCOS
(+/-)
OH KENK
—QSte §
NH2 N NH2 N
H H
chiral separation
N \ N \
—’ | + |
OH OH
Ste 1. 4 4 5 5-tetrameth I 2—meth |a|| | -1 3 2—dioxaborolane
To a suspension of magnesium turning (1.139 g, 46.9 mmol) in THF (65.1 mL) was added
4,4,5,5-tetramethy|-1,3,2—dioxaborolane (5.67 mL, 39.1 mmol) at room ature under
nitrogen. 3-bromomethylpropene (3.97 mL, 39.1 mmol) was added slowly, after 30
min, more 3-bromomethylpropene (3.97 mL, 39.1 mmol) was added, The reaction
mixture was stirred at room temperature for 1 h. heptanes was added, followed by 1N
HCI. The reaction mixture was then extracted by heptanes. The organic was washed by
water and brine, dried and concentrated to yield 4,4,5,5-tetramethyl(2-methylallyl)-
1,3,2-dioxaborolane. The product was used in the next step without purification, 1H NMR
(400MHz ,CDCI3) 6 ppm 4.67 (d, J = 6.7 Hz, 2 H), 1.77 (s, 3 H), 1.34 - 1.20 (m, 12 H).
Ste 2. 5- 2-meth |a|| | razinamine
To a solution of 5-bromopyrazinamine (1 g, 5.75 mmol) in was added 4,4,5,5-
tetramethyl(2-methylallyl)-1,3,2—dioxaborolane (1.360 g, 7.47 mmol), PdC|2(dppf)-DCM
adduct (0.469 g, 0.575 mmol), CsF (2.62 g, 17.24 mmol), purge though nitrogen. The
reaction e was stirred at 100 0C in oil bath for 3h. The reaction mixture was
partitioned between EtOAc and water. The organic was washed with brine, dried and
concentrated. The residue was dissolved in 1N HCI (10 mL) The aqueous layer was back
ted with EtOAc, The aqueous was then neutralized to pH = 8, then extracted by
EtOAc 3 times. The organic was then dried and concentrated. The crude product was
used in next step reaction. LCMS (m/z): 150.5 (MH+), 0.28 min.
Ste 3. N N-di-tert-but | 5- 2-meth |a|| | razin lcarbamate
To a solution of 5-(2-methylallyl)pyrazinamine (235 mg, 1.575 mmol) in DCM (5.2 mL),
Boc20 (731 uL, 3.15 mmol) was added, ed by DMAP (385 mg, 3.15 mmol). The
reaction was stirred at room temperature for overnight. To the reaction was added 30 mL
of DCM and washed with saturated sodium bicarbonate (2x) water (1x), dried sodium
sulfate, ed and concentrated to residue. The crude was purified by silica gel
chromatography eluting with 0-30% ethyl acetate and heptane to yield 250 mg of product.
LCMS (m/z): 350.1 (MH+), 1.12 min; 1H NMR (400MHz ,CDCI3) 8 ppm 8.45 (d, J = 1.2
Hz, 1 H), 8.41 - 8.33 (m, 1 H), 4.92 (s, 1 H), 4.75 (s, 1 H), 3.57 (s, 2 H), 1.73 (s, 3 H), 1.43
(s, 18 H).
Ste 4. +/- -N ert—but | 5- 2-h drox ro | razin lcarbamate
N,N-Di-tert—butyl methylal|y|)pyraziny|)carbamate (120 mg, 0.343 mmol) in
methanol (6.8 mL) was cooled down to - 78 °C ,the ozone was d through for 6 min.
Then en was purged through for 5 min. NaBH4 (39.0 mg, 1.030 mmol) in methanol
(5 mL) was added slowly. The reaction mixture was allowed to return to room temperature.
After 1h, Sat. NH4C| was added slowly. The reaction mixture was partitioned between
EtOAc and water. The c was washed with saturated NaHC03, water and brine,
dried and concentrated. The crude product was used in next step reaction t
purification. LCMS (m/z): 354.1 (MH+), 0.84 min.
Ste 5. +/- 5-amino razin l ro anol
(+/-)-N,N-Di-tert-butyl (5-(2-hydroxypropyl)pyrazinyl)carbamate (110 mg, 0.311 mmol)
in DCM (3.11 mL) was added TFA (1 mL, 12.98 mmol), the reaction mixture was stirred at
room temperature for 30 min, the reaction mixture was coevaporated with toluene. The
crude product was used in next step reaction without purification. LCMS (m/z): 154.1
(MH+), 0.24 min.
Ste 6. +/- 5-aminobromo razin l ro anol
To a solution of (+/-)(5-aminopyrazinyl)propanol (47 mg, 0.307 mmol) in DCM
(3.0 mL) was added NBS (49.1 mg, 0.276 mmol) at 0 °C. The reaction e was stirred
at 0 °C for 10 min. After quenched with sat NaHC03, the reaction mixture was extracted
with EtOAc 3 times. The combined organic layer was washed with water and brine, dried
over ous sodium sulfate. Filtered and concentrated in vacuo. The crude product
was used in next step reaction without purification. LCMS (m/z): 234. 0 (MH+), 0.40 min.
Ste 7. +/- 3-amino 2-h drox ro l razin l-N-benz lfluorobenzamide
To a solution of 1-(5-aminobromopyrazinyl)propanol (30 mg, 0.129 mmol) in
DME (970 uL) was added 4-(benzylcarbamoyl)fluorophenylboronic acid (31.8 mg,
0.116 mmol), dppf)CH2C|2 adduct (10.56 mg, 0.013 mmol), 2M Na2C03 (323 uL).
The reaction mixture was stirred at 120 °C for 10 min in microwave. The reaction mixture
was partitioned between EtOAc and water. the organic was dried and concentrated. the
crude t was purified by Prep HPLC. The pure fraction was combined and desalt to
yield (+/-)(3-amino(2-hydroxypropyl)pyrazinyl)-N-benzylfluorobenzamide.
LCMS (m/z): 381.2 (MH+), 0.67 min; 1H NMR (400MHz, CDSOD) 5 ppm 7.95 - 7.81 (m, 2
H), 7.66 (dd, J = 1.6, 8.2 Hz, 1 H), 7.58 (dd, J = 1.6, 11.7 Hz, 1 H), 7.43 - 7.31 (m, 4 H),
7.31- 7.19 (m, 1 H), 4.62 (s, 2 H), 4.16 - 4.04 (m, 1 H), 2.79 (d, J = 6.3 Hz, 2 H), 1.23 (d,
J = 6.3 Hz, 3 H).
The racemic (+/-)(3-amino(2-hydroxypropyl)pyrazinyl)-N-benzyl
fluorobenzamide was resolved by chiral SFC (ChiralPak 5mic AD column, 4.6x100 (mm),
methanol+0.1%DEA=40%, 5 mL/min). The polar enantiomer, (R)—4-(3-amino(2-
hydroxypropyl)pyrazinyl)-N-benzylfluorobenzamide, was obtained at Rt = 1.39 min.
LCMS (m/z): 381.2 (MH+), 0.67 min. The less polar enantiomer, (S)—4-(3-amino(2-
hydroxypropyl)pyrazinyl)-N-benzylfluorobenzamide was obtained at Rt = 1.97 min.
LCMS (m/z): 381.2 (MH+), 0.67 min. The stereochemistry was assigned arbitrarily.
S nthesis of 3-bromo 2-ethox eth l razinamine
Scheme 43
NH2 $9; NH2
NH2 #0 Steal NHz
NJ\ O’Bv/\0Et N \ Pd/C, H2
I le NBS NIJYBr
—> / N
| —, / N —> / N
Pd(dppf)Cl2
80 %
OEt OEt OEt
Ste 1. E x vin l razinamine
To a solution of 5-bromopyrazinamine (200 mg, 1.149 mmol) in DME (2874 uL) was
added (E)(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (341 mg, 1.724
mmol), PdCI2(dppf)-CH2C|2 adduct (94 mg, 0.115 mmol), and 2M Na2C03 (958 uL). The
reaction mixture was stirred at 130 0C in ave reactor for 20 min. The on
e was filtered through Celite and washed with EtOAc, the filtrate was partition
between EtOAc and water. The aqueous was extracted by EtOAc three times, the
combined organic was dried and concentrated. The crude material was purified by flash
tography to give (E)(2-ethoxyvinyl)pyrazinamine. LCMS (m/z): 166.1(MH+),
0.41 min.
Ste 2. 5- 2-ethox eth l 2-amine
To a solution of (E)(2-ethoxyvinyl)pyrazinamine (75 mg, 0.454 mmol) in ethanol
(4.54 mL) was added Pd/C (48.3 mg, 0.454 mmol). The reaction mixture was purged by
nitrogen for 10 min, and then stirred at room temperature for 2 h under hydrogen balloon.
The reaction mixture was then filtered through Celite and washed with methanol and
EtOAc, then concentrated. The crude product was used in next step reaction without
purification. LCMS (m/z): 168.1 (MH+), 0.33 min.
Ste 3. 3-bromo 2-ethox eth | razinamine
To a solution of 5-(2-ethoxyethyl)pyrazinamine (45 mg, 0.269 mmol) in DCM (897 uL)
was added NBS (43.1 mg, 0.242 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 10 min. After ed with sat. NaHC03, the reaction mixture was ted with
EtOAc 3 times. The combined organic layer was washed with water and brine, dried over
anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was
used in next step reaction without purification. LCMS (m/z): 246.0 (MH+), 0.59 min.
8 nthesis of +/- 5-aminobromo razin l ro anol
Scheme 44
Step_1 NH2 Step g ““2
NH2 Step 3
\ N \
N \ BF3K f)C|2 Nl | 2M HCI
W“ * 2cm / N N
—» /
C32C03 TH F/HZO 100 OC
n(+/-)
NH2 Ste NH2
—9 fl ”HYBr NI \ \
OH (+/-) OH (+/)
To a solution of 5-bromopyrazinamine (200mg, 1.149 mmol) in was added potassium
(3-(benzyloxy)propenyl)trifluoroborate (350 mg, 1.379 mmol), PdC|2(dppf).CH2C|2
adduct (94 mg, 0.115 mmol), Cs2C03 (1124 mg, 3.45 mmol). Purged through Nitrogen.
The on mixture was stirred at 100 0C in oil bath for 6 h. The reaction mixture was
then partitioned between EtOAc and water, combined the organic layers and washed with
water and brine, dried over anhydrous sodium sulfate and trated. The crude
product was purified by flash chromatography to give 5-(3-(benzyloxy)propen
yl)pyrazinamine in 61 % yield. LCMS (m/z): 245.2 (MH+), 0.67 min; 1H NMR (400MHz,
CD30D) 8 ppm 8.26 (d, J = 1.2 Hz, 1 H), 7.96 (d, J :12 Hz, 1 H), 7.34 (d, J = 4.3 Hz, 5
H), 5.91 (s, 1 H), 5.44 (d, J :12 Hz, 1 H), 4.59 (s, 2 H), 4.49 (s, 2 H).
Ste 2. +/- 1- benz lox ro an | razinamine
To a solution of benzyloxy)propeny|)pyrazinamine (91 mg, 0.377 mmol) in
methanol (3771 uL) was added Pd/C (40.1 mg, 0.377 mmol) at room temperature. The
reaction mixture was stirred at room temperature under hydrogen balloon for overnight.
The on mixture was filtered through Celite, washed with methanol and EtOAc. The
crude material was used in next step reaction without purification. LCMS (m/z): 244.2
(MH+), 0.62 min.
Ste 3. +/- o razin | ro anol
A solution of 5-(1-(benzyloxy)propany|)pyrazinamine (80 mg, 0.329 mmol) in 1N HCI
(1096 uL) was heat in oil bath for 7 h, cooling down, The reaction mixture was extracted
by EtOAc, the aqueous was concentrated to dryness to yield the crude product as HCI
salt and used in next step on. LCMS (m/z): 154.1 (MH+), 0.26 min.
Ste 4. +/- 5-aminobromo razin | ro anol
To a solution of 2-(5-aminopyraziny|)propano| (30 mg, 0.196 mmol) in DCM (653 uL)
was added NBS (31.4 mg, 0.176 mmol) at 0 °C. The on mixture was stirred at 0 °C
for 10 min. After quenched with sat NaHC03, the reaction mixture was extracted with
EtOAc 3 times. The combined organic layer was washed with water and brine, dried over
anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was
used in next step reaction without purification. LCMS (m/z): 234.0 (MH+), 0.40 min.
S nthesis of 3- obromo razin l ro rile
Scheme 45
40% 35%
me fl we 5
NHBoc NH2 NH2
NJ\ TFA N)\ NBS
I —> NJVBV
| —> I
DCM / N / N
ON ON ON
Ste 1. N N-di-tert-but l 5-meth l razin lcarbamate
To a solution of 5-methylpyrazinamine (1 g, 9.16 mmol) in CH2C|2 ( 30 mL), Boc20
(4.47 mL, 19.24 mmol) was added, followed by DMAP (1.679 g, 13.75 mmol) at room
temperature. The reaction mixture was d at room temperature for overnight. After
quenched with sat NaHC03, the reaction mixture was extracted with CH2C|2 3 times. The
combined organic layer was washed with water and brine, dried over anhydrous sodium
sulfate. Filtered and trated in vacuo. The desire product was obtained as a white
solid by flash column chromatography (20 % EtOAc in heptane). LCMS (m/z): 310.0
(MH+), 0.93 min.
Ste 2. N N-di-tert-but l 5- bromometh l razin lcarbamate
To a solution of N,N-di-tert—butyl (5-methylpyrazinyl)carbamate (1.37 g, 4.43 mmol) in
CCI4 (14.76 mL) was added NBS (0.828 g, 4.65 mmol), benzoyl peroxide (0.107 g, 0.443
mmol), AIBN (0.073 g, 0.443 mmol). The reaction mixture was stirred at reflux for 8 h.
Work up, the solid was filtered, the organic was concentrated. The crude product was
purified by flash chromatography to give the tile product in 36% yield. LCMS (m/z): 231.1
(MH+-Boc), 1.04 min.
Ste 3. tert-but l5- 2-c anoeth l razin mate
n-Butyl m (2.5 M in hexanes 103 uL, 0.258 mmol) was added into diisopropylamine
(39.3 uL, 0.276 mmol) in dry THF at 0 0C under argon, the mixture was then stirred at 0
0C for 1 h, then cooled down to -78 OC, itrile (14.12 uL, 0.270 mmol) was added
slowly, the reaction mixture was allowed to return to room temperature and stirred at
room temperature for 1 h, cooled down to -78 0C again, and N,N-di-tert-butyl (5-
(bromomethyl)pyrazinyl)carbamate (100 mg, 0.258 mmol) in THF (0.5 mL) was added
slowly, the reaction e was stirred at -78 0C for 10 min, then allowed to return to
room temperature, after 2 h, the reaction was quenched by sat.NH4C| solution, then
extracted by EtOAc. The organic was washed by brine, dried and concentrated. The
crude material was purified by flash chromatography (40% EtOAc/heptane) to give tert-
butyl 5-(2-cyanoethyl)pyrazinylcarbamate in 40% yield. LCMS (m/z): 193.1 (MH+-tBu),
0.70 min; 1H NMR (400MHz ,CDCI3) 6 ppm 9.22 (s, 1 H), 8.12 (s, 1 H), 3.09 (t, J = 7.2 Hz,
2 H), 2.83 (t, J = 7.2 Hz, 2 H), 1.52 - 1.36 (m, 8 H).
Ste 4. 3- 5-amino razin l ro anenitrile
To a solution of utyl 5-(2-cyanoethyl)pyrazinylcarbamate (25 mg, 0.101 mmol) in
DCM (0.336 mL) was added TFA (0.1 mL, 1.298 mmol) at room temperature . The
reaction mixture was d at room temperature for 1 h. After quenched with sat.
NaHC03, the reaction e was extracted with DCM. The combined organic layer was
washed with water and brine, dried over anhydrous sodium sulfate. Filtered and
concentrated in vacuo. The crude product was used in next step reaction without
purification. LCMS (m/z): 149.1 (MH+), 0.24 min.
Ste 5. 3- 5-aminobromo razin l ro rile
To a solution of 3-(5-aminopyrazinyl)propanenitrile (45 mg, 0.304 mmol) in DCM (1519
uL) was added NBS (48.7 mg, 0.273 mmol) at 0 °C. The reaction mixture was stirred at
0 °C for 10 min. After quenched with NaHC03, the reaction mixture was extracted with
EtOAc 3 times. The combined organic layer was washed with water and brine, dried over
anhydrous sodium sulfate. ed and concentrated in vacuo. The crude product was
used in next step reaction without purification. LCMS (m/z): 227/229.1 (MH+), 0.45 min.
8 nthesis of 5- 5-aminobromo razin l i eridinone
Scheme 46
0 OH m1 —9Ste 2 Step;
NHBoc
NHBOC
DPPA NBS N \ —~ W —. NIg NaCN
ka N
t—BuOH, Et3N KfN cat. AIBN Ki
NHB°C
Step 4 8&2 5
N \ O H
IKB“ / N)\ 2
/N + /\Of NaOEt |
\/ cat. Raney Ni
\\N \/
NHBoc NH2 NH2
fiaé m1 Br
N \ N \ N \
I I I
/N HCI /N NBS /N
HN HN HN
o o o
Ste 1. ut |5-meth l razin |carbamate
To solution 5-methylpyrazinecarboxylic acid (2.5 g, 18.1 mmol), tert-butanol (6.92 mL,
72.4 mmol), Et3N (3.78 mL, 27.1 mmol) in 1,4-dioxane (12.5 mL) at 95 °C was dropwise
added diphenylphosphoryl azide (DPPA, 3.23 mL, 18.1 mmol), and the reaction was
heated at 95 °C for 1.5 h, followed by a 2nd portion of DPPA (1 mL, 5.6mmol) and heated
for additional 1.5 h. The reaction mixture was cooled down, concnetrated and the residue
was d with EtOAc (50 mL), washed with water (30 mL), 3 M NaOH( 30 mL), sat.
NaHC03 (30 mL) and brine (30 mL), dried over Na2804, and concnetrated. The residue
was purified by flashed tography on silica gel eluting with gradient EtOAc/CH2C|2
(0-20%) to afford tert-butyl 5-methylpyrazinylcarbamate as white solid. LCMS (m/z):
210.1 (MH+), 0.69 min; 1H NMR (400 MHz, CDCI3) 6 ppm 9.17 (s, 1H), 8.09 (s, 1H), 7.75
(br. s., 1H), 2.51 (s, 3H), 1.56 (s, 9H).
Ste 2. tert-but |5- bromometh l razin lcarbamate
A solution of tert-butyl 5-methylpyrazinylcarbamate (2.79 g, 13.33 mmol), NBS (2.61 g,
14.67 mmol) and AIBN (0.219 g, 1.33 mmol) in CCI4 (45 mL) was purged with Argon, then
the solution was heated with 85 0C oil bath for 4 h. The reaction mixtue was cooled to
room temperature, concentrated and the residue was olved in EtOAc (~50 mL),
washed with dilute aqueous NaOH twice (10 mL 1 N NaOH diluted in 20 mL H20), brine
(30 mL), dried (Na2804) and concentrated. The residue was further ed by flash
chromatography on silica gel eluted with nt EtOAc/CH2C|2 ) and tert-butyl 5-
(bromomethyl)pyrazinylcarbamate was obtained in off-white solid. LCMS (m/z):
288.1/290.1 (MH+), 0.82 min; 1H NMR (400 MHz, CDCI3) 6 ppm 9.26 (s, 1H), 8.32 (d, J =
1.2 Hz, 1H), 7.62 (br. s., 1H), 4.56 (s, 2H), 1.56 (s, 9H).
Ste 3. tert-but |5- c anometh l razin lcarbamate
A mixture of tert-butyl 5-(bromomethyl)pyrazinylcarbamate (0.75 g, 2.60 mmol) and
NaCN (0.255 g, 5.21 mmol) in DMF (5 mL) was stirred at room temperature for 50 min.
The reaction mixture was cooled down to room temperature, diluted with 0.5 N NaOH (10
mL) and extratced with EtOAc (2 x 20 mL), and EtOAc layers were combined, washed
with 0.5 N NaOH (10 mL), dried (Na2804), concentrated and the crude residue was
purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2CI2 )
to afford tert-butyl 5-(cyanomethyl)pyrazinylcarbamate (0.40 g, 65.6% yield). LCMS
(MH+- tBu): 179.0 (MH+), 0.68 min; 1H NMR (400 MHz, CDCI3) 6 ppm 9.28 (s, 1H), 8.32
(s, 1H), 7.59 (br. s., 1H), 3.91 (s, 2H), 1.57 (s, 9H).
Ste 4. eth l4- 5- tert-butox carbon lamino razin lc anobutanoate
To utyl 5-(cyanomethyl)pyrazinylcarbamate (0.32 g, 1.37 mmol) in a mixture
solvent of ethanol/2-methyltetrahydrofuran (5mL/5mL) was added freshly ed
sodium ethoxide (1 M, 1.366 mL), and the mixture was stirred at 0 °C for 10 min, followed
by on of ethyl acrylate (145 ul, 1.366 mmol) and the mixture was stirred at 0 °C for 2
h. The reaction was quenched at this point by adding sat. NaHC03 (5 mL), and the
on mixture was stirred for another 10 min, diluted with EtOAc (20 mL), ed and
the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with
pH 7.0 sodium phosphate buffer, and EtOAc layer was concentrated, and the light brown
al oil was purified by flash column eluted with gradient EtOAc/heptane (0-50%) to
afford ethyl 4-(5-(tert-butoxycarbonylamino)pyrazinyl)—4-cyanobutanoate (100 mg, 22%
yield). LCMS (m/z): 279.2 (MH+-tBu), 0.86 min.
Ste 5. tert-but l5- 6-oxo i eridin l razin lcarbamate
Under Argon, to ethyl 4-(5-(tert-butoxycarbonylamino)pyrazinyl)cyanobutanoate in
ethanol solution (94 mg, 0.281 mmol/8 mL) was added Raney Nickel st ethanol
suspension (Nickel in ~2 mL ethanol, the amount of Raney Nickel was not accurately
measured), and the reaction mixture was stirred under H2 balloon after 3 times air
atomasphere exchange heated with external oil bath at 56 °C for overnight with H2
balloon. The reaction mixture was cooled down to room temperature, and filtered through
a pad of Celite, the filtrate was trated to afford tert-butyl 5-(6-oxopiperidin
yl)pyrazinylcarbamate in a yellow solid.
Ste 6. 5- 5-amino razin l i eridinone
A mixture of tert-butyl 5-(6-oxopiperidinyl)pyrazinylcarbamate (60 mg, 0.205 mmol)
and conc HCI (1 mL) in ol (2 mL) was heated with 70 °C oil bath for 1 hour and the
reaction e was cooled down, concentrated to dryness and the residue was
redissolved in methanol (3 mL), and to it was added NaHC03 (200 mg), and the mixture
was heated with 70 °C oil bath for 2 h. The solid suspension of reaction mixture was
d by filtration, and the filtrate was concentrated and a light yellow solid was
obtained as crude 5-(5-aminopyrazinyl)piperidinone which was used directly in next
step without further purification. LCMS (m/z): 193.1 (MH+), 0.22 min.
Ste 7. 5- 5-aminobromo razin l i eridinone
To 5-(5-aminopyrazinyl)piperidinone (25 mg, 0.13 mmol) acetonitrile (10 mL)
solution at 0 °C was added NBS (23.2 mg, 0.13 mmol) and the reaction mixture was
stirred at 0 °C for 30 min, then at room temperature for 4 h. The reaction mixture was
concnetrated, and the e was basified by 1 N NaOH (140 ul), diluted with methanol
(2 mL), concentrated. The residue was triturated with EtOAc (3 x 1 mL), and the EtOAc
supernatants were ted, combined and concentrated and a light solid was obtained
as crude 5-(5-aminobromopyrazinyl)piperidinone which was used in next step
without further purification. LCMS (m/z): 241/243 (MH+), 0.41 min.
Example 25
S nthesis of 4- 2-amino 6-oxo i eridin l ridin l-N- S 3-chloro hen l
hydroxyethyl )—2-fluorobenzamide
Scheme 47
m1 _28te 2
Br Br N/
\ NaH | Pd(dppf)C|2
I /Si/\/O\/C| \ \
_, I —.
NH \
DMF NVO\/\Si/ ’B\ Na2C03, DME
O o
31% |\
o o “w, 120 0c, 10 min
F mi F Step 5 NH2 Step 5
N \ N \ N \
' ' NHAOH '
/ H2(250psi> / / NBS
—> crude —> —>
/ Pd/C, MeOH 100 °c CH3CN
o N 16h (250 p5”
\ /\/o N HN 54%(3 stem)
,Si/V V\ ,Si V
I l
o o
crude
F o _/
St_eQ E
NH2 N
Pd(dppf)CI2 H
Na2003 DME / CI
pW 120 OC 10min
o HN
crude
Ste 1. 5-bromo 2- trimeth lsil lethox meth l ridin-2 1H -one
To a on of 5-bromopyridin-2(1H)—one (2.01 g, 11.55 mmol) in DMF (30 mL) at 0 °C
was added sodium hydride (0.924 g, 23.10 mmol). The reaction mixture was stirred for 1
h at room temperature. To this, (2-(chloromethoxy)ethy|)trimethylsilane (2.89 g, 17.33
mmol) was added slowly. The on mixture was stirred overnight. LCMS - 0.26 min,
MH+ 304.1 (non-polar method). The reaction was quenched with sat. aq. NH4CI, and then
diluted with ethyl acetate. The reaction mixture was ted with EtOAc. The combined
organics were washed with water and brine, then dried over sodium sulfate, filtered off
WO 66188
and concentrated in vacuo. The crude product was purified by flash chromatography
column using 0-50% EtOAc/ heptane. 5-bromo((2-(trimethylsilyl)ethoxy)methyl)pyridin-
2(1H)—one was obtained as a yellow viscous liquid. LCMS (m/z): 304/306 (MH+), 0.95 min.
Ste 2. 6'-f|uoro 2- trimeth lsil l ethox meth l - 3 3'-bi ridin -6 1H -one
To a solution of 5-bromo((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)—one (568 mg,
1.868 mmol) in DME ( 6227 uL, Ratio: 2.000) was added PdC|2(dppf) (68.3 mg, 0.093
mmol), 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine (500 mg, 2.242
mmol), 2M Na2C03 ( 3113 ul, Ratio: 1.000) at room temperature. The reaction mixture
was heated at microwave synthesizerfor 10 min at 120 °C. To the reaction mixture,
sodium sulfate and EtOAc were added. After filtered off, the volatile materials were
removed in vacuo. The crude product was ed by flash chromatography (gradient
EtOAc in heptane) yielding 6'-f|uoro((2-(trimethylsilyl)ethoxy)methyl)-[3,3'-bipyridin]-
6(1H)—one (52%). LCMS (m/z): 321.3 (MH+), 0.93 min.
Ste 3. 5- 6-fluoro ridin l 2- trimeth lsil lethox meth l i one
To a steel bomb, a on of 6'-f|uoro((2-(trimethylsilyl)ethoxy)methyl)-[3,3'-bipyridin]-
6(1H)-one (311 mg, 0.971 mmol) in MeOH (remaining 60% head space) was added
followed by addition of Pd-C (207 mg, 0.194 mmol). After degassing with nitrogen stream,
the steel bomb was pressurized with hydrogen gas up to 250 psi. The reaction was stirred
at room temperature for 20 h. LCMS - 0.9 min MH+ 325.1 (single major). The on
e was filtered off h Celite (washed with EtOAc). The volatile materials were
concentrated in vacuo to give crude 5-(6-fluoropyridinyl)((2-
(trimethylsilyl)ethoxy)methyl)piperidinone (290 mg, 0.894 mmol, 92%), which was used
for the next step without further purification.
Ste 4. 5- 6-amino ridin l i eridinone
To -(6-f|uoropyridinyl)—1-((2-(trimethylsilyl)ethoxy)methyl)piperidinone (290 mg,
0.894 mmol) in a steel bomb, ammonium ide (34.8 ul, 0.894 mmol) solution was
added (40% head volumn remained). The steel bomb reactor was heated at 150 °C for 44
h (250 psi on pressure guage). LCMS - 0.23 min, MH+ 192.1 (without SEM); 0.66 min,
MH+ 322.1 (with SEM). After diluted with MeOH and toluene, volatile materials were
completely removed in vacuo. 5-(6-aminopyridinyl)piperidinone was used for the
next step.
Ste 5. 5aminobromo ridin l i eridinone
To a solution of 5-(6-aminopyridinyl)piperidinone (132 mg, 0.690 mmol) in
itrile ( 8.00 mL) was added NBS (98 mg, 0.552 mmol) at 0 °C. The reaction mixture
was stirred for 30 min upon warming-up to room temperature. LCMS 0.28 min, MH+
270/272; 0.7 min, MH+ 402.1 (SEM protected one). After quenched with Na28203
solution, the reaction mixture was extracted with EtOAc, which was washed with NaHC03
solution and brine. The organic layer was dried over anhydrous Na2804, filtered off,
concentrated in vacuo. The crude 5-(6-aminobromopyridinyl)piperidinone was
used for the next step.
Ste 6. 4- 2-amino 6-oxo i eridin l ridin l-N- S 3-chloro hen l
hydroxyethyl)—2-fluorobenzamide
To a microwave vial, 5-(6-aminobromopyridinyl)piperidinone (45 mg, 0.167
mmol), (S)—(4-((1-(3-chlorophenyl)hydroxyethyl)carbamoyl)fluorophenyl)boronic acid
(56.2 mg, 0.167 mmol), PdCl2(dppf) (12.19 mg, 0.017 mmol), DME (1111 ul, Ratio:
2.000), and Na2C03 (2M solution) ( 555 uL, Ratio: 1.000) were added. The reaction
mixture was heated at microwave reactor for 10 min at 120 °C. LCMS - 0.58 min, MH+
483.2; 0.85 min, MH+ 613.3. After anhydrous sodium sulfate were added to remove water,
the reaction mixture was filtered off and dried in vacuo. The small n was purified by
prep HPLC ng 4-(2-amino(6-oxopiperidinyl)pyridinyl)—N-((S)—1-(3-
chlorophenyl)hydroxyethy|)f|uorobenzamide as a reomeric mixture (12%).
LCMS (m/z): 483.3 (MH+), 0.56 min; 1H NMR (400MHz, CD30D) 6 ppm 7.89 (m, 1H),
7.80 (m, 2H), 7.42 - 7.30 (m, 3H), 7.30 - 7.24 (m, 2H), 7.25 - 7.15 (m, 1H), 5.18 - 5.03 (m,
1H), 3.87 - 3.64 (m, 2H), 3.47 - 3.35 (m, 2H), 3.11 - 2.97 (m, 1H), 2.46 - 2.30 (m, 2H),
2.08 - 1.91 (m, 2H).
S nthesis of +/- 6-aminobromo ridin lmeth l i eridinone
Scheme 48
Steg1 Ste F Step;
B?“ Pd(dppf)CI2 H2 (250 psi) I NH4OH
NaZCO3 DME Pd/C MeOH 150°C
0w 120°C 10min 16h (1:380
90% 98% [ll
crude (’4')
NH2 NH2
N \ N \
I |
/ NBS /
CH3CN
o N o N
| (+1) I
(+/)
crude crude
To a solution of ro(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolanyl)pyridine (500 mg,
2.242 mmol) was added PdC|2(dppf) (68.3 mg, 0.093 mmol), 4-bromomethylpyridin-
2(1H)—one (351 mg, 1.868 mmol), 2M Na2C03 (4.1 mL) and DME (8.3 mL) at room
ature. The reaction mixture was heated at ave synthesizer for 10 min at 120
°C. The reaction mixture was extracted with EtOAc. The organic layers were washed with
water and brine, dried over anhydrous Na2804, filtered off, and concnetrated in vacuo.
The crude 6-fluoro-1'-methyl-[3,4'-bipyridin]-2'(1'H)—one was purified by flash
tography (gradient EtOAc in DCM). LCMS (m/z): 205.2 (MH+), 0.47 min.
Ste 2. +/- 6-fluoro ridin th l i eridinone
To a steel bomb, a solution of 6-f|uoro-1'-methy|-[3,4'-bipyridin]-2'(1'H)-one (340 mg,
1.665 mmol) in MeOH (remaining 60% head space) was added followed by addition of
Pd-C (Degussa) (354 mg, 0.333 mmol). After degassing with nitrogen stream, the steel
bomb was filled with hydrogen (250 psi). The reaction mixture was stirred overnight. The
reaction mixture was filtered off through Celite d with EtOAc/MeOH). The volatile
materials were concentrated in vacuo to give crude (+/-)(6-f|uoropyridiny|)
methylpiperidinone (341 mg, 1.638 mmol, 98 % yield) which was used for the next step
without further purification. LCMS (m/z): 209.1 (MH+), 0.47 min.
Ste 3. +/- 6-amino ridin lmeth | i eridinone
To a steel bomb, (+/-)(6-fluoropyridiny|)methy|piperidinone (341 mg, 1.638
mmol) was added followed by addition of ammonium hydroxide solution (0.00 mmol) -
remaining 40% head space. The reactor was heat at 150 °C for 20 hr nal pressure
built up to 100 psi upon g). After cooling down, the on was completed. The
whole solvent (transferred to a flask) was removed in vacuo. Toluene was added and co-
ated to remove water. The crude product, (+/-)(6-aminopyridinyl)—1-
methylpiperidinone, was used for the next step without further cation (87%).
LCMS (m/z): 206.1 (MH+), 0.24 min.
Ste 4. +/- 6-aminobromo ridin lmeth | i eridinone
To a solution of (+/-)(6-aminopyridinyl)—1-methy|piperidinone (291 mg, 1.418
mmol) in acetonitrile (14.200 mL) was added NBS (202 mg, 1.134 mmol) at 0 °C. The
reaction mixture was stirred for 30 min upon warming-up to room temperature. After
quenched with Na28203 solution, the reaction mixture was extracted with EtOAc, which
was washed with NaHC03 solution and brine. The organic layer was dried over
anhydrous Na2804, filtered off, concentrated in vacuo. The crude product 4-(6-
aminobromopyridinyl)—1-methylpiperidinone (98%) was used for the next step.
LCMS (m/z): 284/286 (MH+), 0.34 min.
Examples 26, 27, and 28
4- 2-amino 1-meth loxo i eridin | ridin l-N- S 3-chloro hen l
h drox eth lfluorobenzamide 4- 2-amino Rmeth loxo i eridin | ridin-
3- l-N- S 3-chloro hen lh drox eth lfluorobenzamide and 4- 2-amino
S h loxo i | ridin l-N- S 3-chloro hen lh drox eth |-
2-fluorobenzamide
F o Z/OH F o Z/OH F 0 {OH
NH2 N NH2 N NH2 N
H H H
N \ N \ N \
I I I
/ CI / CI / CI
N 0 T O N O
Following Step 6 in Scheme 47, using (+/-)(6-aminobromopyridinyl)—1-
methylpiperidinone and -((1-(3-ch|orophenyl)hydroxyethyl)carbamoy|)—3-
fluorophenyl)boronic acid, 4-(2-amino(1-methyloxopiperidinyl)pyridinyl)—N-((S)—
1-(3-chlorophenyl)hydroxyethyl)—2-fluorobenzamide was obtained as a diastereomeric
mixture (inseparable) (35%). LCMS (m/z): 497.3 (MH+), 0.59 min; 1H NMR (400MHz,
CD3OD) 6 ppm 7.97 (m, 1H), 7.9 (m, 1H), 7.82 (m, 1H), 7.52 - 7.39 (m, 3H), 7.39 - 7.32
(m, 2H), 7.3 (m, 1H), 5.19 (m, 1H), 3.88 (m, 2H), 3.60 - 3.38 (m, 3H), 3.21 - 3.08 (m, 1H),
2.72 - 2.58 (m, 1H), 2.57 - 2.41 (m, 1H), 2.21 - 1.95 (m, 2H). The diastereomeric mixture
was separated by chiral SFC (ChiralPak 5mic AD column, 4.6x100 (mm), 5mL/min,
EtOH+0.1%, DEA= 45% in 5 min). The polar reomer, 4-(2-amino((R)—1-methyl
oxopiperidinyl)pyridinyl)—N-((S)—1-(3-ch|orophenyl)hydroxyethy|)
fluorobenzamide was obtained at Rt = 1.82 min. The less polar diastereomer, 4-(2-amino-
—1-methyloxopiperidinyl)pyridinyl)—N-((S)(3-ch|orophenyl)
hydroxyethyl)fluorobenzamide was obtained at Rt = 2.35 min. The absolute
stereochemistry for both diastereomers was assigned arbitrarily.
Examples 29, 30, and 31
fluoro-N- R hen leth Ibenzamide and 4- 2-amino S meth loxo i eridin
l 3- lfluoro-N- R hen leth mide
F o 2 F o g F o 3
NH2 H/IjN NH2 NH/\© NH2 H/IjN N \ N \ N \
0 (N10
Following Step 6 in Scheme 47, using (+/-)(6-aminobromopyridinyl)—1-
methylpiperidinone and (R)-(3-fluoro((1-phenylethyl)carbamoy|)pheny|)boronic acid,
4-(2-amino(1-methyloxopiperidinyl)pyridinyl)fluoro-N-((R)
phenylethyl)benzamide was obtained as a diastereomeric e (inseparable) (34%).
LCMS (m/z): 447.3 (MH+), 0.58 min;1H NMR (400MHz, CD3OD) 6 ppm 7.85 (m, 1H), 7.72
(m, 2H), 7.41 - 7.20 (m, 6H), 7.18 (m, 1H), 5.17 (m, 1H), 3.51 - 3.29 (m, 3H), 3.13 - 2.98
(m, 1H), 2.88 (s, 3H), 2.60 - 2.48 (m, 1H), 2.48 - 2.30 (m, 1H), 2.10 - 1.85 (m, 2H), 1.58 -
1.38 (m, 3H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic
AD column, 4.6x100 (mm), 100mL/min, IPA+0.1%, DEA = 40%, 5m|/min). The polar
reomer, 4-(2-amino((R)methyloxopiperidinyl)pyridinyl)fluoro-N-((R)-
1-phenylethyl)benzamide was obtained at Rt = 1.67 min. LCMS (m/z): 447.3 (MH+), 0.64
min. The less polar diastereomer, 4-(2-amino((S)methyloxopiperidinyl)pyridin-
3-yl)—2-fluoro-N-((R)phenylethyl)benzamide was obtained at Rt = 2.37 min. LCMS
(m/z): 447.2 (MH+), 0.64 min. The absolute stereochemistry for both diastereomers was
assigned arbitrarily.
Examples 32, 33, and 34
4- 2-amino 1-meth loxo i eridin l ridin l-N- R 3-chloro hen leth l
fluorobenzamide 4- 2-amino Rmeth loxo i eridin l ridin l-N- R 3-
chloro hen leth lfluorobenzamide and 4- o S meth loxo i eridin
yl)pyridinyl)—N-((R)—1-(3-chlorophenyl)ethyl)—2-fluorobenzamide
F o 5 F o g F o 3
NH2 N NH2 N NH2 N
H H H
N \ N \ N \
I I I
/ Cl / Cl / Cl
T o T 0 (kilo
Following Step 6 in Scheme 47, using (R)—(4-((1-(3-chlorophenyl)ethyl)carbamoyl)—3-
fluorophenyl)boronic acid, mino(1-methyloxopiperidinyl)pyridinyl)—N-((R)-
1-(3-chlorophenyl)ethyl)fluorobenzamide was obtained as a reomeric mixture
(inseparable) (33%). LCMS (m/z): 481.3 (MH+), 0.70 min; 1H NMR (400MHz, CD3OD) 6
ppm 7.86 (m, 1H), 7.73 (m, 2H), 7.39 - 7.20 (m, 5H), 7.19 (m, 1H), 5.14 (m, 1H), 3.52 -
3.28 (m, 3H), 3.14 - 2.98 (m, 1H), 2.88 (s, 3H), 2.62 - 2.48 (m, 1H), 2.46 - 2.30 (m, 1H),
2.12 - 1.84 (m, 2H), 1.48 (m, 3H). The reomeric mixture was separated by chiral
SFC (ChiralPak 5mic AD column, 4.6x100 (mm), 5ml/min, EtOH+0.1% DEA=35%). The
polar diastereomer, 4-(2-amino((R)methyloxopiperidinyl)pyridinyl)—N-((R)—1-
(3-chlorophenyl)ethyl)—2-fluorobenzamide was obtained at Rt = 2.83 min. LCMS (m/z):
481.2 (MH+), 0.71 min. The less polar diastereomer, 4-(2-amino—5-((S)—1-methyl
oxopiperidinyl)pyridinyl)—N-((R)—1-(3-chlorophenyl)ethyl)—2-fluorobenzamide was
ed at Rt = 3.53 min. LCMS (m/z): 481.2 (MH+), 0.72. The absolute stereochemistry
for both diastereomers was assigned arbitrarily.
S nthesis of 5- 6-aminobromo ridin lmeth l i eridinone
Scheme 49
Br N \
| '
/ \
I + _>
o’B‘o
0 %—§ /N
Following Scheme 48, using 5-bromomethylpyridin-2(1H)—one, 5-(6-amino
bromopyridinyl)methylpiperidinone was obtained. LCMS (m/z): 284/286 (MH+),
0.34 min.
Examples 35, 36, and 37
4- 2-amino 1-meth loxo i l ridin l-N- S 3-chloro hen l
h drox eth uorobenzamide 4- 2-amino Rmeth loxo i eridin l ridin-
3- l-N- S 3-chloro hen lh drox eth lfluorobenzamide and 4- 2-amino
S meth loxo i eridin l ridin l-N- S 3-chloro hen lh drox eth l-
2-fluorobenzamide
F o :/OH F 0 :/OH F o :/OH
NH2 N NH2 N NH2 N
H H H
N \ N \ N \
I I I
/ CI / CI / CI
/N /N /l\©
O O 0
Following Step 6 in Scheme 47, using 5-(6-aminobromopyridinyl)—1-methy|piperidin-
2-one and (S)—(4—((1-(3-chlorophenyl)hydroxyethyl)carbamoyl)fluorophenyl)boronic
acid, 4-(2-amino(1-methyloxopiperidinyl)pyridinyl)—N-((S)(3-chlorophenyl)
hydroxyethyl)fluorobenzamide was obtained (33%). LCMS (m/z): 497.2 (MH+), 0.61
min; 1H NMR (400MHz, CD3OD) 8 ppm 8.70 (m, 1H), 7.98 (m, 1H), 7.88 (m, 2H), 7.44 (m,
3H), 7.36 (m, 2H), 7.30 (m, 1H), 5.19 (m, 1H), 3.88 (m, 2H), 3.51 (m, 2H), 3.21 (m, 1H),
2.97 (s, 3H), 2.50 (m, 2H), 2.07 (m, 2H). The diastereomeric mixture was separated by
chiral SFC (ChiralPak 5mic AD column, 4.6x100 (mm), EtOH+0.1%DEA=40%
, 5m|/min).
The polar diastereomer, 4-(2-amino((R)—1-methyloxopiperidinyl)pyridinyl)—N-
((S)—1-(3-chlorophenyl)—2-hydroxyethyl)fluorobenzamide was obtained at Rt = 2.22 min.
LCMS (m/z): 497.2 (MH+), 0.61 min. The less polar diastereomer, 4-(2-amino—5-((S)
methyloxopiperidinyl)pyridinyl)—N-((S)(3-chlorophenyl)hydroxyethyl)
fluorobenzamide was obtained at Rt = 3.09 min. LCMS (m/z): 497.3 (MH+), 0.59 min.
Examples 38, 39, and 40
4- 2-amino 1-meth o i eridin l ridin l-N- R 3-chloro hen leth l
fluorobenzamide 4- 2-amino Rmeth loxo i eridin l ridin l-N- R 3-
chloro hen leth uorobenzamide and 4- 2-amino S h loxo i eridin
yl)pyridinyl)—N-((R)—1-(3-chlorophenyl)ethyl)—2-fluorobenzamide
F O 3 F O E F O 3
NH2 N NH2 N NH2 N
H H H
N \ N \ N \
I I I
/ CI / CI / CI
/N /N /l\©
O O 0
Following Step 6 in Scheme 47, using (R)—(4-((1-(3-chlorophenyl)ethyl)carbamoy|)
fluoropheny|)boronic acid and 5-(6-aminobromopyridiny|)methy|piperidinone,
4-(2-amino(1-methyloxopiperidinyl)pyridinyl)—N-((S)—1-(3-chlorophenyl)
hydroxyethy|)f|uorobenzamide was obtained as a diastereomeric mixture (4%). LCMS
(m/z): 481.3 (MH+), 0.69 min. 1H NMR (400MHz, CD3OD) 8 ppm 8.79 - 8.65 (m, 1H), 7.93
- 7.83 (m, 1H), 7.83 - 7.76 (m, 1H), 7.75 - 7.65 (m, 1H), 7.40 - 7.29 (m, 3H), 7.29 - 7.21
(m, 2H), 7.21 - 7.13 (m, 1H), 5.22 - 5.07 (m, 1H), 3.52 - 3.32 (m, 3H), 3.16 - 3.01 (m, 1H),
2.88 (s, 3H), 2.48 - 2.34 (m, 2H), 2.07 - 1.92 (m, 2H), 1.55 - 1.40 (m, 3H). The
diastereomeric mixture was separated by chiral SFC IPak 5mic AD column,
4.6x100 (mm), 5m|/min, MeOH+0.1% DEA = 35%). The polar diastereomer, mino-
-((R)—1-methyloxopiperidinyl)pyridinyl)—N-((R)—1-(3-chlorophenyl)ethyl)—2-
fluorobenzamide was obtained at Rt = 2.98 min. LCMS (m/z): 481.2 (MH+), 0.71 min. The
less polar diastereomer, 4-(2-amino((S)—1-methyloxopiperidinyl)pyridinyl)—N-
((R)—1-(3-chlorophenyl)ethyl)—2-fluorobenzamide was obtained at Rt = 3.93min. LCMS
(m/z): 481.1 (MH+), 0.71 min.
Example 41
4- 2-amino 5-oxo rrolidin l 3- lfluoro-N- S h drox
phenylethyl )benzamide
Scheme 50
WO 66188
F Oyo Step 1 F Step 2 F Step g F
N / O N’ N / /
| N K + N
Pd(dPPf)C|2-DCM | TFA/DCM | Pd-C |
\ —> \ —. —> \ \
o Na2C03, DME MeOH
,B\ o‘ ’I 0
HO OH S\\\©\ 547% / / 80A,
N y' NH NH
o 2’0 o o
F NH2 OH
Step 4 Step § Step § F o _/
N/ N/ _
NaH, CH3I | NH4+ OH' | NBS / ACN N
—> —> \ —> +
DMF 80% 73% >§VO0‘3I 58%
N N
o \
o \
F o :/
H/\©N —93te 1 NHZ
PdCl2(dppf)-CH2C|2 N/
2M Na2C03/ DME
/ o
Ste 1. tert-but l4- 6-fluoro ridin loxo-2 5-dih - rrolecarbox late
To tert-butyl 2-oxo(tosyloxy)-2,5-dihydro-1H-pyrrolecarboxylate (0.8g, 2.037 mmol)
(See Example24 for synthesis) in DME (27 mL) and sodium carbonate (7 mL, 14.00
mmol) (2M) was added (6-fluoropyridinyl)boronic acid (0.431 g, 3.06 mmol) and
PdC|2(dppf).CH2C|2 adduct (0.333 g, 0.407 mmol). Purge with N2 for 5min.The reaction
mixture was heated in oil bath at 90°C fo 2 h. The reaction mixture was partitioned
between ethylacetate and water. The organic layer was separated, washed with brine,
dried over sodium sulfate, filtered and evaporated. Purified by flash chromatography
column using 0-50%EtOAc/ heptane. Fractions contains product were combined and
evaporated to provide tert-butyl 4-(6-fluoropyridinyl)—2-oxo-2,5-dihydro-1 H-pyrrole
carboxylate as an off white solid (54.7%). LCMS (m/z): 223.2 (MH+-‘Bu), 0.743 min.
Ste 2. 4- ro 3- l -1H- rrol-2 5H -one
To utyl 4-(6-fluoropyridinyl)—2-oxo-2,5-dihydro-1H-pyrrolecarboxylate (315 mg,
1.132 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture
was stirred at room temperature for 1h. Reaction mixture was ated. Azeotrope with
toluene (x=3) yielding 4-(6-fluoropyridinyl)-1H-pyrrol-2(5H)—one. Proceed for next step.
LCMS (m/z): 179.2 (MH+), 0.373 min. The crude yield was quantitative.
Ste 3. 4- 6-fluoro ridinl rrolidinone
To 4-(6-fluoropyridinyl)—1H-pyrrol-2(5H)-one(190 mg, 1.066 mmol) in MeOH ( 10 mL)
under N2 atmosphere was added Pd-C (227 mg, 0.213 mmol). The reaction mixture was
stirred under H2 balloon at room temperature for overnight. Reaction mixture was filtered
h , washed with MeOH. te was evaporated. Azeotrope with toluene
(x=3). Yield was 80%. Proceed for next step. LCMS (m/z): 181.0 (MH+), 0.341 min.
Ste 4. 4- 6-fluoro ridin lmeth l rrolidinone
To 4-(6-fluoropyridinyl)pyrrolidinone (200 mg, 0.888 mmol) in DMF (4 mL) in ice
bath was added NaH (42.6 mg, 1.066 mmol) and iodomethane (0.067 mL, 1.066 mmol).
The reaction mixture was d in ice bath for 30 min and room temperature for 1 hour.
LC-MS shows mixture of SM and product (1:1). Added again NaH (42.6 mg, 1.066 mmol)
and thane (0.067 mL, 1.066 mmol), stirred for 1h at room temperature. Complete
reaction by LC-MS. Reaction mixture was diluted with EtOAc and washed with water and
bine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude
was purified by flash chromatography [080%EtOAc ins 10%MeOH) / heptane].
LCMS (m/z): 195.2 (MH+), 0.492 min. Yield 58%
Ste 5. 4- 6-amino ridin lmeth l rrolidinone
To 4-(6-fluoropyridinyl)—1-methy|pyrrolidinone(100 mg, 0.515 mmol) was added
ammonium hydroxide (2 mL, 15.41 mmol). The reaction mixture was heated in heating
block at 140°C for 48h. LC-MS shows 80% product. Reaction mixture was evaporated.
Azeotrope with e (x=3) and proceed for next step. LCMS (m/z): 192.2 (MH+), 0.256
min.
Ste 6. 4- 6-aminobromo ridin lmeth l rrolidinone
To 4-(6-aminopyridinyl)—1-methylpyrrolidinone (90 mg, 0.377 mmol) in Acetonitrile (
3 mL) in ice bath was added NBS (60.3 mg, 0.339 mmol). The reaction mixture was
stirred in ice bath for 15 min and room temperature for 30min. LC-MS shows mixture of
SM and t. Addded 0.1 equiv. more of NBS and stirred another 1h at room
temperature. Reaction mixture was diluted with EtOAc and added 2mL of Satd sodium
onate. Stirred 10min. The organic layer was separated, dried over sodium sulfate,
filtered and evaporated. Proceed for next step (73%). LCMS (m/z): 270.2/272.2(MH+),
0.302 min.
Ste 7. 4- 2-amino 1-meth loxo rrolidin l ridin lfluoro-N- S h drox -
1-phenylethyl mide
To 4-(6-aminobromopyridinyl)—1-methy|pyrrolidinone (18 mg, 0.067 mmol) in DME
( 1.6 mL) and sodium carbonate (0.167 mL, 0.333 mmol) was added (S)—2-fluoro-N-(2-
hydroxyphenylethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide(30.8
mg, 0.080 mmol) and PdC|2(dppf).CH2C|2 adduct (5.44 mg, 6.66 umol). The reaction
mixture was heated in microwave at 120°C for 15 min. The reaction mixture was diluted
with Ethylacetate. The organic layer was separated and evaporated. The crude was
ed by prep HPLC to provide desired product as a TFA salt (29.3%). LCMS (m/z):
449.3 (MH+), 0.52 min; 1H NMR (400 MHz, CD30D) 6 ppm 8.65 (dd, J=7.24, 4.11 Hz, 1
H) 7.97 (d, J=2.35 Hz, 1 H) 7.94-7.83 (m, 2 H) 7.49-7.39 (m, 4 H) 7.36 (t, J=7.63 Hz, 2 H)
7.32-7.24 (m, 1 H) 5.30-5.13 (m, 1 H) 3.94-3.76 (m, 3 H) 3.69 (quin, J=8.31 Hz, 1 H) 3.50
(dd, J=9.59, 7.24 Hz, 1 H) 2.89 (s, 3 H) 2.79 (dd, J=16.82, 9.00 Hz, 1 H) 2.56 (dd,
J=16.82, 8.22 Hz, 1 H).
e 42, 43, and 44
4- 2-amino 1-meth o rrolidin l ridin l-N- S 3—chloro hen l
Following Step 6 in Scheme 50, using 4-(6-aminobromopyridinyl)—1-methy|pyrrolidin-
2-one and (S)—N-(1-(3-chlorophenyl)hydroxyethyl)fluoro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)benzamide, 4-(2-amino(1-methyloxopyrrolidinyl)pyridinyl)—N-
((S)—1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide was obtained as a
diastereomeric mixture (33.3%). LCMS (m/z): 483.3 (MH+), 0.59 min; 1H NMR (400 MHz,
CD3OD) 6 ppm 8.79-8.61 (m, 1 H) 7.97 (d, J=1.96 Hz, 1 H) 7.93-7.82 (m, 2 H) 7.48-7.39
(m, 3 H) 7.39-7.25 (m, 3 H) 5.25-5.14 (m, 1 H) 3.95-3.76 (m, 3 H) 3.69 (quin, J=8.22 Hz, 1
H) 3.50 (dd, J=9.78, 7.43 Hz, 1 H) 2.89 (s, 3 H) 2.80 (dd, J=16.82, 9.00 Hz, 1 H) 2.56 (dd,
J=16.82, 8.22 Hz, 1 H). The diastereomeric mixture was ted by chiral SFC
(ChiralPak 5mic AD column, 4.6x100 (mm), IPA+0.1% DEA=40%, 5mL/min). The polar
reomer, 4-(2-amino((R)methyloxopyrrolidinyl)pyridinyl)—N-((S)—1-(3-
chlorophenyl)hydroxyethyl)fluorobenzamide, was obtained at Rt = 1.41 min. LCMS
(m/z): 483.3 (MH+), 0.586 min; 1H NMR (400 MHz, CD3OD) 6 ppm 7.82 (d, J=1.56 Hz, 1
H) 7.74 (t, J=7.83 Hz, 1 H) 7.35 (d, J=2.35 Hz, 2 H) 7.33-7.15 (m, 5 H) 5.09 (t, J=5.87 Hz,
1 H) 4.48 (s, 1 H) ) 3.83-3.63 (m, 3 H) 3.50 (quint, J=8.22 Hz, 1 H) 3.36 (dd, J=9.39, 7.43
Hz, 1H) 2.78 (s, 3 H) 2.67 (dd, 2, 9.00 Hz, 1 H) 2.42 (dd, J=16.63, 8.41 Hz, 1 H).
The less polar diastereomer, 4-(2-amino((S)methy|oxopyrro|idinyl)pyridiny|)-
N-((S)(3-chlorophenyl)hydroxyethyl)fluorobenzamide, was obtained at Rt = 2.16
min. LCMS (m/z): 483.3 (MH+), 0.585 min; 1H NMR (400 MHz, CD30D) 6 ppm 7.92 (d,
J=2.35 Hz, 1 H) 7.84 (t, J=8.02 Hz, 1 H) 7.51-7.21 (m, 7 H) 5.18 (t, J=5.87 Hz, 1 H) 3.94-
3.72 (m, 3 H) 3.59 (quin, J=8.22 Hz, 1 H) 3.50-3.42 (m, 1 H) 2.88 (s, 3 H) 2.82-2.70 (m, 1
H) 2.51 (dd, 2, 8.61 Hz, 1 H).
Example 45
S nthesis of S 2-Amino 4-meth ltetrah dro-2H- ran | ridin lfluoro-N-
(2-hydroxy—1-phenylethyl)benzamide
Scheme 51
WO 66188
Ste F SteQ ; F m3
F stag g
Pd(dppf)C|2—DCM N\ NI \
/ H NI \
NI \ . / _. / _.
NaZCO3 DME
0 OH I
o o o
8—25 $0 mg $21
NH2 NH2
Br F O _/
NH N \ N \
| I
/ / N
N \ —> —> +
I H03 H
/ E.‘
O o
—25te § F 0 {OH
Pd(dppf)C|2—DCM N \ N/\©H
—> |
NaZCO3, DME
Ste 1. 4- ro ridin Itetrah dro-2H- rancarbaldeh de
To a solution of 5-bromofluoropyridine (2.0 g, 11.36 mmol) in dioxaane (35 mL) was
added tetrahydro-2H-pyrancarbaldehyde (2.59 g, 22.73 mmol), Pd(OAc)2 (0.25 g, 1.14
mmol), cesium carbonate (7.41 g, 22.73 mmol), and water (10.24 uL, 0.57 mmol),
xantphos (0.98 g, 1.70 mmol). The mixture was purged with nitrogen for 5 min, the
resulting mixture was heated to 110 °C in an oil bath for 15 h. The e was diluted
with ethyl acetate, and was washed with water, brine, dried over sodium sulfate and
concentrated. The e was purified by flash column chromatography on silicagel
(ISCO) eluting with 0-80% ethyl acetate in heptane to give 4-(6-fluoropyridin
y|)tetrahydro-2H-pyrancarbaldehyde (560 mg, 2.68 mmol, 23.5 % yield) as red color
oil. LCMS (m/z): 210 (MW), 0.45 min.
Ste 2. 4- 6-Fluoro ridin ltetrah dro-2H- ran lmethanol
To an ice cooled solution of 4-(6-f|uoropyridiny|)tetrahydro-2H-pyrancarbaldehyde
(560 mg, 2.68 mmol) in methanol (18 mL) was added sodium borohydride (91 mg, 2.41
mmol). The reaction solution was stirred at ambient temperature for 30 min. The solvent
was removed under vacuum. The residue was diluted with ethyl acetate, and was
washed with water, brine, dried over sodium sulfate, filtered and concentrated to give (4-
(6-fluoropyridinyl)tetrahydro-2H-pyranyl)methanol (550 mg, 2.60 mmol, 97 %) as
brown color oil. LCMS (m/z): 212 (MW), 0.42 min.
Ste 3. 2-F|uoro 4- iodometh h dro-2H- ran l ridine
To an ice cooled solution of triphenylphosphine (983 mg, 3.75 mmol), iodine (952 mg,
3.75 mmol) in dichloromethane (20 mL) was added imidazole (278 mg, 4.09 mmol). The
solution was stirred at ambient temperature for 1 h, followed by the addition of (4-(6-
fluoropyridinyl)tetrahydro-2H-pyranyl)methanol (360 mg, 1.70 mmol) in 10 mL
dichloromethane. The reaction mixture was heated to 60°C in an oil bath for 48 h. Solid
was ed off, the filtrate was purified by flash column chromatography on silicagel
(ISCO) eluting with 0-80% ethyl e in heptane to give to give 2-fluoro(4-
(iodomethyl)tetrahydro-2H-pyranyl)pyridine (330 mg, 1.03 mmol, 60.3 % yield) as light
yellow color oil. LCMS (m/z): 322 (MW), 0.77 min.
Ste 4. ro 4-meth ltetrah dro-2H- ran l ridine
To a solution of (2-fluoro(4-(iodomethyl)tetrahydro-2H-pyranyl)pyridine (330 mg,
1.03 mmol) in THF (5mL) at -15 °C, was added N-selectride (2.26 mL, 2.26 mmol)
dropwise. The solution was stirred at ambient temperature for 16 h. The solution was
recooled in an ice bath, and 0.3 mL of water was added. The resulting solution was stirred
for 10 min. The solvent was removed under vacuum, and the residue was dissolved in
DCM. lnsoluble solid was ed, and the te was purified by flash column
chromatography on silica gel (ISCO) g with 0-80% ethyl acetate in heptane to give
to 2-fluoro(4-methyltetrahydro-2H-pyranyl)pyridine (110 mg, 0.56 mmol, 54.8 %
yield) as colorless oil with >90% purity. LCMS (m/z): 196 (MH+), 0.64 min.
Ste 5. N- 24-Dimethox benz l 4-meth h dro-2H- ran l ridinamine
To a solution of 2-fluoro(4-methyltetrahydro-2H-pyranyl)pyridine (110 mg, 0.56
mmol) in (2,4-dimethoxyphenyl)methanamine (1016 uL, 6.76 mmol) and DIEA (246 uL,
1.41 mmol) was added potassium carbonate (156 mg, 1.12 mmol). The resulting e
was heated to 160 °C in an oil bath for 16 h, The reaction mixture was diluted with ethyl
e, washed with water, brine, dried over sodium e and concentrated. The
residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-
100% ethyl acetate in heptane to give N-(2,4-dimethoxybenzyl)(4-methyltetrahydro-2H-
pyranyl)pyridinamine (100 mg, 0.29 mmol, 51.8 % yield) as light yellow color solid.
LCMS (m/z): 343 (MW), 0.63 min.
Ste 6. 5- 4-Meth ltetrah - ran l ridinamine
To an ice cold solution of N-(2,4-dimethoxybenzyl)(4-methyltetrahydro-2H-pyran
yl)pyridinamine (100 mg, 0.29 mmol) in DCM (6 mL) was added 10mL 30% TFA in
DCM solution. The resulting solution was stirred at 0°C for 15min. The solvent was
removed via vacuum. The resulting residue was redissolved in ethyl acetate, and the
organic solution was washed with 1M NaOH, brine, dried over sodium sulfate and
concentrated. The residue was purified by flash column chromatography on silicagel
(ISCO) eluting with 0-100% ethyl acetate in heptane to give ethyltetrahydro-2H-
pyranyl)pyridinamine (50 mg, 0.26 mmol, 89 % yield) as white color solid. LCMS
(m/z): 193 (MH+), 0.35 min.
Ste 7. 3-Bromo 4-meth h dro-2H- ran l ridinamine
To an ice cold solution of 5-(4-methyltetrahydro-2H-pyranyl)pyridinamine (50 mg,
0.26 mmol) in DCM (5 mL) was added NBS (50.9 mg, 0.28 mmol) in two portions. The
reaction mixture was d at ambient temperature for 40 min. The reaction solution was
diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate, brine, dried
over sodium sulfate, filtered off, and concentrated to give 3-bromo(4-methyltetrahydro-
2H-pyranyl)pyridinamine (70 mg, 0.26 mmol, 99 % yield) as yellow color residue.
LCMS (m/z): 271/273 (MH+), 0.41 min.
Ste 8. S 2-Amino 4-meth ltetrah dro-2H- ran l 3- lfluoro-N- 2-
hydroxy—1-phenylethyl)benzamide
To a solution of 3-bromo(4-methyltetrahydro-2H-pyranyl)pyridinamine (70 mg,
0.26 mmol) in DME (4 mL) was added (S)f|uoro-N-(2-hydroxyphenylethyl)
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (298 mg, 0.77 mmol) and sodium
carbonate (0.64 mL, 1.29 mmol). The mixture was purged with nitrogen for 10 min, then
PdC|2(dppf)-CH2C|2 (31.6 mg, 0.039 mmol) was added. The reaction mixture was heated
to 120 °C in an oil bath for 2 h. The reaction mixture was diluted with ethyl acetate,
washed with water, brine, dried over sodium sulfate and concentrated. The resulting
residue was purified by flash column tography on silicagel (ISCO) eluting with 0-
100% ethyl e in heptane to give 70mg crude product, which was purified by HPLC
to give (S)(2-amino(4-methyltetrahydro-2H-pyranyl)pyridinyl)—2-fluoro-N-(2-
yphenylethyl)benzamide (40.8 mg, 0.089 mmol, 34.5 % yield) as TFA sa|t.
LCMS (m/z): 450 (MH+), 0.61 min; 1H NMR (400 MHz, CDCI3) 6 ppm 8.22 (t, J=7.83 Hz,
1 H) 7.77 - 7.65 (m, 2 H) 7.50 (dd, J=11.74, 7.43 Hz, 1 H) 7.42 - 7.36 (m, 4 H) 7.33 (d,
J=7.43 Hz, 2 H) 7.21 (d, J=11.74 Hz, 1 H) 5.33 (d, J=4.70 Hz, 1 H) 4.08 - 3.94 (m, 2 H)
3.83 - 3.65 (m, 4 H) 1.97 (ddd, J=13.40, 8.12, 5.09 Hz, 2 H) 1.72 (d, 9 Hz, 2 H)
1.35 (s, 3 H)
Example 46
S nthesis of 4- 3-amino razin l -N-benz lbenzamide
Scheme 52
““2 NH N
N 2
CI Pd(dppf)C|2_DCM H
O + N \ —>
éé‘B 9N| N32003, DME b,“
To a solution of N-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (150
mg, 0.445 mmol), 3-chloropyrazinamine (74.9 mg, 0.578 mmol), and PdCl2(dppf)-
CH2C|2 adduct (36.3 mg, 0.044 mmol) in DME (3.3 mL) was added 2 M Na2C03 (1.11
mL). The reaction mixture was heated at microwave synthesizer (120 °C, 10 min). Diluted
with EtOAc and washed with water twice. Then extracted with 1N HCI (3 X15 mL). The
acidic solution was washed with ether twice (2 X15 mL), and then basified with Na2C03.
ed by extracting with EtOAc (20 mL, 3 times) and then washed by sat NaHC03,
water and brine, dried over Na2804 and filtered off, concentrated. The crude product was
purified with flash chromatography eluting with 0-100% of EtOAc(containing 10% MeOH)
in heptane, then trated on rotavap. The residue was triturated with ether to provide
80.2 mg of desired product. LCMS (m/z): 305.2 (MH+), 0.59 min. 1H NMR (400 MHz,
DMSO-de) 8 ppm 8.74 (d, J=8.22 Hz, 1 H) 8.41 (s, 1 H) 8.06 (dd, J=9.39, 2.74 Hz, 1 H)
WO 66188
8.01 (d, J=8.61 Hz, 2 H) 7.94 (br. s., 1 H) 7.83 (d, J=8.22 Hz, 2 H) 7.40 - 7.34 (m, 2 H)
7.30 (t, J=7.63 Hz, 2 H) 7.22 (d, J=7.43 Hz, 1 H) 6.40 (d, J=9.39 Hz, 1 H) 5.12 - 5.03 (m,
1 H) 3.75 - 3.60 (m, 2 H).
Table 2. Compounds prepared from Method 1 described above
Exampl NMR
Structure Name MH+ Rf
e (mm)
H NMR (400MHz ,CD30D)
6 ppm 7.83 (s, 1 H), 7.78 (t, J =
NH2 (R)_4_(3_amino_ 1 7.6 Hz, H), 7.66 (d, J = 7.8 Hz,
N \ F ”AK: rahydro- H), 7.60 (d, J: 11.3 Hz, 1 H),
/N 7.46 - 7.39 (m, 2 H), 7.35 (t, J =
2H_Wran_4_
47 7.6 Hz, 2 H), 7.27 (d, J: 7.0 Hz,
, 4213 03
y|)pyraz'“'2'y')' 1 H), 5.26 (d, J = 7.0 Hz, 1 H),
Z-flUOVO'N'U' .05 (d, J = 10.6 Hz, 2 H), 3.57
O (t,
phenylethyl)benz J = 10.4 Hz, 2 H), 2.95 (d, J = 4.7
amide Hz, 1 H), 1.96 - 1.78 (m, 4 H),
1.58 (d, J: 7.0 Hz, 3 H)
1H NMR (400MHz
, CD30D)
(R)'4'(3'am'“°', 6 ppm 8.21 (br. s., 1 H), 7.91 -
'(tetrahydr0' 7.80 (m, 2 H), 7.75 - 7.65 (m, 2
2H-pyran H), 7.60 (d, J: 11.7 Hz, 1 H),
F O y|)pyrazmyl)— 7.42 - 7.29 (m, 2 H), 4.15 (d, J =
48 558.3 0.8
NHZ N\ @‘SOQ 2—fluoro-N-(1-((2- .3 Hz, 1 H), 4.10 -4.00 (m, 2 H),
fluorophenyl)sulf 3.68 (d, J = 8.6 Hz, 1 H), 3.57 (dt,
onyl)piperidin J = 23,115 Hz, 2 H), 3.50 - 3.40
(m, 1 zamide H), 3.03 - 2.88 (m, 2 H),
1.99 - 1.78 (m, 5 H), 1.76-1.65
(m, 1 H), 1.65- 1.54 (m, 1 H)
(R)—4—(3-amino- H NMR (400MHz
, CD30D) 6
6-(tetrahydro- ppm 7.89 - 7.75 (m, 4 H), 7.74 -
2H-pyran 7.65 (m, 2 H), 7.65 - 7.56 (m, 3
H), 4.16 (br. s.,1 H), 4.11 -4.00
y|)pyraziny|)-
49 (m, 2 H), 3.57 (dt, J = 25,114
2—fluoro-N-(1 -
Hz, 3 H), 3.00 - 2.89 (m, 1 H),
(phenylsulfony|)p 2.84 - 2.65 (m, 2 H), 1.95 -1.78
iperidin (m, 6 H), 1.69 (dd, J = 3.5, 9.8
y|)benzamide Hz, 1 H), 1.58- 1.43 (m,1 H)
PCT/USZOl4/062913
Exaempl NMR
Structure
(+/-)(3_amino_ 1H NMR (400MHz, CD30D)
6-(tetrahydro- 5PPm 7-77 (S. 1 H). 7-71 (m. 1
2H_pyran_4_ H), 7.64 - 7.48 (m, 2 H), 7.45 -
7.37 (m, 2 H), 7.38 - 7.23 (m, 3
yl)pyrazin_2_yl)_
H), 6.29 - 5.93 (m, 1 H), 5.54 -
50 N_(2 oro_’
.42 (m, 1 H), 4.06 - 3.88 (m, 2
1'phehy'ethy'1'2' H), 3.54 - 3.42 (m, 2 H), 2.92 -
f'UOVObenzam'de 2.76 (m, 1 H), 1.90- 1.67 (m, 4
H NMR (400 MHz, 6) 5
(+l')'4'(3'am'“°',
ppm 9.67 (d, J=9.39 Hz, 1 H)
'(tetrahydr°' 7.88 (s, 1 H) 7.70 - 7.48 (m, 6 H)
2H-pyran 7.47 - 7.22 (m, 4 H) 5.96 (t,
y|)pyraziny|)— J=9.00 Hz, 1 H) 3.87 (d, J=10.96
2-fluoro-N- Hz, 2 H) 3.5 (m, 2 H) 2.92 - 2.70
(2,2,2-trifluoro (m, 1 H) 1-32 - 1-52 (m. 4 H)
phenylethyl)benz
amide
1H NMR (400MHz ,DSMO-D6) 8
4_(3_amino_5_
(tetrahydro-ZH- ppm 7.92 (d, J = 7.0 HZ, 1 H),
7.68 - 7.51 (m, 3 H), 7.43 - 7.26
pyran_4_
. (m, 5 H), 7.21 (d, J = 7.0 Hz, 1
y')pyraz'n'2'y')'
52 H), 4.73 (s, 1 H), 4.49 (s, 1 H),
N'benzyl'z' 3.97 - 3.88 (m, 2 4( m, 2H
‘fluorO-N- hide inside of water peak) 2.90
methylbenzamid (s, 1 H), 2.88 - 2.80 (m, 3 H),
e 1.78-1.69(m,4H)
H NMR (400MHz ,DMSO-d6) 8
(S)'4'(3'am'n°'.
ppm 7.89 (d, J = 3.1 Hz, 1 H),
6'(tetrahydr°'
F O _/OH 7.63 - 7.52 (m, 2 H), 7.45 (t, J =
2 2H-pyran 7.6 Hz, 1 H), 7.38 - 7.31 (m, 3 H),
““2 Tm y|)pyraziny|)- 7.31 - 7.21 (m, 2 H), 5.75 (dd, J =
53 N \ 2-fluoro-N-(2- 451.2 0.66 6.3, 8.6 Hz,1 H), 4.76 (br. s., 1
/N hydroxy H), 4.03- 3.93 (m,1 H), 3.90 (dd,
phenylethyl)—N- J = 2.9, 11.2 Hz, 2 H), 3.40 - 3.35
methylbenzamid (m, 6 H), 2.81 (td, J = 3.2, 6.6 Hz,
0 H), 2.76 (s,1 H), 2.70 (s, 2 H),
1.74 - 1.67 (m, 4 H)
l NMR
Structure
H NMR (400MHz, DMSO-d6)
ppm 7.78 (br. s.,1 H), 7.70 (br.
(S)-(4-(3-amin0- s., 1 H), 7.40 (br. s., 1 H), 7.34
rahydro- (br. s., 1 H), 7.26 (br. s., 1 H),
2H-pyran 6.02 (br. s., 1 H), 5.31 (d, J = 4.3
54 y))pyrazin_2_ Hz, 1 H), 5.04 (br. s., 1 H), 3.91
yl)phenyl)(4_ (d, J = 11.0 Hz, 1 H), 2.82 (br. s.,
phenyloxazolidin H), 2.04 (s,1 H), 1.71 (br. s., 2
H)’ 1'20 (S’ 2 H)
y|)methanone
H NMR (400MHz, CD30D)
F 0 {OH (S)(3-amin0- 8 ppm 7.90 - 7.83 (m, 2H), 7.69
= 6-(tetrahydro-
NHZ N (d, J=8.2 Hz, 1H), 7.64 (d, J=11.7
H 2H-pyran—4—
N \ F
l Hz,)1H), 7.56 (dag, J=2.0, 7.0 Hz, _ 1H,7.45-7.35 m,1H,7.32-
55 /N 0' £2F122Thi24 489__ 0-75 7.18 (m, 1H), 5.18 (t, J=5.9 Hz,
fluorophenyl)_2_ 1H), 4.10 - 4.01 (m, 2H), 3.91 -
3.80 (m, 2H), 3.65-3.53 (m, 2H),
h drox eth
0 y y yI)_2_
3.03 -2.88 (m, 1H), 1.99 - 1.78
fluorobenzamlde.
(m, 4H)
. H NMR (400 MHz, CD30D)
(S)'4'(3'am'n°'
F o {OH 8 ppm 8.56 (br. s., 1 H) 7.89-7.70
= 6'“
NH N (m, 2 H) 7.66-7.46 (m, 2 H) 7.41-
H (methY'SU'f°“Y')p 7.07 (m, 5 H) 5.23-5.01 (m, 1 H)
N/ iperidin 3.90-3.60 (m, 4 H) 2.91-2.62 (m,
\ N y|)pyraziny|)- 514.2 0.6436 H) .61 (m, 4 H)
2-fluoro-N-(2-
y
04%0 ph9nylethyl)benz
amide
H NMR (400 MHz, CD30D)
F O = (R)_4_(3_amino_
8 ppm 8.73 (d, J=6.26 Hz, 1 H)
6_(1_
NH2 N 7.78 (s, 1 H) 7.63 - 7.71-7.63 (m,
mthYISUIfony')“, H
1 H) 7.60-7.47 (m, 2 H) 7.35 (s, 1
\ 'N perldln
CI 532/5 H)7.29-7.13(m, 3 H) 5.07-5.19-
57 |)pyraziny|)-N- 0.85 5.07 (m,1 H) 3.75 (d, 3
(1-(3- Hz, 2 H) ) 2.86-2.65 (m, 6 H)
1.99-1.70 (m, 4 H) 1.53-1.40 (m,
N chloropheny|)eth
0,520 y|) 3 H)
I fluorobenzamide
Exampl 2° NMR
Structure
(min)
Synthesis of (8)- H NMR (400 MHz, CD30D)
methyl 4-(5- 6 ppm 7.65-7.66 (m, 1 H), 7.42 -
.42 (m, 2 H), 7.41-7.05 (m,
amino(3-
H), 5.22-5.00 (m, 1 H) 4.14 (d,
fluoro((2-
J=13.3 Hz, 2 H), 3.63-3.69 (m, 2
hydroxy
58 494.2 0709 H) 3.60 (s, 3 H) 2.99-2.63 (m, 3
phenylethyl)carb H), 1.60 (d, J=12.52 Hz, 2 H),
amoyl)phenyl)py 1.70-1.55 (m, 2 H)
razin
y|)piperidine
carboxylate
thy| 4-(5-
amino(4-((1- 1H NMR (400 MHz, CD30D)
(3-chlorophenyl)- 6 ppm 7.90-7.61 (m, 2 H)7.72-
2- 7.56 (m, 2 H) 7.46 (s, 1 H)7.41-
528.2 7.24 (m, 3 H) 5.19 (t, J=5.67 Hz,
hydroxyethy|)car
59 /530. 0.7771 H)4.23 (d, J=12.91 Hz, 2 H)
bamoyI)
2 3.92-3.76(m,2H) 3.70 (s, 3 H)
fluorophenyl)pyr 3.06-2.62 (m, 3 H) 1.90 (d,
azin J=12.52 Hz, 2 H) 1.72 (qd,
y|)piperidine J=12.52, 4.30 Hz, 2 H)
carboxylate
H NMR (400 MHz, CD30D)
6 ppm 7.61-7.69 (m, 2 H), 7.62-
(S)(6-(1- 7.45 (m, 2 H), 7.09 - 7.37-7.09
acetylpiperidin- (m, 6 H), 6.5(dd,J=8.61, 2.35 Hz,
4-y|) 1 H), 6.50 (dd, J=13.50, 2.15 Hz,
aminopyrazin-Z- 1 H), 5.17-5.01 (m,1 H),4.55 (d,
60 478.2
y|)f|uoro-N-(2- =13.30 Hz, 1 H) 3.94 (d,
hydroxy J=13.69 Hz, 1 H) 3.63-3.63 (m, 2
phenylethyl)benz H) 2.66 (tt, J=11.84, 3.62Hz, 1 H)
2.67 (td, J=12.91, 2.35 Hz, 1 H)
amide
2.03 (s, 3 H)1.96-1.79 (m, 2 H)
.50 (m, 2 H)
H NMR (400 MHz, CD30D)
(S)(6-(1- 6 ppm 7.63-7.70 (m, 2H)7.64-
acetylpiperidin- 7.46 (m, 2 H) 7.37 (s, 1 H) 7.14 -
3- 7.31-7.14 (m, 3 H) 5.15-5.02 (m,
512-2
aminopyrazin-Z- 1 H)4.55 (d, J=13.69 Hz,1 H)
61 \N CI /514- 0-58 01-366 (m, 1 H)3.64-3.67(m,2
y|)-N-(1-(3-
2 H) 2.95-2.60 (m, 1 H) 2.74-2.60
chlorophenyI)
(m, 1 H) 2.03 (s, 3 H)1.93-1.79
hydroxyethy|)
(m, 2 H) 1.76-1.53 (m, 2 H)
fluorobenzamide
Exaempl NMR
Structure
methyl 3-(6- H NMR (400 MHz, CDgOD)
5_(3_ 8 ppm 8.66-8.41 (m, 1 H) 7.98-
fluoro(((S) 7.61 (m, 3 H) 7.51-7.00 (m, 7 H)
.02 (m, 1 H) 3.87-3.67 (m,
hydroxy_1_
3H) 3.61 (s, 3 H) 3.59-3.49 (m, 1
62 phenylethyl)carb 479.2 0.599
H) 3.44-3.28 (m, 3 H) 2.22 (br. S”
amoy'whenyopy 1 H) 2.08-1.86 (m, 1 H)
rIdIn
yI)pyrroIidine
carboxylate
H NMR (400 MHz, CD30D)
4'(2'am'“0'5'(1'. 8 ppm 8.56 (dd, J=7.24, 4.11 Hz,
(methylsulfonylw 1 H) 7.87 (d, J=1.96 Hz, 1 H)
yrrolidin 7.84-7.74 (m, 2 H) 7.42-7.10 (m,
yI)pyridinyI) 8 H) 5.19-5.04 (m, 1 H) 3.84-3.71
f|uoro_N_((S)_2_ 499'20'565(m, 2 H) 3.66 (dd, J=9.78, 7.43
hydroxy_1_ Hz, 1 H) 3.54-3.28 (m, 3 H) 2.84
phenylethymenz (s, 3 H) 2.37-2.22 (m, 1 H) 2.11-
1.93 (m,1 H)
amide
H NMR (400 MHz, DMSO-de) 6
ppm 8.70 (d, J=7.83 Hz, 1H),
(S)_4_(2_amino_ 7.97 (d, J=8.61 Hz, 2H), 7.86 (d,
rahydro- J=1.96 Hz, 1H), 7.53 (d, J=8.22
Hz, 2H), .42 (m, 2H), 7.29
2H_pyran_4_
(t, J=7.63 Hz, 2H), 7.15-7.25 (m,
64 yI)pyridin_3_yl)_
2H), 5.38-5.51 (m, 2H), 5.00-5.14
N'(2'hydr°Xy'1' (m, 1H), 4.91 (t, J=5.87 Hz, 1H),
ethyl)benz 3.85-3.97 (m, 2H), 3.57-3.78 (m,
amide 2H), 3.38 (dt, J=3.72, 10.86 Hz,
2H), 2.56-2.72 (m, 1H), 1.49-1.71
(m, 4H)
1H NMR (400 MHz, METHANOL-
(S)'4'(2'am'“°', d4) 6 ppm 7.76 (d, J=1.96 Hz,
'(tetrahydr0' 1H), 7.66 (d, J=1.96 Hz, 1H),
2H-pyran 7.47 (d, J=7.83 Hz, 1H), 7.31-
yI)pyridinyl)- 7.36 (m, 2H), 7.23-7.31 ,
N-(2-hydroxy 7.15-7.22 (m, 1H), 5.04-5.20 (m,
phenylethyI) 1H), 3.95 (dd, J=2.93, 11.54 Hz,
methylbenzamid 2H), 3.59-3.81 (m, 2H), 3.37-3.52
(m, 2H), 2.67-2.85 (m, 1H), 2.33
(s, 3H), 1.46-1.85 (m, 4H)
Exaempl NMR
Structure
1H NMR (400 MHz, DMSO-de) 5
4'(2'am'“°'5'I
ppm 9.12 (t, J=5.87 Hz, 1H), 8.00
(tetrahdeO-ZH- (d, J=8.61 Hz, 2H), 7.81 (s, 2H),
pyran 7.54 (d, J=8.22 Hz, 2H), 7.08-
66 yI)pyridinyl)- 7.44 (m, 6H), 4.46 (d, J=5.87 Hz,
N- 2H), 3.88 (dd, J=2.35, 11.35 Hz,
benzylbenzamid 2H), 2.66-2.80 (m, 1H), 1.46-1.77
e (m, 4H) (two CH2 proton next to
oxygen were under water)
H NMR (400 MHz, e) 5
4_(2_amino_5_ ppm 9.06 (t, J=5.87 Hz, 1H), 8.00
(tetrahydro-2H- (d, J=8.61 Hz, 2H), 7.85 (d,
J=1.96 Hz, 1H), 7.81
4_ (d, J=1.57
. . Hz, 1H), 7.54 (d, J=8.22 Hz, 3H),
yI)pyr'd'n's'yl)'
67 7.09 (t, J=7.83 Hz, 1H), 6.71 (br.
N'I(3' s., 1H), 6.60 (d, J=5.87 Hz, 2H),
(d'methylam'no)I .40 (d, J=5.87 Hz, 2H), 3.84-
benzyl)benzamid 3.97 (m, 4H), 3.33 (dt, J=2.35,
e 11.35 Hz, 2H), 2.83 (s, 6H), 2.74
(br.s.,1H), 1.50-1.75 (m, 4H)
1H NMR (400 MHz, DMSO-de) 5
ppm 8.92 (d, J=7.83 Hz, 1 H),
(S)'4'(2'am'“°'I 8.17 (d, J=8.61 Hz, 1 H), 7.99 (d,
'(tetrahydr0' J=7.83 Hz, 1 H), 7.87 (d, J=1.96
2H-pyran Hz, 1 H), 7.80 (br. s., 1 H), 7.52
yI)pyridinyI) (d, J=7.83 Hz, 1 H), 7.34 - 7.39
ch|oro-N-(2- (m, 2 H), 7.30 (t, J=7.43 Hz, 2 H),
hydroxy_1_ 7.22 (d, J=7.04 Hz, 1 H), 4.96 -
etWDbenz 5.18 (m, 1 H), 3.91 (dd, 6,
3.13 Hz, 2 H), 3.58 - 3.79 (m, 2
amide
H), 3.43 (2 H),2.68 - 2.91 (m, 1
H), 1.55 - 1.82 (m, 4 H)
1H NMR (400 MHz, DMSO-de) 5
(R)_4_(2_amino_ ppm 8.85 (d, J=8.22 Hz, 1 H),
-(tetrahydro- 8.00 (d, J=8.61Hz, 2 H), 7.69 -
7.87 (m, 2 H), 7.52 (d, J=8.22 Hz,
2H_pyran_4_
2 H), 7.31 - 7.36 (m, 2 H), 7.27 (t,
69 yI)pyridin_3_yl)_
J=7.63 Hz, 2 H), 7.13 - 7.20 (m, 1
N'(1'
H), 5.15 (t, J=7.43 Hz, 1 H), 3.75
Phenylethyl)benz - 3.99 (m, 2 H), 3.36 (br. s., 2 H),
amide 2.66 - 2.84 (m, 1 H), 1.53 - 1.75
(m, 4 H), 1.44 (d, J=7.04 Hz, 3 H)
Exaempl NMR
Structure
1H NMR (400 MHz, DMSO-de) 5
(s)_4_(2_amino_ ppm 8.67 (d, J=7.83 Hz, 1 H),
-(tetrahydro- 7.88 (br. s., 1 H), 7.76 - 7.85 (m,
. . 3:239:12;92::-3
yI)pyr'd'n's'yl)' . m, , . . m,
70 H), 7.14 - 7.20 (m, 1 H), 4.97 -
N'(2'hydroxy'1' 5.10 (m, 1 H), 3.87 (dd, 6,
phenylethy')'3' 3.33 Hz, 2 H), 3.53 - 3.74 (m, 2
methylbenzamid H), 3.33 (d, J=1.96 Hz, 2 H), 2.66
e -2.82 (m, 1 H), 2.11 (s, 3 H),
1.50 - 1.74 (m, 4 H)
1H NMR (400 MHz, DMSO-de) 5
. ppm 8.83 (d, J=8.22 Hz, 1 H),
(S)'4'(2'am'“°' 7.78 - 7.93 (m, 4 H), 7.52 (t,
-(tetrahydr0- J=7.63 Hz, 1 H), 7.30 - 7.35 (m, 2
2H-pyran H), 7.26 (t, J=7.43 Hz, 2 H), 7.14
yI)pyridinyl)—3- — 7.22 (m, 1 H), 4.99 - 5.08 (m, 1
fluoro-N-(2- H), 3.88 (dd, J=10.96, 3.13 Hz, 2
hydroxy_1_ H), 3.57 - 3.72 (m, 2 H), 3.30 (2
mobem H), 2.67-2.79 (m, 1 H), 1.53-
1.71 (m, 4 H),
amide
H NMR (400MHz ,CD30D) 8
(S)—4-(3-amino- ppm 7.79 (s, 1 H), 7.78 - 7.74 (m,
.9. 1 H), 7.56 (dd, J: 1.4, 8.0 Hz, 1
ethoxyethyl)pyra H), 7.51 (dd, J = 1.2, 11.7 Hz, 1
H), 7.36 - 7.31 (m, 2 H), 7.27 (t, J
zin_2_yl)_2_
72 = 7.6 Hz, 2 H), 7.19 (d, J = 7.0
fluorO_N_(2_
Hz,1 H), 5.12 (t, J=6.1 Hz,1 H),
hydroxy'1' 3.83 - 3.71 (m, 2 H), 3.67 (t, J =
Phenylethyl)benz .7 Hz, 2 H), 3.42 (q, J = 7.0 Hz,
amide H), 2.86 (t, J = 6.5 Hz, 2 H),
1.06 (t, J = 7.0 Hz, 3 H)
1H NMR (400 MHz, DMSO-de) 5
. ppm 8.77 (d, J=8.22 Hz, 1 H),
(S)'4'(2'am'“°' 7.82 (d, J=1.96 Hz, 1 H), 7.76 (s,
'(tetrahydr0' 1 H), 7.59 (d, J=1.57 Hz, 1 H),
CI 0
: 2H-pyran 7.52 - 7.56 (m, 1 H), 7.46 (dd,
NH2 N J=8.02, 1.37 Hz, 1 H), 7.32 - 7.37
73 4525 0'59
yI)pyridin-3—yl)—2-
N \ H/\© -N-(2- (m, 2 H), 7.28 (t, J=7.43 Hz, 2 H),
/ y_1_ 7.16 - 7.23 (m, 1 H), 4.93 - 5.02
phewlemobem (m, 1 H), 3.84 - 3.93 (m, 2 H),
3.58 (d, J=7.04 Hz, 2 H), 3.30 (2
amide
0 H), 2.68-2.79 (m,1 H), 1.55-
1.70 (m, 4 H)
WO 66188
Exampl NMR
Structure
1H NMR (400 MHz, CD30D) 5
(S)—4-(2-amino- ppm 8.87 (d, J=8.22 Hz, 1 H),
-(tetrahydro- 7.75 - 7.85 (m, 2 H),7.68 - 7.73
2H-pyran (m, 2 H), 7.63 - 7.68 (m,
H),7.31 - 7.36 (m, 2 H), 7.28 (t,
y|)pyridiny|)—
74 J=7.43 Hz, 2 H), 7.17 - 7.24 (m, 1
N-(2-hydroxy
H), 5.02 - 5.20 (m, 1 H), 3.95 (dd,
phenylethyl)—2- J=11.15, 3.33 Hz, 2 H), 3.65 -
(trifluoromethyl)b 3.86 (m, 2 H), 3.45 (td, J=11.44,
enzamide 2.54 Hz, 2 H), 2.68 - 2.90 (m, 1
H), 1.53 - 1.87 (m, 4 H)
4—(2-amino
(tetrahydro-ZH- 1H NMR (400MHz, DMSO-d6) 5
pyran ppm 8.92 (m, H), 8.69 - 8.49
(m, 2 H), 7.87 (m, 1 H), 7.75 (m,
y|)pyridiny|)—2-
75 1 H), 7.44 - 7.32 (m, 2 H), 7.28
fluoro-N-
(m, 1 H), 5.58 (m, 1 H), 4.63 (m,
(pyrazin 2 H), 3.89 (m, 2 H), 3.38 (m, 2
y|)benzam H), 2.64 (s, 1 H), 1.64 (m, 4 H).
1H NMR (400MHz, CD30D) 5
amino-4—
ppm 7.89 (d, J=2.0 Hz, 1 H) 7.76
(2-amino (dd, J=5.1, 3.1 Hz, 2 H) 7.18-
(tetrahydro-ZH- 7.49 (m, 5 H) 6.84 (d, J=1.6 Hz, 1
pyran H) 6.74 (dd, J=8.0, 1.8 Hz, 1 H)
y|)pyridiny|)— 5.15 - 5.26 (m, 1 H) 4.06 (dd,
N-(2-hydroxy J=11.0, 3.5 Hz, 2 H) 3.78 - 3.95
phenylethyl)benz (m, 2 H) 3.57 (td, J=11.5, 2.3 Hz,
2 H) 2.77 - 2.97 (m, 1 H) 1.68-
amide
1.91 (m, 4 H)
1H NMR (400 MHz, CD30D) 5
ppm 8.81 (d, J=7.83 Hz, 1 H),
(S)—4-(2-amino- 8.05 (d, J=8.61 Hz, 2 H), 7.92 (d,
-(1,1- J=1.96 Hz, 1 H), 7.84 (d, J=1.57
dioxidotetrahydr Hz, 1 H), 7.61 (d, J=8.22 Hz, 2
o-2H-thiopyran- H), 7.39 -7.45 (m, 2 H), 7.35 (t,
yridiny|)— J=7.43 Hz, 2 H), 7.24 - 7.31 (m, 1
N-(2-hydroxy H), 5.24 (q, J=7.04 Hz, 1 H),
phenylethyl)benz 3.89 (d, J=6.65 Hz, 2 H), 3.30 (2
amide H), 3.07 - 3.22 (m, 2 H), 2.99 (tt,
J=10.27, 5.38 Hz, 1 H), 2.17 -
2.40 (m, 4 H)
Exampl NMR
Structure
4—(2—amino 1H NMR (400MHz, DMSO-d6) 5
(1 1 -
, ppm 8.89 - 8.74 (m, 1 H), 7.94 -
dioxidotetrahydr 7.79 (m, 1 H), 7.72 (s,1 H), 7.47
78 o-2H-thiopyran- - 7.28 (m, 8 H), 7.25 - 7.14 (m, 1
4—yl)pyridiny|)— H), 4.47 (d, J = 8.1 Hz, 2 H), 3.14
N-benzyI - 2.98 (m, 2 H), 2.91 - 2.74 (m, 1
fluorobenzamide H), 2.15 - 2.01 (m, 4 H)
(S)—4-(2-amino-
-( 1 ,1 -
otetrahydr 1H NMR (400MHz, CD30D) 5
o-2H-thiopyran- ppm 8.00 - 7.78 (m, 2 H), 7.42
(m, 1 H), 7.41 - 7.21 (m, 7 H), 5.2
79 4—yl)pyridiny|)—
(m, 1 H), 3.91 - 3.78 (m, 2 H),
2—fluoro-N-(2- 3.32 (m, 2 H), 3.09 (m, 2 H), 2.82
hydroxy (m, 1 H), 2.29-2.15 (m, 4 H)
phenylethyl)benz
amide
1H NMR (400 MHz, CD30D) 5
ppm 8.70 (d, J=7.83 Hz, 1 H),
(S)—4-(6-amino- 8.81 (d, J=6.65 Hz, 2 H), 8.58 (d,
J=2.35 Hz, 1
[3,4'-bipyridin]—5- H), 8.11 (d, J=6.65
Hz, 2 H), 8.08 (d, J=2.35 Hz, 1
y|)-N-(2-hydroxy-
H), 7.98 (d, J=8.22 Hz, 2 H), 7.57
(d, J=8.22 Hz, 2 H), 7.30 - 7.38
phenylethyl)benz (m, 2 H), 7.28 (t, J=7.43 Hz, 2
amide H), 7.14 - 7.22 (m, 1 H), 5.10 -
.19 (m, 1 H), 3.80 (d, J=6.65
Hz, 2 H)
1H NMR (400 MHz, CD30D) 5
(S)—4-(6-amino- ppm 8.55 - 8.87 (m, 3 H), 8.47 -
8.55 (m, 1
bipyridin]—5- H), 8.15 (d, J=6.65 Hz,
2 H), 8.07 (d, J=2.35 Hz, 1 H),
y|)f|uoro-N-(2-
81 | 429.3 0.45 (t, J=7.43 Hz, 1 H), 7.31 -
hydroxy 7.42 (m, 4H), 7.27 (t, J=7.63 Hz,
phenylethyl)benz 2 H), 7.15 - 7.22 (m, 1 H), 5.13 (t,
amide J=5.87 Hz, 1 H), 3.70 - 3.85 (m, 2
Exampl NMR
Structure
H NMR (400MHz ,DMSO-D6) 5
ppm 8.78 (d, J = 7.8 Hz, 1 H),
(S)—4-(6-amino- 8.70 (s, 1 H), 8.84 (d, J = 5.5 Hz,
1 1
hy|—3,4'- H), 8.24 (d, J = 2.0 Hz, H),
8.07 (d, J = 8.2 Hz, 2 H), 7.75 (br.
bipyridinyl)—N-
82 s., 2 H), 7.84 (d, J = 8.2 Hz, 2 H),
roxy 7.40 (d, J = 7.4 Hz, 2 H), 7.33 (t,
phenylethyl)benz J = 7.8 Hz, 2 H), 7.25 (d, J = 7.0
amide Hz, 1 H), 5.11 (d, J = 5.5 Hz, 1
H), 3.78 - 3.83 (m, 2 H), 2.48 (s,
3 H)
(S)—4-(6-amino-
1H NMR (300MHz, DMSO-d6) 5
3'-methy|—3,4'-
bipyridinyl)—2- ppm 8.68 (s,1 H),8.62 (s, 2 H),
8.23 (s, 1 H), 7.83 - 7.66 (m, 2
83 fluoro-N-(2-
H), 7.55 - 7.21 (m, 7 H), 5.06 (d,
hydroxy J = 7.3 Hz, 1 H), 3.66 (d, J = 6.4
phenylethyl)benz Hz, 2 H), 2.44 (s, 3 H)
amide
1H NMR (400 MHz, CD30D) 5
4—(2-amino
ppm 7.79 - 7.88 (m, 1 H), 7.75 (d,
((R) J=2.35 Hz, 1 H), 7.31 - 7.44 (m, 8
methylmorpholin H), 7.30 (d, J=2.74 Hz, 1 H), 7.27
o)pyridiny|)—2- (d, J=7.43 Hz, 1 H), 5.19 (t,
fluoro-N-((S) J=8.08 Hz, 1 H), 3.72 - 3.90 (m, 4
hydroxy H), 3.41 - 3.50 (m, 1 H), 3.32 -
phenylethyl)benz 3.38 (m, 1 H), 3.11 (t, J=1.57 Hz,
amide H), 2.98 - 3.02 (m, 2 H), 0.91
(d, J=8.85 Hz, 3 H)
(S)—4-(2-amino-
- 1H NMR (400MHz, CD30D) 8
morpholinopyridi ppm 8.08 (d, J=8.2 Hz, 2 H) 7.87
(d, J=2.7 Hz, 1 H) 7.83 (d, J=8.2
85 ny|)f|uoro-
Hz, 2 H) 7.24 - 7.48 (m, 8 H) 5.19
N-(2-hydroxy 5.30 (m, 1H) 3.90 (m, 2H) - 3.85
phenylethyl)benz (m, 4 H) 3.12 (m, 4 H)
amide
WO 66188
Exampl NMR
Structure
1H NMR (300 MHz, CD30D) 5
4—(2-amino
ppm 8.04 (d, J=8.20 Hz, 2 H),
(tetrahydro-ZH- 7.91 (d, J=2.05 Hz,1 H) 7.78 (d,
pyran J=1.76 Hz, 1 H), 7.81 (d, J=8.20
86 y|)pyridiny|)— Hz, 2 H), 7.22 - 7.43 (m, 4 H),
N-(3- .59 (s, 2 H), 3.93 - 4.13 (m, 2
chlorobenzyl)be H), 3.54 (td, J=11.43, 2.93 Hz, 2
nzamide H), 2.77 - 2.98 (m, 1 H), 1.85 -
1.91 (m, 4 H)
1H NMR (300 MHz, CD30D) 5
4—(2-amino ppm 7.95 (d, J=8.20 Hz, 2 H),
(tetrahydro-ZH- 7.80 (d, J=2.05 Hz, 1 H), 7.89 (d,
J=1.76 Hz, 1 H), 7.51 (d, J=8.20
pyran
Hz, 2 H), 7.28 - 7.38 (m, 2 H),
87 y|)pyridiny|)—
7.13 - 7.28 (m, 2 H), 4.81 (s, 2
N-(2- H), 3.88 - 4.02 (m, 2 H), 3.45 (td,
chlorobenzyl)be J=11.43, 2.93 Hz, 2 H), 2.88 -
nzamide 2.85 (m, 1 H), 1.81 - 1.78 (m, 4
1H NMR (300 MHz, CD30D) 5
4—(2-amino
ppm 7.93 (d, J=8.20 Hz, 2 H),
(tetrahydro-ZH- 7.81 (d, J=2.05 Hz, 1 H), 7.88 (d,
pyran J=1.76 Hz, 1 H), 7.51 (d, J=8.50
idiny|)— Hz, 2 H), 7.28 (d, J=1.17 Hz, 4
N-(4- H), 4.49 (s, 2 H), 3.87 - 4.02 (m,
chlorobenzyl)be 2 H), 3.45 (td, J=11.36, 2.78 Hz,
2 H), 2.88 - 2.85 (m, 1
nzamide H), 1.82 -
1.79 (m, 4 H)
4—(2-amino 1H NMR (300 MHz, CD30D) 5
(tetrahydro-ZH- ppm 7.95 (d, J=8.50 Hz, 2 H),
7.82 (d, J=2.05 Hz, 1 H), 7.88 (d,
pyran
J=1.76 Hz, 1 H), 7.40 - 7.81 (m, 8
89 y|)pyridiny|)—
H), 4.58 (s, 2 H), 3.89 - 4.01 (m,
N-(3- 2 H), 3.45 (td, J=11.43, 2.93 Hz,
(trifluoromethyl)b 2 H), 2.89 - 2.85 (m, 1 H), 1.82 -
enzyl)benzamide 1.77 (m, 4 H)
Exaempl NMR
Structure
(S)'2'(2'am'“°' 1H NMR (300 MHz, CD30D) 6
'(tetrahydr0' ppm 9.29 - 9.42 (m, 3 H), 8.00 (d,
2H-pyran J=2.05 Hz, 1 H), 7.21 - 7.52 (m, 5
yI)pyridinyl)- H), 5.25 (t, J=6.74 Hz, 1 H), 3.98
N-(2-hydroxy - 4.16 (m, 2 H), 3.81 - 3.96 (m, 2
midine_5_ H), 2.85 - 3.05 (m, 1 H), 1.76 -
1'91 (m’ 4 H)
carboxamide
1H NMR (400 MHz, CD30D) 6
. ppm 7.90 (d, J=8.61 Hz, 2 H),
4'(2'am'“°'5' 7.82 (d, J=1.96 Hz, 1 H), 7.68 (d,
(tetrahdeO-ZH- J=1.96 Hz, 1 H), 7.50 (d, J=8.22
pyran Hz, 2 H), 3.95 (dd, J=10.96, 3.52
91 yI)pyridinyl)- Hz, 2 H), 3.45 (td, J=11.64, 2.54
N- Hz, 2 H), 3.18 (d, J=7.43 Hz, 2
(cyclopropylmeth H), 2.71 -2.84 (m, 1 H), 1.58-
yDbenzamide 1.78 (m, 4 H), 0.96 - 1.10 (m, 1
H), 0.38 - 0.52 (m, 2 H), 0.11 -
0.28 (m, 2 H)
1H NMR (400 MHz, CD30D) 6
ppm 8.02 (d, J=8.22 Hz, 2 H),
N_(3_ 7.89 (d, J=1.96 Hz, 1 H), 7.76 (d,
acetamidobenzyl =1-57 HZ! 1 H)! 7'66 (S! 1
-ami“° H???iréd’1fif'3222 21%“
92 (tetrahydro'ZH'
Hz, 1 H), 7.06 -7.13 (m,1 H),
pyran'4' A .53 - 4.63 (m, 2 H), 4.02 (dd,
y|)pyridin , 3.52 Hz, 2 H), 3.53 (td,
y|)benzamide =11.54, 2.35 Hz, 2 H), 2.78 -
.93 (m, 1 H), 2.09 (s, 3 H), 1.64
1.88 (m, 4 H)
1H NMR (400 MHz, CD30D) 6
m'“°'5'.
ppm 8.71 (s,1 H), 8.59 (d,
J=5.09 Hz, 1 H), 8.31 (d, J=8.22
(tetrahdeO-ZH- Hz, 1 H), 7.95 (d, J=8.22 Hz, 2
pyran H), 7.74 - 7.86 (m, 2 H), 7.69 (d,
93 yI)pyridinyl)- J=1.96 Hz, 1 H), 7.53 (d, J=8.22
N_(pyridin_3_ Hz, 2 H), 4.59 -4.68 (m, 2 H),
ylmetWDbenzam 3.94 (dd, J=10.96, 3.52 Hz, 2 H),
3.45 (td, J=11.44, 2.54 Hz, 2
H),2.70 -2.84 (m, 1 H), 1.58 -
1.80 (m, 4 H)
Exampl NMR
1H NMR (400 MHz, CD30D) 5
(2-amino-
ppm 1.60 - 1.77 (m, 4 H) 2.71 -
—(tetrahydro- 2.83 (m, 1 H) 3.45 (td, J=11.44,
2H-pyran 2.54 Hz, 2 H) 3.70 - 3.83 (m, 2 H)
y|)pyridiny|)—2- 3.95 (dd, J=11.35, 3.13 Hz, 2 H)
fluoro-N-(2- 5.09-5.17 (m, 1 H) 7.15 -7.22
hydroxy (m, 1 H) 7.27 (t, J=7.43 Hz, 2 H)
phenylethyl)benz 7.29 - 7.36 (m, 4 H) 7.70 (d,
J=1.96 Hz, 1 H) 7.80
amide (t, J=8.02
Hz, 1 H) 7.84 (d, J=2.35 Hz,1 H).
1H NMR (400MHz, DMSO-d6) 6
(S)—4-(3-amino-
ppm 8.59 (d, J = 8 Hz, 1 H), 7.85
6-(tetrahydro- (s, 1 H), 7.58-7.49 (m, 2 H), 7.44
an (d, J = 8 Hz, 1 H), 7.39 - 7.27 (m,
95 aziny|)— A H), 7.25-7.18 (m, 1 H), 5.02 (m,
N-(2-hydroxy 1 H), 3.93 - 3.87 (m, 2 H), 3.64 -
phenylethyl)—2- 3.57 (m, 2 H), 3.43 (m, 2 H,
methylbenzamid hidden behind DMSO), 2.81 (m,
1 H), 2.33 (s, 3 H), 1.74 - 1.66
(m, 4 H).
4—(2-amino
((28,6R)—2,6— 1H NMR (300 MHz, CD30D) 5
dimethylmorpholi ppm 7.83 - 7.95 (m, 2 H), 7.24 -
7.51 (m, 8 H), 5.22 (t, J=6.01 Hz,
no)pyridiny|)—
96 1 H), 3.71 - 3.94 (m, 4 H), 3.44
2—fluoro-N-((S)—
(d, J=10.84 Hz, 2 H), 2.34 (t,
2-hyd roxy-1 - J=10.99 Hz, 2 H), 1.22 (d, J=6.15
phenylethyl)benz Hz, 6 H)
amide
4—(2-amino 1H NMR (300 MHz, CD30D) 5
((28,6R)—2,6— ppm 8.23 (d, J=7.33 Hz, 2 H),
dimethylmorpholi 8.06 (br. s., 1 H), 7.79 (d, J=7.62
no)pyridiny|)— Hz, 2 H), 7.41 - 7.68 (m, 6 H),
N-((S) 5.41 (br. s., 1 H), 3.87-4.18 (m,
hydroxy A H), 3.62 (d, J=12.31 Hz, 2 H),
phenylethyl)benz 2.52 (t, J=10.70 Hz, 2 H), 1.31 -
1.52 (m, 6 H)
amide
Exaempl NMR
Structure
1H NMR (300 MHz, CD30D) 5
(S)fmethy' 4'(5' ppm 7.98 - 8.12 (m, 2 H), 7.91
'(4'((2' (d, J=1.78 Hz, 1 H), 7.53 - 7.88
hydroxy (m, 2 H) 7.78 (s, 1 H), 7.21 - 7.48
phenylethyl)carb (m, 5 H), 5.24 (d, J=6.74 Hz, 1
amoyl)phenyl)py H),4.26 (d, J=12.89 Hz, 2 H),
3_ 3.89 (d, J=8.74 Hz, 2 H), 3.89 (d,
y|)piperidine—1- J=1.76 Hz, 314), 2.73 - 3.03 (m, 3
H), 1.90 (d, J—12.80 Hz, 2 H),
carboxylate
1.51 - 1.72 (m, 2 H)
4_(3_amino_5_ 1H NMR (400 MHz, CD30D) 5
Cin¥2-yF|))-2Fj1¥|upgro-Clo r0 | raz ppm 8.00 (s, 1H), 7.82 - 7.91 (m,
3H), 7.78 (d, J = 7.8 Hz, 1H),
99 7.83 - 7.89 (m, 2H), 7.59 (dd, J =
N'(3'
11.5,1.4 Hz, 1H), 4.72 (s, 2H),
(methY'SU'f°“¥')b 3.12 (s, 3H), 2.08 (tt, J = 7.9, 5.0
enzyl)benzamlde Hz, 1H), 0.84 - 1.02 (m, 4H)
4_(3_amino_5_ 1H NMR (400 MHz, CD30D) 5
R)—2- ppm 7.94 - 8.01 (m, 3 H) 7.81 -
7.89 (m, 4 H) 7.73 (d, J=7.83 Hz,
methyltetrahydro
1 H) 7.58- 7.85 (m, 1 H)4.89 (s,
_2H_pyran_4_
100 2 H)4.00-4.09 (m, 1 H) 3.53 -
y )pyraz'“'I 2'y )'I
3.85 (m, 2 H) 3.10 (s, 3 H) 2.87 -
N'(3' 2.98 (m, 1 H) 1.74 - 1.92 (m, 3 H)
(methylsulfonyl)b 1.44 - 1.58 (m, 1 H) 1.24 - 1.39
enzyl)benzamide (m, 1 H) 1.19 (d, J=6.26 Hz, 3 H)
4_(3_amino_5_ 1H NMR (400 MHz, DMso-d8) 5
((28.4S) 9.23 (t, J=5.87 Hz, 1 H) 7.99 (d,
J=8.22 Hz, 2 H) 7.78
methyltetrahydro - 7.90 (m, 5
H) 7.57 - 7.89 (m, 2 H) 4.59 (d,
_2H_pyran_4_
101 J=5.87 Hz, 2 H) 3.39 - 3.50 (m, 2
V)pyraz'n'I . 2'y)'I
H) 3.18 (s, 3 H) 2.79-2.91 (m, 1
N'(3' H) 1.58 - 1.84 (m, 3 H) 1.29 -
(methylsuh‘Onyll)b 1.43 (m, 1 H) 1.09 (d, J=8.28 Hz,
enzyl)benzamide 3 H)
1H NMR (400 MHz, CD30D) 8
ppm 7.91 (s, 1 H), 7.87 (t, J = 7.8
(+/')'4'(3'am'“°'. Hz, 1 H), 7.88 (dd, J = 1.8, 8.2
-((1R.3S) Hz, 1 H), 7.84 -7.58 (m,1 H),
hydroxycyclopen 7.44 - 7.31 (m, 4 H), 7.28 (d, J =
tyl)pyraziny|)— 7.0 Hz, 1 H), 4.62 (s, 2 H), 4.39 -
N_benzy|_2_ .31 (m, 1 H), 2.34 (ddd, J = 5.9,
fluorobenzamide 88,137 Hz, 1 H), 2.10 (dd, J =
.A5, 8.0 Hz, 1 H), 1.99 - 1.75 (m,
A H)
Exaempl NMR
Structure
H NMR (400MHz ,CD30D)
ppm 7.91 (s, 1 H), 7.87 (t, J =
(+/')'4'(3'am'“°'. 7.6 Hz, 1 H), 7.68 (dd, J = 1.6,
-((1R13R) 8.2 Hz, 1 H), 7.64 - 7.56 (m, 1 H),
hydroxycyclopen 7.44 - 7.31 (m, 4 H), 7.28 (d, J =
tyl)pyraziny|)— 7.0 Hz, 1 H), 4.62 (s, 2 H), 4.39 -
N_benzy|_2_ .31 (m, 1 H), 2.34 (ddd, J = 5.9,
fluorobenzamide 8.6, 13.7 Hz, 1 H), 2.10 (dd, J =
.5, 8.0 Hz, 1 H), 1.99 - 1.75 (m,
A H)
1H NMR z, CDCIg) 5 ppm
8.25 (t, J = 8.2 Hz, 1 H), 7.98 (s,
1 H), 7.92 (s, 1 H), 7.77 -7.71
(m, 2 H), 7.57 (d, J = 7.8 Hz, 1
H), 7.60 (d, J = 8.2 Hz, 1 H), 7.38
(br. s., 2 H), 7.37 (br. s., 3 H),
4-(3-amin0(3- 7.34 - 7.28 (m, 2 H), 7.13 - 7.04
ycyCIOpe (m, 2 H), 4.72 (d, J = 5.5 Hz, 3
104 ntyI)pyrazin H), 4.63 (br. s., 3 H), 4.02 - 3.97
y|)_N_benzy|_2_ (m, 1 H), 3.97- 3.91 (m, 1 H),
fluorobenzamide 3.37 (d, J = 8.2 Hz, 1 H), 3.33 (s,
3 H), 3.32 (s, 2 H), 3.16 (t, J = 8.8
Hz, 1 H), 2.47 -2.36 (m,1 H),
2.20 - 2.10 (m, 2 H), 2.10 - 2.01
(+/-) Gig/trans mixture
(m, 1 H), 2.01 - 1.94 (m, 1 H),
1.94 - 1.85 (m, 3 H), 1.81 - 1.73
(m, 1 H)
4-(3-amino 1H NMR (500 MHz, METHANOL-
((13,4R)_4_ d4) ) 5 ppm 7.91 - 7.84 (m, 2 H)
hydroxy_4_ 7.71 (dd, J=8.04, 0.79 Hz, 1 H)
7.66 (d, J=11.35 Hz, 1 H) 7.49 (s,
methylcyclohexyl
1 H) 7.42-7.35 (m, 2 H) 7.34-
105 )pyrazin_2_yl)_N_
7.28 (m, 1 H) 5.26-5.18 (m, 1 H)
'(3' 3.88 (dd, J=8.67, 6.15 Hz, 2 H)
ChloropheWD'Z' 2.71 -2.61 (m, 1 H) 2.06— 1.95
hydrOXyethy|) (m, 2 H) 1.85 - 1.73 (m, 4 H) 1.63
fluorobenzamide - 1.52 (m, 2 H) 1.26 (s, 3 H).
WO 66188
Exampl
Structure Rf NMR
e (mm)
4-(3-amino 1H NMR (500 MHz, METHANOL-
((1r,4S)—4- d4) ) 6 ppm 7.93 - 7.85 (m, 2 H)
hydroxy_4_ 7.70 (dd, J=8.04, 1.42 Hz, 1 H)
methy'CYC'OheXY' 3'3? ‘3’4J2=1;'§§(Hr:’2 33 iii ‘3’
106 )pyraz'n'z'yl)'N' 0'71
7.29 (m,1 H) 5.26-5.18 (m, 1 H)
'(3' 3.95 — 3.81 (m, 2 H) 2.78 - 2.69
ChloropheWD'Z' (m, 1 H) 2.00— 1.90 (m, 2 H) 1.85
hydrOXyethy|) - 1.72 (m, 4 H) 1.70 - 1.61 (m, 2
fluorobenzamide H) 1.31 (s, 3 H)
(S)'4'(2'ami“°' 1H NMR (400 MHz, CD30D)
'(1'methyl'1H' 8 ppm 8.18 (d, J = 2.3 Hz, 1H),
pyrazol 7.98 (s, 1H), 7.85 - 7.93 (m, 2H),
yI)pyridinyI) 7.83 (s, 1H), 7.40 - 7.48 (m, 4H),
107 0 58
fluoro-N-(Z- '
7.37 (t, J = 7.4 Hz, 2H), 7.24 -
hydroxy_1_ 7.32 (m, 1H), 5.22 (t, J = 6.1 Hz,
phenYletWDbenz 1H), 3.92 (s, 3H), 3.81 - 3.91 (m,
amide 2H)
(S)—4-(2-amino-
4'f'U0r0'5'U' 1H NMR (400 MHz, MeOD-d4)
methyl-1H- 8 ppm 8.22 (d, J=7.83 Hz, 1 H)
pyrazol 7.91 (d, J=1.96 Hz, 1 H) 7.86-
108 yI)pyridinyI) 0.60 7.72 (m, 2 H) 7.38 - 7.26 (m, 6 H)
fluoro_N_(2_ 7.20 (d, J=7.43 Hz, 1 H) 5.13 (t,
y_1_ J=6.06 Hz, 1 H) 3.85 (s, 3 H)
phenylethyl)benz 3'82 ' 3'69 (m’ 2 H)
amide
4—benzyI
(4,4,55-
ethyl-
132. 1H NMR (400MHz, DMSO-d6)
dioxaborolan-Z- 5PPm 7-91 (S. 1 H). 7-31 (d, J =
”'34" 2'1 32’ 1 33’ iii “’72:? 1'24 -
. Z, , . . m, ,
109 $'2¥§i§2§3§3m[- 431.3 0.73 .79 (s, 2 H). 4.27 (t, J = 5.1 Hz,
’ 2H), 3.94 (td,J=3.1,11.0 Hz,2
(2H)'°“e’ 8'(3' H), 3.57 (t, J = 5.1 Hz, 2 H), 3.50
ammo-5' - 3.35 (m, 2 H), 2.86 (s, 1 H),
(tetrahdeO-ZH- 1.82 - 1.67 (m, 4 H)
pyran
y|)pyraziny|)—
4—benzyl-3,4—
dihydrobenzo[f][
l NMR
Structure
1,4]oxazepin-
(2H)—one
8'(2'am'“°'5' 1H NMR (400MHz, DMSO-d6) 5
(111' ppm 7.91 (d, J = 2.0 Hz, 1 H),
otetrahydr 7.88 (d, J = 7.9 Hz, 2 H), 7.43 -
o-2H-thiopyran- 7.28 (m, 6 H), 7.18 (d, J = 1.7 Hz,
110 4-yI)pyridinyl)- 1 H), 4.80 (s, 2 H), 4.27 (t, J = 5.0
4_benzyl_3,4_ Hz, 2 H), 3.58 (t, J = 5.0 Hz, 2 H),
dihydrobenzo[f][ 3.34 - 3.22 (m, 2 H), 3.19 - 3.07
azepin_ (m, 2 H), 2.94 (s, 1 H), 2.21 -
2.07 (m, 4 H)
(2H)_One
(S)'4'(3'am'“°' 1H NMR (400MHz ,CD30D) 6
F O {OH
2 5-(2- ppm 7.89 (s, 1 H), 7.84 (t, J = 7.8
NH2 3A© hydrOX)/ethy|)loyr Hz, 1 H), 7.84 (dd, J = 1.8, 7.8
NI \ azinyI) Hz, 1 H), 7.58 (dd, J = 1.2, 11.7
111 3972 0'53
/N -N-(2- Hz, 1 H), 7.44 -7.31 (m,4 H),
hydroxy_1_ 7.27 (d, J = 7.0 Hz, 1 H), 5.20 (s,
phenylethymenz 1 H), 3.90 - 3.79 (m, 4 H), 2.87 (t,
OH J=8.5 Hz,2H).
amide
1H NMR 400MHz ,CD30D 5
(S)'4'(3'am'“°',
OH ppm 7.89((s, 1 H), 7.84 (t, J): 7.8
F 0 g/ 6-(2- Hz, 1 H), 7.84 (dd, J = 1.8, 7.8
NH2 3 methoxyethy|)py Hz, 1 H), 7.81 -7.55 (m, 1 H),
razin-2—yl)—2- 7.44 - 7.39 (m, 2 H), 7.34 (t, J =
“2 NI :N 411'3 0'62
K fluoro_N_(2_ 7.8 Hz, 2 H), 7.27 (d, J = 7.4 Hz,
hydroxy_1_ 1 H), 5.19 (d, J = 8.3 Hz, 1 H),
phenylethyl)benz 3.87 - 3.82 (m, 2 H), 3.70 (t, J =
OMe 8.5 Hz, 2 H), 3.32 (s, 3 H), 2.92
amide
(t, J = 8.5 Hz, 2 H).
(R)_4_(2_amino_ 1H NMR (400MHz, CD30D) 5
-(tetrahydro- ppm 7.92 - 7.87 (m, 1 H), 7.88 -
F O
HOWQ 113 F
\ mgflrfiéflmr?’ 0'52 7.23 (m,2 H), 4.54-4.40 (m, 3
H), 4.09 - 3.95 (m, 2 H), 3.59 -
flUIOIVObenzylw'p. 3.44 (m, 2 H), 2.92 - 2.78 (m, 1
erIdIn H), 2.84 (s, 1 H), 2.20- 1.98 (m,
y|)benzamide 3 H), 1.99 - 1.52 (m, 8 H).
Exampl NMR
Structure
1H NMR (400MHz ,CD30D) 8
(S)—4-(3-amino-
ppm 7.94 (s, 1 H), 7.84 (t, J = 7.8
6-(2- Hz, 1 H), 7.69 (d, J = 8.2 Hz, 1
cyanoethyl)pyraz H), 7.63 (d,J = 12.1 Hz,1 H),
iny|)f|uoro- 7.43 - 7.38 (m, 2 H), 7.34 (t, J =
N-(2-hydroxy 7.6 Hz, 2 H), 7.27 (d, J = 7.4 Hz,
phenylethyl)benz 1 H), 5.22 - 5.16 (m, 1 H), 3.89 -
amide 3.79 (m, 2 H), 3.01 (t, J = 7.0 Hz,
H), 2.84 (t, J = 7.2 Hz, 2 H)
1H NMR (400MHz ,CD30D) 8
4-(3-amino- ppm 7.90 - 7.77 (m, 2 H), 7.67
6-(1- (dd, J = 1.6, 8.2 Hz, 1 H), 7.59
(dd, J =1.4,11.9 Hz, 1 H), 7.40 -
115 hydroxypropan-
7.29 (m, 4 H), 7.28 - 7.21 (m, 1
2—yl)pyrazin
H), 4.60 (s, 2 H), 3.76 (dd, J =
y|)-N-benzy|—2- 7.4, 10.6 Hz, 1 H), 3.67 (dd, J =
fluorobenzamide
59,106 Hz, 1 H), 3.02 - 2.93 (m,
1 H), 1.25 (d, J = 7.0 Hz, 3 H)
1H NMR (400 MHz, CD30D) 5
ppm 7.92 - 7.79 (m, 2 H) 7.66
4—(3-amino (dd, J=8.02, 1.37 Hz, 1 H) 7.59
((1 r,4r)—4— (dd, J=11.54, 1.37 Hz, 1 H) 7.43 -
7.30 (m, 4 H) 7.30 - 7.22 (m, 1 H)
methoxycyclohe
116 .61 (s, 2 H) 3.40 - 3.35 (m, 3 H)
xyl)pyraziny|)— 3.26 (t, J=3.91 Hz, 1 H) 2.74 -
N-benzyI 2.61 (m, 1 H) 2.20 (d, J=9.39 Hz,
fluorobenzamide 2 H) 1.99 (d, 1 Hz, 2 H)
1.65 (qd, J=13.04, 3.13 Hz, 2 H)
1.41 - 1.25 (m, 2 H)
1H NMR (00300) 8 ppm 7.95 (s,
(+/-)(3-amino- 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.69
6-(6- (dd, J = 8014 Hz, 1H), 7.61
oxopiperidin (dd, J 1.2 Hz, 1H), 7.31 -
117 y|)pyraziny|)— 7.45 (m, 4H), 7.22 - 7.30 (m, 1H),
N-benzyI .A62 (s, 2H), 3.53 (d, J = 7.8 Hz,
fluorobenzamide H), 3.47 (q, J = 7.4 Hz, 1H),
3.15 - 3.26 (m, 1H), 2.40 - 2.57
(m, 2H), 2.06 - 2.24 (m, 2H), 1.36
(t, J = 7.2 Hz, 1H)
Exaempl NMR
Structure
1H NMR (400MHz, CD30D) 6
4-(2-am|n0-. ppm 8.88 - 8.77 (m, 1H), 8.03 -
-(5- 7.95 (m, 2H), 7.92 - 7.83 (m, 4H),
118 oxopiperidin 419.3 0.55 7.48-7.30 (m, 2H), 7.28 -7.21
yl)pyridin—3—yl)— (m, 1H), 4.69 - 4.54 (m, 2H), 3.56
N_benzy|_2_ - 3.42 (m, 1H), 3.20 - 3.05 (m,
fluorobenzamide 1H), 2.55 - 2.39 (m, 2H), 2.16 -
1.99 (m, 2H)
F O E
' 1H NMR(400MHz, CD30D) 6
NHZ N 4_(2_amino_5_(5_
°X°piperidi“'3' 5‘23 {'971‘HT’;215 77823? 123;)
Kiwi:I IdII- . m, -. m, ,. ,
119 0'
'« )' an 3 Y)
467.3 0.66 7.29-7.16 (m, 1H), 5.31 -5.16
'( '
(m, 1H), 3.59-3.34 (m, 2H), 3.21
ChlorOpheny')eth - 3.05 (m, 1H), 2.59 - 2.38 (m,
NH Y')'2' 2H), 2.19 - 2.01 (m, 2H), 1.57 (m,
0 diastereomeric mixture fluorobenzamide 3H)_
F O
NHZ N 4—(2—amino(2-
N \ HAQ oxopiperidin 1H NMR(400MHz,CD30D)5
| idiny|)- ppm 7.94 (m 7.87-7.74 (m
120 / CI 4672 0'66 3 1H) a .
N-((R)(3- 2H), 7.35 (s, 6H), 5.24 (m, 1H),
chlorophenyl)eth 2.67 - 2.4 (m, 2H), 2.1 - 1.94 (m,
N O y|)_2_ 2H), 1.57 (m, 3H), 1.26 (m, 2H).
diastereomeric mixture fluorobenzamide
4—(2—amino(2-
oxopiperidin 1H ogg'f’ 2330?)”:
mg);I '
r'd'nV)|- ppm - - m, ’ - 3’
121 483.2 0.56 7H), 5.17—5.01 (m, 1H), 3.87-
' ' ' (3'
3.64 (m, 2H), 3.44-3.31 (m, 3H),
ChlorOpheny')'2' 2.62 - 2.24 (m, 2H), 2.12 - 1.74
hydroxyethy|)-'2- (m, 2H).
fluorobenzamlde
reomeric mixture
Exampl Rt NMR
Structu re
e (min)
(S)—4-(2-amino-
- 1H NMR (400 MHz, CD30D) 5
morpholinopyridi ppm 8.06 (d, J=8.2 Hz, 2 H) 7.87
122 (d, J=2.7 Hz, 1 H) 7.63 (d, J=8.2
ny|)-N-(2-
Hz, 2 H) 7.24 - 7.48 (m, 6 H) 5.19
hydroxy - 5.30 (m, 1H) 3.90 (m, 2H) - 3.85
phenylethy|)benz (m, 4 H) 3.12 (m, 4 H)
amide
1H NMR (400 MHz, MeOD-d4) 5
(3-amino-
ppm 7.99 - 7.78 (m, 2 H) 7.72 -
6-(3-
4992'7.52 (m, 2 H) 7.46 (s, 1 H) 7.41 - methoxycyclohe 7.17 (m, 3 H) 5.24 - 5.08 (m, 1 H)
123 xyl)pyraziny|)— 3.86 (t, J=6.06 Hz, 2 H) 3.43 (m,
N-((S)(3- 1H) 3.38 (s, 3 H) 2.75 (ddd,
chlorophenyl)—2- J=12.03, 8.71, 3.52 Hz, 1 H) 2.40
hydroxyethy|) -2.02 (m, 2 H) 1.99 - 1.74 (m, 2
diastereomeric mixture;
cis on cyclohexane ring benzamide H) 1.59 - 1.37 (m, 3 H) 1.18 (dd,
J=11.35, 3.13 Hz, 1 H)
1H NMR (400 MHz, MeOD-d4) 5
(+/-)-cis(3- ppm 8.00 - 7.79 (m, 2 H) 7.74 -
7.52
amino(3- (m, 2 H) 7.43- 7.31 (m, 4
H) 7.30 -7.22 (m, 1 H)4.61 (s,
124 methoxycyclohe
2 H) 3.37 (s, 3 H) 2.73 (t, J=3.33
xyl)pyraziny|)—
Hz, 1 H) 2.27 (d, J=11.74 Hz, 1
yI H)2.14 (d, J=12.13 Hz, 1 H) 1.99
fluorobenzamide -1.82(m,2H)1.52 -1.39 (m,3
H) 1.24 - 1.10 (m, 1 H)
(S)—4-(3-amino- 1H NMR (400MHz, CD30D) 6
6-(tetrahydro- ppm 7.80 (s,1 H), 7.71 (m, 1 H),
7.61 (dd, J = 1.5, 8.0 Hz, 1 2H-pyran H),
7.57 - 7.43 (m, 3 H), 7.32 - 7.15
125 y|)pyraziny|)- 508.3
(m, 2 H), 4.39 (s, 2 H), 3.95 (dd, J
2-fluoro-N-(1-(2- = 26,116 Hz, 2 H), 3.48 (dt, J =
fluorobenzyl)pip 25,117 Hz, 3 H), 2.92 - 2.75 (m,
eridin 1 H), 2.56 (s, 2 H), 1.89 - 1.65
y|)benzamide (m, 10 H).
Exaempl NMR
Structure
1H NMR 400MHz ,CD30D) 5
(R)'4'(3'am'“°'.
ppm 7.91 (s, 1 H), 7.80 (t, J = 7.8
'(tetrahydr°' Hz, 1 H), 7.71 (d, J = 9.4 Hz, 1
2H-pyran H), 7.67 - 7.55 (m, 3 H), 7.41 -
F o ”0%in yl)pyraziny|)— 7.27 (m, 2 H), 4.49 (br. s., 2 H),
126 508'4 0'63
NH2 2-quoro-N-(1-(2- .34 (br. s., 1 H), 4.10 - 4.01 (m,
I fluorobenzyl)pip 2 H). 3-75 (br. 8-. 1 H). 3-64 -
eridin_3_ 3.51 (m, 4 H), 3.02 (d, J = 13.7
yDbenzamide Hz, 1 H), 3.00 - 2.88 (m, 2 H),
2.12 (br. s., 2 H), 1.97 - 1.78 (m,
H), 1.68 (d, J = 10.2 Hz, 1 H)
Method 2
Example 127
S nthesis of S 3-amino 1 3-dimeth I-1H- 4- | razin | -N- 1- 3-
chloro hen Ih drox eth Ifluorobenzamide
Scheme 53
F 0 {0H Steal F 0 {OH $22
NH =
2 2
C) N Pd<dpp0CI2 NH2 N NBS
I + —> H
H —>
K/N HO N’
‘13 Na2003, DME |
1 \ N CI
OH CI
F o :/
F 0 {OH _28t 3 NH2 N
= oH H
NH2 N ‘3/0 f)CI2 N/
+ |
H —>
\ N CI
NI \ I \ Na2003,DME
Kr/N CI
\ \
Br N—N
Ste 1. S o razin l-N- 1- 3-chloro hen lh drox eth l
benzamide
To the reaction mixture of 3-chloropyrazinamine (288 mg, 2.22 mmol), (S)(1-(3-
chlorophenyl)hydroxyethylcarbamoyl)fluorophenylboronic acid (500 mg, 1.48 mmol),
PdC|2(dppf)-DCM (108 mg, 0.148 mmol), DME (1.1 mL), 2M Na2C03 (3.703 mL) was
added. The reaction mixture was heated at microwave synthesizer (120 0C, 12 min). To
the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated.
The crude product was pre-purified by flash chromatography eluting with EtOAc
ining 10% MeOH) in heptane. The pure fractions were combined and concentrated
to provide 389 mg of the desired product in 68% yield. LCMS (m/z): 387 (MH+), 0.69 min.
Ste 2. S 3-aminobromo razin l-N- 1- 3-chloro hen lh drox eth l
fluorobenzamide
To a solution of (S)(3-aminopyrazinyl)-N-(1-(3-chlorophenyl)hydroxyethyl)
fluorobenzamide (389 mg, 1.006 mmol) in acetonitrile (21 mL) was added NBS (171 mg,
0.961 mmol) at 0 °C. The on e was stirred at 0 °C for 20 min. After quenched
with sat NaHC03, and stirr for 30 min. The reaction mixture was extracted with EtOAc 3
times, the organic was washed by sat NaHC03, water and brine, dried, filtered off, and
trated. The crude material was taken to the next step without further purification.
LCMS (m/z): 367 (MH+), 0.88 min.
Ste 3. S 3-amino 1 3-dimeth l-1H- 4- l razin l-N- 1- 3-
chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide
To the reaction mixture of (3-aminobromopyrazinyl)-N-(1-(3-chlorophenyl)
hydroxyethyl)f|uorobenzamide (40 mg, 0.086 mmol), 1,3-dimethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (38.2 mg, 0.172 mmol), PdC|2(dppf)-
DCM (6.28 mg, 8.59 umol), and DME (644 uL), 2 M Na2C03 (215 uL) were added. The
reaction mixture was heated at microwave synthesizer (120 °C, 12 min). To the reaction
mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude
product was purified by auto-prep to provide 25 mg of desired product as a TFA salt.
LCMS (m/z): 481.3 (MH+), 0.73 min; 1H NMR (500 MHz, CD3OD) 6 ppm 8.66 (d, J=6.26
Hz, 1 H) 8.17 (s, 1 H) 8.02 (s, 1 H) 7.76 - 7.51 (m, 3 H) 7.45 - 7.16 (m, 3 H) 5.07 — 4.09
(m, 1 H) 3.72 (s, 3 H) 3.62 (m, 2 H) 2.33 (s, 3 H).
Example 128
S nthesis of S 2-amino 1-meth |-1H-1 2 3-triazoI | ridin | -N- 1- 3-
chloro hen |h drox eth |f|uorobenzamide
Scheme 54
Ste 1 $2;
Pd(dppf)C|2DCM / NBS
Br NH2 0
l +
\ Hog/@LO/ Na2co3 DME N/ CH3CN
Steg3 F O
NH H
LiOH (1 M) 2 ?
N / + H2N
THF MeOH
F O
Stepfl 3/ $12;
NH N
EDC: ”ON 2
H Pd(dppf)C|2, )2
—> N / —,
DIEA, THF Cl KOAc, dioxane
0 :/ F 0 {OH
: Steg§ ?
NH2 N NH2 N
Pd(dppf)CI2—DCM H
N/ N,
| #
0' |
\ , DME \ Cl
o’ o N“ \
Ste 1. meth |4- 2-amino ridin |f|uorobenzoate
To 3-bromopyridinamine (5 g, 28.9 mmol) in 500 mL round bottom flask was added (3-
fluoro(methoxycarbony|)pheny|)boronic acid (7.44 g, 37.6 mmol), PdC|2(dppf)-DCM
(2.115 g, 2.89 mmol), DME (108 mL) and 2M Na2C03 solution (36.1 mL). The reaction
mixture was heated in an oil bath at 110 °C for 4 h. The reaction mixture was diluted with
2014/062913
EtOAc and washed with water three times, dried over NazSO4, filtered and concentrated.
The crude product was purified by flash chromatography eluting with 0-100% of EtOAc
ining 10% of MeOH)/heptane yielding 5.6 g of methyl 4-(2-aminopyridinyl)
fluorobenzoate in 79 % yield. LCMS (m/z): 247.1 (MH+), 0.50 min.
Ste 2. meth l4- 2-aminobromo ridin lfluorobenzoate
To a solution of methyl 4-(2-aminopyridinyl)fluorobenzoate (5.64 g, 22.90 mmol) in
acetonitrile (229 mL) was added NBS (4.16 g, 23.36 mmol) in two portions at 0 °C . The
reaction mixture was stirred at 0 °C for 20 min. After quenched with sat Na28203 and
NaHC03, and stirr for 30 min. The on mixture was extracted with EtOAc 3 times,
the organic washed by sat NaHCOs, water and brine. Dried and concentrated. The crude
material was triturated with ether to provide 7.05 g of methyl minobromopyridin-
2-fluorobenzoate in 95 % yield. LCMS (m/z): 327.1 (MH+), 0.66 min.
Ste 3. 4- 2-aminobromo ridin l f|uorobenzoic acid
To a solution of methyl 4-(2-aminobromopyridinyl)—2-fluorobenzoate (1.9 g, 5.84
mmol) in THF (19.48 mL) and MeOH ( 9.74 mL, Ratio: 1.000) was added LiOH (1 M
aqueous onueous solution) (10.52 mL, 10.52 mmol). The reaction mixture was
stirred for 5 h. After 1N HCI (1.9 mL) was added up to pH 5, the reaction mixture was
worked up with EtOAc, the organic layer was dried over N32804, filtered off and
concentrated in vacuo. The crude 4-(2-aminobromopyridinyl)—2-fluorobenzoic acid
was used for the next step without further purification. LCMS (m/z): 311.1/313.1 (MH+),
0.5 min.
Ste 4. S 2-aminobromo ridin l-N- 1- 3-chloro hen lh drox eth l
fluorobenzamide
To a solution of 4-(2-aminobromopyridinyl)—2-fluorobenzoic acid (300 mg, 0.964
mmol) in THF (8.036 mL) was added (S)amino(3-chlorophenyl)ethanol (331 mg,
1.157 mmol). The reaction mixture was stirred for 15 h. After water was added, the
on mixture was worked up with EtOAc, the organic layer was dried over anhydrous
NaZSO4, filtered off and concentrated in vacuo. The crude (2-aminobromopyridin-
3-yl)-N-(1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide was used for the next step
without further purification. LCMS (m/z): 464.1/466.1 (MH+), 0.69 min.
Ste 5. S 2-amino 4 4 5 5-tetrameth H 3 2-dioxaborolan | ridin | -N- 1-
(3-chlorophenyl )—2-hyd roxyethyl )—2-fluorobenzamide
To a solution of (S)(2-aminobromopyridinyl)-N-(1-(3-chlorophenyl)
hydroxyethyl)f|uorobenzamide (85 mg, 0.183 mmol), bis(pinacolato)diboron (93 mg,
0.366 mmol), and PdC|2(dppf) (26.8 mg, 0.037 mmol) in dioxane (610 uL) was added
ium acetate (54 mg, 0.549 mmol). The reaction mixture was heated at microwave
sizer (120 °C for 20 min). The reaction e was filtered h Celite pad.
After the filtrate was almost concentrated, the crude (S)(2-amino(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)—N-(1-(3-chlorophenyl)hydroxyethy|)
fluorobenzamide was used for the next step without further purification. LCMS (m/z):
430.2 (MH+ for boronic acid), 0.57 min.
Ste 6. S 2-amino 1-meth l-1H-1 2 3-triazol | ridin | -N- 1- 3-
chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide
To a solution of the crude (S)—4-(2-amino(4,4,5,5-tetramethy|—1,3,2-dioxaboro|an
yl)pyridinyl)—N-(1-(3-chlorophenyl)hydroxyethyl)f|uorobenzamide (30 mg, 0.059
mmol) in residual dioxane was added 4-bromomethyl-1H-1,2,3-triazo|e (14.24 mg,
0.088 mmol), PdC|2(dppf) (42.9 mg, 0.059 mmol), DME (195 pl) and 2 M Na2C03 (130 pl)
at room temperature. The on mixture was stirred for 5 h. After water and EtOAc
were added, the organic layer was extracted with EtOAc. The organic layer was washed
with water and brine, dried over anhydrous Na2804, ed off, and concnetrated in
vacuo. The crude product was purified by prep HPLC. The pure fractions were lyophilized
yielding (S)—4-(2-amino(1-methyl-1H-1,2,3-triazolyl)pyridinyl)—N-(1-(3-
chloropheny|)hydroxyethy|)f|uorobenzamide as a TFA salt (25% over 2 steps).
LCMS (m/z): 467.3 (MH+), 0.61 min; 1H NMR (400MHz, CD3OD) 8 ppm 8.64 (m, 1 H),
8.31 (m, 1 H), 8.25 (m, 2 H), 8.2 (m, 1 H), 7.82 (m, 1 H), 7.4 (m, 3 H), 7.28 (m, 2 H), 7.22
(m, 1 H), 5.11 (m, 1 H), 4.07 (s, 3 H), 3.78 (m, 2 H).
e 129
S nthesis of S 3-amino—6- 1 6-dih dro ridin l razin l-N- 2-h drox
phenylethyl mide
Scheme 55
$2.1
NIJTKNH2 O/©)‘\H_/\© Pd(dppf)C|2
jig/3 N32003 DME
O NI/Kfit‘l—/\©
Step g OH/\© Br
Pd(dppf)Cl2, 82(PIN)2 /
—> I
KOAC, dioxane
o’E"o O
F 0 {OH
Stegg NHz N
Pd(dppf)C|2 N \
—. l/N
Na2003, DME
Ste 1. S 3-aminobromo razin l-N- 2-h drox hen leth Ibenzamide
To a solution of 3,5-dibromopyrazinamine (826 mg, 3.27 mmol), (S)—N-(2-hydroxy
phenylethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (600 mg, 1.634
mmol), and PdC|2(dppf).CH2C|2 adduct (133 mg, 0.163 mmol) in DME (12.3 mL) was
added 2 M Na2C03 (4.08 mL). The reaction mixture was heated at microwave synthesizer
(120 °C, 10 min). The reaction mixture was worked uup with EtOAc. The organic layer
was washed with sat NaHC03, water and brine, dried over Na2804, filtered off,
concentrated in vacuo. The crude product was purified with silica flash chromatography
eluting with 0-100% of EtOAc (containing 10% of MeOH) in heptane, and triturated with
ether to e 800 mg of (S)—4-(3-aminobromopyrazinyl)-N-(2-hydroxy
phenylethyl)benzamide. LCMS (m/z): 415 (MH+), 0.73 min.
Ste 2. S 3-amino 4 4 5 5-tetrameth H 3 2-dioxaborolan l razin l -N- 2-
hydroxy—1-phenylethyl)benzamide
To a solution of (S)(3-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrazin
yl)-N-(2-hydroxyphenylethyl)benzamide (50 mg, 0.121 mmol), nacolato)diboron
(61.4 mg, 0.242 mmol), and PdC|2(dppf)-CH2C|2 adduct (9.88 mg, 0.012 mmol) in dioxane
(302 uL) was added potassium acetate (35.6 mg, 0.363 mmol)just right after degassing.
The reaction mixture was heated at microwave synthesizer (120 °C for 20 min). After
d with EtOAc, the reaction mixture was filtered through Celite pad. After
concentrated, the crude (S)(3-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
y|)pyrazinyl)-N-(2-hydroxyphenylethyl)benzamide was used for the next step without
r purification. LCMS (m/z): 379 (MH+ for boronic acid), 0.47 min.
Ste 3. S 3-amino 6-oxo-1 6-dih dro ridin l razin l-N- 2-h drox
phenylethyl)benzamide
To a on of amino(4-(2-hydroxyphenylethylcarbamoyl)phenyl)pyrazin
ylboronic acid (55 mg, 0.145 mmol), opyridin-2(1H)-one (38.0 mg, 0.218 mmol),
and PdCl2(dppf)-CH2Cl2 (11.88 mg, 0.015 mmol) in DME (1091 uL) was added 2M
Na2C03 (364 uL). The reaction mixture was heated at microwave synthesizer (120 °C, 10
min). The reaction mixture was worked up with EtOAc. The organic layer was washed
with sat NaHC03, water and brine, dried over Na2804, filtered off, concentrated in vacuo.
The crude product was purifed by prep HPLC yielding 4.3 mg of (S)—4-(3-amino(6-oxo-
1,6-dihydropyridinyl)pyrazinyl)-N-(2-hydroxyphenylethyl)benzamide as a TFA
salt. LCMS (m/z): 428.2 (MH+), 0.55 min; 1H NMR (400 MHz, DMSO-d6) 3.60 - 3.75 (m, 2
H) 5.03 - 5.12 (m, 1 H) 6.40 (d, J=9.39 Hz, 1 H) 7.22 (d, J=7.43 Hz, 1 H) 7.30 (t, J=7.63
Hz, 2 H) 7.34 - 7.40 (m, 2 H) 7.83 (d, J=8.22 Hz, 2 H) 7.94 (br. s., 1 H) 8.01 (d, J=8.61
Hz, 2 H) 8.06 (dd, J=9.39, 2.74 Hz, 1 H) 8.41 (s, 1 H) 8.74 (d, J=8.22 Hz, 1 H).
S nthesis of S 3-aminobromo razin l-N- 1- 3-chloro hen lh drox eth l-
2 6-difluorobenzamide
Scheme 56
$21 $22 $22
F O O
F o
i 11 Pd(dppf)CI2-DCM
TMSCHN2 0/ NBS
OH ‘0/ 52/500 NH2 —>
_.4E5: N \
Na2C03 DME N/ F
Br F Br F
“W 120°C l
S_2te Step_5
LiOH NH2 N
H2 H2 H
\ F
N/ H/N/ Cl
Ste 1. meth l4-bromo-2 uorobenzoate
To a solution of 4-bromo-2,6-difluorobenzoic acid (800 mg, 3.38 mmol) in MeOH (11 mL)
at room temperature, trimethylsilyldiazomethane (5.63 mL, 3.38 mmol) was slowly added
until yellow solution was turned on. The small amount of AcOH was added until yellow
color disappered. All volatile materials were removed in vacuo yielding methyl o-
2,6-difluorobenzoate (47%). LCMS (m/z): 251.1 (MH+), 0.86 min.
Ste 2. meth l4- 2-amino ridin l -2 uorobenzoate
Followed by Step 1 in Scheme 54, methyl 4-(2-aminopyridinyl)—2,6-difluorobenzoate
was obtained (9%). LCMS (m/z): 485.2 (MH+), 0.64 min; 1H NMR (400 MHz, CD3OD) 8
ppm 8.11 (m, 1 H), 7.76 (m, 2 H), 7.37 (m, 1 H), 7.27 (m, 2 H), 7.20 (m, 3 H), 5.09 (m, 1
H), 4.03 (s, 3 H), 3.73 (m, 2 H).
Ste 3 4 and 5. S 3-aminobromo razin l-N 3-chloro hen l
hydroxyethyl)—2,6-difluorobenzamide
Following Step 2, 3, and 4 in Scheme 54, (S)(3-amino(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyrazinyl)—N-(1-(3-chlorophenyl)hydroxyethyl)-2,6-
difluorobenzamide was obtained. LCMS (m/z): 482/484 (MH+), 0.68 min.
Table 3. Bromide or the corresponding boronic ester intermediates for Suzuki coupling
Structure ' )
4-(3-amino
bromopyrazin-Z-
y|)-N-(3-
(methylsulfony|)b
enzyl)benzamide4611/463l
4-(3-amino
yrazin-Z-
y|)f|uoro-N-(3- 812 0.782
(methylsulfony|)b
enzyl)benzamide
(S)—4-(3-amino-
6-(4,4,5,5-
tetramethyl-
1,3,2-
397.1 (for
dioxaborolan-Z-
boronic 0.49
y|)pyrazin-2—y|)-
acid)
2-fluoro-N-(2—
hydroxy
phenylethyl)benz
amide
(S)—4-(3-amino-
6-bromopyrazin-
2-y|)f|uoro-N-
(2-hydroxy
ethyl)benz
amide 4311/433l
2014/062913
Structure
1H NMR (400 MHz,
CD30D) 6 ppm 8.05 (s, 1
(S)—4-(3-amino- H) 8.00 (d, J=8.22 Hz, 3
6-bromopyrazin- H) 7.83 (d, J=8.22 Hz, 3
2-y|)-N-(2- H) 7.40 - 7.46 (m, 3 H)
413/415
y 7.35 (t, J=7.63 Hz, 2 H)
phenylethyl)benz 7.23 - 7.31 (m, 1 H) 5.23
amide (t, J=6.65 Hz, 1 H) 3.88
(d, J=6.65 Hz, 2 H)
(S)—4-(2-amino-
opyridin-
3-y|)-N-(1-(3-
chlorophenyl)—2—
hydroxyethyl)—2—
methylbenzamid
(S)—4-(2-amino-
—(4,4,5,5-
tetramethyl-
1,3,2-
dioxaborolan-Z-
y|)pyridin-3—y|)—
N-(1-(3-
chlorophenyl)—2—
hydroxyethyl)—2—
methylbenzamid
(S)—4-(2-amino-
—(4,4,5,5-
tetramethyl-
F o 1,3,2-
N dioxaborolan-Z-
NH2 448.2 (for
H y|)pyridin-3—y|)—
N/ boronic 0.65 N/A
| N-(1-(3-
\ acid)
chlorophenyl)—2—
,B hydroxyethy|)-
o ‘o
2,6-
difluorobenzami
Structure
F O (+/-)(3-amino-
6-bromopyrazin-
HNA© (223") 2 fluoro N_ _ _ _ _
427.1/429.1
phenylcycloprop
y|)benzamide
AK) 4-(2-amino- 5—bromopyridin-
23")‘2'fluoro'N' 4262/4282 0.79
phenylcycloprop
y|)benzamide
Chiral resolution of +/- 2-aminobromo ridin l fluoro-N- 1S 2R
phenylcyclopropyl )benzamide
Scheme 57
F O F O F O
A ”All; :
NH2 N E: “HZ ””2 N
H H H
N / N / N / [D
I | I
\ \ \
(+/_)
Br Br peak1 Br peak2
(+/-)(2-aminobromopyridinyl)—2-fluoro-N-((1S,2R)—2-phenylcyclopropyl)benzamide
(121 mg) was resolved by chrial chromatography (AD-H column 0/40, 1mL/min).
The polar compound (Peak1), minobromopyridinyl)—2-fluoro-N-((1R,28)—2-
phenylcyclopropyl)benzamide, was obtained at 7.41 min (50 mg, 41%) and the less polar
compound ), 4-(2-aminobromopyridinyl)—2-fluoro—N-((1S,2R)—2—
phenylcyclopropyl)benzamide, was obtained at 10.26 min (54 mg, 44%). The absolute
stereochemistry was assigned based on biochemical data and docking model of the
corresponding analogs.
Example 130
S nthesis of +/- o 1-meth l-1H- razol l ridin lfluoro-N-
1R28 hen Ic clo ro Ibenzamide
Followed Scheme 59, using (+/-)(2-aminobromopyridiny|)f|uoro-N-((1S,2R)—2-
phenylcyclopropyl)benzamide, (+/-)(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—
2-fluoro-N-((1R,2S)phenylcyclopropyl)benzamide was obtained (11%). LCMS (m/z):
428.2 (MH+), 0.72 min; 1H NMR (400MHz, CD3OD) 8 ppm 8.19 (m, 1 H), 7.91 (s, 1 H),
7.82 (m, 1 H), 7.77 (m, 1 H), 7.64 (m, 1 H), 7.48 - 7.33 (m, 2 H), 7.31 - 7.12 (m, 5 H), 3.91
(s, 3 H), 3.10 (m, 1 H), 2.20 (m, 1 H), 1.33 (m, 2 H).
Example 131
S s of 4- 2-amino 1-meth l-1H- razol l ridin lfluoro-N- 1R28
cyclopropyl )benzamide
Followed by Scheme 59, using 4-(2-aminobromopyridiny|)f|uoro-N-((1R,2S)—2-
phenylcyclopropyl)benzamide, 4-(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—2-
fluoro-N-((1R,2S)—2-phenylcyclopropy|)benzamide was obtained (53%). LCMS (m/z):
428.3 (MH+), 0.69 min; 1H NMR (400MHz, CD3OD) 6 ppm 8.11 - 8.02 (m, 1 H), 7.94 (m, 1
H), 7.97 - 7.88 (m, 2 H), 7.85 - 7.71 (m, 2 H), 7.43 - 7.30 (m, 2 H), 7.26 - 7.14 (m, 2H),
7.14 - 7.02 (m, 2 H), 3.83 (s, 3 H), 3.06 - 2.92 (m, 1 H), 2.19 - 2.02 (m, 1 H), 1.35 - 1.17
(m, 2 H). The absolute stereochemistry was assigned based on biochemical data and
docking model.
Example 132
4- 2-amino1-meth l-1H- razol l ridin lfluoro-N- 1S 2R
hen lc clo ro mide
Followed by Scheme 59, using 4-(2-aminobromopyridinyl)—2-fluoro-N-((1S,2R)—2-
phenylcyclopropyl)benzamide, 4-(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—2-
fluoro-N-((1S,2R)—2-phenylcyclopropyl)benzamide was obtained (42%). LCMS (m/z):
428.3 (MH+), 1H NMR z, CD3OD) 6 ppm 8.09 - 8.02 (m, 1 H), 8.01 - 7.95 (m, 1
H), 7.96 - 7.88 (m, 2 H), 7.84 - 7.70 (m, 2 H), 7.42 - 7.29 (m, 2 H), 7.25 - 7.02 (m, 4 H),
3.83 (s, 3 H), 3.10 - 2.87 (m, 1 H), 2.24 - 2.00 (m, 1 H), 1.33 - 1.15 (m, 2 H). The absolute
stereochemistry was assigned based on biochemical data and g model.
Example 133
S nthesis of S 2-amino1-deuterido-meth l5-meth l-1H- razol l ridin l-
N-g1-(3-chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide
Scheme 58
Stepl Step; m;
\ lfl CDI 3 <\:N| o o nBuLI- NBS
\ D + “8/, \ '1‘ —’ D
NH 7< —’ —’
\O’ ‘O/
NaH D Et20 XD MeCN
D D
47% 59% 92%
{OH OH
F 0 _r_>Ste 4 F O =/
NH2 N NH2
W H PdCl2(dppf) 3
+ N \ N/
—, |
N_N><D I
/ Cl DME,Na2C03 \ C'
D D
B 9%
or \O \
D D
Ste 1.1-deuterido-meth l-1H- razole
To a on of NaH (1.851 g, 46.3 mmol) in 2-methyl THF (80 mL) was added 1H-
pyrazole (3 g, 44.1 mmol) in 2-methyl THF (30 mL) at 0 °C. The reaction mixture was
warmed up to room temperature and stirred for 1 h. To this, CD3| (3.02 mL, 48.5 mmol)
was slowly added. The reaction mixture was stirred for overnight. After quenched with
NH4CI solution, the reaction mixture extracted with EtOAc. The organic layer was washed
with water and brine, ed off, and concentrated in vacuo. The crude product was
distlled off yielding 1-deuterido-methyl-1H-pyrazole (47%) (b.p. ~130 °C, bath temp was
~200 °C). LCMS (m/z): 86 (MH+), 0.24 min; 1H NMR (500MHz, CDCI3) 6 ppm 7.55 - 7.42
(m, 1H), 7.39 - 7.28 (m, 1H), 6.28 - 6.15 (m, 1H).
Step 2. 1-deuterido-methyl,5-methyl-1H-pyrazole
To a solution of n-BuLi (2.5 M in hexanes) (4.14 mL, 10.34 mmol) in ether (20 mL) at -30
°C was slowly added a on of 1-deuterido-methyl-1H-pyrazole (880 mg, 10.34 mmol)
in ether (2 mL). The reaction mixture was allowed to warm up to room temperature and
stirred for 2 h. After being cooled to 0 °C, a solution of dimethyl sulfate (0.931 mL, 9.82
mmol) in ether (3 mL) was slowly added to the reaction mixture. The reaction e was
stirred at room temperature for 3 h. After quenched with sat. NH4C| on, the reaction
mixture was extracted with ether (x2), but s phase still contained product. Then,
the aqueous phase was extracted with DCM (x2). The combined organic phase was dried
over anhydrous NazSO4, filtered off, and concentrated in vacuo. The crude product was
purified by distillation ng erido-methyl,5-methyl-1H-pyrazole (59%). LCMS
(m/z): 100.0 (MH+), 0.24 min; 1H NMR (400MHz, CHLOROFORM-d) 6 ppm 7.36 (m, 1H),
6.00 (m, 1H), 2.27 (s, 3H).
Step 3. 4-bromodeuterido-methyl,5-methyl-1H-pyrazole
To a solution of 1-deuterido-methyl,5-methyl-1H-pyrazole (100 mg, 1.009 mmol) in MeCN
(3.362 mL) was added NBS (171 mg, 0.958 mmol) slowly at 0 °C. After the ice bath was
removed, the reaction e was stirred for 30 min. After quenched with sodium sulfite
solution, the reaction mixture was extracted with EtOAc. The organic layer was washed
with sodium ate solution and brine, dried over sodium e, filtered off and
concentrated in vacuo. The crude 4-bromodeuterido-methyl,5-methyl-1H-pyrazole was
obtained and was used for the next step without further purification (92%). LCMS (m/z):
178, 180 (MH+), 0.61 min.
Ste 4. S 2-amino 1-deuterido-meth l5-meth l-1H- razol l ridin l-N- 1-
(3-chlorophenyl d roxyethyl )—2-fluorobenzamide
Following Step 6 in Scheme 54, using 4-bromodeuterido-methyl,5-methyl-1H-pyrazole,
(S)(2-amino(1-deuterido-methyl,5-methyl-1H-pyrazolyl)pyridinyl)—N-(1-(3-
chlorophenyl)hydroxyethyl)fluorobenzamide was obtained as a free base (9%).
LCMS (m/z): 483.2 (MH+), 0.67 min; 1H NMR (500MHz, CD3OD) 6 ppm 8.00 (d, J=1.9
Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.58 - 7.23 (m, 8H), 5.19 (t, J=5.8 Hz, 1H), 3.93 - 3.77 (m,
2H), 2.37 (s, 1H).
Example 134
S nthesis of S 2-amino c anometh l ridin lfluoro-N- 2-h drox
phenylethyl )benzamide
Scheme 59
0 _/
0 {OH
no L NH2 N
+ Ho, / F 0© —>
N \ F g Nl \
l /
/ OH
Bl‘ \
To a on of (S)(2-aminobromopyridinyl)f|uoro-N-(2-hydroxy
phenylethyl)benzamide (40 mg, 0.093 mmol) and isoxazolylboronic acid (20.99 mg,
0.186 mmol) in DME (697 pl) was added PdC|2(dppf)-CH2C|2 (7.59 mg, 9.30 umol) and 2
M Na2C03 solution (232 pl). The reaction mixture was heated in microwave at 120 °C for
min. The reaction mixture was oned n EtOAc and water, The organic layer
was dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The
crude product was purified by prep HPLC. The pure fractions were collected and
lyophilized yielding (S)—4-(2-amino(cyanomethyl)pyridinyl)f|uoro-N-(2-hydroxy
phenylethyl)benzamide as a TFA salt in 7% yield. LCMS (m/z): 391.2 (MH+), 0.51 min; 1H
NMR (400MHz ,CD30D) 8 ppm 8.66 (br. s., 1 H), 7.99 - 7.95 (m, 1 H), 7.92 - 7.82 (m, 2
H), 7.44 - 7.39 (m, 4 H), 7.38 - 7.32 (m, 2 H), 7.31 - 7.25 (m, 1 H), 5.25 - 5.18 (m, 1 H),
3.92 - 3.90 (m, 2 H), 3.90 - 3.80 (m, 2 H).
Example 135
S nthesis of S o 2 2 6 6-tetradeuterido-tetrah dro-2H- ran | razin
yl)—N-§2—hydroxyQhenylethy|)benzamide
Scheme 60
Steal
o o o TSOH
O I \ O
“W —> W
AWAO O benzene /\O O/\
Stegg
Stegg
TSOH
LiAID /—\ O O
4 D D
_. DWD + o:
benzene
HO OH D D
92% o
74% D D
SteQA Ste9§ F
o Q~J<
—> + I _, O
54% D D ’N
o CI 21% \
D D
D D
a: 4+ m w
o B’ PdC|2(dPPf) B
\ é —»
D D O O \
KOAc
O D D
W 0 /OH
0‘ ,o Step 1
B NH2
+ N/\©H \ N \ .
D D /N 20% (over2steps)
D D
0 _/OH O /OH
NH2 N Stegfi NH2 N
H H
NI \ H2/Pd-C N \
/N —’ I
D D D D
D D O
D D
Ste 1. dieth | 2 2'- 1 3-dioxolane-2 2-di | diacetate
A solution of diethyl 1,3-acetonedicarboxylate (12 g, 59.3 mmol), ethyleneglycol (9.93 mL,
178 mmol), and p-toluenesulfonic acid monohydrate (564 mg, 2.97 mmol) in benzene (80
mL) was refluxed under heating removing water for 10 h by Dean-Stark trap. The
benzene layer was washed with a ted aqueous sodium bicarbonate solution and
brine. The solvent was distilled away and the residue obtained was purified by flash
tography (10 to 40% EtOAc in heptanes) yielding diethyl 2,2'-(1,3-dioxolane-2,2-
diyl)diacetate (42%). LCMS (m/z): 247.2 (MH+), 0.65 min; 1H NMR (400 MHz, CDCI3)
6 ppm 4.17 (q, J=7.04 Hz, 4 H) 4.03 (s, 4 H) 2.95 (s, 4 H) 1.27 (t, J=7.24 Hz, 6 H).
Ste 2. 2 2'- 1 3-dioxolane-2 2-di | diethanol-d4
To a suspension of LiAlD4 in THF (2.46 g, 58.7 mmol in 40 mL) between -10 to 0 °C was
added a solution of diethyl 2,2'-(1,3-dioxolane-2,2-diyl)diacetate (6.06 g) in THF (20 mL)
over 10 min. The reaction mixture was stirred at 0 °C for 1 h and ed by sequential
addition of water (2.5 mL), 15 wt% NaOH (2.5 mL), and water (7.5 mL). The precipitates
of the ed mixture were removed by filtration and the filter cake was rinsed carefully
with THF. The filtrate was trated and crude 2,2'-(1,3-dioxolane-2,2-diyl)diethanol-
d4 was obtained (92%). 1H NMR (400 MHz, CDCI3) 6 ppm 4.06 (s, 4 H) 2.49 (s, 2 H) 1.98
(s, 4 H).
Step 3. 1,4,8—trioxaspiro|4.5|decane-d4
A mixture of 2,2'-(1,3-dioxolane-2,2-diyl)diethanol-d4 (3.57 g, 21.5 mmol) and 4-
methylbenzenesulfonic acid hydrate (0.204 g, 1.07 mmol) and benzene (150 mL) were
heated for 3 h at ing temperature with Dean-Stark apparatus to remove water. The
reaction mixture was cooled down, washed with sat. NaHC03 (20 mL x 2), and the
aqueous layers were combined, extracted wuth Et20(2 x 20 mL), the organic layers were
combined, washed with brine (30 mL), dried (Na2804), filtered off, and trated
under 20 mbar via rotavap, and a light yellow oil was obtained as crude 1,4,8-
trioxaspiro[4.5]decane-d4 (2.34 g, 73.5% . 1H NMR (400 MHz, CDCI3) 6 ppm 3.98 (s,
4 H) 1.73 (s, 4 H).
Ste 4. dih dro-2H- ran-4 3H 4
The 1,4,8—trioxaspiro[4.5]decane-d4 (2.34 g, 15.8mmol), formaldehyde(37%, 4.6 mL, 63.2
mmol) and pyridine 4-methylbenzenesulfonate(0.198 g, 0.79mmol) were equally splitted
into two microwave vials. Each vial was heated at 80 °C for 30 min and additional 15 min.
The reaction mixtures were combined saturated with NaCl, extracted with EtZO until no
d product found in aqueous layer by 1H-NMR. The ether extracts were combined,
concentrated and the e was purified by flash column chromatography on silica gel
(gradient EtZO/n-pentane) twice yielding dihydro-2H-pyran-4(3H)-one-d4. 1H NMR (400
MHz, CDCI3) 6 ppm 2.50 (s, 4 H).
Step 5. 3,6-dihydro-2H-pyranyl trifluoromethanesulfonate-d4
To a freshly prepared LDA (10.6 mmol) in THF (10 mL) between -75 to -65 °C was
dropwise added a solution of dihydro-2H-pyran-4(3H)—one-d4 (1.05 g) in THF (3.5 mL)
over 10 min. The resulting reaction mixture was stirred at -75 °C for 3 h, followed by
addition of N-(5-chloropyridinyl)-1,1,1-trifluoro-N-
((trifluoromethyl)sulfonyl)methanesulfonamide in THF (4.16 g/5 mL) over 10 min. The
reaction mixture was stirred at -75 °C for 1 h, then with temperature gradually warming up
to room temperature overnight. The reaction mixture was cooled to 0 °C, ed with
D20(10mL), and the two layers were separated, the organic layer was washed
sequentially with D20(10 mL), citric acid (3 x 10 mL, 3 g citric acid in 30 mL water), 1M
NaOH (2 x 10 mL), brine (30 mL), dried (Na2804), trated and the crude oily
product was purified by flash chromatography on silica gel eluted with nt EtZO/n-
pentane (0-60%). The purified product was further purified by distillation purification by
Kugelrohr at 105°C/3 mbar yielding 3,6-dihydro-2H-pyranyl trifluoromethanesulfonate-
d4 (500 mg, 21% yield). 1H NMR (400 MHz, coc13)5 ppm 5.82 (s, 1 H) 2.45 (s, 2 H).
Ste 6. 2- 3 6-dih dro-2H- ran | -4 4 5 5-tetrameth H 3 2-dioxaborolane-d4
A mixture of 3,6-dihydro-2H-pyranyl trifluoromethanesulfonate-d4 (500 mg, 2.12
mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (806 mg, 3.18 mmol),
potassium acetate(644 mg, 6.56 mmol), PdC|2(dppf)-CH2C|2 (86 mg, 0.106 mmol) and p-
dioxane (5 mL) was charged into a microwave reactor vial, purged with argon for 5min,
sealed and heated at 80 °C overnight via oil bath. The reaction mixture was cooled down
to room temperature, diluted with EtOAc(10mL), filtered through a neutral alumina plug
(1 .25' H x 0.75' D), and the filter cake was washed thoroughly with EtOAc. The filtrate
was concentrated yielding crude -dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-d4 in light brown solid . LCMS (m/z): 215.2 (MH+), 0.78 min.
Ste 7. S 3-amino 3 6-dih dro-2H- ran | razin l-N- 2-h drox
phenylethyl)benzamide-d4
A e of 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-d4
(300 mg, 1.4 mmol), (S)(3-aminobromopyrazinyl)-N-(2-hydroxy
phenylethyl)benzamide (694mg, 1.68 mmol), aqueous Na2C03 (2 M, 2.8 mL), and
PdCl2(dppf)-CH2Cl2 (57.2 mg, 0,07mmol) and p-dioxane (6 mL) were charged into a
ave reactor vial, purged with argon for 5 min, sealed and heated at 115 °C for 30
min. The reaction mixture was diluted with EtOAc (15 mL), filtered and the filtrate was
washed with 1M HCI (4 x 30 mL), and the aqueous layers were combined, basified by
solid NaOH to pH 12, extracted with EtOAc (60 mL), dried (Na2804), concentrated and
the first crop of product was ed with some impurities. The EtOAc layer after
aqueous HCI washes was trated and the residue was diluted with DMSO, purified
by C18 reverse phase prep HPLC, and the product fractions were combined, saturated
with Na2C03, extracted with EtOAc (60 mL), and a second crop pure product was
obtained in light yellow solid. The first crop product was purified by flash chromatography
on silica gel eluted with nt e/CH2C|2 ). The two crops of product were
combined and (S)(3-amino(3,6-dihydro-2H-pyranyl)pyrazinyl)-N-(2-hydroxy
phenylethyl)benzamide-d4 (179 mg, 27.9% yield) was obtained. LCMS (m/z): 421.2
(MH+), 0.65 min.
Ste 8. S 3-amino 2 2 6 6-tetradeuterido-tetrah dro-2H- ran l razin l -N-
(2-hydroxy—1phenylethyl)benzamide
A mixture of (S)—4-(3-amino(3,6-dihydro-2H-pyranyl)pyrazinyl)-N-(2-hydroxy
phenylethyl)benzamide-d4 (175 mg) and Pd/C (10%, 22mg) in methanol was stirred
under hydrogen balloon at room temperature for 2 h. The reaction mixture was filtered
through a thin layer of Celite pad, and the filtrate was concentrated to afford crude white
solid. The crude product was ed by flash tography (0-60% acetone/CHZCIZ)
and pure product was dissolved in acetonitrile/water (1:1, 10 mL), frozen and lyophilized
to (S)—4-(3-amino(2,2,6,6-tetradeuterido-tetrahydro-2H-pyranyl)pyrazinyl)-N-(2-
hydroxyphenylethyl)benzamide in a white powder (64%). LCMS (m/z): 423.2 (MH+),
0.60 min; 1H NMR (400 MHz, CDCI3) 6 ppm 7.93 - 8.01 (m, 2 H), 7.92 (s, 1 H), 7.82 - 7.89
(m, 2 H), 7.38 - 7.47 (m, 4 H), 7.31 - 7.37 (m, 1 H), 6.90 (d, J=7.04 Hz, 1 H), 5.32 (dt,
J=6.95, 4.55 Hz, 1 H), 4.68 (br. s., 2 H), 4.06 (d, J=4.30 Hz, 2 H), 2.93 (tt, 4, 4.40
Hz, 1 H), 1.79 - 1.99 (m, 4 H).
Examples 136 and 137
hydroxy-1phenylethyl)benzamide
Scheme 61
0 /OH
NH2 N/\©H 1. Pd/C, H2
NI \ NI \ OH/\©+ ON/\©
/ N 2. chiral separation
O O 0
To a solution of (S)(3-amino(furanyl)pyrazinyl)-N-(2-hydroxy
phenylethyl)benzamide (75 mg, 0.187 mmol) in MeOH (1.873 mL) was added platinum
(IV) oxide (12.76 mg, 0.056 mmol). The on was degassed by N2 stream for 15 min.
After flushed with hydrogen gas and equipped with a hydrogen balloon, the reaction
mixture was stirred for 24 h. The reaction mixture was filtered h Celite. After volatile
materials were d, the crude product was re-setup the reaction. The reaction
mixture was stirred for another 24 h. LCMS (m/z): more side products were formed. The
reaction mixture was ed through Celite. After volatile materials were removed, to a
solution of the crude product in MeOH (1.873 mL) was added Pd-C (100 mg, 0.094
mmol). The solution was degassed by N2 stream for 15 min. After flushed with hydrogen
gas and ed with a hydrogen balloon, the reaction mixture was stirred for 24 h.
LCMS (m/z): all s.m. disappeared. The reaction mixture was filtered through Celite. After
volatile materials were removed, the crude t was purified by flash chromatography
(EtOAc in DCM) ng 4-(3-amino(tetrahydrofuranyl)pyrazinyl)-N-((S)
hydroxyphenylethyl)benzamide (9 mg, 12%). LCMS (m/z): 405.2 (MH+), 0.58 min; 1H
NMR (400MHz, CD3OD) 6 ppm 7.96 - 7.86 (m, 2 H), 7.80 (s, 1 H), 7.77 - 7.70 (m, 2 H),
7.38 - 7.32 (m, 2 H), 7.30 - 7.21 (m, 2 H), 7.21 - 7.12 (m, 1 H), 5.14 (m, 1 H), 4.08 - 3.97
(m, 1 H), 3.99 - 3.89 (m, 1 H), 3.89 - 3.67 (m, 4 H), 3.56 - 3.38 (m, 1 H), 2.33 - 2.04 (m, 2
H), 1.24 - 1.13 (m, 2 H). The racemic product was resolved in chrial HPLC (AD column,
5mL/min, MeOH= 30%, SFC) yielding 4-(3-amino((S)—tetrahydrofuranyl)pyrazin
yl)-N-((S)hydroxyphenylethyl)benzamide and 4-(3-amino((R)-tetrahydrofuran
yl)pyrazinyl)-N-((S)hydroxyphenylethyl)benzamide — 3.4 mg of polar enantiomer
(Rt = 2.12 min) and 3.5 mg of less-polar enantiomer (Rt = 2.66 min). The absolute
stereochemistry was arbitrarily assigned.
Table 4. nds ed using Method 2 described above.
Example Structure Name MH+ Rf NMR
(mm)
o {OH (S)—4-(3-am|no-
138 N/:\© 6-(furan yl)pyraziny|)—
N|\ 01.2 2.84
ydroxy_1_
/ N phenylethyl)benz
amide
Examplem MH+ R-t NMR
(mm)
H NMR (400MHz ,CD30D)
0 8 ppm 8.43 (s, 1
“1va H), 8.40 (d, J =
NH N 5.1 Hz,1 H), 8.24 (s, 1 H), .01
'(3'am'n9'§'(3'. (d, J = 8.2 Hz, 2 H), 7.96 (s, 1
1 H), 7.89 (d, J = 8.6 Hz, 2 H),
[N SOZMe methy'pfl'd'wr'
y|)pyraZIny|)- 7.84 (s, 1
139 4741 049 H), 7.72 (s, 1 H),
/ N-(3- 7.63 - 7.58 (m, 1 H), 7.55 (d, J
l (methylsulfony|)b :51 Hz, 1 H),4.69 (s, 2 H),
benzamide 3.10 (s. 3 H), 2.48 (s. 3 H)
1H NMR (400MHz ,CD30D)
(2'am'“°'.
F 0 (OH 5 ppm 8.97 (s, 1 H), 8.65 — 8.53
F 5-(1-methyl-1H- (m, 1 H), 8.18 (d, J = 2.3 Hz, 1
“”2 E/\© imidazol H), 7.88 (t, J = 7.4 Hz, 1 H),
140 N\/ y|)pyridiny|)—2— 7.74 (d, J = 2.3 Hz, 1 H), 7.67
| 4322 0'46
luorO-N-(2- (d, J = 1.6 Hz,1 H), 7.47-7.39
hydroxy_1_ (m, 4 H), 7.36 (t, J = 7.6 Hz, 2
/ N/ phewletWDbenz H), 7.31 - 7.25 (m, 1 H), 5.34 -
N=/ 5.17 (m, 1 - 3.78 (m, 5
amide H), 3.98
Synthesis of (S)— 1H NMR (400 MHz, CD3OD) 6
A_(2_amino_5_(1_ 8.11 (m, 1 H), 7.76 (m, 2 H),
methyl-1 H-1 23_ 7.37 (m, 1 H), 7.27 (m, 2 H),
7.20 (m, 3 H), 5.09 (m, 1
l_5_ H),
F o ?/ 4.03 (s, 3 H), 3.73 (m, 2 H)
yl)pyridin_3_yl)_
141 NH2 485.2 0.64
N/ F
I HAQ N-(1-(3- chlorophenyl)—2-
\ Cl hydroxyethy|)-
2,6-
\N\N=\N
difluorobenzami
WO 66188
Example (nfitn) NMR
1H NMR (400MHz, DMSO-d6)
8 8.89 (s, 1 H), 8.70 (m, 2 H),
(S)—4-(3-amino- 8.65 (m, 1 H), 8.22 (m, 2 H),
6-(pyridin 7.80 - 7.62 (m, 3 H), 7.49 - 7.20
y|)pyraziny|)— (m, 5 H), 7.08 (m, 1 H), 5.03
142 2—fluoro-N-(2- 0.53 (m, 1 H), 3-65 (d, J = 4 H212 H)
hydroxy
phenylethyl)benz
amide
1H NMR (400MHz, DMSO-d6)
8 8.72 - 8.51 (m, 4 H), 8.43 (s,
1 H), 7.78 - 7.53 (m, 3 H), 7.40
methylpyridin £3753? (m; 4H?)’570-:2( (ma 1H?)
y|)pyraziny|)— ' m’ ’ ' m’ ’
143 0.52 3.65 (d, J — 8 Hz, 2 H)_
2—fluoro-N-(2-
y
phenylethyl)benz
amide
1H NMR (400MHz ,CD30D) 8
9.86 (d, J = 1.2 Hz, 1 H), 9.20
(3-amino- (d, J = 5.9 Hz, 1 H), 8.82 (s, 1
6-(pyridazin_4_ H), 8.49 (dd, J = 2.3, 5.9 Hz, 1
y|)pyraziny|)— H), 7.87 - 7.78 (m, 1 H), 7.70 -
7.62 (m, 2 H), 7.40
144 2—fluoro-N-(2 7.32 (m, 2
H), 7.27 (t, J = 7.4 Hz, 2 H),
hydroxy_1_
7.20 (d, J = 7.4 Hz, 1 H), 5.14
pheny'ethy'wenz (t, J = 6.1 Hz, 1 H), 3.85 - 3.72
amide
(m, 2 H)
1H NMR (400 MHz, CD30D) 6
-(3-amino ppm 8.17 (s, 1 H) 8.03-7.95 (m,
(1,3-dimethyl- 2 H) 7.93-7.83(m, 2 H) 7.76 (d,
1H_pyrazol_4_ J=8.22 Hz, 2 H) 7.72-7.59 (m, 2
145 H) 4-72 (3’ 2 H) 3-86 (S! 4 H)
y|)pyraziny|)— 0.65
3.12 (s, 3 H) 2.47 (s, 3 H)
2—fluoro-N-(3-
(methylsulfony|)b
enzyl)benzamide
Example MH+ Rf NMR
(mm)
1H NMR (400MHz, CD30D) 8
8.17 - 8.09 (m, 1 H), 8.03 - 7.90
(m, 3 H), 7.88 - 7.73 (m, 3 H),
7.38 - 7.30 (m, 2 H), 7.31 - 7.23
(m, 2 H), 7.21 - 7.14 (m, 1 H),
.21 -5.10(m, 1
146 4153 059 H), 3.84 (s, 3
H), 3.82 - 3.75 (m, 2 H)
N_(2_hydroxy_1_
ethyl)benz
amide
1H NMR (400 MHz, CD30D) 5
ppm 8.30 (t, J=8.02 Hz, 1 H)
"(3'amm0'5'(1', 8.05 (s, 1 H) 7.97-7.83 (m, 4H)
methyl-1 H' 7.75-7.67(m, 2 H) 7.64-7.55
pyrazol (m, 2 H) 4.82 (d, J=5.87 Hz, 2
147 yI)pyrazinyl)- 481.3 0.633 H) 3.99 (s, 3 H) 3.07 (s, 3 H)
2—fluoro-N-(3-
lsulfony|)b
enzyl)benzamide
H NMR z, CD30D) 8
{0H 8.25 (s, 1 H), 8.05 (s, 1 H),
F (S)_4_(3_amino_
7.92 (s,1 H), 7.89-7.79 (m, 1
NH2 6'(1'methy"1H'
H), 7.77 - 7.59 (m, 2 H), 7.47 -
N / Mmpyrazo'jA" 7.39 (m, 2 H), 7.39 - 7.31 (m, 2
148 \ 'N y|)pyraZ|ny|)- 4332 054 H), 7.31 -7.21 (m, 1 H), 3.91
2-1‘|Uor0-N-(2- (s, 3 H), 3.89 - 3.78 (m, 1 H),
/ hydroxy 1.42- 1.28 (m, 1 H)
N—KJ phenylethyl)benz
/ amide
1H NMR (400 MHz, CD30D) 5
/OH (S)(2-am'“°-
ppm 8.73 (d, J=7.83 Hz, 1 H)
? 5-(1-methyl-1H- 8.08 (d, J=2.35 Hz, 1 H) 7.93-
NH2 MD1,2,3-triazol 7.73 (m, 1 H) 7.48 (d, J=7.83
N \ yI)pyridinyl)- Hz, 1 H) 7.41 - 7.07 (m, 6 H)
149 | 5.22 - 5.01 (m. 1 H) 4.04 (S. 3
/ CI N-(1-(3- 463.3 0.61
chlorophenyl)—2- H) 3.86 - 3.57 (m, 2 H) 2.44 -
/ I‘l/ hydroxyethy|) 2'24 (m’ 3 H)
N=N methylbenzamid
Example (nfitn) NMR
1H NMR (400MHz,
METHANOL-d4) 5 ppm 8.82 -
8.62 (m, 1H), 8.12 (d, J=2.0 Hz,
150 0'67
1H), 8.00 - 7.76 (m, 2H), 7.58 -
7.17 (m, 7H), 6.49 (d, J=2.0 Hz,
1H), 5.20 (d, J=5.9 Hz, 1H),
3.95 - 3.69 (m, 5H)
1H NMR z,
METHANOL-d4) 5 ppm 7.90
(m, 1 H), 7.85 (m, 1 H), 7.81
1H-pyrazol (m, 1 H), 7.55 (s, 1 H), 7.42 -
y|)pyridiny|)- 7.34 (m, 3 H), 7.30 - 7.24 (m, 2
151 069
N-(1-(3- H), 7.21 (m,1 H), 5.10 (m,1
chlorophenyl)—2— H), 3.82 - 3.71 (m, 2 H), 3.75
hydroxyethyl)—2— (S: 3 H): 2-31 (S. 3 H)
1H NMR (400MHz,
(S)—4-(2-amino— METHANOL-d4) 5 ppm 7.92
- (m,1 H), 7.87 (m, 1 H), 7.81
1H_pyrazol_4_ (m, 1 H), 7.76 (s, 1 H), 7.41 -
- - 7.34 (m, 3 H), 7.30 - 7.24 (m, 2
152 gm'3'yl)' 0.69 H), 7.21 (m,1 H), 5.10 (m,1
'( '( '
H), 3.85 - 3.67 (m, 2 H), 3.76
chlorophenyl)—2-
(S, 3 H), 2.26 (S, 3 H)
hydroxyethyl)—2—
luorobenzamide
1H NMR (400MHz,
(S)_N_(2_amino_
METHANOL-d4) 5 ppm 7.88
1_phen,ylethyI)_4_
(m, 2 H), 7.84 (m, 1 H), 7.74
(2-am'n0<1a3- (m, 1 H), 7.44 - 7.33 (m, 6 H),
153 0-55 7.33- 7.27
(m, 1 H), 5.40 (m, 1
H), 3.76 (s, 3 H), 3.38 (m, 2 H),
2.25 (s, 3 H)
Rt NMR
Example
(min)
1H NMR (400MHz, CD30D) 5
7.77 (m, 3 H), 7.37 (m, 2 H),
7.27 (m, 1 H), 5.1 (m, 1 H),
3.76 (m, 2 H), 3.67 (s, 3 H),
2.18 (s, 3 H), 2.11 (s,3 H)
154 0.63
1H NMR (400MHz, CD30D) 8
8.18 (s, 1 H), 7.98 (s, 1 H),
_(3_amino_6_(1_
7.84 (s, 1 H), 7.74 (m, 1 H),
methyl'1 H'
7.68 - 7.62 (m, 2 H), 7.31 - 7.12
pyraz°"4' (m, 5 H), 3.84 (s, 3 H), 3.01 (m,
155 y|)pyraziny|)- 0.81 1 H), 212 (m, 1 H), 124 (m, 2
2—fluoro-N-(2- H)
phenylcycloprop
y|)benzamide
H NMR (400MHz, CD30D) 8
8.03 (s, 1 H), 7.77 (m, 1 H),
7.64 (m, 1 H), 7.41 (m, 1 H),
7.34 (m, 2 H), 7.27 (m, 2 H),
7.19 (m, 1 H), 5.13 (m, 1 H),
155 0-74 3.77
(m, 2 H), 2.46 (s, 3 H),
2.30 (s, 3 H)
1H NMR z, CD30D) 8
8.86 (m, 1 H), 8.19 (m, 1 H),
7.77 (m, 1 H), 7.68 - 7.56 (m, 2
methylisoxazol— H), 7.36 - 7.31 (m, 2 H), 7.30 -
_y|)pyrazin_2_ 7.23 (m, 2 H), 7.18 (m, 1 H),
157 0-74 5.12
yl)_2_fluoro_N_(2_ (m, 1 H), 3.77 (m, 2 H),
2.62 (S, 3 H)
hydroxy—1-
phenylethyl)benz
amide
Example MH" R-t NMR
(mm)
1H NMR z, CD30D) 8
8.19 (d, J = 2.3 Hz, 1 H), 7.91
(s, 1 H), 7.85 (m, 1 H), 7.77 (d,
methylisoxazol— J = 0.7 Hz, 1 H), 7.65 (d, J =
-y|)pyridiny|)— 2.3 Hz, 1 H), 7.51 - 7.23 (m, 6
158 433-3 0-51
2_fluorO_N_(2_ H), 5.29-5.11 (m,1 H), 3.99-
3.77 (m, 5 H)
hydrOXy
phenylethyl)benz
amide
(S)—4-(2-amino-
'(3'Cya“°'1' 1H NMR z, CD30D) 8
methyl-1H- 8.3 (m, 1 H), 8.08 (s, 1 H), 7.88
(m,1 H), 7.73 (m, 1 H), 7.48 -
159 475.3 0.64 7.7.33 (m, 3 H), 7.28 (m, 1 H),
luoro-N-(1-(3— 7.17 (m, 1 H), 7.01 (m, 1 H),
|uoropheny|)—2- 5-21 (m. 1 H). 3-99 (S. 3 H).
3.88 (m, 2 H)
'(3'Cya“°'1' 1H NMR (400MHz, CD30D) 8
methyl-1H- 8.82 (m1 H), 8.17 (m, 1 H),
pyrazol 8.07 (s 1 H), 7. 95 (m, 1 H),
180 y|)pyridiny|)— 491.1 0.88 7.80 (m, 1 H), 7. 38 (m, 3 H),
N-(1-(3- 7.27 (m, 3 H),7 .21 (m, 1 H),
chlorophenyl)—2- 5-10 (m, 1 H).3-92 (S. 3 H).
3.78 (m, 2 H)
1H NMR (400MHz, CD30D) 8
8.59 (m, 1 H), 8.12 (m, 1 H),
1H-Imldazol. .
7.88 (m, 1 H), 7.88 (m, 1 H),
y|)pyridiny|) 7.53 (s, 1 H), 7.48 - 7.38 (m, 5
161 4462 0'45
luoro-N-(2- H), 7.41 -7.31 (m,1 H), 7.31 —
y 7.23 (m, 1 H), 5.23 (m, 1 H),
phenylethyl)benz 3.95 - 3.77 (m, 2 H), 3.70 (s, 3
amide H), 2.88 (s, 3 H).
Example MH+
1H NMR (400MHz, CD30D) 8
8.88 (m, 1 H), 8.12 (m, 1 H),
1H-imidazoI 7.88 (m, 1 H), 7.70 (m, 1 H),
y|)pyridiny|)— 7.53 (s, 1 H), 7.50 - 7.39 (m, 3
162 0.56
N-(1-(3- H), 7.35 (m, 2 H), 7.32 (m, 2
chlorophenyl)—2- H), 5.28 - 5.11 (m, 1 H), 3.90 -
yethy|) 3.78 (m, 2 H), 3.70 (s, 3 H),
2.88 (s, 3 H)
(S)—4-(2-amino- 1H NMR (400MHz, CD30D) 8
8.84 (m, 1 H), 8.12 (m, 1 H),
1H-imidazoI 7.88 (m,1 H), 7.88 (s, 1 H),
7.52 (s,1 H), 7.45 (m, 1 H),
163 0.48 7.43 (m, 1 H), 7.38 (m, 1 H),
luoro-N-(1-(3-
7.25 (m, 1 H), 7.18 (m, 1 H),
|uoropheny|)—2- 7.01 (m, 1 H),4.91 (m, 1 H),
3.87 (m, 2 H), 3.7 (s, 3 H), 2.88
(s, 3 H)
1H NMR (400MHz ,CD30D) 8
9.17 (s, 1 H), 8.90 (s, 1 H),
8.85 (br. s.,1 H), 8.28 (d, J =
2.0 Hz,1 H), 8.18 (d, J = 2.0
164 luoro-N-(2- 0.57
Hz,1 H), 7.91 (t, J = 7.8 Hz,1
hydroxy- 1-
H), 7.55 - 7.25 (m, 8 H), 5.23
phenylethyl)benz (d, J = 5.1 Hz,1 H), 3.96 - 3.75
(m, 2 H)
1H NMR (400MHz, CD30D) 8
8.58 (m 1 H) 8.53 (s, 1 H)
methylisoxazol- 8.00 (m 1 H) 788 (m, 1 H
ridiny|)— 7.81 (m, 1 H) 738 (m,2H
165 0.62
2-fluoro-N-(1-(3- 7.29 (m 1 H), .15(m, 1 H
|uoropheny|)—2- 7.08 (m 1 H) 93 (m, 1 H
.13(m,1 H) 78 (m,2H
2.49 (s,3 H)
Rt NMR
Example
(min)
1H NMR (400MHz, CD30D) 8
ppm 8.32 (s, 1 H), 8.06 (m, 1
H), 8.02 (m, 1 H), 7.91 (m, 1
166 0'7
H), 7.57 - 7.4 (m, 4 H), 7.39 -
7.24 (m, 4 H), 5.19 (m, 1 H),
3.86 (m, 2 H), 2.41 (s, 3 H)
1H NMR z, CD30D) 8
1,2,4-triazoI 8.71 - 8.54 (m, 1 H), 8.29 (d, J
= 2.2 Hz,
. . 1 H), 7.94 (m, 2 H),
167 fiffirgln'3'y')‘ 0.59 7.81 (m, 1 H). 7.38 (m, 3 H).
7.28 (m, 2 H), 7.22 (m, 1 H),
Ch'oroF’he“y')'2' 5.12 (m, 1 H), 3.95 (s, 3 H),
hydrOXyethy|) 3.86 - 3.65 (m, 2 H)
luorobenzamide
(S)'4'(2'am'“°' 1H NMR (400MHz, CD30D) 8
'(1'methyl'3' ppm 8.54 (m, 1 H), 7.94 - 7.84
uoromethy|)- (m, 1 H), 7.83- 7.74 (m, 1 H),
1H-Pyrazol 7.75 - 7.68 (m, 1 H), 7.63 - 7.54
168 yI)pyridinyI) 0.66 (m, 1 H), 7.41 - 7.30 (m, 4 H),
luoro-N-(2- 7.29 - 7.22 (m, 2 H), 7.21 - 7.11
hydroxy_1_ (m,1 H), 5.21 -5.06 (m, 1 H),
phenylethymenz 4.02 - 3.93 (m, 3 H), 3.86 - 3.65
(m’ 2 H)
amide
1H NMR (400MHz, CD30D) 8
7.87 (d, J = 2.0 Hz, 1 H), 7.91
1H_pyrazol_4_ (d, J = 2.3 Hz,1 H), 7.81 (t, J =
. . 7.8 Hz,1 H), 7.75 (s, 1 H), 7.41
yl)pyr'd'n_3_yl)'2'
169 0.61 - 7.30 (m, 4 H), 7.27 (t, J = 7.6
luorO'N'Q'
Hz, 2 H), 7.20 (d, J = 7.0 Hz, 1
hydroxy'1' H), 5.13 (t, J = 5.9 Hz, 1 H),
phenylethyl)benz 3.84 - 3.69 (m, 5 H), 2.26 (s, 3
amide H)
2014/062913
Example MH+ Rf NMR
(mm)
1H NMR (400MHz, CD30D) 8
7.97 (d, J = 2.0 Hz, 1 H),7.93
1H-pyrazol (d, J = 2.0 Hz, 1 H), 7.89 (t, J =
yl)pyridiny|)—2— 7.8 Hz, 1 H), 7.63 (s, 1 H), 7.48
170 446's 0'62
luoro-N-(2- - 7.31 (m, 6 H), 7.27 (d, J = 7.0
y Hz, 1 H), 5.20 (t, J = 5.9 Hz, 1
H), 3.91 - 3.74 (m, 5 H), 2.41 -
2.36 (m, 3 H)
1H NMR (400MHz, CD30D) 8
8.16 (d, J = 2.0 Hz, 1 H), 8.13
(d, J = 2.3 Hz, 1 H), 8.09 (s,1
1H-pyrazoI H), 7.94 - 7.88 (m, 2 H), 7.51 -
. . 7.40 (m, 4 H), 7.37 (t, J = 7.6
171 y|)pyrldln 3 yl) 2_ _ _ _ 476.3 0.6
Hz, 2 H), 7.29 (d, J = 7.0 Hz, 1
luorO'N'Q'
H), 5.23 (d, J = 6.7 Hz, 1 H),
hydroxy'1' 4.33 (t, J = 5.1 Hz, 2 H), 3.94 -
3.80 (m, 2 H), 3.75 (t, J = 5.1
Hz, 2 H)
1H NMR (400MHz, CD30D) 8
8.17 (d, J = 2.3 Hz, 1 H), 8.12
(d, J = 2.0 Hz, 1 H), 8.09 (s,1
1H-pyrazol H), 7.94 - 7.88 (m, 2 H), 7.52 -
172 yl)pyridiny|)— 510.3 0.67 7.44 (m, 3 H), 7.38 — 7.32 (m, 2
N-(1-(3- H), 7.31 (d, J = 2.3 Hz, 1 H),
chlorophenyl)—2- 5-20 (S. 1 H). 4-33 (t. J = 5.1
hydroxyethyl)—2— HZ, 2 H), 3.93 - 3.80 (m, 2 H),
3'75 (t’ J = 5'1 HZ’ 2 H)
luorobenzamide
Method 3
Example 173
S nthesis of 4- 3-amino tetrah dro-2H- ran | razin | -N- 3-chlorobenz |
fluorobenzamide
2014/062913
Scheme 62
—Qe ‘St 1
MHz F 0 m;
NJ\(BV O
NH2 0/
I / Pdd fCI-DCM
/N 0 (pp) 2
HO N|\ LiOH(1M)
‘ila ’
F , DME / N
OH THF,MeOH
670/0
F 0
Step;
F O
NH2 OH
NI \ NH2
PyBrop,HOBt 3
/N + HZN —> N \
DIEA,DMF /N Cl
C' 87%
Ste 1. meth l4- 3-amino tetrah dro-2H- ran l razin uorobenzoate
To a solution of methyl 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate
(259 mg, 1.308 mmol), 3-bromo(tetrahydro-2H-pyranyl)pyrazinamine (225 mg,
0.872 mmol), and PdC|2(dppf) (64 mg, 0.087 mmol) was added DME (6.5 mL) and 2 M
Na2C03 solution (3.2 mL). The reaction mixture was heated at the microwave synthesizer
(120 °C, 10 min). The reaction mixture was worked up with EtOAc. The organic layer was
washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and
concentrated in vacuo. The crude product was purified by flash chromatography (gradient
EtOAc in e) to yield the desired product (192 mg, 67%). LCMS (m/z): 332.2 (MH+),
0.63 min.
Ste 2. 4- 3-amino tetrah dro-2H- ran l razin lfluorobenzoic acid
To a solution of methyl 4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)—2-
fluorobenzoate (104 mg, 0.314 mmol) in THF (698 uL) and MeOH (349 uL) was added
LiOH (1 M solution) (565 uL, 0.565 mmol). The reaction mixture was stirred for 1 h at
room temperature. The reaction mixture was quenched with 1N HCI on up to pH 5,
and worked up with EtOAc. The organic layer was washed with water and brine, dried
2014/062913
over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product
was used forthe next step. LCMS (m/z): 318.3 (MH+), 0.5 min.
Ste 3. 4- 3-amino tetrah dro-2H- ran l 2- l-N- 3-chlorobenz l
fluorobenzamide
To a solution of mino(tetrahydro-2H-pyranyl)pyrazinyl)f|uorobenzoic
acid (17 mg, 0.054 mmol) and (3-chlorophenyl)methanamine (8.34 mg, 0.059 mmol) in
THF (268 uL) was added PyBroP (27.5 mg, 0.059 mmol), DIEA (28.1 uL, 0.161 mmol)
and HOBT (9.02 mg, 0.059 mmol). The reaction mixture was stirred overnight at room
temperature. All volatile al was removed in vacuo and dissolved in DCM. The crude
product dissolved in DCM was loaded to flash chromatography column (gradient EtOAc in
heptane) providing 4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)—N-(3-
chlorobenzyl)f|uorobenzamide in 87% yield. LCMS (m/z): 441.1 (MH+), 0.79 min. 1H
NMR (400MHz, DMSO-dg) 8 ppm 7.92 (s, 1 H), 7.74 (m, 1 H), 7.63 (m, 2 H), 7.35 (m, 4
H), 6.14 (s, 1 H), 4.48 (m, 2 H), 3.92 (m, 2 H), 3.43 (m, 2 H), 1.73 (m, 4 H).
Example 174
S nthesis of S -N- 2-amino 3-chloro hen l eth l 3-amino tetrah dro-2H- ran-
4- l razin lfluorobenzamide
Scheme 63
F O
F o /NHBoc
NH2 OH {NHBoc ME
NH2 N
/ 3
N EDC,HOAt
IN + HZN —. N|\
\ ’N Cl
DIEA,THF
0 O
F 0 {NH2
Step 6
NH2 H
_. I
DCM EN
Ste 1. S -tert-but l 2- 4- 3-amino tetrah dro-2H- ran l razin l
fluorobenzamido)—2-(3-chlorophenyl )ethyl )carbamate
To a solution of mino(tetrahydro-2H-pyranyl)pyrazinyl)f|uorobenzoic acid
(35 mg, 0.110 mmol) in DMF ( 368 uL) was add (S)—tert-butyl (2-amino(3-
chlorophenyl)ethyl)carbamate (33.9 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol),
EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 uL, 0.331 mmol). The reaction mixture was
stirred at room ature for 3 h. The reaction mixture was partitioned n EtOAc
and water. The organic layer was washed by NaHC03, water and brine, dried over
anhydrous sodium e, filtered off, and concentrated in vacuo yielding crude (S)—tert—
butyl (2-(4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)f|uorobenzamido)(3-
chlorophenyl)ethyl)carbamate (>99%).
Ste 2. S -N- 2-amino 3-chloro hen l eth l 3-amino—6- tetrah dro-2H- ran
yl)pyrazinyl)—2-fluorobenzamide
The crude rt-butyl (2-(4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)
fluorobenzamido)—2-(3-chlorophenyl)ethyl)carbamate was dissolved in DCM (1.0 mL).
After TFA (0.3 mL) was added, the reaction mixture was stirred at room temperature for
min. The reaction mixture was diluted with toluene and trated to dryness. The
crude product was purified by reverse phase prep HPLC. The pure fractions were
combined and lyophilized yielding (S)—N-(2-amino(3-chlorophenyl)ethyl)(3-amino
hydro-2H-pyranyl)pyrazinyl)f|uorobenzamide as TFA salt (50% yield over 2
steps). LCMS (m/z): 470.1 (MH+), 0.67 min; 1H NMR (400MHz, CD3OD) 6 ppm 7.95 -
7.85 (m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.64 (d, J=12.1 Hz, 1H), 7.55 (s, 1H), 7.49 - 7.38 (m,
3H), 5.49 (dd, J=5.7, 8.8 Hz, 1H), 4.04 (dd, J=3.1, 11.3 Hz, 2H), 3.57 (dt, J=2.0, 11.5 Hz,
2H), 3.51 - 3.41 (m, 2H), 2.98 - 2.88 (m, 1H), 1.97 - 1.76 (m, 4H).
Example 175
S nthesis of 4- 3-amino 1r4S h drox c clohex l razin l-N- S 3-bromo-
-fluorophenyl )—2-hyd roxyethyl )—2-fluorobenzamide
Scheme 64
2014/062913
Steg 1 Step 2
O Pd(dppf)CI2DCM
OH 1—>)(COCI)2 :OJ< BISPIN KOAc
2)t—BuOH DMF 100°C 64hr
Br F
Steg g
o OJ<
—N Pd(dppf)C|2-DCM
(/NfNH2 2M Na2003 NH2 0J<
O + —>
\B F
I DME, 100°C, 4hr N \ F
O CI
Ste w Stegg
NB NI/KKEj/KO Pd<dppf>CI2-DCM
2M Na2co3 DME
CH3CN o 00
100°C, 2 h,
Br 0 O
F O F O J<
F O
0J< NH2 NH2 0
NH2 OJ<
N/ N/
I S—Qte Q I steal N/
\ N \ N
H2, Pd—C \
3 N HCI
—> —>
MeOH/DCM, 6 h
MeCN/water
O O O O
F O J< F O J<
NH2 0 NH2 0
N/ _l231€ § N/ _l231€ 2&1—
| |
\ N \ N
NaBH4 1. TBSCI
MGOH, THF 2. 4 M HCI in dioxane
-78 °C, 2 h
0 crude (trans:cis ~8: 1) (3H
F o F 0 {OH
Step
\ N —> /N Br
+ CIHH2N
DIEA
trans only Br
Ste 1. tert-But | 4-bromofluorobenzoate
To a stirred solution of 4-bromofluorobenzoic acid (60 g, 274 mmol) in anhydrous THF
(700 mL) at 0 0C was added DMF (2 mL) followed by oxa|y| chloride (48 mL, 548 mmol)
portionwise over 1 hour. The mixture was stirred at 0 °C for 30 min, and then at room
temperature for 1 hour. The solvent was d under reduced pressure, and the
residue dissolved in DCM (700 mL). tert-Butyl alcohol (97 g, 1315 mmol) and pyridine
(150 mL) were added, and the on mixture was stirred at room temperature for 64 h.
The mixture was transferred to a separating funnel and washed with water (400 mL), 2 N
NaOH s solution (400 mL) and brine (2 x 200 mL), dried over magnesium sulfate,
ed and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (0 to 5% ethyl acetate in heptane over 30 min) to give tert-
butyl 4-bromofluorobenzoate (60 g, 80%) as an oil. LCMS (m/z): 218 / 220 (MH+ (-
tBu)), 1.11 min; 1H NMR (500 MHz, CDCI3) 6 ppm 7.81 - 7.71 (m, 1 H) 7.39 - 7.30 (m, 2
H) 7.29 (s, 1 H) 1.68 - 1.55 (m, 9 H).
Step 2. tert—Butyl 2-f|uoro(4,4,5,5-tetramethyI-1,3,2-dioxaboro|any|)benzoate
A 2 L bottomed flask was charged with tert—butyl 4-bromofluorobenzoate (30 g,
114 mmol), bis(pinoco|ato)diboron (41.5 g, 164 mmol), potassium acetate (32.1 g, 327
mmol), PdCI2(dppf)-CH2C|2 (2.67 g, 3.27 mmol) and 1,4-dioxane (500 mL). The reaction
mixture was degassed with argon for 15 min, then heated to 95 OC and maintained at this
temperature for 16 h. After cooling down, the reaction mixture was evaporated to
dryness, dissolved in DCM (300 mL), and filtered over celite washing with DCM (3 x 100
mL). The filtrate was washed with water (200 mL) and brine (2 x 200 mL), dried over
magnesium sulfate, filtered and concentrated. The e was ed using flash
chromatography on silica gel (0 to 10% EtOAc in heptane over 30 min), giving tert—butyl 2-
(4,4,5,5-tetramethyl-1,3,2-dioxaboro|anyl)benzoate (27 g, 90%) as a solid.
LCMS (m/z): 267 (MH+ ), 1.23 min; 1H NMR (500 MHz, DMSO-dg) 8 ppm 7.83 (t, 1
H) 7.57 (d, 1 H) 7.43 (d, 1 H) 1.62 -1.46 (m, 9 H) 1.34 - 1.25 (m, 12 H).
Ste 3. tert—But |4- 3-amino razin |f|uorobenzoate
A 2 L bottomed flask was charged with tert—butyl 2-fluoro(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)benzoate (54 g, 151 mmol), 2-aminochloropyrazine (19.54 g,
151 mmol), 2 N sodium carbonate (158 mL, 317 mmol) and DME (600 mL). The on
mixture was degassed for 10 min using argon, and then PdCl2(dppf)-CH2Cl2 (6.16 g, 7.54
mmol) was added. The reaction mixture was heated to 100 oC and maintained at this
temperature for 4 h. After cooling down, the reaction mixture was poured into water (400
mL) and extracted with EtOAc (3 x 200 mL). The combined organics were washed with
brine (3 x 200 mL), dried over magnesium sulfate, filtered and concentrated. The crude
al was purified using flash tography on silica gel (0 to 70% EtOAc in
heptane over 50 min), giving tert—butyl 4-(3-aminopyraziny|)f|uorobenzoate (37.7 g,
86%) as a solid. LCMS (m/z): 290 (MH+), 0.80 min; 1H NMR (400 MHz, DMSO-dg) 8
ppm 7.98 (d, 1 H) 7.91 -7.81 (m, 2 H) 7.65 -7.46 (m, 2 H) 6.35 (br. s., 2 H) 1.54 (s, 9 H).
Ste 4. terf-but |4- 3-aminobromo razin |f|uorobenzoate
To a d solution of tert—butyl 4-(3-aminopyraziny|)f|uorobenzoate (37.7 g, 130
mmol) in acetonitrile (800 mL) at 0 0C was added N-bromosuccinimide (23.19 g, 130
mmol) in one portion. The reaction was stirred at 0 °C for 2 h, then quenched with
saturated NaHC03 solution (200 mL) and stirred at 0 °C for 30 min. The mixture was
diluted with water (300 mL) and extracted with EtOAc (3 x 250 mL). The combined
organics were washed with water (200 mL) and brine (2 x 200 mL), dried over
magnesium sulfate, filtered and concentrated. The crude material was purified using
flash chromatography on silica gel (0 to 40% EtOAc in heptane over 40 min), giving tert-
butyl 4-(3-aminobromopyrazinyl)f|uorobenzoate (30.9 g, 64%) as a solid. LCMS
(m/z): 368/370 (MH+), 1.03 min; 1H NMR (400 MHz, DMSO-dg) 8 ppm 8.14 (s, 1 H) 7.97
-7.74 (m, 1 H) 7.62 - 7.39 (m, 2 H) 6.64 (s, 2 H) 1.54 (s, 9 H).
Ste 5. Tert-but |4- 3-amino 1 4-dioxas iro 4.5 decen | razin |
fluorobenzoate
To utyl minobromopyrazinyl)fluorobenzoate (5.17 g, 46.2 mmol) in
DME (115 mL) were added 4,4,5,5-tetramethyl(1,4-dioxaspiro[4.5]decenyl)-1,3,2-
dioxaborolane (15.36 g, 57.7 mmol), PdC|2(dppf).CH2C|2 adduct (1.885 g, 2.309 mmol),
and then 2 M aqueous solution sodium carbonate (19.57 g, 185 mmol). The reaction
mixture was heated at 100 °C overnight. LCMS indicated the reaction was ted.
The reaction was coolded down. To the mixture was added 1000 mL of EtOAc and 300
mL of water. The resulting mixture was d for 30 min, and the organic layer was
separated. The aqueous layer was ted with EtOAc (3 X 200 mL). The organic
layers were combined, washed with water three times and brine, dried over sodium
sulfate, filtered off, and concentrated in vacuo. The crude product was triturated by ether
to provide tert-butyl 4-(3-amino(1,4-dioxaspiro[4.5]decenyl)pyrazinyl)
fluorobenzoate (19.5 g, 45.6 mmol, 99%) as a light yellow solid. LCMS (m/z): 428.1
(MH+), 1.02 min.
Ste 6. Tert-but |4- 3-amino 1 4-dioxas iro 4.5 8- | razin l
fluorobenzoate To a solution of tert-butyl 4-(3-amino(1,4-dioxaspiro[4.5]decen
yl)pyrazinyl)f|uorobenzoate (11 g, 25.7 mmol) in DCM (100 mL) and MeOH (100
mL) at room temperature was added Pd/C (5 g, 25.7 mmol) (10% in carbon, wet). The
resulting mixture was vacuumed, and then refilled with hydrogen. The process was
repeated three times. Then the on was stirred at room temperature under H2
atmosphere for 6 h. Catalyst was filtered out through Celite®, and washed with DCM. The
filtrate was concentrated, and the residue was ved in DCM (60 mL), filtered and
concentrated. The crude product was purified by flash chromatography eluting with 0-
100% of EtOAc/heptane to provide tert-butyl 4-(3-amino(1,4-dioxaspiro[4.5]decan
yl)pyrazinyl)—2-fluorobenzoate (8.18 g, 19.04 mmol, 74%) as a light yellow solid. LCMS
(m/z): 430.2 (MH+), 0.99 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.98 - 7.82 (m, 2 H),
7.71 - 7.49 (m, 2 H), 8.13 (s, 2 H), 3.85 (s, 4 H), 3.30 (s, 1 H), 2.77 - 2.55 (m, 1 H), 2.48
(dt, J = 362,191 Hz, 2 H), 1.88 - 1.85 (m, 6 H), 1.83 - 1.48 (m, 10 H).
Ste 7. Tert-but l4- 3-amino 4-oxoc clohex l razin lfluorobenzoate
To tert-butyl 4-(3-amino(1,4-dioxaspiro[4.5]decanyl)pyrazinyl)fluorobenzoate
(14.34 g, 33.4 mmol) were added acetonitrile (250 mL), water (160 mL) and then 3 M
aqueous solutionueous HCI (55.6 mL, 167 mmol). The reaction mixture was stirred at 25
°C for 30 min which was monitored by LCMS. The mixture was basified with 2 M NaOH
aqueous solution under stirring to pH 9. Light yellow solid was precipitated out.
Acetonitrile was removed under reduced pressure at room temperature. The solid was
filtered and washed with water (2 X 30 mL), and dried under high vacuum overnight to
afford tert-butyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)fluorobenzoate (12 g, 31.1
mmol, 93%) as a light yellow solid. LCMS (m/z): 386.1 (MH+), 0.89 min; 1H NMR (400
MHz, ACETONITRILE-d3) 6 ppm 8.05 - 7.89 (m, 2 H) 7.73 - 7.51 (m, 2 H), 5.14 (br. s., 2
H), 3.30 - 3.08 (m, 1 H), 2.64 - 2.48 (m, 2 H), 2.40 (br. s., 2 H), 2.30 - 2.17 (m, 2 H), 2.12
- 1.99 (m, 2 H), 1.96 (dt, J = 4.99, 2.40 Hz, 4 H), 1.61 (s, 9 H).
Ste 8. Tert-but l4- o 4-h drox c clohex l razin lfluorobenzoate
A solution of tert-butyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)fluorobenzoate (9 g,
23.35 mmol) in methanol (125 mL) and THF (125 mL) was cooled down to -78 °C, and
then NaBH4 (2.297 g, 60.7 mmol) was added n wise. The reaction mixture was then
stirred at -78 0C for 40 min, and LCMS indicated the reaction was completed. Some over-
reduction product was observed. The ratio of trans to cis was about 8:1. 100 mL of sat.
NH4C| was added slowly at -78 °C, and then the mixture was warmed up gradually to
room temperature. The reaction mixture was quenched by sat. , and extracted by
EtOAc (2 X 200 mL). The c layers were combined, dried over Na2804, filtered off,
concentrated and dried under high vacumm to provide tert-butyl 4-(3-amino(4-
ycyclohexyl)pyrazinyl)—2-fluorobenzoate (8.9 g, 22.97 mmol, 98%), which was
used in next step t further purification. LCMS (m/z): 388.2 (MH+), 0.86 min.
Ste 9 &10. 4- o 1r4r h drox c clohex l razin lfluorobenzoic acid
Tert-butyl 4-(3-amino(4-hydroxycyclohexyl)pyrazinyl)fluorobenzoate (8.8 g, 22.71
mmol) was dissolved in THF (100 mL), and then TBDMSCI (8.22 g, 54.5 mmol) and
imidazole (5.57 g, 82 mmol) were added. The reaction e was stirred at room
temperature for 3 h. The reaction mixture was diluted by EtOAc (150 mL), washed by
water and brine, dried over Na2804, filtered off, and concentrated. The crude al
was purified by flash chromatography eluting with 0-100% of acetone/DOM (10%
acetone/DOM in DCM, 10 to 50 %, 40 min duration, 320 g silica gel column) to afford tert-
butyl 4-(3—amino((1s,4s)((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazinyl)
fluorobenzoate (7.7 g, 15.35 mmol, 67.6%). LCMS (m/z): 502.3 (MH+), 0.96 min. To a
solution of tert-butyl 4-(3-amino((1s,4s)((tert-
imethylsi|y|)oxy)cyclohexyl)pyraziny|)fluorobenzoate (7.789 g, 15.52 mmol) in
4 N HCI in dioxane was stirred at room temperature for 48 h. The reaction mixture was
concentrated. To the light yellow e was added 50 mL of EtZO, sonicated for 15 min,
filtered, washed with 15 mL of EtZO twice, and dried under vacumm suction for 2 h to
provide 4-(3-amino((1r,4r)hydroxycyclohexyl)pyrazinyl)f|uorobenzoic acid (11,
6.0 g, 15.99 mmol, 100 % yield) as a light yellow solid. LCMS (m/z): 332.0 (MH+, acid),
0.48 min; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.06 - 7.79 (m, 2 H). 7.69 - 7.50 (m, 2 H),
3.63 -3.30 (m, 3 H) 2.62 - 2.50 (m, 1 H), 1.97 -1.71 (m, 4 H), 1.34 -1.11 (m, 2 H), 1.63 -
1.42 (m, 2 H),
Ste 11. 4- 3-amino 1r4S h drox c clohex l razin l-N- S 3-bromo
fluoro hen lh drox eth lfluorobenzamide
4-(3-amino((1r,4r)hydroxycyclohexyl)pyraziny|)fluorobenzoic acid (670 mg,
2.022 mmol) in DMF (16.80 mL) was added aza-HOBt (413 mg, 3.03 mmol), EDC (581
mg, 3.03 mmol), DIEA (1.059 mL, 6.07 mmol) and (S)amino(3-bromo
phenyl)ethanol hydrochloride (547 mg, 2.022 mmol). The reaction mixture was
stirred at room temperature for 3 h. LCMS indicated the product. The reaction mixture
was diluted with EtOAc, washed with sat NaHC03, water and brine, dried over Na2804,
filtered off, and concentrated. The residue was purified with flash chromatography eluting
with 0-100% of EtOAc (containing 10% heptane to provide mino((1r,4S)—
4-hydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromofluorophenyl)hydroxyethyl)
fluorobenzamide (920 mg, 1.66 mmol, 82%). LCMS (m/z): 547/549 (MH+), 0.72 min; 1H
NMR (500 MHz, DMSO-d6) 6 ppm 8.74 (dd, J = 1.9, 7.9 Hz, 1H), 7.92 (s, 1H), 7.81 - 7.70
(m, 1H), 7.68 - 7.55 (m, 2H), 7.52 - 7.39 (m, 2H), 7.30 (d, J = 9.5 Hz, 1H), 6.11 (s, 2H),
.09 (t, J = 5.7 Hz, 2H), 4.58 (d, J = 4.4 Hz, 1H), 3.69 (dt, J = 2.4, 5.8 Hz, 2H), 3.49 - 3.40
(m, 1H), 2.55 (t, J = 3.5 Hz, 1H), 1.98 - 1.76 (m, 4H), 1.55 (dd, J = 2.8, 12.6 Hz, 2H), 1.29
(d, J = 13.6 Hz, 2H).
8 nthesis of S -N- 2-amino 3-chloro hen l eth l -N-meth l
nitrobenzenesulfonamide
Scheme 65
Stepl
{OH _/OH
2N fl). BocHN
THF Step 3
Cl Cl
TMAD
THF, (n—Bu)3P
0 CC to rt, 16 h
N020
“:0 methylamine
00‘ Step 4_
"'_\N HCI
\ 02
BocHN/\© 50—70% (2 steps) H2NA©OZ
Ste 1. S -tert-but l 1- ro hen lh drox eth lcarbamate
To a mixture of (s)amino(3-chlorophenyl)ethanol (4 g, 19.22 mmol) in THF (64.1 mL)
was added NaHC03 (1.776 g, 21.15 mmol), ed by Boc20 (4.91 mL, 21.15 mmol)
and DMAP (0.235 g, 1.922 mmol). The reaction mixture was then stirred at room
temperature overnight. LCMS indicated the reaction was not completed. TEA (5.36 mL,
38.4 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h.
Water was added, and the reaction mixture was extracted by EtOAc. The organic layer
was washed with brine, dried over sodium e, filtered and concentrated. The crude
material was purified by flash chromtography eluting with 0-100% of EtOAc/heptane to
afford (S)—tert—buty| (1-(3-chlorophenyl)hydroxyethyl)carbamate (4.0 g, 14.72 mmol,
77%). LCMS (m/z): 216.1 (MH+-56), 0.75 min.
Step 2. yInitrobenzenesulfonamide
A solution of 2-nitrobenzenesulfonyl chloride (4 g, 18.05 mmol) in DCM (60.2 mL) was
cooled down to 0 °C with an ice water bath. TEA (7.55 mL, 54.1 mmol) and 2 M
methylamine in tetrahydofuran (13.54 mL, 27.1 mmol) were added. The resulting solution
was stirred at room temperature for 6 h. The reaction mixture was d with DCM,
washed with sat. NaHC03 (2 x 100 mL), brine (100 mL) and then dried over magnesium
sulphate. The solution was filtered before concentrating under d pressure, and
triturated in ether to afford N-methylnitrobenzenesulfonamide (3.12 g, 14.44 mmol, 80
% yield). LCMS (m/z): 217.1 (MH+), 0.53 min.
Ste 3. S -tert-but l 1- 3-chloro hen l N-meth lnitro hen lsulfonamido eth l-
carbamate
N-methyInitrobenzenesulfonamide (3.50 g, 16.19 mmol) in THF (56.6 mL) was added
(S)—tert-butyl (1-(3-chlorophenyl)hydroxyethyl)carbamate (4 g, 14.72 mmol) and
tributylphosphine (3.87 g, 19.14 mmol). Then (E)-di-tert-butyl diazene-1,2-dicarboxylate
(3.29 g, 19.14 mmol) in THF (56.6 mL) was added slowly at 0 °C. The on mixture
was stirred at room temperature overnight. LCMS indicated there was slightly starting
material left. The reaction was diluted with EtOAc, washed with sat. NaHC03, water and
brine, dried over Na2804, filtered off, and trated.The crude product was purified by
flash chromatography g with 0-100% of heptane to afford (S)—tert—buty| (1-(3-
chlorophenyl)(N-methylitrophenylsulfonamido)ethyl)carbamate (7 g, 14.9 mmol,
100%). LCMS (m/z): 370.1 (MH+-100), 1.05 min.
Ste 4. S -N- 2-amino 3-chloro hen leth l-N-meth lnitrobenzenesulfonamide
(S)—tert-butyl (1-(3-chlorophenyl)(N-methylitrophenylsulfonamido)ethyl)carbamate (7
g, 14.9 mmol) in DCM (149 mL) was added HCI (4 M in dioxane) (14.90 mL, 59.6 mmol).
The reaction mixtue was stirred at room temperature for 4 h. LCMS indicated that the
reaction was completed. White precipitate was filtered out and washed well with DCM to
provide 2.8 g of (S)—N-(2-amino(3-chlorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide as a HCI salt. The residue was evaporated to dryness, and
d in DCM (20 mL) for 30 min. Solid was filtered and washed well with DCM to
provide another 400 mg of (S)-N-(2-amino(3-chlorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide which t total yield to 52.9% with 95% purity. LCMS (m/z):
370.1 (MH+-100), 0.67 min; 1H NMR (500 MHz, METHANOL-d4) 6 ppm 8.09 - 7.99 (m
1H), 7.92 - 7.77 (m, 3H), 7.60 (s, 1H), 7.53 - 7.35 (m, 3H), 4.74 - 4.62 (m, 1H), 3.93 (dd,
J=9.0, 14.7 Hz, 1H), 3.53 (dd, J: 5.4, 14.8 Hz, 1H), 2.98 (s, 3H).
Example 176
S nthesis of S 3-amino tetrah dro-2H- ran l razin l-N- 1- 3-
chloro hen l meth lamino eth lfluorobenzamide
Scheme 66
Step1F O J<
OOJ< W NH2 0
NIN\ Pd(dppf)CI2DCM
2M Na2C03 | H2, Pd-C
+ —>\ N —>
KKN \
DME, 110 0C, 16 MeOH/DCM, 5 h
h \
Br 0 85% 80%
F o J< Stegg F
NH2 0 NH2
N/ N \ DEN/Q EDC HOAt
IN TFA,DCM 02
I _/N\
\ ’
>99% H2N1é>\©
o 0 CI
9 St a; H
8:0 /N\
mg ,(I F O —
F O / \
E gfigog, NH2 ”(5)
NH2 ”(3) N| \
DMF NI \ Hooc—O—SH /N Cl
82% /N Cl
40°C,16
h 85%
Ste 1. ut l4- 3-amino 3 6-dih dro-2H- ran | razin lfluorobenzoate
To a solution of tert-butyl 4-(3-aminobromopyrazinyl)f|uorobenzoate (21 g, 57.0
mmol) in DME (127 mL) was added PdC|2(dppf).CH2C|2 adduct (2.329 g, 2.85 mmol), 2-
(cyclohex—1-eny|)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.18 g, 62.7 mmol), and 2
M Na2C03aqueous solution (63.4 mL). The reaction was heated at 110 °C for 16 h. To the
on mixture was added 200 mL of ethyl acetate, washed with water (2 x 100 mL),
brine, dried over sodium sulfate, filtered and concentrated. The e was purified by
flash chromatography eluting with 0-100% of EtOAc/DCM to provide tert-butyl 4-(3-amino-
6-(3,6-dihydro-2H-pyranyl)pyrazinyl)f|uorobenzoate (18 g, 48.5 mmol, 85%).
LCMS (m/z): 372.3 (MH+), 0.95 min.
Ste 2. Tert-but l4- 3-amino tetrah dro-2H- ran | razin lfluorobenzoate
To a suspension of tert-butyl 4-(3-amino(3,6-dihydro-2H-pyranyl)pyrazinyl)
fluorobenzoate (15 g, 40.4 mmol) in MeOH (800 mL) was added DCM (100 mL) until the
suspension turned to a homogeneous solution. After degassed by N2 stream for 15 min,
Pd/C (10 g, 9.40 mmol) was added to the reaction e. To this mixture, hydrogen
balloon was equipped afterflushed with hydrogen gas three times. The reaction mixture
was d for 6 h. After the reaction mixture was ed through Celite® pad, the volatile
als were removed in vacuo. The residue was dissolved in MeOH (200 mL) by
heating and cooling down to room temperature and standing overnight. The brown
precipitate was filtered off, which ed 4.5 g of tert-butyl 4-(3-amino(tetrahydro-2H-
pyranyl)pyrazinyl)fluorobenzoate. The flitrate was concentrated and dissolved in
EtOH (200 mL) by heating. The second brown precipitate was filtered off to afford 3.9 g of
2014/062913
tert-butyl mino(tetrahydro-2H-pyranyl)pyrazinyl)fluorobenzoate (55.7%
combined yield). LCMS (m/z): 374.7 (MH+), 0.90 min.
Ste 3. 4- 3-Amino tetrah dro-2H- ran l razin lfluorobenzoic acid
To a solution of tert-butyl 4-(3-amino(tetrahydro-2H-pyranyl)pyraziny|)
fluorobenzoate (4.5 g, 12.05 mmol) in DCM (60.3 mL) was added TFA (60.3 mL). The
reaction mixture was stirred for 2 h. After diluted with toluene (30 mL), the volatile
materials were d in vauco twice to provide 4-(3-amino(tetrahydro-2H-pyran
azinyl)fluorobenzoic acid (5.2 g, 12.06 mmol, 100%) as a TFA salt. The crude
product was used for the next step without further purification. LCMS (m/z): 318.5 (MH+),
0.55 min.
Ste 4. S 3-amino tetrah dro-2H- ran l razin l-N- 1- 3-chloro hen l
(N-methylnitrophenylsulfonamido)ethyl )—2-fluorobenzamide
To a solution of 4-(3-amino(tetrahydro-2H-pyranyl)pyraziny|)fluorobenzoic acid
(1.55 g, 4.88 mmol) in DMF (16.28 mL) was added HOAt (0.997g, 7.33 mmol), EDC
(1.498 g, 7.82 mmol). DIEA (2.61 m l, 14.65 mmol) and (S)—N-(2-amino(3-
phenyl)ethyl)-N-methylnitrobenzenesulfonamide (2.084 g, 5.13 mmol). The
reaction mixture was stirred at room temperature for 3 h, and LCMS indicated the reaction
was completed. The reaction mixture was diluted with EtOAc, and the organic was
washed by sat.Na2C03, water and brine, dried over Na2804, filtered off, and
concentrated. The crude material was purified by flash chromatography eluting with 50%
DCM/EtOAc (10% methanol) to provide (3-amino(tetrahydro-2H-pyran
yl)pyrazin-2—yl)—N-(1-(3-chlorophenyl)(N-methylnitrophenylsulfonamido)ethyl)
fluorobenzamide (2.68 g, 4.01 mmol, 82%). LCMS: 669.1 (MH+), 0.95 min.
Ste 5. S 3-amino tetrah dro-2H- ran l razin l-N- 1- 3-chloro hen l
(methylamino)ethyl )—2-fluorobenzamide
To a solution of (S)(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)—N-(1-(3-
phenyl)(N-methylnitrophenylsulfonamido)ethyl)fluorobenzamide (2.68 g,
4.01 mmol) in DMF (20 mL) was added 4-mercaptobenzoic acid (1.235 g, 8.01 mmol) and
K2C03 (2.214 g, 16.02 mmol). The reaction mixture was heated at 40 °C overnight under
nitrogen. Water (50 mL) was added, and the mixture turned into homogenous. The
reaction was stirred at room temperature for 30 min, and then water (150 mL) was added
slowly. Light yellow solid was precipitated out. The mixture was stirred for another 30 min,
and the suspension was filtered out. The solid was washed well with water, followed by
heptane, and air dried for 1 h. The solid was ded in water and stirred at room
temperature for 1 h, and then filtered. To the solid was added EtOAc, and slowly rotated
on rotavap to remove excess ethyl acetate until about 20 mL of EtOAc left, the white
solid was filtered, and redissolved in acetoniltrile and water, lyophilized. The solution was
dried on lyophilizer to afford (3-amino(tetrahydro-2H-pyranyl)pyrazinyl)-N-
(1-(3-chlorophenyl)(methylamino)ethyl)fluorobenzamide (1.31 g, 2.69 mmol, 67.2%).
LCMS (m/z): 484.3 (MH+), 0.66 min; 1H NMR (500 MHz, METHANOL-d4) 6 ppm 7.90 (s,
1H), 7.83 (t, J = 7.7 Hz, 1H), 7.70 (dd, J: 1.1, 8.0 Hz, 1H), 7.63 (d, J: 10.7 Hz, 1H), 7.48
(s, 1H), 7.38 (d, J: 5.4 Hz, 2H), 7.32 (dt, J: 1.9, 4.6 Hz, 1H), 5.33 (dd, J = 5.2, 9.0 Hz,
1H), 4.05 (dd, J: 3.5, 11.0 Hz, 2H), 3.57 (dt, J: 1.9, 11.8 Hz, 2H), 3.12 - 3.04 (m, 1H),
3.04 - 2.88 (m, 2H), 2.48 (s, 3H), 1.89 - 1.88 (m, 1H), 1.96 - 1.76 (m, 4H).
8 nthesis of S -tert-but l2-amino hen leth lcarbamate
/NHBoc
Following Scheme 9, using (R)—2-aminophenylethanol, rt-butyl 2-amino
phenylethylcarbamate was obtained in 47% yield. LCMS (m/z): 237.5 (MH+), 0.54 min. 1H
NMR z ,CDCI3) 6 ppm 7.42 - 7.32 (m, 5 H), 4.81 (br. s., 1 H), 4.11 - 4.00 (m, 1 H),
3.44 - 3.28 (m, 1 H), 3.28 - 3.13 (m, 1 H), 1.49 - 1.35 (m, 9 H).
S nthesis of S f|uoro hen lethanamine
Scheme 67
Step_1 Step_2 Step 3
©/\:OH perfluorobutane NH2
CszSu ©/\/OH'2 yl fluoride HZNNHZ ?
0 O
N F
Et3N 3HF DIEA GNP ©/\/
To a solution of (S)aminophenylethanol (3 g, 21.87 mmol) in water (26.5 mL), and
itrile (46.4 mL) was added 2,5-dioxopyrrolidinyl methyl phthalate (5.76 g, 20.78
mmol) at room temperature. The on mixture was d at room ature for
overnight. After acetonitrile was removed in vacuo, the reaction e was then
extracted with EtOAc. The organic was washed by water and brine, dried over anhydrous
sodium sulfate, filtered off, and concentrated in vacuo yielding (S)—2-(2-hydroxy
phenylethyl)isoindoline-1,3-dione (2.2 g, 40%). LCMS (m/z): 268 (MW), 0.79 min.
Ste 2. S 2-fluoro hen leth lisoindoline-1 3-dione
To a solution of (S)—2-(2-hydroxyphenylethyl)isoindoline-1,3-dione (1.5 g, 5.61 mmol)
in PhCF3 (18.71 mL) was added triethylamine trihydrofluoride (5.48 mL, 33.7 mmol),
perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol), DIEA (14.70 mL, 84 mmol) at
room temperature. The reaction mixture was stirred at room temperature for 1 h, then
more perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol) was added. After 5 h, the
reaction mixture was quenched with NaHC03 and extracted with EtOAc. The combined
organic layers were washed with water and brine, dried over anhydrous sodium sulfate,
filtered off, and concentrated in vacuo. The crude product was purified by flash
tography (0-10% EtOAC in heptane) yielding (S)—2-(2-fluoro
phenylethyl)isoindoline-1,3-dione (30% yield). LCMS (m/z): 270.1 (MH+), 0.96 min.
Ste 3. S fluoro hen lethanamine
To a solution of (S)—2-(2-fluorophenylethyl)isoindoline-1,3-dione (290 mg, 1.077 mmol)
in MeOH (3.59 mL) was added hydrazine (0.507 mL, 16.15 mmol). The reaction mixture
was stirred at 80 °C for 3 h. The white precipitate was filtered off. The filtrate was
concentrated to yield the crude (S)—2-fluorophenylethanamine, which was used in next
step t further purification. LCMS (m/z): 140.1 (MH+), 0.28 min; 1H NMR (400MHz,
CDCI3) 8 ppm 7.43 - 7.34 (m, 4 H), 7.34 - 7.27 (m, 1 H), 4.57 (dd, J = 3.7, 8.8 Hz, 1 H),
4.49 - 4.38 (m, 1 H), 4.38 - 4.32 (m, 1H), 4.32 - 4.25 (m, 1 H).
S nthesis of S azido 3-bromofluoro hen l ethanamine
Scheme 68
in 1 m2
(OH (OH (OMS
F B0020 : MsCl :
F F
H2N —> BocHN —’ BocHN
Br Br Br
Step; Step 4
_/N3 {N3
NaN3 E HCI F
F F
—> BocHN —> H2N
Br Br
Ste 1. S but l 1- 3-bromofluoro hen lh drox eth mate
To a solution of (S)amino(3-bromofluorophenyl)ethanol (4.4 g, 16.26 mmol) in
DCM (80 mL) was added TEA (6.80 mL, 48.8 mmol) followed by Boc anhydride (5.32 g,
24.4 mmol) at room temperature. The reaction mixture was stirred at room temperature
for 16 h. The reaction mixture was extracted with EtOAc. The organic layer was washed
with sat NaHC03, water and brine, dried over anhydrous Na2804, filtered off, and
concentrated. The crude t was purified by flash chromatography ent EtOAc in
heptane) to provide (S)—tert-butyl (1-(3-bromofluorophenyl)hydroxyethyl)carbamate
(4.8 g, 88%). LCMS (m/z): 280 (MH+-tBu), 0.79 min.
Ste 2. S tert-butox carbon lamino 3- bromofluoro hen leth l
methanesulfonate
To a stirred solution of (S)—tert—butyl (1-(3-bromofluorophenyl)
hydroxyethyl)carbamate (4.8 g, 14.36 mmol) in anhydrous DCM (100 mL) at 0 °C was
added triethylamine (4.00 mL, 28.7 mmol) followed by esulfonyl chloride (1.343
mL, 17.24 mmol). The reaction was stirred at 0 °C for 1 hr, by which time the LCMS
indicated the reaction had gone to completion. The reaction mixture was poured into
saturated NaHC03 solution (100 mL). The e was shaken, the layers separated and
the aqueous layer was extracted with DCM (2 x 50 mL). The ed organics were
washed with NaHC03 solution (50 mL) and brine (50 mL), dried ), filtered and
trated, giving (S)((tert-butoxycarbonyl)amino)(3- bromofluorophenyl)ethyl
methanesulfonate (5.92 g, 14.36 mmol, 100 % yield) as a very pale orange solid. 1H
NMR (500 MHz, DMSO-d6) 8 ppm 7.75 (d, J=8.83 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.31 (d,
J=9.46 Hz, 1 H), 4.86 - 5.00 (m, 1 H), 4.30 (dd, 9, 5.04 Hz, 1 H), 4.24 (t, J=9.30
Hz, 1 H), 3.16 - 3.23 (m, 3 H), 1.36 - 1.44 (m, 9 H).
Step 3. (S)—tert—butyl (2-azido(3- bromofluorophenyl)ethyl)carbamate
(S)((tert-butoxycarbonyl)amino)(3- bromofluorophenyl)ethyl methanesulfonate
(5.92 g, 14.36 mmol) was dissolved in anhydrous DMF (60 mL). Sodium azide (2.80 g,
43.1 mmol) was added, and the reaction heated to 70 °C and maintained at this
temperature for 2 h. After cooling, the reaction mixture was poured into water (100 mL)
and extracted with EtOAc (3 x 80 mL). The combined organics were washed with water
(50 mL) and brine (3 x 50 mL), dried (MgSO4), filtered and concentrated. Flash
tography (AnaLogix, 80 g column, loaded in DCM, 0 to 40% EtOAc in heptane
over 30 min) gave (S)-tert-butyl (2-azido(3- bromofluorophenyl)ethyl)carbamate
(4.29 g, 11.94 mmol, 83 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 6 ppm
7.73 (d, J=8.83 Hz, 1 H), 7.48 (t, J=4.26 Hz, 2 H), 7.29 (d, J=9.77 Hz, 1 H), 4.80 (d,
J=8.20 Hz, 1 H), 3.47 (d, J=7.88 Hz, 2 H), 1.44 - 1.38 (m, 9 H), 1.36 (br. s., 1 H).
Ste 4. S azido—1- 3- bromofluoro hen l ethanamine
To a stirred solution of (S)-tert-butyl do(3- bromofluorophenyl)ethyl)carbamate
(3.15 g, 8.77 mmol) in dioxane (40 mL) was added hydrochloric acid (10.96 mL, 43.8
mmol) (4N solution in dioxane). The reaction was heated to 40 °C and maintained at this
temperature for 2 h. After cooling the reaction mixture was evaporated to dryness, giving
(S)azido(3- bromofluorophenyl)ethanamine hydrochloride (2.59 g, 8.76 mmol,
100 % yield) as a white solid.
S nthesis of S azido rofluoro hen l ethanamine
Following Scheme 68, using (S)amino(3-chlorofluorophenyl)ethanol, (S)azido-
1-(3-ch|orofluorophenyl)ethanamine was obtained. LCMS (m/z): 215.1 (MH+), 0.48 min.
S nthesis of S azido 3-chloro hen l ethanamine
Following Scheme 68, using (S)amino(3-chlorophenyl)ethanol, azido(3-
ch|orof|uorophenyl)ethanamine was obtained. LCMS (m/z): 197 (MH+), 0.5 min.
Synthesis of (S)—3-ghenylmorgholine
Scheme 69
Step; 1 SteQ 2 Steg g
CI\)J\CI o NaH LiAIH4
(3) CI\)J\N (3)
—> —> —> (S)
H2N OH HN HN
DMAP, Et3N
OH H 0&0 K/o
Ste 1. S ch|oro-N- 2-h drox hen leth mide
To a solution of (S)aminophenylethanol (0.852 g, 6.21 mmol), Et3N (0.952 mL, 6.83
mmol), DMAP (76 mg, 0.621 mmol) in CH2C|2 (10 mL) at 0 °C was added 2-ch|oroacety|
chloride (0519 mL, 6.52 mmol), and the resulting mixture was stirred at 0 °C for 15 min.
The reaction mixture was washed with aqueous HCI (1 M, 20 mL), then sat. NaHC03 (20
mL), dried (Na2804), concentrated, further dried under high vacuum and (S)—2-chloro-N-
(2-hydroxyphenylethyl)acetamide (0.60 g, 45.2% yield) was ed as white solid.
LCMS (m/z): 214 (MH+), 0.44 min.
Step 2. (S)—5-phenylmorpholinone
To a on of (S)—2-chloro-N-(2-hydroxyphenylethyl)acetamide (600 mg, 2.8 mmol) in
anhydrous THF solution at 0 °C was added NaH mineral oil suspension (247 mg, 6.18
mmol). The resulting mixture was stirred overnight at room temperature. The reaction
mixture was concentrated to dryness, and the residue was partitioned between
CH2C|2/brine/H20 (20mL/18mL/2mL). CH2C|2 layer was dried over anhydrous Na2804,
filtered off, concentrated in vacuo. The crude product, (S)phenylmorpholinone, was
obtained as a white solid (498 mg, 97%). The crude product was used directly in next
step without r purification. LCMS (m/z): 178.2 (MH+), 0.47 min.
Step 3. (S)—3-phenylmorpholine
To a LiAlH4/THF slurry (0.47g/2 mL) was added dropwise (S)—5-phenylmorpholinone in
THF solution (481 mg in 6mL) at room temperature over 5min. The resulting mixture was
stirred aat room temperature thereafter for 1 hour, then was heated with 72 °C oil bath
ght, then was cooled down to 0 °C, quenched by sequential addition of H20 (0.47
mL), 3M s solutionueous NaOH (0.47 mL) and H20 (1.4 mL), and the quenched
residue was diluted with EtZO (30 mL), stirred for 10 min and the etheral on was
ted by filtration. The filtrate was concentrated, further dried under vacuum and (S)-
3-phenylmorpholine (424 mg, 96% yield) was obtained as colorless solid. LCMS (m/z):
164.2 (MH+), 0.33 min.
S nthesis of S -tert-but l 2-amino 3-chloro hen leth l meth lcarbamate
Scheme 70
OH SteQZ
©/'\/ _
NHBoc
Boczo
(R) Q/K/N\Boc
Step;
NH2 BOO
[21800 Hydrazine4E?/\/N\
DtBAD ©NN\
Ste 1. R ro hen l meth lamino ethanol
(R)—tert-butyl (2-(3-chlorophenyl)hydroxyethyl)carbamate (2.489, 9.13 mmol), prepared
in Scheme 9, was dissolved THF (30.4 mL), and LiAlH4 (1.039 g, 27.4 mmol) was added.
The on mixture was heated at reflux for 6 h and then cooled down. Water (1.06 mL)
was added, followed by aqueous NaOH (15%, 3 mL), and water (1.06 mL). The reaction
mixture was stirred at room temperature for 1 h. Solid precipitate was filtered through
Celite® and rinsed well with EtOAc. The filtrate was concentrated. The crude product (R)-
1-(3-chlorophenyl)(methylamino)ethanol (1.75 g, 9.43 mmol, 100%) was used in next
step reaction without further cation. LCMS (m/z): 186.1 (MH+), 0.43 min.
Step 2. (R)—tert—butyl (2—(3-chlorophenyl)—2-hydroxyethyl)(methyl)carbamate
(R)—1-(3-chlorophenyl)—2-(methylamino)ethanol (1.75 g, 9.43 mmol) was dissolved in THF
(31.4 mL), and then Boc ide (2.298 mL, 9.90 mmol) was added. The reaction
mixture was stirred at room temperature for 2 h. LCMS indicated that the reaction was
completed. The reaction mixture was concentrated, and purified by flash chromatography
to afford (R)—tert—butyl (2-(3-chlorophenyl)hydroxyethyl)(methyl)carbamate (2.0 g, 7.00
mmol, . LCMS (m/z): 212.1 (MH+-56), 0.94 min.
Ste 3. S -tert-but | 2- 3-chloro hen l 1 3-dioxoisoindolin
yl)ethyl )(methyl)carbamate
To a mixture of (R)—tert-butyl (2-(3-chlorophenyl)hydroxyethyl)(methyl)carbamate (2.0
g, 7.00 mmol) in THF (23.33 mL) was added phthalimide (1.339 g, 9.10 mmol) and PPh3
(3 mmol of PPh3/1 g of resin, 2.34 g, 7.02 mmol). Then DTBAD (1.660 g, 7.21 mmol) in
THF was slowly added at room temperature, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was filtered through Celite® and washed with
EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with sat. Na2C03,
water and brine, dried over sodium sulfate, filtered off, and trated. The crude
product was purified by flash chromatography to afford (S)—tert-butyl chlorophenyl)-
2-(1,3-dioxoisoindolinyl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol, 67.5%). LCMS
(m/z): 315.1 (MH+-100), 1.19 min.
Step 4. (S)—tert—butyl (2-amino(3-chlorophenyl)ethyl)(methyl)carbamate
To a solution of (S)—tert-butyl (2-(3-chlorophenyl)(1,3-dioxoisoindolin
yl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol) in ethanol (15.75 mL) was added
hydrazine hydrate (2.296 mL, 47.2 mmol). The reaction mixture was heated at 60 °C for 2
h. The reaction mixture was then filtered through Celite pad and the filtrate was
concentrated. The residue was re-dissolved in ethanol and ed h Celite® pad to
remove extra white solid. NMR showed there was impurity in crude material. The crude
product was filtered through a plug of silica, washed by DCM/EtOAc (2:1 ratio) and
flashed with DCM/EtOAc (20% ol, 0.5 % NH3 in methanol) (1 :1 ratio) to provide
(s)-tert-buty| no(3-chlorophenyl)ethyl)(methyl)carbamate (1.2 g, 89% yield).
LCMS (m/z): 285.1 (MH+), 0.65 min; 1H NMR (400 MHz, CDCI3) 6 ppm 7.37 (s, 1H) 7.26 (
3H), 4.20 (br. s., 1H), 2.85- 2.77 (m, 3H), 1.51 - 1.38 (m, 9H).
S nthesis of S aminoc clo ro lbut—3- nol
Scheme 71
meth | ro anesulfinamide
3.0 M ethyl magnesium bromide in EtZO (0.360 mL, 1.081 mmol) was added to a solution
of ethynylcyclopropane (71.5 mg, 1.081 mmol) in THF (4 mL). The solution was heated
to 50 °C for 1 h, then the resulting Grignard was added to a -78 °C solution of (S,E)—N-(2-
((tert-butyldimethylsi|y|)oxy)ethy|idene)methy|propanesulfinamide (100 mg, 0.360
mmol) in DCM (4.00 mL), and the reaction was allowed to warm to room temperature.
After 3h, the reaction was quenched with sat. aq. NH4CI.The layers were separated and
the organics were dried over magnesium sulfate and trated to provide (S)—N-((S)—
1-((tert-butyldimethylsilyl)oxy)cyclopropylbutynyl)methy|propanesulfinamide,
which was used directly. LCMS (m/z): 344.1 (MH+), 1.23 min.
Ste 2. S aminoc clo ro lbut nol
4.0 N HCI in e (0.873 mL, 3.49 mmol) was added to a room temperature solution of
(S)—N-((S)—1-((tert-butyldimethylsi|y|)oxy)cyclopropylbutynyl)methylpropane
sulfinamide (120 mg, 0.349 mmol) in MeOH (4 mL). After 30 min, the on was
concentrated, then azeotroped with benzene to e (S)aminocyclopropylbut
ynol as the HCI salt. LCMS (m/z): 126.2 (MH+), 0.50 min.
S nthesis of S amino 3-fluoro meth lthio hen l ethanol
Scheme 72
Steg_1 Steg_2
NaSMe, DIEA HCI
Xanphos, Pd2(dba)3
Ste 1: S -tert-but l4- 3-fluoro meth lthio hen l-2 2-dimeth loxazolidine
carboxylate
A mixture of Xantphos (13.91 mg, 0.024 mmol), Pd2(dba)3 (22.02 mg, 0.024 mmol), (S)-
tert-butyl 4-(3-bromofluoropheny|)-2,2-dimethyloxazolidinecarboxylate (300 mg,
0.802 mmol), DIEA (700 pl, 4.01 mmol)and sodium methanethiolate (112 mg, 1.603 mmol)
in toluene (2.6 mL) was microwave heated at 110 °C for 18 min. EtOAc was added, and
washed with sat NaHC03, water, and brine. The mixture was ed off, concentrated
and purified with flash chromatography eluting with 0-60% of EtOAc/heptane to e
(S)—tert-butyl 4-(3-fluoro(methylthio)phenyl)-2,2-dimethyloxazolidinecarboxylate (278
mg, 102%) as an oil. LCMS (m/z): 286.1 (MH+-56), 1.14 min.
Ste 2: S amino ro meth lthio hen lethanol
A solution of (S)—tert—butyl 4-(3-fluoro(methylthio)phenyl)-2,2-dimethyloxazolidine
carboxylate (278 mg, 0.814 mmol) in 4 M HCI in dioxane (2.4 mL) was heated to 80 °C
overnight. There was still some starting material left. More 4 M HCI in dioxane (2.035 mL,
8.14 mmol) was added, and heated at 80 °C for r 10 h. Solvent was removed
under reduced vacuum to e (S)amino(3-fluoro(methylthio)pheny|)ethano|
(194 mg, 0.814 mmol, 100%). LCMS (m/z): 170.1 (MH+-56), 0.26 min.
S nthesis of S no 3- meth lthio hen l ethanol
Following Scheme 72, using (S)—tert-butyl 4-(3-bromophenyl)-2,2-dimethyloxazolidine
carboxylate, (S)—2-amino(3-(methylthio)phenyl)ethanol was obtained. LCMS (m/z): 184
NH), 0.41 min.
8 nthesis of S amino 3- chlorometh l fluoro hen l ethanol
Scheme 73
o\_ Step 1 ><O\: Step 2 _/OH
><N CI
' F A F :
N HCI F
I N \ N I
—> H2N
B +
00 BOC
)L A DMSO
CI N
OH CI
Ste 1. S but l4- 3- chlorometh lfluoro hen l-2 2-dimeth loxazolidine
carboxylate
To a on of (S)—tert-butyl 4-(3-fluoro(hydroxymethyl)pheny|)-2,2-
dimethyloxazolidinecarboxylate (330 mg, 1.014 mmol) in anhydrous DMSO (2. 028 mL)
was added 2,4,6-trichloro-1,3,5-triazine (112 mg, 0.609 mmol) portionwise. The mixture
was stirred at room temperature for 30 min. The mixture was diluted with EtOAc, and
separated. The organic phase was washed with H20 (5 x 30 mL), dried over anhydrous
Na2804, filtered off and concentrated under reduced pressure. The residue was purified
with flash chromatography g with 0-100% heptane to provide (S)—tert-buty| 4-
(3-(chloromethyl)—5-fluorophenyl)-2,2-dimethyloxazolidinecarboxylate (329 mg, 94%).
LCMS (m/z): 288.1 (MW-56), 1.12 min.
Ste 2: S amino 3- chlorometh uoro hen l ethanol
To a solution of (S)-tert-butyl 4-(3-(chloromethyl)fluorophenyl)-2,2-dimethyloxazolidine-
3-carboxylate (140 mg, 0.407 mmol) in anhyd DCM (1.357 mL) was added 4 N HCI in
Dioxane (1.018 mL, 4.07 mmol) portionwise. The mixture was refluxed at 80 °C overnight.
The reaction was not completed. More 4N HCI in dioxane (1. 018 mL, 4.07 mmol) was
added, and refluxed for another 24 h. Solvent was d under reduced vaccum to
provide (S)amino(3-(chloromethyl)fluorophenyl)ethanol (70 mg, 84%). LCMS
(m/z): 204 (MH+), 0.41 min.
S nthesis of S no 3-fluoro fluorometh l hen l ethanol
Scheme 74
9a) IN
Step 6
Br Br
nBuLI, DMF. DAST F
BH3.THF -
DCM THF -78°C
THF 0 C0
33% F Crude
Crude.
Step_4
O\S\k HY
CuSO4,660°C O/\—>MgBr
0.15 eq. ZnMe2
2 step 60%
-78 °C
Ste96&z Stegsge
NHBOC NHHCI
0,3/NaBH4 -
)HCI/dioxane -78 C0 (s)
2) Boczo )HCI/Dioxane
Ste 1. 3-bromofluoro hen Imethanol
To a suspension of 3-bromofluorobenzoic acid (4.51 g, 20.59 mmol) in THF (41.2 mL)
at 0 oC, BH3.THF (41.2 mL, 41.2 mmol) was added se over 30 min, the reaction
mixture was then allowed to return to room temperature and stirred at room temperature
ovenight. Methanol (40mL) was added slowly and stirred at room temperature for 1 h.
THF and Methanol was removed in vacuo. The residue was then extracted by EtOAc, and
washed with sat.NaHC03, The c was dried and concentrated. The crude product
was used in next step on without purification. LCMS (m/z): 187.2 (MH+'18), 0.66 min.
1H NMR (400MHz, CDCI3) 8 ppm 7.32 (s, 1H), 7.19 - 7.14 (m, 1H), 7.05 (tdd, J=0.7, 1.5,
9.1 Hz, 1H), 4.70 (br. s., 2H), 1.78 (br. s., 1H).
Ste 2. 1-bromofluoro meth | benzene
To a solution of (3-bromo—5-fluorophenyl)methanol (4 g, 19.51 mmol) in DCM (39.0 mL) at
0 OC, DAST (3.35 mL, 25.4 mmol) was added. The reaction mixture was allowed to return
to room temperature and stirred at room temperation overnight. Sat. NaHC03 was added,
the on mixture was then extracted by DCM. The organic was dried and concentrated.
The crude material was purified by flash tography (0-10% EtOAc/heptanes) to
yield the final product as colorless oil. LCMS (m/z): no mass (MH+), 0.86 min. 1H NMR
(400MHz, CDCI3) 8 ppm 7.30 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.41
(s, 1H), 5.29 (s, 1H).
Step 3. 3-fluoro(fluoromethyl)benzaldehyde
1-bromofluoro(fluoromethyl)benzene (1.30 g, 6.28 mmol) was dissolved in THF
(31.4 mL), then cooling down to -78 oC, butyllithium (2.5M in Hexanes) (2.76mL, 6.91
mmol) was added at -78 0C, the reaction mixture was then stirred at -78 °C for 30 min.
DMF (0.972 mL, 12.56 mmol) was added, after strirred at -78 °C for 1h, The reaction
mixture was quenched by HCI and the reaction mixture was then ted by EtOAc, the
organic was dried and concentrated to yield the crude product. The crude material was
used in next step reaction without purification. LCMS (m/z): no mass (MH+), 0.60 min.1H
NMR (400MHz, CDCI3) 6 ppm 10.08 - 9.93 (m, 1H), 7.68 (s, 1H), 7.56 (d, J=8.2 Hz, 1H),
7.37 (d, J=7.8 Hz, 1H), 5.53 (s, 1H), 5.42 (s, 1H)
Ste 4. R E -N- 3-fluoro fluorometh lbenz lidene h | ro anesulfinamide
To a solution of 3-fluoro(fluoromethyl)benzaldehyde (890 mg, 5.70 mmol) and (R)—2-
methylpropanesulfinamide (760 mg, 6.27 mmol) in DCE (19.0 mL) was added copper(|l)
sulfate (anhydrous) (1.820 g, 11.40 mmol), the suspension was stirred under nitrogen at
60 0C in an oil bath for overnight. The suspention turned to light blue color. Cooling down,
the reaction mixture was filtered though a plug of Celite and rinsed with DCM, the filtrate
was concentrated to yield the crude product. The crude product was purified by flash
tograph (0-30% EtOAc in heptane) to yield the (R,E)—N-(3-fluoro
(fluoromethyl)benzylidene)methylpropanesulfinamide (900 mg, 60.9 % yield) as light
yellow color oil. LCMS (m/z): 260.1 (MH+), 0.88 min. 1H NMR (400MHz, CDCI3) 8 ppm
8.57 (s, 1H), 7.60 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.26 - 7.22 (m, 1H), 5.50 (s, 1H), 5.38 (s,
1H), 1.29 - 1.23 (m, 9H)
Ste 5. R-N- R 3-fluoro fluorometh l hen lall lmeth l ro sulfinamide
Dimethyl Zinc (2M in Tolune) (0.434 mL, 0.868 mmol) and vinylmagnesium bromide (1M
in THF) (4.51 mL, 4.51 mmol) was mixed at room temperature for 20 min under argon
before cooling down to -78 0C, then (R,E)-N-(3-fluoro(fluoromethyl)benzylidene)—2-
methylpropanesulfinamide (0.900 g, 3.47 mmol) in dry THF (11.57 mL) as added
dropwise, maintain the internal temperature between -74 0C to -72 0C, after addition the
on mixture was d at -78 0C for 1h, the reaction was quenched by sat.NH4Cl,
THF was removed in vacuo, then extracted by EtOAc. The organic was washed by water
and brine, dried over anhydrous , filtered and concentrated. The crude product
was purified by flash chromatography (0-30% EtOAc/heptaneatane) to yield product 660
mg, LCMS (m/z): 288.0 (MH+), 0.83 min. 1H NMR (400MHz, CDCI3) 8 ppm 7.14 (s, 1H),
7.03 (d, J=9.0 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 5.90 (ddd, J=7.4, 10.1, 17.3 Hz, 1H), 5.45
- 5.35 (m, 2H), 5.35 - 5.25 (m, 2H), 5.01 - 4.94 (m, 1H), 3.45 (br. s., 1H), 1.30 - 1.22 (m,
Ste 6. R 3-fluoro fluorometh l hen l ro enamine
(R)—N-((R)—1-(3-fluoro(fluoromethyl)phenyl)al|y|)methylpropanesulfinamide (660
mg, 2.297 mmol) in MeOH (7.66 mL), was added HCI (4 M in dioxane) (5.742 mL, 22.97
mmol) at 0 0C, the reaction mixture was stirred at room temperature for 2 h, The reaction
mixture was concentrated to dryness. Sat. Na2C03 was added, the reaction mixture was
then extracted by EtOAc. The organic was was dried and concentrated to yield the crude
product. The crude t was used in next step reaction without purification. LCMS
(m/z): 184.1 (MH+), 0.40 min.
Ste 7. R -tert-but | 1- 3-fluoro fluorometh | hen lall |carbamate
To a solution of (3-fluoro(fluoromethyl)phenyl)propenamine (421 mg, 2.30
mmol) in DCM (7.6 mL) was added Boc2O (640 pl, 2.76 mmol), the reaction mixture was
stirred at room temperature overnight, concentrated. The crude product was purified by
flash chromatography (0-20% EtOAc/heptane) to yield (R)—tert-butyl (1-(3-fluoro
omethyl)phenyl)allyl)carbamate. LCMS (m/z): 228.1 (MH+-56)), 0.91 min. 1H NMR
(400MHz, CDCI3) 6 ppm 7.08 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 5.95 (ddd, J=5.5, 10.6, 16.8
Hz, 1H), 5.42 (s, 1H), 5.30 (s, 1H), 5.30 - 5.13 (m, 3H), 4.86 (br. s., 1H), 1.44 (s, 9H).
Ste 8. S -tert-but | 1- ro fluorometh | hen lh drox eth |carbamate
(R)—tert-butyl fluoro(fluoromethyl)phenyl)allyl)carbamate (410 mg, 1.447 mmol) in
DCM (14.5 mL) was cooled down to -78 °C, The reaction mixture was bubbled by 03
(from ozone generator) for 5 min.The reaction e is light blue color, N2 was bubbled
through to get rid of 03, then NaBH4 (547 mg, 14.47 mmol) in ethanol (10 mL) was added,
the reaction e was stirred at -78 0C for 10 min, then d to return to room
temperature. After 30 min, sat. NH4C| was added followed methanol, the reaction e
was concentrated, then extracted by EtOAc. The organic was washed by sat. NaHC03,
water and brine, dried and concentrated to yield crude product.The crude product was
purified byflash chromato graphy to give the (S)—tert-butyl (1-(3-fluoro
(fluoromethyl)phenyl)hydroxyethyl)carbamate (223 mg, 54% yield). LCMS (m/z): 232.2
(MH+-56), 0.73 min.1H NMR (400MHz, CDCI3) 6 ppm 7.10 (s, 1H), 7.02 (d, J=9.4 Hz, 2H),
.43 (s, 1H), 5.35 - 5.28 (m, 1H), 4.78 (br. s., 1H), 3.95 - 3.78 (m, 2H), 1.44 (br. s., 9H).
Ste 9. S amino 3-fluoro fluorometh | hen lethanol
To a solution of (S)—tert-butyl (1-(3-f|uoro(fluoromethyl)phenyl)
hydroxyethyl)carbamate (220 mg, 0.766 mmol) in DCM (2.5 mL), HCI (4M in dioxane) (1.9
mL 7.66 mmol) was added at room temperature, the reaction mixture was stirred at room
temperature for 1h.The reaction mixture was then concentrated to dryness. The residue
was recrystalized from DCM and heptane. The solid was filtered and air dry to yield (S)—2-
amino(3-fluoro(fluoromethyl)phenyl)ethanol (145 mg, 0.908 mmol, 100 % yield) HCI
salt as white solid. LCMS (m/z): 188.2 (MH+), 0.32 min.
WO 66188
Examples 177 and 178
S nthesis of 4- 3-amino 1r4S h drox c clohex | razin-2— Ifluoro-N- S 3-
fluoro fluorometh | hen | h drox eth | benzamide and 4- 3-amino 1s 4R
h drox c clohex | 2— Ifluoro-N- S 3-fluoro fluorometh | hen I
hydroxyethyl )benzamide
Scheme 75
Steg l Steg g
F o F
””2 PdCIzdpprHzCIZ
“1&0 / NH 0
DME/NaZCO3 NH2 0 2
NBS |
+ —> —.
V“| N /
HO\Bflows N / I
100 00,311 | quant.
90% K/N KVN
F O
F O St Q§
NH2 0/ St 11
NH2 0/ o
‘B’ N /
PdCI2(dppf).CH20l2 adduct
{(I (Z) DME, Sodium Carbonate 2M \ N H2, Pd-C
+ —> \ N i
100 0 E)
C' 1'5 h
MeOH/EtOAC
O O 85%
O O
F O
F O
/ St 96
NH —
2 O J‘Ste 5
NH2 0/
\ lN HCI 3M aq N/ NaBH4
ACN/water
\ N —,
MeOH/THF
60% over two step
0 0C
O O 99%
O (trans/cis 4:1)
F 0
F o Stegz
/ NH OH
NH2 0 2
N/ N/
I LiOH I =
\ N \ N —. + C|H3N
quant
6H 5”
F 0 (OH F o {0
Stepfi ? =
F F
NH2 N NH2 N
H H
N / N /
|EA IN + 'N
_. \ \
F F
5H OH
Ste 1. Meth l4- 3-amino razin lfluorobenzoate
To 3-chloropyrazinamine (27 g, 208 mmol) in DME (391 mL) and sodium carbonate
(66.3 g, 625 mmol) was added methyl 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
enzoate (64.2 g, 229 mmol) and PdC|2(dppf).CH2C|2 adduct (8.51 g, 10.42 mmol).
The reaction mixture was purged with N2 and heated in oil bath at 100 °C for 3h. The
reaction mixture was partitioned between EtOAc and water. The organic layer was
separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The
crude product was recrystallized by EtOAc and heptane (2:3) to give methyl 4-(3-
aminopyraziny|)fluorobenzoate in 84% yield. LCMS (m/z): 248.1 (MH+), 0.58 min.
Ste 2. Meth l4- 3-aminobromo razin lfluorobenzoate
To a suspension of methyl 4-(3-aminopyrazinyl)fluorobenzoate (31.5 g, 127 mmol)
in acetonitrile (430 mL) at 0 0C was added NBS (23.9 g, 134 mmol). The reaction mixture
was stirred in ice bath for 1 h, sat. sodium bicarbonate was added, d 30 min and
product was ted with ethylacetate. The organic extracts were combined, washed
with brine, dried over sodium sulfate, filtered and ated.The crude product was
recrystallized in EtOAc and heptane to give methyl 4-(3-aminobromopyrazinyl)—2-
fluorobenzoate as brown color solid in 96% yield. LCMS (m/z): 326.0/328.0 (MH+), 0.87
min.
Ste 3. Meth l4- 3-amino 1 4-dioxas iro 4.5 decen l razin l
fluorobenzoate
To a solution of methyl 4-(3-aminobromopyrazinyl)fluorobenzoate ( 10 g, 30.7
mmol) in DME (77 mL) was added 4,4,5,5-tetramethyI(1,4-dioxaspiro[4.5]decen
y|)-1,3,2-dioxaboro|ane (9.79 g, 36.8 mmol), PdCI2(dppf).CH2C|2 adduct (1.252 g, 1.533
mmol), H20 (25.6 mL) and then last sodium carbonate (9.75 g, 92 mmol). The reaction
was heat at 100 °C in oil bath for 2 h. Cooled down. The reaction mixture was extracted
by EtOAc 3 times, the organic was washed with water and brine, dried and concentrated.
The crude material was recrystallized in DCM and heptane (1:1) to give product methyl
4-(3-amino(1,4-dioxaspiro[4.5]decenyl)pyrazinyl)f|uorobenzoate in 75%
yield. LCMS (m/z): 382.2 (MH+), 0.82 min.
Ste 4. Meth l4- 3-amino 1 as iro 4.5 decan l razin lfluorobenzoate
Methyl 4-(3-amino(1,4-dioxaspiro[4.5]decenyl)pyrazinyl)fluorobenzoate (6.1
g, 15.83 mmol) was dissolved in MeOH (150 mL) and EtOAc (80 mL) the reaction mixture
was flushed with N2 for 15 min, Then Pd-C (DEGASSA) (6 g, 5.64 mmol) was added, the
reaction mixture was then charged with hydrogen balloon and stirred at room temperature
overnight. The on mixture was filtered through Celite, which was washed with EtOAc
and methanol. The filtrate was concentrated to yield the crude product, which was used in
the next step reaction t purification. LCMS (m/z): 388.0 (MH+), 0.79 min.
Ste 5. Meth l4- 3-amino 4-oxoc clohex l razin uorobenzoate
To a solution of methyl 4-(3-amino(1,4-dioxaspiro[4.5]decanyl)pyraziny|)
benzoate (6.2 g, 16.00 mmol) in Acetonitrile (100 mL), Water (40 mL) was added
3M aqueous solution HCI (13.34 mL, 80 mmol). The reaction was stirred at room
temperature for 30 min. The reaction mixture was basified with 6M NaOH (10 mL), then
use sat. NaHC03 to adjust to pH 8. After acetonitrile was removed in vacuo, the solid
suspension e was filtered and washed with water and e, air-dried to give
methyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)fluorobenzoate as light yellow solid
in 67 % yield. LCMS (m/z): 344.0 (MH+), 0.70 min.
Ste 6. Meth l4- 3-amino 1r4r h drox c clohex l razin lfluorobenzoate
To a solution of methyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)f|uorobenzoate
(3.25 g, 9.47 mmol) in Methanol (100 mL) and THF (20 mL) at 0 °C, NaBH4 was added
(0.358 g, 9.47 mmol). After 30 min, saturated NH4C| was added slowly, then stirred at
room ature for 1 h. ol and THF was removed in vacuo. The residue was
extracted by EtOAc 3 times, the combined organic was washed with NaHC03 and water,
dried and concentrated. The crude product was used in next step reaction without
purification. LCMS (m/z): 346.4 (MH+), 0.63 min ) and 0.66 min (cis); trans/cis
(~4 :1).
To a solution of methyl 4-(3-amino((1r,4r)hydroxycyclohexyl)pyraziny|)
fluorobenzoate (3.25 g, 9.41 mmol) in MeOH (15.68 mL) and THF (15.68 mL) and then
LiOH 1M aqueous solution (23.53 mL, 23.53 mmol). The on was stirred at room
temperature for 2 h, 6 M HCI (3.9 mL )was added slowly. Methanol and THF was
removed in vacuo, the residue (yellow solid suspension) was filtered. The solid was
washed with water and heptane, air dry to yield the crude product. The crude product was
used in next step reaction without purification. LCMS (m/z): 332.1 (MH+), 0.49 min (trans)
and 0.53 min (cis).
Ste 8. 4- 3-amino 1r4S h drox c clohex l 2- lfluoro-N- S 3-
fluoro fluorometh l hen l h drox eth l benzamide and 4- 3-amino 1s 4R
h drox c clohex l razin lfluoro-N- S 3-fluoro fluorometh l hen l
hydroxyethy|)benzamide
To a mixture of 4-(3-amino((1r,4r)hydroxycyclohexyl)pyrazinyl)f|uorobenzoic
acid and mino((1s,4s)hydroxycyclohexyl)pyrazinyl)f|uorobenzoic acid
(19.45 mg, 0.053 mmol) was added NMP (0.5 mL), Hiinig’s base (0.042 mL, 0.240 mmol)
and (S)amino(3-fluoro(fluoromethyl)phenyl)ethanol-HCI (9 mg, 0.048 mmol).
Then HATU (36.6 mg, 0.096 mmol) was added. The reaction was stirred for 1 h at room
temperature, followed by LCMS. To the crude reaction was added 0.5 mL of NMP,
filtered, purifed by prep HPLC with both s isolated 4-(3-amino((1r,4S)—4-
hydroxycyclohexyl)pyrazinyl)fluoro-N-((S)(3-fluoro(fluoromethyl)phenyl)
WO 66188
yethyl)benzamide as trans and minor 4-(3-amino((1s,4R)—4-
hydroxycyclohexyl)pyrazinyl)—2-fluoro-N-((S)—1-(3-fluoro(fluoromethyl)phenyl)—2-
hydroxyethyl)benzamide as cis. Both products were lyophilized to TFA salts. For trans
diastereomer, 1H NMR (400 MHz, CD3OD) 6 ppm 7.84 - 7.70 (m, 2 H), 7.64 - 7.47 (m, 2
H), 7.19 (s, 1 H), 7.09 (d, J=9.78 Hz, 1 H), 6.98(d, J=9.00 Hz, 1 H), 5.36 (s, 1 H), 5.24 (s,
1 H), 5.13 (t, J=5.87 Hz, 1 H), 3.87 - 3.70 (m, 2 H), 3.59 -3.45 (m, 1 H), 2.62 - 2.49 (m, 1
H), 2.05 - 1.92 (m, 2 H), 1.91- 1.79 ( m, 2 H), 1.57 (qd, J=12.98 Hz, 2.93 Hz, 2 H), 1.39-
1.24 For cis diastereomer, 1H NMR (400 MHz, CD3OD) 6 ppm 7.93-7.81 (m, 2H) 7.75-
7.58 (m, 2H) 7.29 (d, J=9.78 Hz, 1 H), 7.19 (d, J=9.78 Hz, 1H), 7.07 (d, J=9.00 Hz, 1H),
.45 (s, 1 H), 5.33 (s, 1 H), 5.22( t, J=5.67 Hz, 1H), 4.01 (br. s., 1 H), 3.94 -3.77 (m, 2 H),
2.80 — 2.68 ( m, 1 H), 2.12 — 1.96 (m, 2 H) 1.91- 1.80 (m, 2 H), 1.77-1.60 (m, 4 H).
S nthesis of S -N- 2-amino 3-fluoroiodo hen l eth l -N-meth l
nitrobenzenesulfonamide
Scheme 76
S_Q 2 S_62 é S_r2 A
Step Q \1/ MQ
: N9”,6 NHBoc /OH
o‘S‘N —.F\E;/\/68t:>ZF\©/\/—eas—>SBocHN/KQ/F _. |
H ;F I
ma Step3 Step_11
{N3 BocHN NH2 ALQOZ
Ste 1. Meth |3-aminofluorobenzoate
3-bromofluorobenzoic acid (6.12 g, 33.1 mmol) was dissolved in MeOH (10 mL) and
cooled in ice-water bath and toluene (50 mL) and then TMS-diazomethane (19.84 mL,
39.7 mmol) was added se. Reaction miature was allowed to return to room
temperature for 1 h and concentrated in vacuo and the residue dissolved in DCM/Ether
and filtered through a short plug of silica and the filtrate evaporated in vacuo to afford the
desired product which was then dissolved in MeOH (60 mL) and Pd/C 10wt% 3.3 g was
added and the mixture evacuated and stirred under 1 atm of hydrogen overnight and
LCMS indicated desired product next morning. The reaction mixture was filtered through
Celite and the te was concnetrated in vacuo and the residue azeotroped with toluene
twice and taken to the next step as such (99%). LCMS (m/z): 211.1 (MH+), 0.55 min.
Step 2. Methyl 3-fluoroiodobenzoate
Methyl ofluorobenzoate was dissolved in 5.0 N HCI (68.5 mL, 343 mmol) and
cooled to 0 °C. NaNOz (2.51 g, 36.4 mmol) dissolved in 3.0 mL water was added
dropwise. Then Kl (6.59 g, 39.7 mmol) dissolved in 45 mL water was added over 30 min
and the mixture stirred at room temperature for 1 h and the reaction mixture was
extracted with EtZO twice (200 mL) and then dried sium sulfate), filtered and
concentrated in vacuo to give the crude product which was purified by flash
tography (0-20%EtOAc/heptane) to afford 5.49 g of the desired product as a
yellow syrup (59 %). 1H NMR (400 MHz, CDCI3) 6 ppm 8.18 (s, 1H), 7.69 (d, J=9.0 Hz,
1H), 7.63 (dd, J=7.6, 1.4 Hz, 1H), 3.93 (s, 3H).
Ste 3. roiodo hen lmethanol
Methyl 3-fluoroiodobenzoate (5.49 g, 19.60 mmol) was dissolved in DCM (100 mL) and
cooled to -78 °C. DIBAL-H (49.0 mL, 49.0 mmol) was added dropwise over 30 min and
then after 1 h r n of DIBAL-H (49.0 mL, 49.0 mmol) was added. Reaction
mixture agitated at -78°C for 4 h and poured carefully onto ice-cold 1N HCI. The mixture
was agitated for 10 min and the layers separated and the aq. layer extracted with DCM
and the ed organic extract was dried (magnesium sulfate), filtered and
concentrated in vacuo to afford the desired product in quantitative yield. LCMS not
conclusive.
Step 4. 3-fluoroiodobenzaldehyde
(3-fluoroiodophenyl)methanol (9.79 g, 35.0 mmol mmol) was dissolved in DCM (94 mL)
and then silica gel (18.0 g) was added. To the mixture at room temperature was added
PCC (18.3 g, 45.0 mmol) portion-wise and the mixture ed at room ature for 1
h and followed by TLC. After 1 h, TLC indicated complete conversion of the SM to a non-
polar (presumably aldehyde). The reaction mixture was filtered over 1-inch plug of silica
pad and eluted with 30% Ether in DCM (200 mL). The filtrate was concentrated in vacuo
to afford the crude product, which was taken to the next step without further purification.
Ste 5. R E -N- 3-fluoroiodobenz lidene meth l ro anesulfinamide
To a solution of 3-fluoroiodobenzaldehyde (8.75 g, 35 mmol) and (R)—(+)—t—
Butylsulfinamide (4.67 g, 38.5 mmol) in DCE ( 117 mL) was added copper(|l) sulfate
(anhydrous) (16.76 g, 105 mmol) and the resulting suspension was heated at 60 °C
overnight. LCMS indicated d t formation. Reaction mixture was filtered
through Celite and the filtrate concentrate in vacuo and then taken to the next step as
such. LCMS (m/z): 354.1 (MH+), 1.08 min.
Ste 6. R-N- R 3-fluoroiodo hen lall th l ro anesulfinamide
Dimethyl zinc (1.2M in toluene) (7.29 mL, 8.75 mmol) and agnesium bromide (45.5
mL, 45.5 mmol) was mixed at room temperature for 20 min under argon before cooling
down to -78 °C, then (R,E)-N-(3-fluoroiodobenzylidene)methylpropanesulfinamide
in dry THF ( 117 mL) as added dropwise about 30 min. The internal temperature
between -74 C to -72 °C, after addition the on mixture was stirred at -78 °C for 1 h,
sample was taken quenched by Water, LCMS showed the desired product along with
unreacted starting material. More vinylmagnesium bromide (12 mL, 12.0 mmol)) was
added and reaction monitored by LCMS and after 30 min, reaction was deemed
complete. The reaction mixture was poured over ice-cold by sat.NH4Cl and water, THF
was removed in vacuo and the product extracted by EtOAc. The organic layer was
washed by water and Brine, dried over anhydrous Na2804, filtered and concentrated and
the crude product was purified by flash chromatography (0-70% EtOAc/heptane) to
provide 8.99 g of (R)—N-((R)—1-(3-fluoroiodophenyl)allyl)methy|propanesulfinamide
as the desired product as a ess yellow syrup. Yield (67.4%). The yield is for the 4
step sequence. Note: The major side-product corresponds to inated d
product. LCMS (m/z): 382.5 (MH+), 0.96 min; 1H NMR (400 MHz, CDCI3) )6 ppm 7.48 (s,
1H), 7.37 (dt, J=7.6, 1.9 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.85 (ddd, J=17.0, 10.0, 7.4 Hz,
1H), 5.25-5.47 (m, 3H), 4.90 (d, J=7.0 Hz, 1H), 3.23-3.66 (m, 1H), 1.26 (s, 9H).
Step 7. (R)—tert-butyl (1-(3-fluoroiodophenyl)allyl)carbamate
(R)—N-((R)—1-(3-fluoroiodophenyl)allyl)methy|propanesulfinamide (8.99 g, 23.58
mmol) was dissolved in MeOH (40 mL) and treated with 4 N HCI (11.79 mL, 47.2 mmol)
and the mixture agitated at room temperature for 1 h and concentrated in vacuo. The
residue was dissolved water and Sat'd Na2CO3 was added. The t was extracted
with 3:1 CHCl3:lPA and the organic layer was dried (magnesium sulfate), filtered and
concentrated in vacuo. The residue was dissolved in DCM (60 mL) and Boc—anhydride
(6.79 mL, 29.2 mmol) was added. The mixture was agitated overnight at room
temperature and the next morning, the reaction mixture was concentrated in vacuo and
the crude product (R)—tert-butyl (1-(3-fluoroiodophenyl)allyl)carbamate taken to the next
step without any r cation. LCMS (m/z): 322.1 (MH+-56), 1.11 min.
Step 8. (S)—tert—butyl (1-(3-fluoroiodophenyl)—2-hydroxyethyl)carbamate
(R)—tert—butyl (1-(3-fluoroiodophenyl)allyl)carbamate (8.89 g, 23.58 mmol) was
dissolved in DCM (236 mL) and cooled to -78 °C. Ozone was purged through the mixture
until blue color persisted. Reaction mixture was then purged with en and NaBH4
(8.92 g, 236 mmol) was added in one portion followed by addition of MeOH (120 mL) and
the mixture was agitated at same temperature for 2 h and then acetone 20 mL was
added. Reaction mixture was ed for another 1 h and then poured over saturated
NH4C| and then extracted with DCM (500 mL) and then with 3:1 CHCI3/IPA (200 mL) and
the organic extracts were combined and dried (magnesium sulfate), and the solvent
concentrated in vacuo and the residue purified by flash tography to afford 6.74 g
(17.7 mmol) of (S)—tert-butyl (1-(3-fluoroiodophenyl)hydroxyethyl)carbamate (75%).
LCMS (m/z): 326.1 (MH+-56), 0.90 min.
Step 9. (S)—tert—butyl (2-azido(3-fluoroiodophenyl)ethyl)carbamate
(S)—tert—butyl (1-(3-f|uoroiodophenyl)—2-hydroxyethyl)carbamate (4.8112 g, 12.62 mmol)
was dissolved in DCM (100 mL) and cooled to 0 °C. Et3N (2.62 mL, 18.93 mmol) was
added next and then MsCl (1.180 mL, 15.15 mmol) was added se. The reaction
mixture was agitated at same temperature for 30 min after which RM quenched with Sat'd
NaHC03 and water. The product was extracted with DCM and the combined organic
layer was dried (magnesium sulfate), filtered and concentrated in vacuo to afford the
crude product which was dissolved in DMF (25 mL, ca 0.5 M). NaN3 (2.462 g, 37.9 mmol)
was added next and the mixture heated at 70 °C. After 6 h, the reaction mixture was
cooled to room temperature and diluted with EtOAc and water and the product ted
with EtOAc. The combined organic extract was washed with water thrice and dried
(magnesium sulfate), filtered and concentrated in vacuo and the residue purified by flash
chromatography (0-50%) EtOAc/heptane to afford 4.03 g of (S)—tert-butyl (2-azido(3-
fluoroiodophenyl)ethyl)carbamate as desired product. LCMS (m/z): 351.0 6),
1.05 min.
Step 10. (S)—tert—butyl (1-(3-fluoroiodophenyl)(2-
nitrophenylsulfonamido)ethyl)carbamate
(S)—tert-butyl (2-azido(3-fluoroiodophenyl)ethyl)carbamate (288 mg, 0.709 mmol)
was dissolved in MeOH (7.09 mL) and then polymer-bound PPh3 (7.09 mmol) was
added. RM agitated at 70 °C overnight. The next morning, LCMS indicated ion of
desired t. RM filtered through Celite and the filter-cake washed with DCM and
MeOH and the filtrate concentrated in vacuo to afford the crude amine which was taken to
the next step without any further cation. The crude amine was dissolved in DCM (7
mL) and cooled to 0 °C and then Triethylamine (0.198 mL, 1.418 mmol) was added.
Then 2-nitrobenzenesulfonyl de (189 mg, 0.851 mmol) was added in one portion.
The reaction mixture was agitated at room temperature for 1 h and quenched with water
and the product extracted with DCM. The organic layer was washed with brine and dried
(magnesium sulfate), filtered and concentrated in vacuo and the residue purified by flash
chromatography (0-40% EtOAc/heptane) to afford 290 mg of (S)—tert-butyl (1-(3-fluoro
iodophenyl)(2-nitrophenylsulfonamido)ethyl)carbamate as the desired product. LCMS
(m/z): 524.0 (MH+-56), 1.10 min.
Ste 11. S -N- 2-amino 3-fluoroiodo hen leth l-N-meth l
enzenesulfonamide (S)—tert-butyl fluoroiodophenyl)(2-
nitrophenylsulfonamido)ethyl)carbamate (290 mg, 0.513 mmol) was dissolved in DMF
(5.1 mL) and K2C03 (142 mg, 1.026 mmol) followed by iodomethane (48.1 ul, 0.769
mmol) were added. The mixture was agitated at room temperature for 1 h upon which
complete reaction observed. RM diluted with water and EtOAc. The organic layer was
washed with water twice and dried (magnesium sulfate), filtered and concentrated in
vacuo to give relatively pure product which was dissolved in DCM (5 mL) and treated
with 4N HCI in e (2 mL) and the mixture agitated at room temperature overnight
and the mixture concentrated in vacuo to afford the desired product (S)—N-(2-amino(3-
fluoroiodophenyl)ethyl)-N-methylnitrobenzenesulfonamide as the hydrochloride salt.
LCMS (m/z): 480.4 (MH+), 0.72 min.
e 179
S nthesis of S -N- 2-amino 3-fluoroiodo hen l eth l o tetrah dro-2H-
ran l razin uorobenzamide
Scheme 77
NH2 OH {N3
3 EDC HOAt
N \ F
I + HZN NI \
/N polymer-
DMF D'EA bound PPh3
O O O
Ste 1. S 3-amino tetrah dro-2H- ran l razin l-N- 2-azido 3-fluoro
iodo hen |eth lfluorobenzamide
4-(3-Amino(tetrahydro-2H-pyranyl)pyrazinyl)fluorobenzoic acid TFA adduct
(126 mg, 0.292 mmol) and HOAt (0.060 g, 0.438 mmol) was dissolved in DMF(1 mL) and
DIEA (0.156 mL, 0.876 mmol). (S)—2-azido(3-fluoroiodophenyl)ethanamine
hydrochloride salt (100 mg, 292 mmol), ed from the reaction of (S)—tert-butyl (2-
azido(3-fluoroiodophenyl)ethyl)carbamate with 4M HCI in dioxane (Step 9 in
Scheme 76), was added, followed by EDC (0.090 g, 0.467 mmol). The reaction mixture
was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc
and water, and the organic layer was washed with water twice and then with saturated
Na2C03. The organic layer was dried over magnesium sulfate, filtered and concentrated
in vacuo providing crude (S)(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)-N-(2-
azido(3-fluoroiodophenyl)ethyl)fluorobenzamide without further purification.
Ste 2. S -N- 2-amino 3-fluoroiodo hen l eth l o tetrah dro-2H-
pyranyl inyl )—2-fluorobenzamide
The crude (S)(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)-N-(2-azido(3-
fluoroiodophenyl)ethyl)fluorobenzamide was dissolved in THF (5 mL), and
triphenylphosphine er bound, 3 mmol/g) (0.97 g, 3.70 mmol) was added dropwise.
The e was heated at 70 °C for 3 h. LCMS indicated absence of starting material (at
this stage, the phosphorylimine intermediate is likely present in solid phase). Water (4.5
mL) and THF (5 mL) were added, and the mixture was heated at 80 °C for 3 h and then
filtered. The filter cake was washed with DCM and then filtrate was concentrated in
vacuo. The residue was dissolved in DCM and washed with water and the organic layer
dried over magnesium sulfate, filtered and concentrated in vacuo to afford the residue
which was purified by flash chromatography (0-60% DCM/10% MeOH in EtOAc
containing 0.5% , and the product fractions were collected and trated.
The residue was dissolved in acetonitrile and water, and lyophillized to obtain 101.2 mg
of (S)—N-(2-amino(3-f|uoroiodophenyl)ethyl)(3-amino(tetrahydro-2H-pyran
azinyl)fluorobenzamide as the desired product. LCMS (m/z): 580.1 (MH+),
0.70 min. 1H NMR (CD30D) 6 (ppm): 7.92 (s, 1H), 7.85 - 7.79 (m, 1H), 7.73 (dd, J=8.0,
1.4 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.50 - 7.43 (m, 1H), 7.23 (d, J=9.5 Hz, 1H), 5.12 (t, J=6.9
Hz, 1H), 4.07 (dd, J=11.2, 3.3 Hz, 2H), 3.60 (td, J=11.7, 2.0 Hz, 2H), 3.09 - 2.83 (m, 3H),
2.02 - 1.76 (m, 4H).
8 nthesis of S -tert-but l 2-amino 3-bromofluoro hen leth lcarbamate
Scheme 78
O (S)8 Step_2 H5)S‘o Step_3
Br —
(E) N|H -
F Os)< B;H
zéQ é
HN 0 Step; A HN’ so Step 5 ”HZ
Br ? Br NHBoc
NH2 NHBoc
F F
Ste 1. S E -N- 3-bromo—5-fluorobenz lidene meth l ro sulfinamide
To a solution of 3-bromofluorobenzaldehyde (5 g, 24.63 mmol) and (S)—2-
methylpropanesulfinamide (3.28 g, 27.1 mmol) in DCE (82 mL) was added copper(|l)
sulfate (anhydrous) (7.86 g, 49.3 mmol). The suspension was stirred under nitrogen at 60
°C ght. The reaction mixture was cooled down, filtered through a plug of celite, and
rinsed with DCM. The filtrate was concentrated to yield the crude t. The crude
product was purified by flash chromatograph eluting with 0-30% EtOAc in heptane to yield
the product (S,E)—N-(3-bromofluorobenzylidene)methy|propanesulfinamide (7.5 g,
24.49 mmol, 99 % yield) as a light yellow color oil. LCMS (m/z): 306.1/308.1 (MH+), 1.04
min.
Ste 2. S -N- S ofluoro hen lnitroeth lmeth l ro ane
sulfinamide
Nitromethane (1.0 mL, 17.20 mmol) was dissolved in THF (34.4 mL), then BuLi (2.5 M in
hexanes) (7.22 mL, 18.06 mmol) was added at -78 °C. The reaction mixture was stirred at
-78 °C for 10 min, then warmed up to room temperature for 20 min. After cooling down to
-78 °C, (S,E)-N-(3-bromofluorobenzylidene)methy|propanesulfinamide (4.74 g,
.48 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at -78
°C for 20 min, warmed up to room temperature, and stirred at room temperature for 5 h.
The reaction mixture was quenched by sat NH4CI, and extracted by EtOAc. The organic
was dried over Na2804, filtered and concentrated. The crude product was purified by
flash chromatography (0-40%-100% EtOAC/ heptane). Pure fractions were combined to
yield (S)—N-((S)—1-(3-bromofluorophenyl)nitroethyl)methylpropanesulfinamide
(2.2 g, 5.99 mmol, 38.7 % yield). LCMS (m/z): 367.1/369.1 (MH+), 0.89 min; 1H NMR
z, CDCI3) 6 ppm 7.31 (s, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.03 (q, J=5.7 Hz, 1H), 4.87
- 4.78 (m, 2H), 4.48 (d, J=5.1 Hz, 1H), 1.33 - 1.25 (m, 9H).
Ste 3. S -N- S amino 3-bromofluoro hen leth th l ro ane
sulfinamide
(S)—N-((S)—1-(3-bromofluorophenyl)nitroethyl)methy|propanesulfinamide (2.2 g,
.99 mmol) was dissolved in MeOH (19.97 mL), d with N2 for 10 min, and then Pt02
(0.408 g, 1.797 mmol) was added. The reaction mixture was charged with hydrogen
balloon and stirred at room temperature overnight. The reaction mixture was filtered
through celite and washed by methanol and EtOAc. The filtrate was dried over ,
filtered and concentrated. The crude material was used in next step reaction t
further purification. LCMS (m/z): 337.1/339.1 (MH+), 0.64min.
Ste 4. tert-but | S 3-bromofluoro hen l S -1 1-dimeth leth lsulfinamido
ethyl)carbamate
(S)-N-((S)amino(3-bromof|uorophenyl)ethyl)methy|propanesulfinamide (1.75
g, 5.19 mmol) was dissolved in DCM (17.30 mL), and then Boc20 (1.325 mL, 5.71 mmol)
was added. The reaction e was stirred at room temperature for 3 h, and then
concentrated. The crude product was ed to yield the product tert-butyl -(3-
bromofluorophenyl)((S)-1,1-dimethylethylsulfinamido)ethyl)carbamate (1.78 g, 78%).
LCMS (m/z): 439.1 (MH+), 0.99 min.
Step 5. (S)—tert—butyl (2-amino(3-bromofluorophenyl)ethyl)carbamate
To a solution of tert-butyl ((S)(3-bromof|uorophenyl)((R)-1,1-
ylethylsulfinamido)ethyl)carbamate (1 .78 g, 4.07 mmol) in DCM (13.57 mL) was
added HCI (4M in dioxane ) (4.07 mL, 16.28 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized to
pH = 7, then extracted by EtOAc to give the desired (S)-tert-butyl (2-amino(3-bromo
fluorophenyl)ethyl)carbamate (300 mg) as a free base. LCMS (m/z): 317.1/319.1 (MH+),
0.66 min.
S nthesis of S -tert-but | 2-amino 3-bromo hen leth lcarbamate
Br '
mHBoc
Following Scheme 78, using 3-bromobenzaldehyde, (S)-tert-butyl (2-amino(3-
bromophenyl)ethyl)carbamate was obtained as a HCI salt. LCMS (m/z): 315.1/317.1
(MH+), 0.66 min.
S nthesis of S -meth l 2-amino 3-bromofluoro hen leth lcarbamate
Scheme 79
\l/ O O
,é\ /NH
Hlj \O o :
Br + —> F
F Br
To a solution of (S)—N-((S)—2-amino(3-bromofluorophenyl)ethyl)methylpropane
amide (100 mg, 0.297 mmol) in DCM (988 pl) was added TEA (124 pl, 0.890 mmol)
and methyl chloroformate (24.12 pl, 0.311 mmol). The reaction mixture was stirred at
room temperature for 1 h. The reaction e was extracted by EtOAc and the organics
were washed with water and brine, dried over sodium sulfate, filtered off, and
concentrated in vacuo. The residue was dissolved in EtZO (1 mL), then HCI (4M in
dioxane) (148 pl, 0.593 mmol) was added. The reaction mixture was stirred at room
temperature for 30 min. After the solvent was decant out, the residue solid was used in
next step without further purification. LCMS (m/z): 291 .2/293 (MH+), 0.49 min.
8 -meth | 2-amino o hen leth Icarbamate
/OYO
Following Scheme 79, using (S)—N-((S)—2-amino(3-bromophenyl)ethyl)—2—
methylpropanesulfinamide, (S)—methyl (2-amino(3-bromophenyl)ethyl)carbamate
was obtained. LCMS (m/z): 273.0/2750 (MH+), 0.46 min.
(S)—methyl (2-amino(3-chlorophenyl)ethyl)carbamate
Following Scheme 79, using (S)—N-((S)—2-amino(3-chlorophenyl)ethyl)
methylpropanesulfinamide, thyl (2-amino(3-chlorophenyl)ethyl)carbamate
was obtained. LCMS (m/z): 229.2 (MH+), 0.42 min.
8 nthesis of S -N- 2-amino 3-bromofluoro hen | eth | acetamide
Scheme 80
\l/ YO
ngl’séo o o {NH
Br - + AOJK F
F Br
(S)—N-((S)—2-amino(3-bromofluorophenyl)ethyl)methylpropanesulfinamide (100
mg, 0.297 mmol) was dissolved in DCM (988 pl), followed by pyridine (71.9 ul, 0.890
mmol) and acetic ide (28.0 ul, 0.297 mmol). The reaction e was stirred at
room temperature for 1 h, extracted by EtOAc, washed by water and brine, dried over
Na2804 and concentrated. The residue was dissolved in EtZO (1 mL), then HCI (4 M in
dioxane) (148 pl, 0.593 mmol) was added. The reaction mixture was stirred at room
temperature for 30 min. After the solvent was decant out, the residue solid was used in
next step reaction without purification. LCMS (m/z): 275.1/277.1 (MH+), 0.41 min.
Synthesis of (S)—N-(2-amino(3-bromophenyl)ethyl)acetamide
WO 66188
Following scheme 80, using (S)—N-((S)—2-amino(3-bromophenyl)ethyl)
methylpropanesulfinamide, (S)-N-(2-amino(3-bromophenyl)ethyl)acetamide was
obtained. LCMS (m/z): 257.1/259.1 (MH+), 0.40 min.
Example 180
S nthesis of S -N- 2-amino 3-bromofluoro hen | eth | o tetrah dro-
2H- ran | razin lfluorobenzamide
Scheme 81
F O /NHBOC
NH2 OH /NHBocF Ste Ste
N \ EDC HOAt
N \ N \
I + HzN
DIEA DMF
0 o o
Ste 1. S -tert-but | 2- 4- 3-amino tetrah dro-2H- ran | razin l
fluorobenzamido 3-bromofluoro hen | eth | carbamate
To a solution of 4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)fluorobenzoic acid
(35 mg, 0.110 mmol) in DMF (368 pl) was added rt—butyl (2-amino(3-bromo
fluorophenyl)ethyl)carbamate (40.8 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol),
EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 ul, 0.331 mmol). The reaction mixture was
stirred at room temperature for 3 h, and then partitioned between EtOAc and water. The
organic was washed by NaHC03, water and brine, dried over Na2804 and concentrated.
The crude rt-butyl (2-(4-(-3amino---6(tetrahydro-H-p-yran-yl)pyrazin--y-|)
fluorobenzamido)(3-bromofluorophenyl)ethyl)carbamate was used in next step
reaction without further purification. LCMS (m/z): 632.1/634.1 (MH+), 0.97 min.
Ste 2. S -N- 2-amino 3-bromofluoro hen | eth | 3-amino tetrah dro-2H-
pyranyl )pyrazinyl )—2-fluorobenzamide
To a solution of rt-butyl (2-(4-(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)
benzamido)(3-bromofluorophenyl)ethy|)carbamate (69 mg, 0.110 mmol) in
DCM ( 1.0 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 h. The
on mixture was concentrated to dryness, then dissolved in DMSO and subject to
prep HPLC. Pure fraction was combined and lyophilized to yield final product as a TFA
salt. LCMS (m/z): 532.1/534.1 (MH+), 0.69 min; 1H NMR (400 MHz, Methanol-d4) 6 ppm
7.94 - 7.84 (m, 2H), 7.73 (dd, J=1.4, 8.0 Hz, 1H), 7.66 (dd, J=1.4, 11.9 Hz, 1H), 7.55 (s,
1H), 7.49 - 7.39 (m, 1H), 7.29 (d, J=9.4 Hz, 1H), 5.48 (t, J=7.2 Hz, 1H), 4.04 (dd, J=2.9,
11.5 Hz, 2H), 3.57 (dt, J=2.2, 11.6 Hz, 2H), 3.51 - 3.41 (m, 2H), 3.01 - 2.85 (m, 1H), 1.97 -
1.76 (m, 4H).
Example 181
S s of S -N- 2-amino 3-chlorofluoro hen | eth | 3-amino tetrah dro-
2H- ran | razin lfluorobenzamide
Scheme 82
F 0 $21 F o {N3 m; F o ””2
: a
F F
NHg OH /N3 NH; N \P/ NHZ N
g H H
N/ F
HzN EDC,HOAt N’ N/
E I I
\ N + —.
4— \ N 0' \ N 0'
DIEA,DMF pyridine, NHAOH
Ste 1. S 3-amino tetrah dro-2H- ran | razin l-N- 2-azido 3-chloro
fluoro hen leth lfluorobenzamide
To a solution of mino(tetrahydro-2H-pyranyl)pyrazinyl)fluorobenzoic acid
(126 mg, 0.398 mmol) in DMF (1328 ul) was added (S)azido(3-chloro
fluorophenyl)ethanamine (100.0 mg, 0.398 mmol), DIEA (348 pl, 1.991 mmol), EDC (153
mg, 0.797 mmol), and aza-HOBt (81 mg, 0.597 mmol). The reaction mixture was stirred
for 15 h. After water was added, the reaction mixture was worked up with EtOAc. The
organic layer was dried over Na2804, filtered off, and concentrated in vacuo. The crude
product was ed by flash chromatography (gradient EtOAc in heptane) to provide (8)-
4-(3-amino(tetrahydro-2H-pyran-4—yl)pyrazinyl)-N-(2-azido(3-chloro
fluorophenyl)ethy|)fluorobenzamide (118 mg, 58%). LCMS (m/z): 514.2 (MH+), 0.91
min.
Ste 2. S -N- 2-amino 3-chloro—5-fluoro hen l eth l 3-amino tetrah dro-2H-
pyranyl )pyrazinyl )—2-fluorobenzamide
To a solution of (S)(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)-N-(2-azido(3-
chlorofluorophenyl)ethyl)fluorobenzamide (118 mg, 0.230 mmol) in pyridine (2 mL)
was added NH4OH (200 pi) and hylphosphine (344 pl, 0.344 mmol) tially at
room temperature. The reaction mixture was stirred for 2 h. After EtOH (1 mL) was
added, the reaction mixture was concentrated in vacuo. The crude t was purified
by flash tography (20% MeOH in DCM containing 0.5% NH3 / DCM) to provide
89.6 mg of (S)—N-(2-amino(3-chlorofluorophenyl)ethyl)(3-amino(tetrahydro-2H-
pyranyl)pyrazinyl)f|uorobenzamide (79%). LCMS (m/z): 488.2 (MH+), 0.66 min.
1H NMR (500MHz, METHANOL-d4) 8 ppm 7.98 - 7.89 (m, 1H), 7.89 - 7.79 (m, 1H), 7.74
(td, J=1.4, 8.0 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.41 - 7.28 (m, 1H), 7.27 - 7.08 (m, 2H), 5.27 -
.12 (m, 1H), 4.07 (dd, J=3.8, 11.0 Hz, 2H), 3.69 - 3.52 (m, 2H), 3.14 - 3.03 (m, 2H), 2.96
(tt, J=3.9, 11.7 Hz, 1H), 2.02 - 1.77 (m, 4H).
8 nthesis of S -N- 2-amino 3-bromofluoro hen l eth l -N-meth l
nitrobenzenesulfonamide
Scheme 83
HN’S‘b c m2 1 Step_2
\ ,0
Br 023’ N02
+ —> N02 2
mg Q‘HBOC 8&2 A 2“”3“ Step_5
Br Br
. at: . it:
enzenesulfonamide
(S)—N-((S)—2-amino(3-bromofluorophenyl)ethyl)methylpropanesulfinamide (3.3
g, 9.78 mmol) was ved in DCM (32.6 mL) at 0 °C, then TEA (1.405 mL, 10.08
mmol), and 2-nitrobenzenesu|fony| chloride (2.169 g, 9.78 mmol) were added. The
reaction e was stirred at room temperatur for 3 h. The reaction mixture was
concentrated in vacuo and the crude product was purified to yield N-((S)—2-(3-bromo
fluorophenyl)((S)-1,1-dimethylethylsulfinamido)ethyl)nitrobenzenesulfonamide.
LCMS (m/z): 522.1/524.1 (MH+), 0.94 min.
Ste 2. S -N- 2-amino ofluoro hen l eth l nitrobenzenesulfonamide
N-((S)(3-bromofluorophenyl)((R)—1,1-dimethylethylsulfinamido)ethyl)
nitrobenzenesulfonamide (3.55 g, 6.80 mmol) in EtZO (22.65 mL), and HCI (4 M in
dioxane) (3.40 mL, 13.59 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was neutrailized by Na2C03 solution and
extracted by EtOAc. The organic layer was washed with water, dried, filtered off, and
concentrated in vacuo providing the crude (S)-N-(2-amino(3-bromo
fluorophenyl)ethyl)nitrobenzenesulfonamide, which was used in next step reaction
without further purification. LCMS (m/z): 418.2/420.2 (MH+), 0.62 min.
Step 3. (S)—tert—buty| (1-(3-bromofluorophenyl)—2-(2-
nitrophenylsulfonamido)ethyl)carbamate
(S)—N-(2-amino(3-bromofluorophenyl)ethyl)nitrobenzenesulfonamide (1.55 g, 3.71
mmol) was dissolved in CH2C|2 (12.35 mL), and then TEA (0.517 mL, 3.71 mmol) and
hydride (1.119 mL, 4.82 mmol) were added. The reaction mixture was stirred at
room temperature for 1 h, and concentrated. The crude product was purified by flash
chromatography to yield (S)—tert-buty| (1-(3-bromof|uoropheny|)(2-
nitrophenylsulfonamido)ethyl)carbamate. LCMS (m/z): 462.0/464.0 6), 0.99 min.
Ste 4. S -tert-but l 1- 3-bromofluoro hen l N-meth lnitro hen lsulfonamido
ethy|)carbamate
(S)—tert-butyl (1-(3-bromofluorophenyl)(2-nitrophenylsulfonamido)ethyl)carbamate
(2.3 g, 4.44 mmol) was dissolved in DMF (14.79 mL). K2C03 (1.226 g, 8.87 mmol) and
Mel (0.416 mL, 6.66 mmol) were added. The on mxiture was stirred at room
temperature for 2 h, and then water was added. The reaction mixture was ted by
EtOAc. The organic was washed by water and brine, dried and concentrated. The crude
product was purified by flash chromatagrapghy to yield (S)—tert-buty| (1-(3-bromo
fluorophenyl)(N-methylnitrophenylsulfonamido)ethyl) carbamate (2.3 g, 4.32 mmol,
97% yield).
Ste 5. S -N- 2-amino 3-bromofluoro hen leth l-N-meth l
nitrobenzenesulfonamide
(S)—tert-butyl (1-(3-bromofluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)
carbamate (2.3 g, 4.32 mmol, 97 % yield) was dissolved in CH2C|2 and HCI (4 M in
dioxane, 4.44 mL, 17.75 mmol) wad added. The reaction mixture was d at room
temperature overnight. Heptane was added. The solid was filtered, and dried by air to
yield (S)—N-(2-amino(3-bromofluorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide (1.8 g, 3.84 mmol, 87% yield). LCMS (m/z): 432.2/434.1 (MH+),
0.69 min.
(S)—N-(2-amino(3-bromofluorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide hydrochloride salt was ed as follows:
OH OH O\ O\
/ _/ ’ ' /
: o=s =
' NalO4 / RuCl3.H20
3 07,5
F (Boc)20/TEAIDCM E SOCIZ/Py/CHECN F F
F \N O \N
H2” —’ —>
BocHN —> / /
B0° CHSCN Boo
step 2
ste 1 step 3
p Br Br
Br Br
“S".N/ [11 IU
CE H 3/ \ N
HCI/Dioxane :/ \
N02 - F :
—.BOCHN
DCM, RT
KOH. CHBCN. RT. 1 h 60% yield, 4 steps
step 4 Br Br
step 5
Step 1: (S)—tert—butyl (1-(3-bromofluorophenyl)hydroxyethyl)carbamate.
To an ice water cooled solution of (S)amino(3-bromofluorophenyl)ethanol (30 g,
111 mmol) (HCI salt) in DCM (390 mL) was added TEA (46.5 mL, 333 mmol) followed by
Boc—anhydride (26.4 mL, 114 mmol in 50 ml of DCM). The addition was completed in 15
minutes. The ice water bath was removed and the reaction e was stirred at room
ature for 16 hours. The reaction e was concentrated, (the water bath
temperature was kept below 300C), the e was diluted with 500 ml of EtOAc,
washed with 100 ml of 1N NaOH, 100 ml of water and 100 ml of brine, dried over
Na2804, filtered and concentrated to afford the crude product as an viscous liquid, (in
smaller , it was a semi-solid). To this viscous (or semi-solid) product was added
120 ml of EtZO and the resultant mixture was then sonicated for 5 minutes. The e
was concentrated to about 60 ml of total volume. After 1 hour at room temperature, a
white crytalline solid precipitated out. (if no crystal , ~ 2 mg of the seed was
added). After 4 hours, the white solid was filtered, washed with a mininal amount of ether
and dried (over house vacumm for at least 1 hour) to afford a total of 30.5 g of the white
solid as the desired product. Recovery was improved if the filtrate was concentrated and
the above procedure was repeated. (S)—tert-butyl (1-(3-bromofluorophenyl)
hydroxyethyl)carbamate: 30.5 g, 82 % yield. LC-MS: ( MW—56): 279.8 m/z at 0.84 min.
1H NMR (400 MHz, DMSO) ppm 1.29 - 1.43 (m, 8 H) 3.38 - 3.55 (m, 2 H) 4.39 - 4.61 (m,
1 H) 4.84 (t, J=5.67 Hz, 1 H) 7.15 (d, J=9.39 Hz, 1 H) 7.24 - 7.44 (m, 3 H).
Step 2: (4S)—tert-butyl 4-(3-bromofluorophenyl)-1,2,3-oxathiazolidinecarboxylate 2-
oxide. To a solution of SOCI2 (19.98 mL, 274 mmol) in acetonitrile (280 ml) at -40 -450C (
inner temperature, dry ice-acetone bath temperature around -55C) under nitrogen
atmosphere was added (S)—tert-butyl (1-(3-bromofluorophenyl)
hydroxyethyl)carbamate (30.5 g, 91 mmol) in CH3CN (175 ml). The addition was
completed in about 30 s. After about 20 minutes stirring at 450C, pyridine (40.6
mL, 502 mmol) was added ( in about 10 minutes). After stirring for 10 minutes at -400C,
the g bath was removed, the mixture was warmed to room temeperature and stirred
for 2 hours. LC-MS shown two diastereomeric products, and some amount of dimer by-
product. The mixture was diluted with 400 ml of EtOAc, washed with brine (200 ml) three
times, dried over Na2804, filtered and concentrated (water bath around 400C, about 2
hours) to afford 35.7 grams of the crude product as a light yellow viscous liquid, which
was used immediately in the next step or stored at 4°C. (4S)—tert-butyl 4-(3-bromo
fluorophenyl)-1,2,3-oxathiazolidinecarboxylate 2-oxide: LC-MS: (MW-100): 281.8 at
1.02 min.
Step 3: (S)—tert-butyl 4-(3-bromo—5-fluorophenyl)-1,2,3-oxathiazolidinecarboxylate 2,2-
dioxide. To an ice water cooled solution of ert—butyl 4-(3-bromofluorophenyl)-
1,2,3-oxathiazolidinecarboxylate 2-oxide (34.6 g, 91 mmol) in acetonitrile (420 mL)
under stirrring was added NalO4 (29.2 g, 137 mmol), and ium trichloride hydrate
(0.359 g, 1.729 mmol), ed by water (320 ml). The reaction mixture was stirred at
0°C for 2 hours. The mixture was diluted with EtOAc (500 ml), washed with brine (200
ml) twice, dried over Na2804, filtered and concentrated to afford the crude product, which
was used directly at the next step. 40.3 grams of the crude product was obtained. LC-
MS: (MW + Na): 419.9 m/z at 1.01 min.
S£p_4: (S)—tert—butyl (1-(3-bromofluorophenyl)(N-methyl
nitrophenylsulfonamido)ethyl)carbamate. To a solution of N-methyl
nitrobenzenesulfonamide (18.69 g, 86 mmol) in acetonitrile (400 ml) at room temperature
was added KOH (10.21 g, 182 mmol, commercial, powder form). The resultant mixture
was stirred at room temperature for about 15 minutes before (S)—tert—butyl 4-(3-bromo
fluorophenyl)-1,2,3-oxathiazolidinecarboxylate 2,2-dioxide (36.1 g, 91 mmol) in 180 ml
of CH3CN was added (addition was ed in 15- 20 minutes). The resultant mixture
was stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to
about 200 ml of total volume. To the residue was added 600 ml of EtOAc, followed by
g with 180 ml of 3N HCI, 200 ml of 1N NaOH, and brine (200 ml), twice. The
solution was dried by Na2804, filtered through a filter funnel with celite ( ~30 g) and silica
gel ( 20 g). The ed solution was concentrated to afford 40.3 grams of the product as
a viscous liquid, which was used at the next step directly. (S)—tert-butyl (1-(3-bromo
fluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)carbamate: LC-MS: (MW + Na):
555.8 m/z at 1.07 min. (40.3 g, 76 mmol, 83 % yield).
S£p_5: (S)—N-(2-amino(3-bromofluorophenyl)ethyl)-N-methyl
nitrobenzenesulfonamide hloride salt. To a solution of (S)—tert-butyl (1-(3-bromo
fluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)carbamate (40 g, 75 mmol) in
DCM (420 ml) at room temperature was added HCI (4M in dioxane, 150 ml, 601 mmol).
The ant solution was stirred at room temperature for 4 hours during which time a
white solid precipitated out. The reaction mixture was filtered, the white solid was washed
with DCM ( 50ml x2), and vacumm dried to afford 23.8 grams of the desired product as a
white solid. ( HCI salt). (S)—N-(2-amino(3-bromofluorophenyl)ethyl)-N-methyl
enzenesulfonamide (23.8 g, 68 % yield over four steps). LC-MS: ( M+1): 433.9
m/z at 0.66 min. 1H NMR (400 MHz, <dmso>) ppm 2.86 (s, 3 H) 3.56 - 3.82 (m, 2 H)
4.61 (t, J=7.24 Hz, 1 H) 7.42 - 7.61 (m, 2 H) 7.68 (d, J=1.57 Hz, 1 H) 7.75 -8.05 (m, 4 H).
S nthesis of S -N- 2-amino 3-bromofluoro hen l eth l -N- 2-fluoroeth l
nitrobenzenesulfonamide
Brm\
[/0 N02
I ’8 F O/
ing steps 4 and 5 in scheme 83, using 1-bromofluoroethane, (S)—N-(2-amino
(3-bromofluorophenyl)ethyl)-N-(2-fluoroethyl)nitrobenzenesulfonamide was
obtained. LCMS (m/z): 464.1/466.1 (MH+), 0.71 min.
Example 182
S nthesis of 4- 3-amino 18 38 4S fluoroh drox c clohex l razin l-N- S -
1-( ofluorophenyl )—2-hyd roxyethyl )—2-fluorobenzamide
Scheme 84
F o J< m1 F o J< m; F o F O
Step g
NH2 0 BoczN O OJ< BOCZN BocZN OJ<
N/ 80620, MeCN N/ LiHMDS N’ Selectfluor N’
I I I I
\ N —’ \ N —. —’
\ N \ N
cat. DMAP TESCI MeCN
73—95% 84%
(+/-)
crude
0 0 OTES 0
F 0 J< mi F o J<
Step e F 0
NH2 0 NH2 0
NaBHA chiral resolution NH2 0J<
N / —> N / —.
\ IN 91% IN N ’
\= 830/ I
= \ N
= (+/-) : (+/.) g 40%
27% 44%
Ste ; 4
"'F Q’F Rt: 1.84 min
4M HCI in dioxane MM_L_ OH polar M [g OH
60% (2 steps) p_0lar MMJ _HPLC
+ + +
F O J< F o J< F O J<
NH2 0 NH2 0 NH2 0
N / N /
I I N /
\ N K/N \ N
(+/.) : +/_
' ( )
13% O 47%
"’F Rt: 2.87 min
_ "IF F
0 6H 5H
F O J< F o
F 0 {OH
NH2 0 NH2 OH F
$21 Stegg NH;
NK/IN/ / /OH H
g N/
' '
In dioxane NK/IN 4M HCI \_ F EDC HOAt |
, DIEA, DMF
+ HCI HZN \xN BI
' '
33% (2 steps) ?
CrLIde
”'F ”'F
OH OH Q.'1F
Ste 1. Imidodicarbonic acid 4- 3- tert-butox carbon | amino 4-
oxoc clohex | razin lfluorobenzoate 1 3-bis 1 1-dimeth leth | ester
To a solution of tert-butyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)-2—fluorobenzoate (3
g, 7.78 mmol) in acetonitrile (130 mL) was added Boc20 (6.33 mL, 27.2 mmol) and DMAP
(0.048 g, 0.389 mmol). The on mixture was stirred overnight at room temperature.
After volatile materials were removed on rotavap under reduced pressure, the crude
t was purified by flash chromatography eluting with 0-50% of heptane to
provide imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)(4-
oxocyclohexyl)pyrazinyl)fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (4.34 g,
7.41 mmol, 95%). LCMS (m/z): 586.5 (MH+), 1.24 min; 1H NMR (500 MHz,
CHLOROFORM-d) 6 ppm 8.52 - 8.41 (m, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.61 - 7.44 (m, 2H),
3.46 - 3.30 (m, 1H), 2.68 - 2.52 (m, 4H), 2.38 (dd, J=3.0, 13.7 Hz, 2H), 2.28 - 2.10 (m,
2H), 1.69 - 1.61 (m, 9H), 1.42 - 1.29 (m, 18H).
Step 2. lmidodicarbonic acid, 4-(3-((tert—butoxycarbonyl)amino)—6-(4-
trieth lsil lox c clohexen l razin lfluorobenzoate 1 3-bis 1 1-
dimethylethyl) ester
To a solution of imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)(4-
oxocyclohexyl)pyrazinyl)fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (12.1 g,
.66 mmol) in THF (68.9 mL) was slowly added LiHMDS (1 M in THF) (22.73 mL, 22.73
mmol) at -78 °C. After stirring for 30 min, triethylchlorosilane (3.67 mL, 21.69 mmol) was
added. The reaction mixture was warmed to room temperature and stirred for 1 h.
Saturated sodium bicarbonate solution was added, and the mixture was extracted with
EtOAc. The c layer was washed well with water and brine, dried over ous
NaHCOS, filtered off, and concentrated in vacuo. The crude product was purified by flash
chromatography eluting with 5% of heptane to e imidodicarbonic acid, 4-(3-
—butoxycarbonyl)amino)(4-((triethylsilyl)oxy)cyclohexenyl)pyrazinyl)
fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (12.1 g, 17.29 mmol). LCMS (m/z,
neutral-nonpolar method): 701.8 (MH+), 1.14 min; 1H NMR (400 MHz, CDCI3) 6 ppm 8.41
(s, 1H), 8.00 - 7.88 (m, 1H), 7.57 - 7.46 (m, 2H), 4.97 (br. s., 1H), 3.16 - 3.00 (m, 1H),
2.49 - 2.38 (m, 2H), 2.38 - 2.23 (m, 1H), 2.19 - 1.94 (m, 3H), 1.61 (s, 9H), 1.33 (s, 18H),
1.06 - 0.94 (m, 8H), 0.77 - 0.64 (m, 6H).
Ste 3. lmidodicarbonic acid 4- 3- tert-butox carbon l amino 3-fluoro
oxoc clohex l razin lfluorobenzoate 1 3-bis 1 1-dimeth leth l ester
To a solution of imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)(4-
((triethylsi|y|)oxy)cyclohexeny|)pyrazinyl)f|uorobenzoate, 1,3-bis(1,1-
dimethylethyl) ester (12.1 g, 17.29 mmol) in acetonitrile (57.6 mL) was added Selectfluor®
(7.96 g, 22.47 mmol) at 0 °C. The reaction mixture was warmed up to room temperature
and stirred overnigt. After quenched with sat. NaHC03 solution, the reaction e was
extracted with EtOAc. The organic layer was washed with water and brine, dried over
Na2804, filtered and concentrated in vacuo to provide icarbonic acid, 4-(3-((tert-
butoxycarbonyl)amino)(3-fluorooxocyclohexyl)pyrazinyl)fluorobenzoate, 1,3-
bis(1,1-dimethylethyl) ester (10.44 g, 17.29, 100%), which was used for the next step
without further purification. LCMS (m/z, neutral—nonpolar method): 604.3 (MH+), 1.12
min.
Ste 4. +/- -tert-but |4- 3-amino 1R 3R fluorooxoc clohex l razin l
fluorobenzoate
To a solution of lmidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)(3-fluoro
oxocyclohexyl)pyrazinyl)fluorobenzoate, s(1,1-dimethylethyl) ester (10.44 g,
17.29 mmol) in THF (57.6 mL) was added 4 M HCI in dioxane (130 mL, 519 mmol) at
room temperature. The reaction mixture was stirred for 3-4 h, which was monitored by
LCMS to prevent more of the t-butyl ester from hydrolyzing to carboxylic acid. The
reaction was cooled in water bath, and neutralized with saturated sodium carbonate. The
resulting mixture was ted with EtOAc three times. The combined organic layers
were washed with brine, dried over Na2804, filtered and concentrated. The residue was
purified by flash tography eluting with 0-100% of EtOAc/heptane to provide (+/-)-
utyl 4-(3-amino((1R,3R)—3-fluorooxocyclohexyl)pyrazinyl)f|uorobenzoate
(1.9 g, 4.71 mmol, 27.2%) and tert-butyl 4-(3-amino((1S,3S)—3-fluoro
lohexyl)pyrazinyl)—2-fluorobenzoate (926 mg, 2.295 mmol, 13.3%). LCMS (m/z):
404.3 (MH+), 0.84 min and 404.3 (MH+), 0.84 min respectively.
Ste 5. +/- -Tert-but |4- 3-amino 18 38 4S fluoroh drox c clohex l razin
yl)—2-fluorobenzoate
To a on of (+/-)-tert-butyl 4-(3-amino((1R,3R)—3-fluorooxocyclohexyl)pyrazin
yl)f|uorobenzoate (1.9 g, 4.71 mmol) in MeOH (47.1 mL) was added NaBH4 (0.267 g,
7.06 mmol) at 0 °C. The reaction mixture was d for 2 h. After quenched with sat.
NaHC03 solution, the reaction mixture was extracted with EtOAc. The organic layer was
washed with water and brine, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography eluting with flat 35% of
EtOAc in heptane to provide (+/-)-tert-buty| 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyraziny|)fluorobenzoate (839 mg, 2.07mmol, 43.9%) and (+/-)-
tert-butyl 4-(3-amino((1R,3R,4R)—3-fluorohydroxycyclohexyl)pyraziny|)
2014/062913
fluorobenzoate (900 mg, 2.22 mmol, 47%). LCMS (m/z): 406.3 (MH+), 0.85 min and 406.3
(MH+), 0.85 min tively.
Ste 6. Tert-but |4- 3-amino 18 38 4S -3—fluoroh drox c clohex l razin l
fluorobenzoate
Tert-butyl 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)—2-
fluorobenzoate (839 mg, 2.07mmol) was subjected to chiral tion (ChiralPak 5mic
AD column, 4.6x100 (mm), OH+0.1% DEA=70/30, SFC=5m|/min) to provide single
enantiomer tert-butyl 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazin-2—
yl)fluorobenzoate (Rt = 1.61 min, 336 mg, 0.829 mmol, 40%) and the less polar
enantiomer (Rt = 2.45 min, 43%).
Ste 7. 4- 3-amino 18 38 4S fluoroh drox c clohex l razin l
fluorobenzoic acid
To a solution of tert-butyl utyl 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazin-2—yl)—2-fluorobenzoate (90 mg, 0.22 mmol) in DCM (0.444 mL)
was added 4 M HCI in dioxane (3.7 mL, 14.80 mmol). The reaction mixture was stirred
overnight at room temperature. After the volatile materials were evaporated in vacuo, the
reaction e was triturated with Et2O, and filtered off to provide 4-(3-amino
((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)f|uorobenzoic acid (86 mg, 0.22
mmol, 100%) as a HCI salt, which was used for the next step without any further
purification. LCMS (m/z): 350.2 (MH+), 0.51 min.
Ste 8. 4- 3-amino 18 38 4S fluoroh drox c clohex l razin l-N- S 3-
bromofluorophenyl)—2-hydroxyethyl )—2-fluorobenzamide
To a solution of 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)—2-
fluorobenzoic acid (20 mg, 0.057 mmol) in DMF (573 uL) was added (S)amino(3-
bromofluorophenyl)ethanol HCI salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69 mg,
0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 ul, 0.172 mmol). The
reaction mixture was d for 15 h. Water was added, and the reaction mixture was
extracted with EtOAc three times. The organic layers were dried over NazSO4, filtered and
concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were
lyophilized to provide 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazin
2014/062913
((S)(3-bromofluorophenyl)hydroxyethyl)f|uorobenzamide (12.9 mg, 0.019
mmol, 32.8%) as a TFA salt. LCMS (m/z): 565.1/567.1 (MH+), 0.72 min; 1H NMR (400
MHz, CD3OD) 6 ppm 7.78 (s, 2H), 7.63 - 7.47 (m, 2H), 7.37 (s, 1H), 7.22 - 7.02 (m, 2H),
.15 - 5.03 (m, 1H), 4.43 - 4.15 (m, 1H), 3.77 (t, J = 5.7 Hz, 2H), 3.62 - 3.47 (m, 1H), 2.76
(br. s., 1H), 2.19 (dd, J: 3.1, 6.3 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.89 - 1.66 (m, 2H), 1.56
(dd, J = 3.3, 12.3 Hz, 1H), 1.42 (br. s., 1H). The absolute stereochemistry was determined
based on the information of X—ray co-structure of 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazinyl)—N-((S)(3-bromofluorophenyl)hydroxyethyl)
fluorobenzamide.
Example 183
S nthesis of 4- 3-amino 1R 3R 4R fluoroh drox c clohex | razin l-N- S -
1- 3-bromofluoro hen lh drox eth lfluorobenzamide
Scheme 85
F o J< F o
F o {oH
NH2 0 NH2 OH F
Step 1 NH2
OH Step g N
N / N / _/
I I
= N /
\ N 4M HCI In dioxane_ . \ N F EDC, HOAt I
DIEA, DMF
HCI HZN
+ \ N Br
41% (2 steps)
crude
F F
L L F
6H 6H
fluorobenzoic acid
To a solution of tert-butyl 4-(3-amino((1R,3R,4R)fluorohydroxycyclohexyl)pyrazin-
2-y|)fluorobenzoate (Scheme 84: 365 mg, 0.9 mmol) in DCM (2 mL) was added 4 M
HCI in dioxane (8 mL, 32.0 mmol). The reaction mixture was stirred for 3 days at room
temperature. After the volatile materials were ated in vacuo to yield 4-(3-amino
((1R,3R,4R)—3-fluorohydroxycyclohexyl)pyrazinyl)fluorobenzoic acid, which was
used for the next step without further purification. LCMS (m/z): 350.3 (MH+), 0.48 min.
Ste 2. 4- 3-amino 1R 3R 4R oroh drox c clohex | razin l-N- S 3-
bromofluorophenyl)—2-hydroxyethyl )—2-fluorobenzamide
To a solution of 4-(3-amino((1R,3R,4R)—3-fluorohydroxycyclohexyl)pyrazinyl)
fluorobenzoic acid (20 mg, 0.057 mmol) in DMF (573 uL) was added (S)—2-amino(3-
bromofluorophenyl)ethanol HCI salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69 mg,
0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 pl, 0.172 mmol). The
reaction mixture was stirred for 15 h. Water was added, and the reaction e was
extracted with EtOAc three times. The organic layers were dried over Na2804, ed and
concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were
lyophilized to provide 4-(3-amino((1R,3R,4R)—3-fluorohydroxycyclohexyl)pyrazin
yl)-N-((S)(3-bromofluorophenyl)hydroxyethyl)f|uorobenzamide (16.1 mg, 0.023
mmol, 41%) as a TFA salt. LCMS (m/z): 565.1/567.1 (MH+), 0.72 min; 1H NMR (400 MHz,
CD3OD) 6 ppm 7.86 - 7.69 (m, 2H), 7.65 - 7.47 (m, 2H), 7.40 - 7.30 (m, 1H), 7.22 - 7.06
(m, 2H), 5.08 (t, J=5.7 Hz, 1H), 4.41 - 4.14 (m, 1H), 3.85 - 3.67 (m, 2H), 3.63 - 3.48 (m
1H), 2.74 (t, J=11.5 Hz, 1H), 2.17 (td, J=3.1, 6.3 Hz, 1H), 2.04 - 1.89 (m, 1H), 1.84 - 1.66
(m, 2H), 1.65 - 1.30 (m, 2H). The absolute stereochemistry was determined based on the
information of X—ray co-structure in ERK2 of 4-(3-amino((1R,3R,4R)—3-fluoro—4-
hydroxycyclohexyl)pyrazinyl)—N-((S)(3-bromofluorophenyl)hydroxyethyl)
fluorobenzamide.
Example 184
S nthesis of 4- 3-amino 18 38 4S f|uoroh drox c clohex | razin l-N- S -
1- 3-bromofluoro hen | meth lamino eth | f|uorobenzamide
Scheme 86
E 5
DMF DIEA Br HOZCQ
"'F Q
Ste 1. 4- o 18 38 4S fluoroh drox c clohex | razin l-N- S 3-
bromofluoro hen l N-meth lnitro hen namido eth lfluorobenzamide
To a solution of 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)
benzoic acid (156 mg, 0.403 mmol) in DMF (1.28 mL) was added (S)—N-(2-amino
(3-bromofluorophenyl)ethyl)-N-methylnitrobenzenesulfonamide (180 mg, 0.384
mmol), HOAt (105 mg, 0.768 mmol), DIEA (402 pl, 2.8 mmol), and EDC.HC| (147 mg,
0.768 mmol). The reaction mixture was stirred at room temperature for 15 h, LCMS
indicated the t. The mixture was diluted with EtOAc and washed with water and
once with saturatedd Na2C03 and the organic layer was dried (magnesium sulfate),
filtered and concentrated in vacuo providing 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide. The crude t was purified by ISCO column chromatography (0-
100% EtOAc in heptane) leading to 4-(3-amino((1S,3S,4S)—3-fluoro-4—
hydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromofluorophenyl)(N-methyl
nitrophenylsulfonamido)ethyl)fluorobenzamide (99%).
Ste 2. 4- o 18 38 4S fluoroh drox c clohex l razin l-N- S 3-
bromofluorophenyl)—2-( methylamino)ethyl )—2-fluorobenzamide
To a solution of 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)-N-
((S)—1-(3-bromofluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)
fluorobenzamide (293 mg, 0.38 mmol) in DMF (3.8 mL) was added K2C03 (371 mg, 2.69
mmol) and 4-mercaptobenzoic acid (207 mg, 1.34 mmol). The reaction mixture was
heated in microwave synthesizer at 45 °C for 55 min. After the reaction, water was added,
and the mixture was extracted with EtOAc three times. The organic layers were ed
and washed with water three times. The combined organic layer was dried over sodium
sulfate, filtered off, and concentrated in vacuo. The residue was purified with flash
tography eluting with EtOAc (containing 20% MeOH and 0.5 % ammonia in water
)/DCM to provide 150 mg of 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazinyl)-N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide. LCMS (m/z): 578, 580 (MH+), 0.64 min. 1H NMR (400 MHz, CDSOD)
8 ppm 7.80 (s, 1H), 7.76 - 7.68 (m, 1H), 7.59 (dd, J=1.6, 7.8 Hz, 1H), 7.53 (dd, J=1.2,
11.7 Hz, 1H), 7.37 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.11 (d, J=9.4 Hz, 1H), 5.27 - 5.10 (m,
1H), 4.42 - 4.13 (m, 1H), 3.65 - 3.49 (m, 1H), 2.97 - 2.88 (m, 1H), 2.87 - 2.79 (m, 1H),
2.74 (t, J=11.7 Hz, 1H), 2.35 (s, 3H), 2.22 - 2.11 (m, 1H), 2.04 - 1.92 (m, 1H), 1.85 - 1.68
(m, 2H), 1.55 (dq, J=3.1, 12.9 Hz, 1H), 1.46 - 1.33 (m, 1H).
2014/062913
Alternatively, mino((18,38,4S)fluorohydroxycyclohexyl)pyrazin
yl)-N-((S)(3-bromofluorophenyl)(methylamino)ethyl)fluorobenzamide can be
synthesized as follows:
,4S)—ethyl 4-( (tert-butyldimethylsilyl )oxy)—3-fluorocyclohexanecarboxylate
COOEt COOEt
TBSCI
"’F "’F
OH OTBS
To a 500 mL flask was added (1 S)—ethyl rohydroxycyclohexane-
carboxylate (17 g, 89.3 mmol, 97.9% ee), TBSCI (17.5 g, 116.1 mmol) and DCM (200
mL). Imidazole ( 12.1 g, 178 mmol) was added to the resultant clear solution and the
reaction mixture was d for 16 hours. Water (100 mL) was added and the mixture
was stirred for a further 10 minutes. The phases were separated and the organic layer
was washed with water (100 mL) and concentrated under reduced pressure (40:5 °C, 50
~ 250 mbar). Purification by flash chromatography on silica eluting with a mixture of
heptane and ethyl acetate (100:1) gave (1R,3S,4S)—ethyl 4-((tert-butyldimethylsilyl)oxy)
fluorocyclohexanecarboxylate as a colorless oil (20.6 g, yield 75.7%). 1H NMR (400MHz,
DMSO-ds): 4.38 ~ 4.52 (m, 1 H), 4.03 ~ 4.08 (dd, J: 1 2 Hz, J: 8 Hz, 2 H), 3.77 ~ 3.81(
m, 1 H), 2.54 ~2.60 (m, 1 H), 1.93 ~2.06 (m, 1 H), 1.58 ~ 1.86 (m, 4 H), 1.46~1.50 (m, 1
H), 1.17 ~ 1.20 (t, J: 12 Hz, J: 6 Hz, 3 H), 0.85( s, 9 H), 0.03 ~ 0.04 (d, J: 4 Hz, 8 H),
[M+H]+= 305.1 via GC-MS (Instrument: Agilent logies, GC 6890N, MS 5975C.
GC conditions: Column : HP — 5 MS, Capillary: 30.0 m x 250 um x 0.25 pm, Detecor
parameters: Temperature: 350 °C, Flow H2 : 40 mL / min, Airflow: 400 mL / min, Makeup
(He): 40 mL / min. Injector parameters: temperature : 200 °C. Split ratio: 100:1. Carrier
gas: He, Flow: 2.0 mL/ min, Mode: Constant flow. Oven parameters: 0 min, 50 °C; 2.0
min, 50 °C; 5.33 min, 100 °C; 15.83 min, 270 °C. Injection volume: 1 uL, Syringe wash
solvent: acetonitrile. MS conditions: Volt: 70 EV, Scan range: m/z = 50 ~ 550)
24- tert-but ldimeth lsil lox fluoroc clohex l 2 5-dimeth l-1H-
rrol l razine
A A A A A A
A NH} NIJ; ”(j N|\ NJ}/ COzEt N)\
N /N /N N /N bN I
N)\ +
? 002H + —’
—> =C02El + ”C02Et —>
+ .u002H F
/N OTBSF u, u,
OTBSF OTBSF F F w .,l
,F F
3' 0TBS 0TBS onss OTBS
overall yield of 4 steps: 51.8%
To a 1 L flask was added 2-bromo(2,5-dimethyl-1H-pyrrolyl)pyrazine (23 g,
67 mmol), ,4S)—ethyl 4-((tert-butyldimethylsilyl)oxy)
fluorocyclohexanecarboxylate (28 g, 83 mmol), {[P(t—Bu)3]PdBr}2 (800 mg, 1 mmol)
followed by toluene (250 mL). The reaction mixture was degased three times by purging
with nitrogen and then cooled to -35i5°C. To the reaction mixture was added NaHMDS
(47 mL, 2 M in THF, 94 mmol), dropwise. The temperature was raised to room
temeperature over a one hour period and stirred for a further 30 minutes. The reaction
mixture was quenched with 8% aqueous ammonium chloride (200 mL), the phases
ted, and the aqueous layer extracted with heptane (300 mL). The combined
organic layer was washed with 10% brine (400 mL), concentrated under reduced
pressure(45i5 °C, 50 ~ 100 mbar) to give 48 g of (1RS,3S,4S)-ethyl 4-((tertbutyldimethylsilyl
1-(5-(2,5-dimethyl-1H-pyrrolyl)pyrazinyl)
fluorocyclohexanecarboxylate as a mixture of 1R and 1S diastereomers. This material
was used for next step without further purification. HPLC retention time = 8.274 min
HPLC method d: Instrument : Agilent Technologies 1200 series. Column: Waters
Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35 oC. Flow rate: 0.70 mL / min.
Detection: 210 nm/ DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B:
acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B. LC-MS
method: [M+H]+= 476.2706, 1H NMR(400MHz, DMSO-ds): 8.47 (s. 1 H), 8.43 (s, 1 H),
.85(s, 2 H), 4.39 ~ 4.52 (m, 1 H), 4.14 (dd, J =1 2 Hz, J = 8 Hz, 2 H), 3.59 ~ 3.66 (m, 1
H), 2.28 ~ 2.94 (m, 1H), 2.06 (s, 6 H), 1.84 ~ 1.97 (m, 3 H), 1.46 ~ 1.52 (m, 3 H), 1.14 ~
1.17 (t, J: 1 2 Hz, J: 8 Hz, 2H), 0.81 (s, 9 H), 0.01( d, J: 4 Hz, 6 H).
To a 1 L flask was added ,4S)—ethyl rt-butyldimethylsilyl)oxy)(5-
(2,5-dimethyl-1H-pyrrolyl)pyrazinyl)fluorocyclohexanecarboxylate (48g, 67 mmol),
ethanol (250 mL) followed by 11% aqueous NaOH solution (112 g, 300 mmol). The
on e was stirred at 30:5 °C for 16 hours, and then was quenched with 10%
aqueous HCI (70 mL) to pH = 6~7. After distillation of ethanol under reduced pressure
(50:5 °C, 50 ~ 100 mbar), the pH of the resulting mixture was adjusted to between 4 and
with 10% HCI. The aqueous solution was extracted twice with lPAc (200 mL X2). The
combined organic layers were washed with 10% brine (200 mL) and concentrated under
reduced pressure (50:5 °C, 50 ~ 100 mbar) to give 46 g of (1RS,3S,4S)((tert-
imethylsilyl)oxy)(5-(2,5-dimethyl-1H-pyrrolyl)pyrazinyl)
cyclohexanecarboxylic acid which was used for next step without further
purifications. HPLC retention time = 7.390 min (Instrument: Agilent logies 1200
series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column ature: 35 OC.
Flow rate: 0.70 mL / min. Detection: 210 nm/ DAD. Mobile phase composition: A: 0.1%
H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min
100% B), LC-MS: [M+H]+= 448.2415.
To a 500 mL flask was added (1 4S)—4-((tert-butyldimethylsilyl)oxy)(5-
(2,5-dimethyl-1H-pyrrolyl)pyrazinyl)fluorocyclohexanecarboxylic acid (46 g),
toluene (250 mL) and HOAc (0.8 g, 13.3mmol) under nitrogen. The reaction mixture was
refluxed for 1 hour and then cooled to room ature before adding 6% aqueous
NaHC03 (200 mL). The phases were separated and the aqueous layer was extracted
with heptane (250 mL). The combined organic layer was washed with 10% brine (200
mL) and trated under reduced pressure (50:5 °C, 50 ~ 100 mbar) to give an oil.
After the addition of 80 mL methanol to the residue, the mixture was heated to 55:5 °C
and stirred for 1 hour. The temperature was cooled to 25:5 °C over a 2 hour period and
stirred for a further 2-3 hours. The ing suspension was filtered and the wet cake
was dried under reduced re (50:5 °C, 50 ~ 100 mbar) for 3 hours to give 8.6 g of
2-((1S,3S,4S)—4-((tert-butyldimethylsilyl)oxy)fluorocyclohexyl)(2,5-dimethyl-1H-
pyrrolyl)pyrazine as a crystalline solid (dr > 99:1 ). The mother liquor was
concentertaed under reduced pressure (50:5 °C, 50 ~ 100 mbar) to give 34.5 g (71
mmol) dark oil. To this residue was added tBuOH (200 mL), followed by tBuOK (8.0 g, 71
mmol). The reaction e was heated to 90:5 °C and stirred for 3 hours. After the
temperature was cooled to room temperature, 10% aqueous NaHC03 (150 mL) was
added followed by heptane (200 mL) and the mixture was stirred for a further 10 minutes.
The phases were separated and the aqueous layer was washed with heptane (200 mL).
The combined organic layers were washed with 10% brine (150 mL) and concentrated
under reduced pressure (50:5 °C, 50 ~ 100 mbar) to give an oil residue. To this residue
WO 66188
was added methanol (60 mL), and the mxiture was heated to 55:5 °C. After stirring for 1
hour, the temperature was cooled to 25:5 °C over a 2 hour period followed by stirring for
a further 2 hours. The suspension was filtered and the resulting wet cake was dried
under reduced pressure (50:5 °C, 50 ~ 100 mbar) for 3 hours to give the second batch of
24- tert-but ldimeth lsil lox oroc clohex l 2 th l-1H-
pyrrolyl)pyrazine as a crystalline solid (5.6 g, dr = 98:2). The overall yield of the 4
steps starting from 2-bromo(2,5-dimethyl-1H-pyrrolyl)pyrazine is 51.8%. mp =
100.6°C ~ 102.9 °C. LC/MS: [M+H]+= 404.2459, 1H NMR(400MHz, DMSO-de): 8.53 (s, 1
H), 8.50 (s, 1 H), 5.75 (s, 2 H), 4.25 ~ 4.43 (m, 1 H), 3.60 ~ 3.69 (m, 1 H), 3.25 (s, 6 H),
2.93 ~ 3.00 (m, 1 H), 2.19 ~ 2.27 (m, 1 H), 1.98 (s, 6 H), 1.72 ~ 1.90 (m, 3 H), 1.39 ~ 1.61
(m, 2 H), 0.80 (s, 9H), 0.01 (d, J: 4 Hz, 6 H)., HPLC (Instrument : t Technologies
1200 series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35
oC. Flow rate: 0.70 mL / min. Detection: 210 nm/ DAD. Mobile phase composition: A:
0.1% H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11
min 100% B) retention time: 8.084 min for 2-((1S,3S,4S)—4-((tert—butyldimethylsilyl)oxy)—3-
fluorocyclohexyl)(2,5-dimethyl-1H-pyrrolyl)pyrazine, 8.324 min for 2-((1R,3S,4S)—4-
((tert-butyldimethylsilyl)oxy)fluorocyclohexyl)(2,5-dimethyl-1H-pyrrolyl)pyrazine.
2-bromo 2 5-dimeth l-1H- rrol l razine
NI \8N8o N
/N —> I/N
BI‘ Br
To a 250 mL flaks was added 5-bromopyrazinamine (18 g, 10.35 mmol),
hexane-2,5-dione (14.5g, 12.41 mmol) and PPTS (0.9 g, 0.36 mmol) in toluene (60 mL).
The reaction mixture was heated to reflux in a Dean-Stark trap for 16 hours. The reaction
mixture was cooled to room rature and then concentrated under reduced pressure
(55:5 °C, 50 ~ 100 mbar) to give 2-bromo 2 5-dimeth l-1H- rrol l razine as an
oil (28 g, containing ~10% toluene : 95%). This material was used t
, assay yield
further purification. LC/MS: [M+H]+= 252.0139, 1H NMR(400MHz, DMSO-de): 8.87 (s,
1H), 8.63 (s, 1 H), 5.86 (s, 2 H), 2.10 (s, 6 H). HPLC retention time = 6.21 min,
Instrument: Agilent Technologies 1200 . Column: Waters Xbridge C18, 150*3.0
2014/062913
mm, 3 um. Column temperature: 35°C. Flow rate: 0.70 mL / min. Detection: 210 nm/
DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B: acetonitrile. Gradient: 0
min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B.
54- tert-but Idimeth lsil lox fluoroc clohex l razinamine
N H2N
NJ}. NJ}
K/N NHZOH.HC| \ N
E —> ?
"'F F
OTBS OTBS
To a stirred suspension of 2-((1S,3S,4S)—4-((tert-butyldimethylsilyl)oxy)—3-
cyclohexyl)(2,5-dimethyl-1H-pyrrolyl)pyrazine (1250 g, 3097 mmol) in ethanol
(7.5 kg) was added hydroxylamine hloride (860.9 g, 12388.2 mmol) followed by
triethylamine (642.5 g, 6349.0 mmol). The on mixture was heated to reflux (77-78
°C) for 42 hours, and then cooled to about 40°C. After distillation of 6 kg of ethanol under
vacuum (<100 mbar ) at 40°C, the mixture was cooled to room temperature, diluted with
MTBE (7.0 kg) and water (8.0 kg). After stirring for 10 minutes, the organic layer was
separated and the aqueous layer was extracted with MTBE (6.0 Kg). The combined
organic layers were washed successively with 2X12 kg of water and 8 kg of 10% brine.
The MTBE layer was concentrated under vaccum (<100 mbar ) to give 1.2 kg yellow solid
as crude product. The crude product was dissolved in 2 kg DCM and further purified via
silica column chromatography g with EtOAc and e (1/6, v/v) to recover 2-
((1S,3S,4S)—4-((tert—butyldimethylsilyl)oxy)fluorocyclohexyl)(2,5-dimethyl-1H-pyrrol-
1-yl)pyrazine (310 g), then eluting with EtOAc and heptane (1/3, v/v) to give 54- tert-but Idimeth lsil lox fluoroc clohex l razinamine (650 g,
64.5 % yield) as light yellow solid, mp 113-116 °C. ESl-MS (m/z): 326.1940 ([M+H]+,
100). HPLC (method A), retention time 12.26 min. 1H NMR (400 MHz, CDCI3): 7.93 (s,
1H), 7.86 (s, 1H), 4.50 (br. s, 2H), 4.41-4.46, 4.27-4.31 (m, 1H), 3.65-3.74 (m, 1H), 2.68-
2.74 (m, 1H), 2.24-2.30 (m, 1H), 1.97-2.02 (m, 1H), 1.74-1.87 (m, 2H), 1.44-1.63 (m, 2H),
0.91 (s, 9H), 0.10 (d, J = 8Hz, 6H).
ut |4- 3-amino 18 38 4S tert—but Idimeth Isil |0X
fluoroc clohex l razin lfluorobenzoate
o O
F F O
HZN HzN 0
N23 NJYBF o’B‘o N ’ /T
: E ;
QWF QWF Pd(dppf)C|2 DCM, ,
DME, reflux Q'UF
OTBS 0TBS OTBS
A solution of 5-((1S,3S,4S)—4-((tert-butyldimethylsilyl)oxy)—3-
fluorocyclohexyl)pyrazinamine (620.0 g, 1904.8 mmol) in DMSO (5 L) and water (400
mL) was cooled to ~4 °C. NBS (389.8 g, 2190.5 mmol) was added in 10 ns within 1
hour and the reaction temperature was controlled under 5°C with continuous stirring for
minutes. After addition of 0.3 M aqueous Na2C03 (8.5 kg) the reaction temperature
was increased to 35°C. MTBE (4.5 kg) was added and the mixture was stirred for a
further 10 minutes. After phase separation, the aqueous layer was extracted with MTBE
(4 kg). The combined organic layers were washed successively with 0.3 M s
Na2C03 (8.5 kg) and water (8 kg), and concentrated under vacuum at 30-40°C to give
crude product 3-bromo((1S,3S,4S)—4-((tert-butyldimethylsilyl)oxy)—3-
fluorocyclohexyl)pyrazinamine as a foam (770 g). This crude product was used in next
step without further purification. ESl-MS (m/z): 404.1105, 406.1093 ([M+H]+, 100). HPLC
(method A), retention time = 14.38 min. 1H NMR (400 MHz, CDCI3): 7.81 (s, 1H), 4.99
(br. s, 2H), .42, 4.25-4.30 (m, 1H), .72 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.29
(m, 1H), 1.97-2.02 (m, 1H), 1.74-1.87 (m, 2H), 1.44-1.63 (m, 2H), 0.91 (s, 9H), 0.10 (d, J
= 8 Hz, 6H).
To a solution of 3-bromo((1S, 3S, 4S)—4-((tert-butyldimethylsilyl)oxy)—3-
fluorocyclohexyl)pyrazinamine (760.0 g, 1879.4 mmol) and tert—butyl 2-fluoro
,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate (605.5 g, 1879.4 mmol) in DME
(3.0 kg) was added 2.0 M aqueous Na2C03 (1880 mL, 3760 mmol) and Pd(dppf)C|2-DCM
(38.4 g, 47.0 mmol). After degassing with N2 three times, the reaction mixture was
heated to reflux (79-80 °C) and stirred at this temperature for 3 hours. The reaction
temperature was cooled to room temperature and MTBE (2.5 kg) was added followed by
water (4.0 kg). The mixture was stirred for 10 minutes before phase separation, and the
aqueous layer was extracted with MTBE (1.8 kg). The ed organic layers were
washed with water (2X4 kg), and concentrated under vacuum at 30-40 °C to give crude
product tert—butyl 4-(3-amino((1S, 3S, 4S)—4-((tert-butyldimethylsilyl)oxy)
fluorocyclohexyl)pyrazinyl)f|uorobenzoate (ca. 1 kg). The mixture of this crude
product and EtOH (95%, 3.2 kg) was heated to reflux (78-80°C) for 30 minutes to give a
solution. The temperature was cooled to 40°C within 100 minutes followed by addtion of
water (800 g) within 30 minutes. The temperature was cooled to ~5°C within 100 minutes
and stirring at this temperature was continued for a further 60 s. The solid
precipitation was filtered and the wet cake was washed with EtOH/water (1.2 L, 5/1,
l). After drying under vaccum at 50°C for 5 hours, tert—butyl 4-(3-amino((1S, 38,
4S tert-but h lsil lox fluoroc clohex l razin uorobenzoate was
obtained as a brown powder (755g, 76.4% yield over 2 steps, assay purity is 98.8%). mp
169-172 °C. ESl-MS (m/z): 520.2739 ([M+H]+, 100). HPLC (method A) retention time
.76 min. 1H NMR (400 MHz, CDCI3): 7.98 (t, J = 8 Hz, 1H), 7.91 (s, 1H), 7.61 (d, J = 8
Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 4.68 (br. s, 2H), 4.42-4.48, 4.30-4.36 (m, 1H), 3.67-3.76
(m, 1H), .83 (m, 1H), 2.28-2.36 (m, 1H), 1.98-2.05 (m, 1H), 1.83-1.92 (m, 2H), 1.46-
1.68 (m, 2H), 1.62 (s, 9H), 0.92 (s, 9H), 0.11 (d, J = 8 Hz, 6H).
4- 3-amino 183848 fluoroh drox c clohex l razin lfluorobenzoic acid
\2 N i) HCI, EtOH \ N
"’F ii) NaOH
Q’F OTBS
To a suspension of tert—butyl 4-(3-amino((1S, 3S, 4S)—4-((tert-
butyldimethylsilyl)oxy)fluorocyclohexyl)pyraziny|)fluorobenzoate (685.0 g, 1318.0
mmol) in EtOH (3.6 kg) was added aqueous HCI (36%, 400.5 g, 3954.2 mmol). The
reaction e was heated to 30°C and stirred for 4 hours. The reaction temperature
was lowered to 5°C and a on of NaOH (342.7g, 8567.5 mmol) in water (1.6 kg) was
added. The reaction mixture was heated to 30°C and stirred at this temperature for 18
hours. The pH of the reaction mixture was adjusted to 5 using 4 N aqueous HCI to form a
solid itation. After distillation of EtOH under vacuum at 40-50 °C, water (2.5 kg)
was added to the residue and the ature was cooled to 5°C within 1 hour. The
suspension was filtere, the solid was collected and dried under vacuum (<100 mbar) at
50-60°C for 24 hours to give 4-(3-amino((1S,3S,4S)—3-fluoro
hydroxycyclohexyl)pyrazin-2—yl)fluorobenzoic acid as a brown powder (460 g, HPLC
purity at 230 nm was 98.2%, quantitative yield). Mp 226-228 °C. ESl-MS (m/z):
350.1282 +, 100). HPLC (method A), retention time 5.93 min. 1H NMR (400 MHz,
DMSO-D6): 13.32 (br. s, 1H), 8.00 (t, J = 8 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J = 8 Hz, 1H),
7.65 (d, J = 8 Hz, 1H), 6.24 (br. s, 2H), 5.16 (br. s, 1H), 4.44—4.49, 4.30-4.35 (m, 1H),
3.50-3.60 (m, 1H), 2.79-2.84 (m, 1H), 2.20-2.25 (m, 1H), 1.92—1.99 (m, 1H), 1.72-1.83 (m,
2H), 1.50-1.60 (m, 1H), 1.36-1.46 (m, 1H).
4- 3-amino 183848 fluoroh drox c clohex l razin l-N- S 3-bromo
fluoro hen l meth lamino eth lfluorobenzamide
I: ] : |
SQ2 302 F O /NH
N NO '
F O :/ \ 2
F O {N\ N02 F
' F : NHZ N
OH H2N ' F H
H N2 NH2
_ N NI \
N/ HCI
N \ LiOH DMF {N Br
K!“ Br
bN ,
: —. =
: o
EDCI, HOAT "’F
”F "IF OH
OH OH HS
To a solution of 4-(3-amino((1S,3S,4S)—3-fluorohydroxycyclohexyl)pyrazin
yl)fluorobenzoic acid (300 g, 95% assay, 815.8 mmol) and (S)—N-(2-amino(3-
-fluorophenyl)ethyl)-N-methy|nitrobenzenesulfonamide hydrochloride (397.7 g,
848.5 mmol) in DMF (2.5 kg) was added DIPEA (421.8 g, 3263.4 mmol), followed by
EDCI (312.8 g, 1631.7 mmol) and HOAt (222.1g, 1631.7 mmol). Afterthe on
mixture was stirred at 25 °C for 18 hours, the reaction temperature was lowered to 10°C
before IPAC (3.5 kg) and water (4.0 kg) was added. The mixture was stirred for 10
minutes and then the layers were separated. The aqueous layer was extracted with IPAC
(2.5 kg). The combined organic layers were washed successively with 10% aqueous
Na2C03 (4.5 kg) and water (2X4 kg), and then concentrated under vacuum (<100 mbar)
at 40-45 °C to give 4-(3-amino((1S,3S,4S)—3-fluorohydroxycyclohexyl)pyraziny|)-
N-((S)—1-(3-bromo—5-fluorophenyl)(N-methylnitrophenylsulfonamido)ethyl)
fluorobenzamide as a foam (670 g, assay purity is 93%), which was used in next step
without further purification. ESl-MS (m/z): 16, 765.1161 +, 100). Mp=115-
117 OC. HPLC (method A), retention time = 10.57 min. 1H NMR (400 MHz, CDCI3): 8.11
(t, J = 8 Hz, 1H), 7.99 (m, 1H), 7.91 (s, 1H), 7.59-7.72 (m, 5H), 7.35 (s, 1H), 7.19 (d, J =
8 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 5.46 (br. s,1H), 4.77 (br. s, 2H), 4.48-4.55, 4.35-4.42
(m, 1H), 3.93 (q, J1 = 12 Hz, J1 = 16 Hz, 1H), 3.73-3.82 (m, 1H), 3.33 (q, J1 = 4 Hz, J1=
12 Hz, 1H), 3.00 (s, 3H), 2.78-2.85 (m, 1H), 2.31-2.37 (m, 1H), 2.12-2.20 (m, 1H), 1.84-
1.96 (m, 2H), 1.60-1.71 (m, 1H), .56 (m, 1H).
To a suspension of 4-(3-amino((1S,3S,4S)—3-fluorohydroxycyclohexyl)-pyrazinyl)-
N-((S)—1-(3-bromofluorophenyl)(N-methylnitrophenyl-sulfonamido)ethyl)
fluorobenzamide (500 g crude product from previous step) in DMF (2.0 kg) was added 4-
mercaptobenzoic acid (161.5 g, 1047.7 mmol). The on mixture became a solution
after 5 minutes and then was cooled to 10°C. After addition of LiOH-H20 (137.3 g,
3274.0 mmol) in one portion, the mixture was stirred at 25°C for 3 hours before the
ature was cooled to 10°C. The reaction mixture was diluted with water (3.0 kg)
and extracted with IPAC (3*2.5 kg). The IPAC layers was first washed with 15% aqueous
Na2C03 (2*3.0 kg) followed by water (2*3.0 kg), and then trated under vacuum
(<100 mbar) at 40-45 °C. To the resulting residue was added MeCN (1.8 kg) to give a
clear solution, which was heated to 50°C and stirred for 30 minutes. The mixture was
further cooled to 10°C in 2 hours and d at this temperature for a further 1 hour. After
filtration of the resulting suspension, the solid cake was washed with pre-cooled MeCN
(400 g, 5 °C). The wet cake was dried under vacuum (<100 mbar) at 80°C for 18 hours to
give 4- 3-amino 1S 3848 fluoroh drox c clohex l razin l -N- S 3-
bromofluorophenyl)—2-(methylamino)ethyl)—2-fluorobenzamide as a crystalline solid
(245 g, overall yield for 2 steps is 66%, HPLC purity = 98.3%, chiral purity = 99.0% ). Mp
115-117°C. ESl-MS (m/z): 578.1381, 580.1381 ([M+H]+, 100). HPLC (method A),
retention time = 7.24 min. 1H NMR (400 MHz, 6): 8.82 (d, J = 8 Hz, 1H), 8.0 (s,
1H), 8.82 (t, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.53 (s, 1H),
7.48 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 6.21 (br. s, 2H), 5.18 (m, 2H), 4.46-4.52,
WO 66188
4.32-4.37 (m, 1H), 3.52-3.60 (m, 1H), 2.80-2.94 (m, 3H), 2.36 (s, 3H), .25 (m, 1H),
.98 (m, 1H), 1.76-1.86 (m, 3H), 1.51-1.62 (m, 1H), 1.39-1.48 (m, 1H).
The free base form of 4-(3-amino((1S,38,4S)—3-fluoro
hydroxycyclohexyl)pyrazin-2—yl)—N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide was prepared by suspending 4-(3-amino((1S,38,4S)—3-fluoro
hydroxycyclohexyl)pyrazin-2—yl)—N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide (200mg) was suspended in 4ml of nitromethane at room temperature.
The suspension was heated to 55°C until the solution was clear. Eight heat-cool cycles
were conducted in the temperature range 55°C to 5°C. The solid was generated by
filtration and dried under vacuum at 40°C overnight. An X-ray powder diffraction pattern
of the free base form was determined in Figure 1. A A graph of the free
base of 4-(3-amino((18,38,48)fluorohydroxycyclohexyl)pyrazinyl)—N-((S)—1-(3-
bromofluorophenyl)(methylamino)ethyl)fluorobenzamide is provided in Figure 2.
The HCl salt form of 4-(3-amino((1S,38,4S)—3-fluoro
ycyclohexyl)pyrazin-2—yl)—N-((S)—1-(3-bromofluorophenyl)(methylamino)ethyl)-
2-fluorobenzamide was prepared by dissolving amorphous mino((1S,38,4S)—3-
fluorohydroxycyclohexyl)pyrazinyl)—N-((S)(3—bromofluorophenyl)
(methylamino)ethyl)fluorobenzamide (120mg) in 0.5N HCl ethanol solution (414uL)
with stirring at room temperature. A precipitate is observed after 5 minutes of stirring. A
DSC/TGA thermograph of the highly crystalline HCl salt form of 4-(3-amino
((1S,38,48)fluorohydroxycyclohexyl)pyrazinyl)—N-((S)—1-(3-bromo
fluorophenyl)(methylamino)ethyl)fluorobenzamide is provided in Figure 4. An X-ray
powder diffraction pattern of the free base form was determined in Figure 3. The most
significant peaks in the XRPD of Figure 3 are shown in the table:
Angle 2-theta Intensity %
12.346 9.9
.57 10.8
16.195 15.3
16.652 59.3
18.245 4.5
WO 66188
19.118 47.7
19.26 100
19.642 39.3
.029 5.4
21.509 22.2
21.777 22.2
22.568 68.9
23.611 36.3
24.334 88
24.733 18.9
.748 10.9
26.826 16
27.421 13.6
28.46 15.5
28.837 13.6
29.177 17.3
29.382 10.1
29.88 19.1
.14 20.5
31.361 7.8
31.424 7.8
32.751 21.2
33.787 12.3
34.649 17
.391 26.9
37.057 11.4
38.005 6.1
40.657 6.2
40.954 5.1
41.658 5.1
42.926 5.8
44.201 17.7
Examples 185 and 186
S nthesis of 4- 3-amino 1R BR 48 f|uoroh drox c clohex | razin I-N- S -
1- 3-bromofluoro hen | h drox eth | f|uorobenzamide and 4- 3-amino
18 38 4R f|uoroh drox c clohex | razin I-N- S 3-bromo
fluoro hen Ih drox eth Ifluorobenzamide
Scheme 87
F o J< F 0
F 0 :/OH
NH2 0 NH2 OH T
Slag; m1 “”2
N/ N/ fl
I I
\ N \ N N/
/OH \ N Br
41% crude ?
' F
F o OJ<
_ HC1H2N 7 Rt—1.58 mm
F F
NH 2 U F
S1eg1 0” 0H
' 5’
N, 0H
K/NI chiral resomtlon 4M HC1 In dloxane
EDC. HOAt DIEA. DMF
» + —.
E (+/-)
86% F O J<
F O
F O /OH
"'F NHZ O E
; NH2 OH F
N/ NH2 N
K/IN H
\ $21 I Ste N’
_ |
E 45% KKN \ N Br
0 : crude 5
-. Rt = 2 42 mm
0H 0%. O
; "F
absulute stereochemistry
ed arily
Ste 1. ut |4- 3-amino 18 38 4S f|uoroh drox c clohex | razin I
fluorobenzoate
tert-butyl 4-(3-amino((1R,3R,4S)f|uorohydroxycyclohexy|)pyrazinyI)
fluorobenzoate (154 mg, 0.38 mmol) was subjected to chiral separation (ChiraIPak 5mic
AD column, 4.6x100 (mm), CO2/IPA+0.1% DEA=75/25, SFC=5mI/min) to provide polar
enantiomer, tert-butyl 4-(3-amino((1R,3R,4S)—3-fluorohydroxycyclohexyl)pyrazin
y|)f|uorobenzoate (Rt = 1.86 min, 63 mg, 0.155 mmol, 41%) and the less polar
enantiomer, tert-butyl 4-(3-amino((1S,38,4R)fluorohydroxycyclohexyl)pyrazin
y|)f|uorobenzoate (Rt = 2.91, 70 mg, 0.173 mmol, 46%). The absolute stereochemistry
was assigned arbitrarily.
Ste 2 and 3. 4- 3-amino 1R 3R 4S fluoroh drox c clohex l razin l
benzoic acid and 4- 3-amino 18 38 4S f|uoroh drox c clohex | razin
| orobenzoic acid
To a solution of each ester (1 mmol) in DCM (2 mL) was added 4 M HCI in dioxane (30
mL). The reaction mixture was stirred at room temperature for 2 days. After the volatile
materials were evaporated in vacuo, the reaction mixture was triturated with EtZO and
filtered off to e 4-(3-amino((1R,3R,4S)—3-fluorohydroxycyclohexyl)pyrazin
y|)f|uorobenzoic acid (60 mg from 63 mg of the ester) and 4-(3-amino((1S,3S,4R)—3-
hydroxycyclohexyl)pyrazinyl)—2-fluorobenzoic acid (59 mg from 70 mg of the
ester) as a HCI salt respectively, which was used for the next step without any further
purification. LCMS (m/z): 350.2 (MH+), 0.5 min (for each acid).
Ste 4 and 5. 4- o 1R 3R 4S fluoroh drox c clohex l razin l -N-
S 3-bromofluoro hen l h drox eth l f|uorobenzamide and 4- 3-amino
18 3S 4R oroh drox c clohex l razin-2— l-N- S 3-bromo
fluoro hen lh drox eth lfluorobenzamide
To a solution of each acid (20 mg, 0.057 mmol) in DMF (573 uL) was added (S)—2-amino-
2-(3-bromof|uorophenyl)ethanol HCI salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69
mg, 0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 ul, 0.172 mmol). The
reaction mixture was stirred for 15 h. Water was added, and the reaction mixture was
extracted with EtOAc three times. The organic layers were dried over , filtered and
concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were
lyophilized to provide the d product (11 mg, 0.016 mmol, 28%) as a TFA sa|t
respectively. For 4-(3-amino((1R,3R,4S)—3-fluorohydroxycyclohexyl)pyrazinyl)-N-
((S)—1-(3-bromof|uorophenyl)hydroxyethyl)fluorobenzamide, LCMS (m/z):
565.1/567 (MH+), 0.74 min; 1H NMR (400 MHz, CD3OD) 6 ppm 7.95 - 7.79 (m, 1H), 7.76 -
7.59 (m, 1H), 7.46 (s, 1H), 7.33 - 7.14 (m, 2H), 5.24 - 5.10 (m, 1H), 4.75 - 4.49 (m, 1H),
4.16 (br. s., 2H), 3.96 - 3.77 (m, 4H), 2.80 (t, J=12.5 Hz, 2H), 2.25 (dq, J=7.6, 11.9 Hz,
2H), 2.08 - 1.78 (m, 7H), 1.76 - 1.55 (m, 4H). For 4-(3-amino((1S,3S,4R)—3-f|uoro
hydroxycyclohexyl)pyrazinyl)—N-((S)(3-bromof|uoropheny|)hydroxyethy|)
benzamide, LCMS (m/z): 565.1/567.1 (MH+), 0.74 min; 1H NMR (400 MHz, CD30D)
6 ppm 7.84 - 7.70 (m, 2H), 7.66 - 7.49 (m, 2H), 7.37 (s, 1H), 7.24 - 7.05 (m, 2H), 5.09 (d,
J=5.5 Hz, 1H), 4.66 - 4.41 (m, 1H), 4.07 (br. s., 1H), 3.88 - 3.65 (m, 2H), 2.71 (t, J=12.9
Hz, 1H), 2.16 (dq, J=7.4, 12.0 Hz, 1H), 1.99 - 1.70 (m, 3H), 1.66 - 1.47 (m, 2H). The
absolute stereochemistry was not determined yet.
Examples 187 and 188
S nthesis of 4- o 1R 3S 4R f|uoroh drox c clohex | razin I-N- S -
1- 3-bromofluoro hen | h drox eth | f|uorobenzamide and 4- 3-amino
1S 3R 4S f|uoroh drox c clohex | razin I-N- S 3-bromo
fluoro hen |h drox eth |f|uorobenzamide
Scheme 88
F o J< F O J<
F o F 0
NH2 O NH O
0J< NH2 OH
Steg l w $2 g NH2
N / N / N/ \ IN NaBH4 \ IN chiral resolution N / mg
| |
—> —. \ N \ N
(+/-) 91 /oo (+/-)
Qular M Mil HPLC- crude
36°/°
. F "F
EM _ "’F
0 relative stereochemistry C:)H OH
confirmed by NMR 4M HCI in dioxane
F O J< F o
NH2 0 NH2 OH
OH l N /
F O _/ I
$2 i a \_ N \,N
NH2 N E 467% $2 4— ; crude
(OH N /
? F
\ N Br F
HCI HZNAQ/ OH OH
absolute chemistry assigned arbitrarily
Br ,'
. ’F
EDC, HOAt 6”
DIEA, DMF
F 0 :/OH
NH2 N
K/NI Br
; F
Ste 1. +/- -tert-but l4- 3-amino 1R 3S 4R fluoroh drox c clohex l razin
yl)—2—fluorobenzoate
To a solution of (+/-)-tert-buty| 4-(3-amino((1R,3S)fluorooxocyclohexyl)pyrazin
yl)fluorobenzoate (208 mg, 0.516 mmol) in MeOH (3.017 mL) was added NaBH4 (29.3
mg, 0.773 mmol) at 0 °C. The reaction mixture was stirred for 2 h. LCMS showed ~4:1
ratio of two diastereomers. After ed with NaHC03 solution, the on mixture
was extracted with EtOAc. The organic layer was washed with water and brine, dried over
sodium sulfate, filtered off and concentrated in vacuo. The major reomer was
separated by neutral prep HPLC. After lyophilzation, (+/-)-tert-butyl 4-(3-amino
((1R,3S,4R)—3-fluorohydroxycyclohexyl)pyrazinyl)fluorobenzoate was obtained in
.8% yield. (74.9 mg). LCMS (m/z): 406.3 (MH+), 0.80 min. The relative stereochemistry
of (+/-)-tert-butyl 4-(3-amino((1R,3S,4R)—3-fluorohydroxycyclohexyl)pyrazin-2—yl)—2—
fluorobenzoate was confirmed by NMR.
Ste 2. tert-but |4- 3-amino 1R 3S 4R f|uoroh drox c clohex | razin |
fluorobenzoate and utyl 4-(3-amino((1S,3R,4S)—3-fluoro
hydroxycyclohexyl )pyrazin-2—yl )—2-fluorobenzoate
(+/-)-Tert-buty| 4-(3-amino((1R,3S,4R)fluorohydroxycyclohexy|)pyraziny|)
fluorobenzoate (74.9 mg, 0.185 mmol) was subjected to chiral SFC lPak 5mic AD
, 4.6x100 (mm), C02/EtOH+0.1%, DEA=80/20, SFC=5mL/min) to provide polar
enantiomer, tert-butyl 4-(3-amino((1R,3S,4R)f|uorohydroxycyclohexy|)pyrazin
y|)f|uorobenzoate (Rt = 1.95 min, 33 mg, 44 %) and the less polar enantiomer, tert-
butyl 4-(3-amino((1S,3R,4S)—3-fluorohydroxycyclohexyl)pyrazinyl)—2-
fluorobenzoate (Rt = 3.17, 35 mg, 46%). The absolute stereochemistry was assigned
arbitrarily.
Ste 3 and 4. 4- 3-amino 1R 3S 4R f|uoroh drox c clohex | razin |
fluorobenzoic acid and 4- 3-amino 1S 3R 4S fluoroh drox c clohex l razin
l fluorobenzoic acid
To a solution of each ester (1 mmol) was added 4 M HCI in e (111 mL). The
reaction mixture was stirred at room temperature for 2 days. After the volatile als
were evaporated in vacuo, the reaction mixture was triturated with EtZO and filtered off to
provide 4-(3-amino((1R,3S,4R)fluorohydroxycyclohexyl)pyraziny|)
fluorobenzoic acid (31 mg from 33 mg of the ester), LCMS (m/z): 350.2 (MH+), 0.47 min,
and 4-(3-amino((1S,3R,4S)f|uorohydroxycyclohexyl)pyrazinyl)f|uorobenzoic
acid (33 mg from 35 mg of the ester), LCMS (m/z): 350.2 (MH+), 0.48 min, as a HCI salt
respectively, which was used for the next step without any further purification.
Ste 5 and 6. 4- 3-amino 1R 3S 4R f|uoroh drox c clohex | razin | -N-
S 3-bromofluoro hen | h drox eth | orobenzamide and 4- 3-amino
1S 3R 4S f|uoroh drox c clohex | razin-2— l-N- S 3-bromo
fluoro hen |h drox eth uorobenzamide
Following Step 8 in Scheme 85, using 4-(3-amino((1R,3S,4R)—3-fluoro
hydroxycyclohexyl)pyrazin-2—yl)f|uorobenzoic acid, 4-(3-amino((1R,3S,4R)—3-f|uoro-
4-hydroxycyclohexyl)pyraziny|)-N-((S)(3-bromofluorophenyl)hydroxyethy|)
fluorobenzamide was obtained. LCMS (m/z): 567.1 (MH+), 0.71 min; 1H NMR
(400MHz, CD3OD) 6 ppm 7.93 - 7.78 (m, 2H), 7.73 - 7.55 (m, 2H), 7.46 (s, 1H), 7.33 -
7.13 (m, 2H), 5.17 (t, J=5.9 Hz, 1H), 3.95 - 3.78 (m, 2H), 3.75 - 3.42 (m, 1H), 3.09 - 2.93
(m, 1H), 2.32 - 2.14 (m, 1H), 2.05 - 1.79 (m, 5H), 1.80 - 1.59 (m, 1H). Using 4-(3-amino
((1S,3R,4S)—3-fluorohydroxycyclohexyl)pyrazinyl)fluorobenzoic acid, 4-(3-amino-
6-((1S,3R,4S)—3-fluorohydroxycyclohexyl)pyrazinyl)-N-((S)(3-bromo
fluorophenyl)hydroxyethyl)f|uorobenzamide was obtained. LCMS (m/z): 565.0/567.1
(MH+), 0.71 min; 1H NMR (400MHz, CD3OD) 6 ppm 7.95 - 7.80 (m, 2H), 7.75 - 7.56 (m,
2H), 7.46 (s, 1H), 7.33 - 7.12 (m, 2H), 5.17 (t, J=5.9 Hz, 1H), 3.96 - 3.78 (m, 2H), 3.76 -
3.55 (m, 1H), 3.10 - 2.95 (m, 1H), 2.31 - 2.12 (m, 1H), 2.08 - 1.82 (m, 5H), 1.79 - 1.62 (m,
1H).
Example 189
S nthesis of 4- 3-amino 18 38 4S f|uoroh drox c clohex | 2- |
f|uoro-N- S 3-fluoroiodo hen lh drox eth Ibenzamide
Scheme 89
F o
F o I/OH
Steal Step2 =
NH2 OH F
3 z N
F 4M HCI F
K/N|
EDC HOAt
, N
BocHN —— HZN + —>
in dioxane K/IN
3 DIEA, DMF _
' crude E
| crude |
"’F "’F
Ste 1. S amino 3-fluoroiodo hen lethanol h oride
rt-buty| (1-(3-f|uoroiodophenyl)—2-hydroxyethyl)carbamate (2.507 g, 6.58 mmol)
was dissolved in DCM (60 mL) and treated with 4 N HCI in dioxane (4.93 mL, 19.73
mmol). The mixture was stirred overnight at room temperature. After the majority of the
solvent was evaporated carefully in vacuo, the slurry was titurated with EtZO to afford
1.525 g of a fine white HCI salt of (S)—2-amino(3-fluoroiodophenyl)ethanol (72%),
which was isolated by suction filtration. LCMS (m/z): 282.4 (MH+), 0.46 min.
Ste 2. 4- 3-amino 18 38 4S fluoroh drox c clohex l razin lfluoro-N-
((8)4 -(3-f|uoroiodopheny| )—2-hydroxyethy|)benzamide
To a solution of 4-(3-amino((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)—2-
fluorobenzoic acid (16 mg, 0.046 mmol) in DMF (0.46 mL) was added (S)—2-amino(3-
fluoroiodophenyl)ethanol hydrochloride (17.5 mg, 0.055 mmol), HOAt (9.35 mg, 0.069
mmol), EDC (17.6 mg, 0.092 mmol), and DIEA (24 pl, 0.137 mmol). The reaction e
was stirred for 15 h. After water was added, the reaction mixture was extracted with
EtOAc and the organic layer was washed with water twice. The organic layer was
separated and dried over Na2804, filtered off and concentrated in vacuo. The crude
product was purified by flash ography eluting with 0-100% EtOAc/heptane to
provide crude product, which was triturated with 70% of DCM/ether to e 9.3 mg of
4-(3-amino((18,38,4S)fluorohydroxycyclohexyl)pyrazinyl)fluoro-N-((S)(3-
fluoroiodophenyl)hydroxyethyl)benzamide as a TFA salt (28%). LCMS (m/z): 613.1
(MH+), 0.74 min; 1H NMR (400MHz, CD3OD) 6 ppm 7.93 - 7.78 (m, 2H), 7.76 - 7.57 (m,
3H), 7.73 - 7.56 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.21 (d, J=9.4 Hz, 1H), 5.15 (t, J=5.9 Hz,
1H), 4.37 (m, 1H), 3.83 (m, 2H), 3.63 (m, 1H), 2.84 (t, J=11.7 Hz, 1H), 2.27 (dd, J=2.9,
9.2 Hz, 1H), 2.14 - 1.98 (m, 1H), 1.96 - 1.75 (m, 2H), 1.65 (dq, J=3.3, 13.0 Hz, 1H), 1.56 -
1.34 (m, 1H).
8 s of S 4- 3-amino 18 38 4S fluoroh drox c clohex l razin l-
2-fluorobenzamido)—2-(3-fluoroiodophenyl)ethyl dihydrogen phosphate
Step;
i. >rO‘P’OK
' 0114’
St 1 >r .
OH _62_ OH N 7<
_/ O
: -
F wr F
HzN (s) Fmoc-Chloride. FmoCHN F
ole HCI, FmocHN
THE, Water, Imidazole, DMF
Sodium bicarbonate
2. Hydrogen Peroxide 30%
I —> I
73% yield 86% yield
>(O‘5’OKI
F o
F O /o
NH2 OH F
o 9 o NHZ N
Step; ‘p’ / H
Cl) N Steg4_
I N/
/ \ N I
= \ N l
% piperidine in DMF F ; _
H N HATU, DIEA, NMP
2 +
—> —>
61% yield (two steps)
[F W,
| F
9 OH
Ho—Fll—OH
F o /
—ES‘e é NH2 N
1. MeOH I
2. HC|4M in Dioxane \ N l
94% yield
[ 1":
Ste 1. S - 9H-fluoren Imeth | 1- 3-fluoroiodo hen lh drox eth lcarbamate:
To (S)—2-amino(3-fluoroiodophenyl)ethanol (4500 mg, 14.17 mmol) was added THF
(Volume: 40 mL, Ratio: 2.67) and water (Volume: 15 mL, Ratio: 1.000), followed by
NaHC03 (4762 mg, 56.7 mmol). The e was d for 2 minutes then cooled to 0°C
in an ice bath. To the reaction was added (9H-fluoren-9—yl)methyl carbonochloridate
(5499 mg, 21.26 mmol) and the reaction was stirred at 0 °C for 30 minutes, allowed to
warm to room temperature and stirred for a further 60 minutes, before conducting LCMS.
Ethyl acetate was added to the crude on mixture. The mixture was washed with
water (2x), saturated salt solution, dried sodium e, ed and concentrated to
residue. The crude product was purified by silica gel chromatography using a 300 g
column (solid load) eluting from 0-60% ethyl acetate in heptane. The desired fractions
were concentrated to constant mass to give as white solid 5375 mg of the desired product
as free base used as is, (73% yield). LCMS (m/z): 504.1 (MH+), 1.05 min. 1H NMR
(<cd3od>) d: 7.78 (d, J=7.4 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H), 7.53 (s, 1H), 7.33-7.43 (m,
3H), 7.25-7.33 (m, 2H), 7.07 (d, J=9.2 Hz, 1H), 4.64 (t, J=5.9 Hz, 1H), 4.31-4.46 (m, 2H),
4.21 (t, J=6.3 Hz, 1H), 3.66 (d, J=3.1 Hz, 2H).
Ste 2. S - 9H-fluoren lmeth l 2- di-tert-butox hos ho lox 3-f|uoro
iodopheny|)ethyl)carbamate: To (S)-(9H-f|uorenyl)methyl (1-(3-fluoroiodophenyl)
hydroxyethy|)carbamate (5260 mg, 10.45 mmol) was added imidazole (818 mg, 12.02
mmol), imidazole HCI (1857 mg, 17.77 mmol), and DMF (Volume: 50 mL). The reaction
was stirrred to dissolve under argon for 2-3 s. Then t-butyl
diisopropylphosphoramidite (4928 mg, 17.77 mmol) was added drop wise over 2-3
minutes and stirred at room temperature for 2 hours. The reaction was ed by
neutral LCMS and by TLC eluting with 1:1 ethyl e/heptane. The crude reaction was
placed in a water bath, hydrogen peroxide 30% (5.34 mL, 52.3 mmol) was added slowly,
and the mixture was stirred at room temperature for 30 minutes, followed by LCMS. The
crude reaction was placed in an ice bath and excess saturated sodium thiosulphate was
added (carefully) drop wise over 5-10 minutes. To the crude reaction mixture was added
800 ml of ethyl e washed with water (3x), ted salt solution, dried sodium
sulfate, filtered and concentrated to residue. The crude was purified by silica gel
chromatography using 300 g column eluting from 0-55% ethyl acetate in heptane. The
desired peak was concentrated to constant mass to give 6560 mg of the desired product
as free base used as is, (86% yield). LCMS (m/z): 696.3 (MH+) weak, 1.25 min. Note: -
112 fragment at 584.2 is major ion in LCMS as expected from loss of two t-buty|
protecting . 1H NMR (<cd3od>) d: 7.79 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.3 Hz, 2H),
7.58 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.34-7.42 (m, 2H), 7.22-7.32 (m, 2H), 7.12 (d, J=9.1
Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 4.41-4.48 (m, 1H), 4.31-4.40 (m, 1H), 4.21 (t, J=6.6 Hz,
1H), 4.08 (t, J=6.3 Hz, 2H), 1.42 (s, 9H), 1.40 (s, 9H).
Ste 3. S amino 3-fluoroiodo hen leth ldi-tert-but l hos hate: To (S)—(9H-
nyl)methyl (2-((di-tert-butoxyphosphoryl)oxy)(3-f|uoro
iodopheny|)ethy|)carbamate (6450 mg, 9.27 mmol) was added DMF (Volume: 90 mL)
ed by piperidine (25 mL, 253 mmol) and stirred at room temperature for 30 minutes,
followed by LCMS. To the crude reaction mixture was added 750 ml of ethyl acetate,
washed with saturated sodium bicarbonate (2x), water (5x), saturated salt solution, dried
sodium sulfate, and filtered. The solvent was concentrated off to constant mass under
high vacuum to give the desire crude product which includes FMOC piperidine impurity,
used as is. LCMS (m/z): 474.2 (MH+), 0.80 min.
Ste 4. S 4- 3-amino 18 38 4S fluoroh drox c clohex l razin l
fluorobenzamido 3-fluoroiodo hen leth Idi-tert-but | hos hate: To a solution of
WO 66188
4-(3-amino((18,38,4S)—3-fluorohydroxycyclohexy|)pyraziny|)f|uorobenzoic acid
(3927 mg, 9.3 mmol) in NMP (Volume: 60 mL) was added (S)—2-amino(3-fluoro
iodophenyl)ethyl di-tert-butyl phosphate (4740 mg, 9.30 mmol), DIEA (9.75 mL, 55.8
mmol), and then HATU (5304 mg, 13.95 mmol). The reaction mixture was stirred at room
temperature for 2 hours followed by LCMS. To the crude reaction was added 850 ml of
ethyl acetate washed with saturated bicarbonate (2x), water (3x), saturated salt on,
dried sodium sulfate, filtered and dried to residue. The crude product was purified by
silica gel chromatograph 330g column eluting with 0-70% (EtOAc with 10% MeOH)/
e . The desired peak was concentrated to constant mass to give 5.75 grams of
crude product. The material was re-purified by silica gel chromatograph 330g column
eluting with 0-60% (EtOAc with 10% MeOH) / heptane to give 5.03 grams of crude
product. The material was further purified by adding 1200 ml of ethyl acetate to dissolve
and 200 ml of heptane, washed with 200 ml of 0.5 N HCI (5x), water, saturated sodium
bicarbonate, water (3x), saturated salt solution, dried sodium sulfate, filtered and
concentrated to nt mass to give 4.70 grams of desired product, yield used as is.
(61% yield over two steps). LCMS (m/z): 805.4 (MH+), 0.99 min. 1H NMR (<cd3od>) d:
7.90 (s, 1H), 7.77-7.86 (m, 1H), .73 (m, 2H), 7.63 (dd, , 1.2 Hz, 1H), 7.42-
7.52 (m, 1H), 7.26 (d, J=9.5 Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 4.30-4.49 (m, 1H), 4.28 (t,
J=6.3 Hz, 2H), 3.58-3.72 (m, 1H), 2.83 (t, J=11.6 Hz, 1H), 2.27 (dt, J=6.2, 3.1 Hz, 1H),
2.02-2.13 (m, 1H), 1.77-1.94 (m, 2H), 1.58-1.74 (m, 1H), 1.48-1.55 (m, 1H), 1.45 (d, J=5.8
Hz, 18H).
Ste 5. S 4- 3-amino 18 38 4S fluoroh drox c clohex | razin l
benzamido)—2-(3-fluoroiodophenyl)ethyl dihydrogen phosphate: (S)—2-(4-(3-
amino((1S,38,4S)f|uorohydroxycyclohexyl)pyraziny|)f|uorobenzamido)(3-
fluoroiodophenyl)ethy| di-tert-butyl phosphate (4600 mg, 5.72 mmol) was fully
dissolved in MeOH (Volume: 70 mL). Then HCI 4M in Dioxane (14.29 mL, 57.2 mmol)
was added and stirred at room temperature for 3 hours, followed by LCMS. The t
was concentrated mostly off. Then MeOH e: 70 mL) was added and the solvent
was concentrated off to residue, additional MeOH (Volume: 70 mL) was added and the
residue concentrated to constant mass. The product was dissolved in 90 ml of 1:1
ACN/water and lyophilized to give 3.99 grams of the desired product as HCI salt. (94%
yield). LCMS (m/z): 692.9 (MH+), 0.63 min. 1H NMR (<cd3od>) d: 7.84-7.93 (m, 1H),
7.75 (s, 1H), 7.60-7.71 (m, 3H), 7.45-7.51 (m, 1H), 7.26 (dt, J=9.7, 1.6 Hz, 1H), 5.40 (t,
J=5.9 Hz, 1H), 4.31-4.50 (m, 1H), 4.22-4.30 (m, 2H), 3.64 (tdd, J=11.7, 8.6, 5.1 Hz, 1H),
2.82-2.98 (m, 1H), 2.32 (ddt, J=11.7, 5.8, 2.8 Hz, 1H), 2.01-2.15 (m, 1H), 1.89-1.97 (m,
1H), .89 (m, 1H), 1.58-1.72 (m, 1H), 1.42-1.55 (m, 1H). 31PNMR(<cd3od>) d:
0.00 (s, 1P).
Conversion of HCI salt to di-sodium salt: To the above desired product as HCI salt (24
mg, 0.035 mmol) was added water e: 17 mL) then titrated with 2M sodium
carbonate to pH10-11 and then extracted with 15 ml of DCM (4x). The basic water was
directly loaded on to a 12 gram Grace Reveleris C18 e phase column, eluted with
0-20% ACN/water over 18 minutes at flow rate of 15 ml/minute, with no buffers. The
desired fractions were lyophilized to give 18 mg of the desire t (S)—2-(4-(3-amino-
6-((1S,3S,4S)fluorohydroxycyclohexyl)pyrazinyl)fluorobenzamido)(3-fluoro-
-iodophenyl)ethyl dihydrogen phosphate as the di-sodium salt, determined by counterion
is. (70% yield). LCMS (m/z): 692.9 (MH+), 0.64 min. 1H NMR (<cd3od>) d: 7.82-
7.92 (m, 2H), 7.64-7.72 (m, 2H), 7.58 (dd, J=11.4, 1.2 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H),
7.28 (d, J=9.5 Hz, 1H), 5.17 (dd, J=6.9, 4.1 Hz, 1H), 4.25-4.49 (m, 1H), 4.02-4.20 (m, 2H),
.73 (m, 1H), 2.83 (t, J=11.6 Hz, 1H), 2.27 (dd, J=6.1, 3.6 Hz, 1H), 1.98-2.14 (m,
1H), 1.78-1.94 (m, 2H), 1.59-1.73 (m, 1H), 1.40-1.55 (m, 1H).
Example 190
S nthesis of 4- o 1R 3R 4R fluoroh drox c clohex l razin l
fluoro-N- S 3-fluoro—5-iodo hen lh drox eth lbenzamide
F 0 :/OH
NH2 N
\ N |
To a solution of 4-(3-amino((1R,3R,4R)fluorohydroxycyclohexyl)pyrazinyl)
fluorobenzoic acid (18 mg, 0.052 mmol) in DMF (0.52 mL) was added (S)—2-amino(3-
fluoroiodophenyl)ethanol hydrochloride (19.6 mg, 0.062 mmol), HOAt (10.52 mg, 0.077
mmol), EDC (19.76 mg, 0.103 mmol), and DIEA (27 ul, 0.155 mmol). The reaction mixture
was stirred for 15 h. After water was added, the reaction mixture was extracted with
WO 66188
EtOAc and the organic layer was washed with water twice. The organic layer was
separated and dried over Na2804, filtered off and concentrated in vacuo. The crude
product was purified by flash chromtography eluting with 0-100% heptane to
provide 15.8 mg of 4-(3-amino((1 R)—3-fluorohydroxycyclohexyl)pyrazinyl)-
2-f|uoro-N-((S)(3-f|uoroiodopheny|)hydroxyethy|)benzamide as a free base (50%).
LCMS (m/z): 613.1 (MH+), 0.74 min; 1H NMR (400MHz, CD3OD) 6 ppm 7.89 - 7.69 (m,
2H), 7.66 - 7.47 (m, 3H), 7.39 - 7.26 (m, 1H), 7.12 (d, J=9.4 Hz, 1H), 5.05 (t, J=5.9 Hz,
1H), 4.43 - 4.14 (m, 1H), 3.84 - 3.66 (m, 2H), 3.64 - 3.45 (m, 1H), 2.74 (t, J=11.7 Hz, 1H),
2.17 (td, J=3.1, 6.0 Hz, 1H), 2.05 - 1.87 (m, 1H), 1.84 - 1.66 (m, 2H), 1.65 - 1.47 (m, 1H),
1.47 - 1.27 (m, 1H).
8 nthesis of S 4- 3-amino 1R 3R 4R fluoroh drox c clohex l razin l-
2-f|uorobenzamido 3-fluoroiodo hen |eth Idih dro en hos hate
03,0 NH OH F
2 NH2 N
%/ I? N / Step 1 H
O \|< | N /
_/ \ N I
\ N I
HZN + HATU, DIEA, NMP
77% yield
. F
HO—F|’—OH
F o {O
Step 2 F
NHz ”
HCI 4M in Dioxane N /
MeOH |
\ N |
72% yield
Ste 1. S 4- 3-amino 1R 3R 4R fluoroh drox c clohex l razin l
fluorobenzamido 3-fluoroiodo hen Ieth Idi-tert-but | hos hate: To a solution of
4-(3-amino—6-((1R,3R,4R)fluorohydroxycyclohexyl)pyrazinyl)fluorobenzoic acid
(215 mg, 0.509 mmol) in NMP (Volume: 4 mL) was added (S)—2-amino(3-fluoro
iodophenyl)ethyl t-butyl phosphate (260 mg, 0.509 mmol), DIEA (0.534 mL, 3.06
mmol) and then HATU (290 mg, 0.764 mmol). The reaction mixture was stirred at room
temperature for 1 hour, followed by LCMS. To the crude reaction was added 150 ml of
ethyl acetate washed with saturated onate (2x), water (3x), saturated salt solution,
dried sodium sulfate, filtered and dried to residue. The crude product was purified by
silica gel chromatograph 24g column (DCM g) eluting with 0-80% (EtOAc with 10%
MeOH) / heptane. The desired fractions were concentrated to constant mass to give 315
mg of desired product as free base. (77% . LCMS (m/z): 805.3 (MH+), 1.01 min.
Ste 2. S 4- 3-amino 1R 3R 4R fluoroh drox c clohex l razin l
fluorobenzamido)—2-(3-fluoroiodophenyl)ethyl dihydrogen phosphate: To a solution of
(S)—2-(4-(3-amino((1R,3R,4R)—3-fluorohydroxycyclohexyl)pyrazin-2—yl)
fluorobenzamido)(3-fluoroiodophenyl)ethyl di-tert-butyl phosphate (315 mg, 0.392
mmol) was added HCI 4M in dioxane (5 mL, 20.00 mmol) and methanol (Volume: 0.5
mL). The reaction mixture was stirred at room ature for 1 hour followed by LCMS.
The solvent was concentrated off. The crude material was basified and dissolved with
3M NaOH on with minimal MeOH added. The material was purified by 12 gram
Grace Reveleris C18 reverse phase column eluted with 0-15% ACN/water over 18
minutes at a flow rate of 15 ml/minute, without buffers. The desired fractions were
ted, acidified with 1 M HCI to pH of 1 and extrated with ethyl acetate (5x). The
combined organic layer (800 ml) was washed with minimal water (3x 25 ml) to remove
salts. The solvent was concentrated off, dissolved in 1:1 ACN/water and lyophilized to
give 207 mg of the desired product as HCL salt. (72% yield). LCMS (m/z): 693.2 (MH+),
0.64 min. 1H NMR (<cd3od>) d: 7.87 (s, 1H), 7.81-7.86 (m, 1H), .72 (m, 2H), 7.61
(dd, J=11.7, 1.6 Hz, 1H), 7.46 (ddd, J=8.0, 2.3, 1.4 Hz, 1H), 7.26 (dt, J=9.5, 1.9 Hz, 1H),
.38 (t, J=5.7 Hz, 1H), 4.29-4.49 (m, 1H), 4.18-4.29 (m, 2H), 3.64 (tdd, J=11.6, 8.6, 4.9
Hz, 1H), 2.76-2.92 (m, 1H), 2.27 (ddd, J=8.8, 5.9, 2.5 Hz, 1H), 2.01-2.13 (m, 1H), 1.76-
1.94 (m, 2H), 1.58-1.71 (m, 1H), 1.39-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.16 (br. s.,
1P).
es 191 and 192
S nthesis of 4- 3-amino 1r4S aminoc clohex l 2- l -N- S 3-
chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide and 4-(3-amino((1s,4R)—4-
aminoc clohex l razin l-N- S 3-chloro hen lh drox eth l
fluorobenzamide
Scheme 90
Steal
F O F O
Stegg
NH2 0/ NH2 0
1. H2N/\©
N / N /
I I pd—C, MeOH N/
N I
\ N \ en
21 1 —>
2. NaBH4, MeOH
trans/ois_
—> 83% yield
2:1 trans/cis
93% yield
0 HN. J: ]
Step 5
F O
Step 3 Step 4
NH2 OH (OH
| H2N (S)
hydride, 1M aq LiOH, \ N
DCM, TEA THF, MeOH 2:1 trans/Cis
—, —> CI
78% yield HATU, Huenig's base
DMSO
HN O —>
E; \K 83% yield (two steps)
0 {OH F 0 (OH
NHZ N NH2 N
H H
N / N/
DCM, TFA \ CI \ N Cl
$in 17% yield
34% yield NH2
Ste 1. meth l4- 3-amino 4- benz lamino c clohex | razin l fluorobenzoate
To methyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)—2-fluorobenzoate (300 mg, 0.874
mmol) was added MeOH (4 mL), phenylmethanamine (112 mg, 1.048 mmol) and last dry
4 A molecular sieves. The on was stirred at room temperature for 16 h. Then NaBH4
(165 mg, 4.37 mmol) was added and stirred at room temperature for 2 h followed by
LCMS. To the reaction was added 150 mL of ethyl acetate, washed with saturated
sodium bicarbonate, water (2x), saturated salt solution, dried over sodium sulfate, filtered
and concentrated to resdiue to give 352 mg of the desired product in 2:1 trans to cis ratio,
used as is (93 %). LCMS (m/z): 435.3 (MH+), 0.68 min and 0.72 min.
Ste 2. meth l4- 3-amino 4-aminoc clohex | razin | fluorobenzoate
WO 66188
To methyl 4-(3-amino(4-(benzylamino)cyclohexyl)pyrazinyl)—2-f|uorobenzoate (350
mg, 0.806 mmol) in a round bottom flask that was flushed with argon was added Pd-C
% degaussa, wet (171 mg, 0.161 mmol). Then under argon with syringe, was added
MeOH (5 mL) and last a hydrogen balloon. The flask was evacuated and refilled with
hydrogen six times. The reaction was stirred at room temperature for 14 h. The reaction
was purged with argon, then Pd-C 10% degaussa, wet (171 mg, 0.161 mmol) was
carefully added. Then a hydrogen balloon was added, and the flask was evacuated and
refilled with hydrogen six times. The reaction was stirred for onal 10 h to give a total
of 24 h, followed by LCMS. The on was flushed with argon and 35 mL of DCM was
added. The crude mixture was filtered through a Celite plug, and concentrated to
constant mass to give 230 mg of desired product (which is 2:1 trans to cis ratio), used as
is (83%). LCMS (m/z): 345.2 (MH+), 0.48 min and 0.51 min.
Ste 3. meth l4- 3-amino 4- tert-butox carbon lamino c clohex l razin l
f|uorobenzoate
To methyl 4-(3-amino(4-aminocyclohexyl)pyrazinyl)f|uorobenzoate (230 mg,
0.668 mmol) was added DCM (5 mL), TEA (0.233 mL, 1.670 mmol), and Boc—anhydride
(0.186 mL, 0.801 mmol). The reaction was stirred at room temperature for 1 h, followed
by LCMS. To the reaction was added 150 mL of ethyl acetate, washed with saturated
sodium bicarbonate, water twice, saturated salt solution, dried over sodium sulfate,
filtered and concentrated to constant mass to give 233 mg of the desired product (which
is 2:1 trans to cis ratio), used as is (78%). LCMS (m/z): 445.2 (MH+), 0.92 min for both.
Ste 4. 4- 3-amino 4- tert-butox carbon lamino c clohex l razin l
benzoic acid
To methyl 4-(3-amino(4-((tert-butoxycarbonyl)amino)cyclohexy|)pyrazinyl)—2-
benzoate (230 mg, 0.517 mmol) was added MeOH (2 mL), THF (2 mL) and then
lithium hydroxide 1M aqueous solution (1.552 mL, 1.552 mmol). The reaction was stirred
at room ature for 1 h. he solvent was concentrated to residue, then THF (20 mL)
was added and concentrated to residue. Then THF (20 mL) was added again and re-
concentrated to residue to nt mass to give the desired product (which is 2:1 trans
to cis ratio), used as is. Assume quanitative yield (0.517 mmol). LCMS (m/z): 431.2
(MH+), 0.78 min for both.
WO 66188
Ste 5. S -tert-but l 4- 5-amino 4- 1- 3-chloro hen lh drox eth lcarbamo l
fluoro hen l razin lc clohex lcarbamate
To 4-(3-amino(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazinyl)fluorobenzoic
acid (222 mg, 0.516 mmol) was added DMSO (4 mL), Hiinig’s base (0.450 mL, 2.58
mmol), (S)amino(3-chlorophenyl)ethanol (133 mg, 0.774 mmol) and then HATU
(392 mg, 1.031 mmol). The reaction was stirred for 1 h at room temperature. To the
reaction was added 50 mL of ethyl acetate, washed with water twice, saturated salt
solution, dried over sodium sulfate, filtered and concentrated to residue. The crude was
purified by flash tgraphy using 12 gram column (solid load) eluting with 10-95%
ethyl acetate in heptane. The d fractions were concentrated to constant mass to
give 252 mg of product (which is 2:1 trans to cis ratio), used as is (83% over two steps).
LCMS (m/z): 584.3 (MH+), 0.91 min for both.
Ste 6. 4- 3-amino 1r4S noc clohex l razin l-N- S 3-chloro hen l-
oxyethyl)fluorobenzamide and 4-(3-amino((1s,4R)—4-
aminoc clohex l razin l-N- S 3-chloro hen lh drox eth l
fluorobenzamide
To (S)—tert-butyl (4-(5-amino(4-((1-(3-chlorophenyl)hydroxyethyl)carbamoyl)
fluorophenyl)pyrazinyl)cyclohexyl)carbamate (252 mg, 0.431 mmol) was added DCM
(8 mL) and then TFA (2 mL, 26.0 mmol). The reaction was stirred for 1 h at room
temperature. The solvent was concentrated, redissolved in DMSO, filtered, and purified
by prep HPLC with both isomer collected. With major isomer, trans eluted out first and
mior, cis s eluted out second. After lypholization, 87 mg of trans product 4-(3-
amino((1r,4S)aminocyclohexyl)pyrazinyl)-N-((S)(3-chlorophenyl)
hydroxyethyl)fluorobenzamide was obtained as TFA salt in 34% yield. LCMS (m/z):
484.2 (MH+), 0.58 min; 1H NMR (CD3OD) 6 ppm 7.79 (s, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.58
(dd, J=7.8, 1.6 Hz, 1H), 7.52 (dd, J=11.9, 1.4 Hz, 1H), 7.36 (s, 1H), 7.30 - 7.23 (m, 2H),
7.22 - 7.16 (m, 1H), 5.10 (t, J=5.9 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.08 (tt, J=11.7, 3.9 Hz,
1H), 2.69 - 2.49 (m, 1H), 2.06 (d, J=10.6 Hz, 2H), 1.97 (d, J=12.9 Hz, 2H), 1.75 - 1.57 (m,
2H), 1.55 - 1.31 (m, 2H).
In addition, after lypholization 43 mg of the cis product 4-(3-amino((1s,4R)
aminocyclohexyl)pyrazinyl)-N-((S)(3-chlorophenyl)hydroxyethyl)
fluorobenzamide was obtained as TFA salt, in 17% yield. LCMS (m/z): 484.2 (MH+), 0.61
min; 1H NMR (CD3OD) 8 ppm 7.87 (s, 1H), 7.81 - 7.72 (m, 1H), 7.60 (dd, J=8.0, 1.4 Hz,
1H), 7.55 (d, J=11.7 Hz, 1H), 7.36 (s, 1H), 7.26 (d, J=5.9 Hz, 2H), 7.22 - 7.16 (m, 1H),
.10 (t, J=5.7 Hz, 1H), 3.87 - 3.67 (m, 2H), 2.91 - 2.80 (m, 1H), 1.98 (q, J=8.9 Hz, 2H),
1.90 - 1.71 (m, 6H).
Example 193
S nthesis of 4- 6- 1r 4S tamidoc clohex l amino razin l -N- S 3-
F o Z/OH
I N/\©H
\ N CI
To 4-(3-amino((1r,4S)—4-aminocyclohexyl)pyrazinyl)-N-((S)(3-chlorophenyl)
hydroxyethyl)fluorobenzamide (15 mg, 0.025 mmol) were added DCM ( 0.25 mL), THF
(0.75 mL) and TEA (10.49 pl, 0.075 mmol) at 0 °C. Then acetic anhydride (2.367 pl, 0.025
mmol) was added. The on was stirred for 30 min at 0 °C. The reaction was
concentrated, dissolved in 1 mL of DMSO, filtered, purified by prep HPLC, and lyophilized
to give 5.4 mg of the desired product 4-(6-((1r,4S)acetamidocyclohexy|)
aminopyrazinyl)—N-((S)—1-(3-ch|oropheny|)hydroxyethy|)f|uorobenzamide as a
TFA salt (33% yield). LCMS (m/z): 526.3 (MH+), 0.67 min; 1H NMR (CD30D) 8 ppm 7.71-
7.82 (m, 2H), 7.58 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=11.7 Hz, 1H), 7.37 (s, 1H), 7.22-
7.29 (m, 2H), .22 (m, 1H), 5.10 (t, J=5.9 Hz, 1H), 3.71-3.84 (m, 2H), 3.52-3.66 (m,
1H), 2.51-2.65 (m, 1H), 1.86-2.02 (m, 4H), 1.83 (s, 3H), 1.53-1.69 (m, 2H), 1.22-1.39 (m,
2H).
Example 194
S s of 4- 3-amino 1r4S meth Isulfonamido c clohex | razin | -N- S -
1- ro hen |h drox eth |fluorobenzamide
F o {0
I MAE:H
\ N Cl
To 4-(3-amino((1r,4S)—4-aminocyclohexy|)pyrazinyl)-N-((S)(3-chlorophenyl)
hydroxyethyl)fluorobenzamide (15 mg, 0.025 mmol) was added DCM ( 0.25 mL, Ratio:
1.000), THF (0.250 mL), TEA (10.49 pl, 0.075 mmol) d to ve and cooled to 0
°C, and then methanesulfonyl chloride (1.955 pl, 0.025 mmol) was added. The reaction
was stirred for 30 min at 0 °C, followed by LCMS. The reaction was concentrated
dissolved in 1 mL of DMSO, filtered, purified by prep HPLC, and lyophilized to give 1.6
mg of the desired product 4-(3-amino((1r,4S)—4-
(methylsulfonamido)cyc|ohexy|)pyrazinyl)-N-((S)(3-ch|oropheny|)hydroxyethyl)
fluorobenzamide as TFA salt (9% yield). LCMS (m/z): 562.2 (MH+), 0.69 min. 1H NMR
(CD30D) 8 ppm 7.70-7.82 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.53 (d, J=11.7 Hz, 1H), 7.37
(s, 1H), 7.22-7.30 (m, 2H), 7.13-7.21 (m, 1H), 5.09 (t, J=5.9 Hz, 1H), 3.68-3.89 (m, 2H),
2.87 (s, 3H), 2.48-2.60 (m, 1H), 2.05 (d, J=14.9 Hz, 2H), 1.84-1.95 (m, 2H), 1.54-1.74 (m,
2H), 1.38 (q, J=12.9 Hz, 2H).
Example 195
S nthesis of meth | 18 4r 5-amino 4- S 3-chloro hen |
hyd roxyethyl )carbamoyl )—3-fluorophenyl )pyrazinyl )cyclohexyl )carbamate
2014/062913
F 0 :/OH
I NDH
\ N Cl
HN\n/O\
To 4-(3-amino((1r,4S)—4-aminocyclohexyl)pyrazinyl)-N-((S)(3-ch|oropheny|)
hydroxyethyl)fluorobenzamide (15 mg, 0.025 mmol) was added DCM (0.25 mL), THF
(0.250 mL), TEA (10.49 pl, 0.075 mmol) stirred to dissolve and cooled to 0 °C, and then
methyl chloroformate (1.943 pl, 0.025 mmol) was added. The reaction was d for 30
min at 0 °C, followed by LCMS. The reaction was concentrated dissolved in 1 mL of
DMSO, filtered, purified by prep HPLC, and lyophilized to give 4.5 mg of the desired
product methyl ((1S,4r)(5-amino(4-(((S)(3-chlorophenyl)
hydroxyethyl)carbamoyl)fluorophenyl)pyrazinyl)cyclohexy|)carbamate as TFA salt
(27% yield). LCMS (m/z): 542.3 (MH+), 0.75 min. 1H NMR (CD3OD) 8: 7.73-7.81 (m, 2H),
7.58 (dd, J=8.0, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.37 (s, 1H), 7.23-7.30 (m, 2H), 7.15-7.22
(m, 1H), 5.10 (t, J=5.9 Hz, 1H), 3.69-3.84 (m, 2H), 3.53 (s, 3H), 3.31-3.36 (m, 1H), 2.48-
2.62 (m, 1H), 1.84-2.00 (m, 4H), 1.51-1.68 (m, 2H), 1.21-1.44 (m, 2H)
Example 196
S nthesis of 4- 3-amino 1r4S 2-h drox acetamido c clohex | 2- | -N-
S 3-chloro hen |h drox eth |fluorobenzamide
F o :/
N/IWWQH
\N CI
HN\n/\OH
2014/062913
To 4-(3-amino((1r,4S)—4-aminocyclohexy|)pyrazinyl)-N-((S)(3-ch|oropheny|)
hydroxyethyl)fluorobenzamide (11 mg, 0.018 mmol) were added NMP (0.4 mL), 2-
hydroxyacetic acid (2.80 mg, 0.037 mmol), Hiinig’s base (0.013 mL, 0.074 mmol) and
then HATU (17.49 mg, 0.046 mmol). The reaction was stirred for 30 min at room
temperature. The reaction was concentrated, dissolved in 0.75 mL of DMSO, filtered,
purified by prep HPLC, and lyophilized to give 3.6 mg of the desired product 4-(3-amino-
,4S)(2-hydroxyacetamido)cyc|ohexy|)pyraziny|)-N-((S)(3-ch|oropheny|)
hydroxyethyl)fluorobenzamide as TFA salt (29%). LCMS (m/z): 542.2 (MH+), 0.63 min.
1H NMR ) 6 ppm 7.83 - 7.72 (m, 2H), 7.59 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=11.7
Hz, 1H), 7.37 (s, 1H), 7.32 - 7.23 (m, 2H), 7.22 - 7.16 (m, 1H), 5.10 (t, J=5.9 Hz, 1H), 3.86
(s, 2H), 3.82 - 3.63 (m, 3H), 2.65 - 2.50 (m, 1H), 2.02 - 1.86 (m, 4H), 1.72 - 1.56 (m, 2H),
1.48 - 1.33 (m, 2H).
Example 197
S nthesis of S -N- 2-amino 3-chloro hen | eth | 3-amino 4 4-
difluoroc clohex | razin |f|uorobenzamide
Scheme 91
F O
F O
m; m;
NH2 0 StepL / O
NH2 0
N/ F H2N _.\\\ A
IN N/ o
l m \
' \ N /‘\
\O/\/N\/\O/
NaOH 1M aq
THF, MeOH
—> —>
31% yield.
HATU, Huenlgsbase. ,
O 100% yield
F F
DMSO
12% yield
/NH :/ 2
ma F 0
F 0
NH N
HCI 4M In dioxane N’
N/ |
|N ’ \ N CI
\ CI
33% yield
F F
F F
Ste 1. meth |4- 3-amino 4 4-difluoroc clohex | razin |fluorobenzoate
To methyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)f|uorobenzoate (250 mg, 0.728
mmol) was added DCM (10 mL) and the solution was cooled to 0 °C in ice bath. Then
Deoxo-fluoro solution in toluene 50% (805 mg, 1.820 mmol) was added at 0 °C. The
reaction was allowed to warm up to room temperature and stirred for 2 h. To quench the
reaction, TEA (1.522 mL, 10.92 mmol) was added and stirred for 1 h at room
temperature. The solvent was concentrated off to residue and the crude was purified by
flash chromotgraphy (dry load) using 12 gram column eluting with 5-75% ethyl acetate in
heptane. The desired fractions were concentrated to constant mass to give 83 mg of the
d product as a free base, used as is (31% yield). LCMS (m/z): 366.2 (MH+), 0.87
min.
Ste 2. 4- o 4 4-difluoroc clohex l razin lfluorobenzoic acid
To methyl 4-(3-amino(4,4-difluorocyclohexyl)pyrazinyl)f|uorobenzoate (83 mg,
0.227 mmol) was added MeOH (1.5 mL), THF (1.5 mL) and then 1 M aqueous solution
NaOH (0.909 mL, 0.909 mmol). The reaction was stirred at room temperature for 6 h. The
reaction was concentrated to residue. THF was added and concentrated to residue again.
Then the mixture was dissolved in 1:1 ACN/water, acidified with 6 M HCI and lized
to give desired product as HCI sa|t used as is. Assume quanitative yeiId, (0.227 mmol).
LCMS (m/z): 352.1 (MH+), 0.71 min.
Ste 3. S -tert-but | 2- 4- 3-amino 4 4-difluoroc clohex l 2- l
benzamido)—2-(3-chlorophenyl )ethyl )carbamate
To 4-(3-amino(4,4-difluorocyclohexyl)pyraziny|)fluorobenzoic acid (48 mg, 0.124
mmol) werr added DMSO (1 mL), Hiinig’s base (0.108 mL, 0.619 mmol), (S)-tert-butyl (2-
amino(3-chlorophenyl)ethyl)carbamate (50.3 mg, 0.186 mmol) and then HATU (94 mg,
0.248 mmol). The reaction was d for 1 h at room temperature. To the reaction was
added 0.5 mL of DMSO, filtered, purified by prep HPLC, and lyophilized to give 11 mg of
the d product used as is (12% yield). LCMS (m/z): 604.2 (MH+), 1.05 min.
Ste 4. S -N- o 3-chloro hen l eth l 3-amino 4 4-
difluoroc clohex l razin lfluorobenzamide
To (S)-tert-butyl (2-(4-(3-amino(4,4-difluorocyclohexyl)pyraziny|)
f|uorobenzamido)(3-ch|oropheny|)ethy|)carbamate (11 mg, 0.018 mmol) was added
HCI 4M in dioxane (1 mL, 4.00 mmol). The reaction was stirred for 1 h at room
temperature. The solvent was removed and concentrated to residue, which was dissolved
in 1:1 acetonitrile/ water, filtered and lyophilized to HCI salt. The crude salt residue was
dissolved in 1 mL of DMSO, purified by prep HPLC and lyophilized to give 3.8 mg of the
desired product (S)—N-(2-amino(3-chlorophenyl)ethyl)(3-amino(4,4-
difluorocyclohexyl)pyraziny|)f|uorobenzamide as a TFA salt (33%). LCMS (m/z):
504.2 (MH+), 0.74 min; 1H NMR ) 6 ppm 7.85 - 7.73 (m, 2H), 7.62 (dd, J=8.0, 1.4
Hz, 1H), 7.54 (dd, J=12.1, 1.2 Hz, 1H), 7.46 (s, 1H), 7.38 - 7.28 (m, 3H), 5.39 (dd, J=9.0,
.9 Hz, 1H), 3.40 - 3.33 (m, 2H), 2.72 (br. s., 1H), 2.12 - 1.98 (m, 2H), 1.96 - 1.73 (m, 6H).
Examples 198 and 199
S nthesis of omericall enriched reomers of cis 3-amino 3-
h drox c clohex | razin l-N- S 3-chloro hen lh drox eth l
fluorobenzamide
Scheme 92
NHZ Ste NH2 9: Ste 2 NH2
N)\ le 0
\ Br
chiral separation NI NB N \
I —> | o
/ N / N / N
OTBDMS OTBDMS OTBDMS
OTBDMS
(+/-))cis diastereomer
polar less polar polar or less polar
F O
MN?” F O F O {OH
:‘ENJag NHZ +HH2N“© —~Ste NH2 N
N a
OTBDMS OTBDMS
OTBDMS
[30’6" or less [JO/af polar or less polar
polar or less polar
F O /OH
Step g Q yum
cis diastereomer cis diastereomer
from polarprecursor from less polarprecursor
WO 66188
Step 1. Polar and less polar enantiomerically enriched cis(3-((tert—
but ldimeth lsil lox c c|ohex l razinamines
-(3-((tert—butyldimethylsilyl)oxy)cyclohexyl)pyrazinamine (500 mg, 1.626 mmol),
prepared from Scheme 29, was resolved by chiral SFC (ChiraIPak 5mic OD column,
0 (mm), Cog/IPA+0.1% DEA=90/10, SFC=5mL/min). For polar enantiomer (peak
1) (230 mg, 0.748 mmol, 46.0% yield), Rt = 1.58 min. For less polar enantiomer (peak 2)
(230 mg, 0.748 mmol, 46.0% yield), Rt = 2.36 min.
Ste 2 3 4 5 and 6. cis 3-amino 3-h drox c c|ohex | razin I-N- S 3-
chlorophenyl)—2-hydroxyethy|)—2-f|uorobenzamide diastereomers
Following Steps 2, 3, and 7 in Scheme 75, each omeric enriched cis(3-((tert—
butyldimethylsilyl)oxy)cyclohexyl)pyrazinamine underwent bromination ed by
Suzuki coupling with 3-fluoro(methoxycarbonyl)phenyl)boronic acid. After hydrolysis,
following Step 8 in Scheme 75, using (S)amino(3-ch|oropheny|)ethano| and each
enantiomer, each diastereomer of cis(3-amino(3-hydroxycyclohexyl)pyraziny|)-N-
((S)(3-chlorophenyl)hydroxyethyl)f|uorobenzamide was obtained respectively. For
cis diastereomerfrom polar precursor, LCMS (m/z): 485.0 (MH+), 0.70 min; 1H NMR (400
MHz, METHANOL-d4) 6 ppm 7.90 - 7.69 (m, 2 H) 7.64 - 7.48 (m, 2 H) 7.37 (s, 1 H) 7.30 -
7.09 (m, 3 H) 5.10 (t, J=6.06 Hz, 1 H) 3.89 - 3.69 (m, 2 H) 3.66 - 3.47 (m, 1 H) 2.79 - 2.60
(m, 1 H) 2.06 (d, 4 Hz, 1 H) 1.97 - 1.68 (m, 3 H) 1.52 - 1.26 (m, 3 H) 1.24 -0.99 (m,
1 H). For cis diastereomer from less polar precursor, LCMS (m/z): 485.0 (MH+), 0.70 min.
1H NMR (400 MHz, OL-d4) 6 ppm 7.88 - 7.70 (m, 2 H) 7.65 - 7.49 (m, 2 H)
7.37 (s, 1 H) 7.32 - 6.98 (m, 3 H) 5.10 (s, 1 H) 3.76 (t, J=6.06 Hz, 2 H) 3.58 (s, 1 H) 2.79-
2.59 (m, 1 H) 2.06 (d, J=12.13 Hz, 1 H) 1.97 - 1.61 (m, 3 H) 1.54 - 1.30 (m, 3 H) 1.25 -
0.96 (m, 1 H).
Absolute stereochemistry on cyc|ohexane ring for both diastereomers has not been
determined.
Examples 200 and 201
S nthesis of 4- 3-amino tetrah dro-2H- ran l razin l f|uoro-N- 1S 2R
hen |c c|o ro |benzamide and 4- 3-amino tetrah dro-2H- ran | razin |
fluoro-N- 1R2S hen |c c|o ro |benzamide
WO 66188
Scheme 93
O F O F O
NH2 N' "'1 NH2 N' "’1 NH2 N“'
H H H
N \ N \ N \
/N resolution I I
,N /N
(+/-) Peak1 Peak2
O O 0
Following Step 2 in Scheme 89, using (+/-)-transphenylcyclopropanamine, EDC (30.2
mg, 0.158 mmol), HOAt (17.2 mg, 0.126 mmol), and DIEA (0.033 mL, 0.189 mmol), (+/-)-
trans(3-amino(tetrahydro-2H-pyranyl)pyraziny|)f|uoro-N-(2-
phenylcyclopropyl)benzamide was obtained (19 mg, 70%). LCMS (m/z): 433.2 (MH+),
0.82 min; 1H NMR z, CDCI3) 8 ppm 8.29-8.22 (m, 1 H), 7.94 (s, 1 H), 7.76-7.71
(m, 1 H), 7.63-7.56 (m, 1 H), 7.35-7.18 (m, 4 H), 7.04-6.94 (m, 1 H), 4.67 (s, 2 H), 4.09
(m, 2 H), 3.35 (m, 2 H), 3.15 (m, 1 H), 2.93 (m, 1 H), 2.22 (m, 1 H), 2.90-1.8 (m, 4 H),
1.43-1.23 (m, 3 H).
The racemic product was resolved by chiral SFC (ChiralPak 5mic AD-H column, 4.6x100
(mm), heptane:EtOH= 50/50, 1mL/min). For polar mino(tetrahydro-2H-pyran
yl)pyrazinyl)f|uoro-N-((1S,2R)—2-phenylcyclopropyl)benzamide (27%) at Rt = 11.0
min, LCMS (m/z): 433.2 (MH+), 0.81 min. For less polar 4-(3-amino(tetrahydro-2H-
4-yl)pyrazinyl)f|uoro-N-((1R,2S)pheny|cyclopropyl)benzamide (+/-)-trans
(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)f|uoro-N-(2-
phenylcyclopropyl)benzamide (27%) at Rt = 15.8 min, LCMS (m/z): 433.2 (MH+), 0.81
min. The absolute stereochemistry was assigned based on biochemical data and docking
model.
Examples 202 and 203
S nthesis of 4- 3-amino—6- 1r4S h drox c clohex | razin |f|uoro-N- 1S 2R -
2- hen lc clo ro lbenzamide and 4- 3-amino 1r4R h drox c clohex | razin-
2- |f|uoro-N- 1R2S hen lc clo ro lbenzamide
Scheme 94
F o F o F o
NH2 N' NH2 N' NH2 N
H H H
N’ N’ N’
\ N resolution \ N \ N
: —> : :
(+/—)
peak1 peak2
OH OH OH
Following Step 2 in Scheme 89, using (+/-)-transphenylcyclopropanamine (48.6 mg,
0.37 mmol), EDC (127 mg, 0.66 mmol), HOAt (67.8 mg, 0.498 mmol), and DIEA (0.174
mL, 0.996 mmol), (+/-)-trans(3-amino(tetrahydro-2H-pyranyl)pyrazinyl)—2-
fluoro-N-(2-phenylcyclopropyl)benzamide was obtained (40 mg, 97%), which was
separated by chiral SFC (ChiralPak 5mic OJ column, 4.6x100 (mm), C02/IPA+0.1%
/40, SFC=5m|/min). The polar diasteremer was 4-(3-amino((1r,4S)—4-
hydroxycyclohexyl)pyrazinyl)fluoro-N-((1S,2R)—2-phenylcyclopropyl)benzamide (Rt =
1.38 min)._LCMS (m/z): 447.3 (MH+), 0.76 min; 1H NMR (500MHz, CD30D) 6 ppm 7.89 -
7.78 (m, 2H), 7.72 - 7.53 (m, 2H), 7.33 - 7.23 (m, 2H), 7.24 - 7.10 (m, 3H), 3.68 -3.53 (m,
1H), 3.14 - 3.03 (m, 1H), 2.74 - 2.56 (m, 1H), 2.27 - 2.13 (m, 1H), 2.12 - 1.88 (m, 4H),
1.77 - 1.57 (m, 2H), 1.52 - 1.29 (m, 4H). The less polar diastereomer was 4-(3—amino
((1r,4R)—4—hydroxycyclohexyl)pyrazinyl)fluoro-N-((1R,2S)—2-
phenylcyclopropyl)benzamide (Rt = 1.82 min). LCMS (m/z): 447.3 (MH+), 0.75 min; 1H
NMR (500MHz, CD3OD) 6 ppm 7.89 - 7.78 (m, 2H), 7.72 - 7.53 (m, 2H), 7.33 - 7.23 (m,
2H), 7.24 - 7.10 (m, 3H), 3.68 - 3.53 (m, 1H), 3.14 - 3.03 (m, 1H), 2.74 - 2.56 (m, 1H),
2.27 - 2.13 (m, 1H), 2.12 - 1.88 (m, 4H), 1.77 - 1.57 (m, 2H), 1.52 - 1.29 (m, 4H). The
absolute stereochemistry was ed based on biochemical data and docking model.
Example 204
S nthesis of 4- 2-amino tetrah dro-2H- ran | 3- l-N-benz lc ano
fluorobenzamide
Scheme 95
$2 1 $2 2 $9g
F F F F
DOOM Pd(OAc)2 COZH 052003 COZMe CuCN COzMe
—> —> —>
Mel DMF
CI Ph|(OAC)2. I2 (31 I CI I CI CN
NH20 _QSte 4&5 Ste
NH2 H2
N \ 1. Pd(PPh3)4
N :NN/\©
/ Na2C03 T3P TEA I
2 LiOH
Ste 1. 4-chlorofluoroiodobenzoic acid
To a 250 mL flask were added rofluorobenzoic acid (4 g, 22.92 mmol), Pd(OAc)2
(0.257 g, 1.146 mmol), iodobenzene diacetate (8.12 g, 25.2 mmol), iodine (6.40 g, 25.2
mmol) and DMF (60 mL). The solution was heated under a nitrogen atmosphere at 100
°C for 20 h. LCMS showed about half of 4-chlorofluorobenzoic acid was converted to
the product (LCMS retention time 0.98 min, no MH+ peak). After cooling to room
temperature, the solution was diluted with EtOAc and washed three times with 1 N HCI.
The aqueous layers were combined and extracted once with EtOAc. The organic layers
were combined, dried over Na2804 and concentrated to give a dark brown oil (16.4 g,
42% pure), which was taken to the next step t purification.
Step 2. Methyl 4-chlorofluoroiodobenzoate
4-Chlorofluoroiodobenzoic acid (16.4 g, 22.93 mmol, along with 4-chloro
fluorobenzoic acid) were dissolved in DMF (30 mL). Cs2C03 (8.96 g, 27.5 mmol) was
added, followed by Mel (1.577 mL, 25.2 mmol). After 90 min at room temperature. LCMS
showed the reaction was completed (retention time 1.06 min, no MH+ peak). It was
diluted with EtOAc and ed through a piece of filter paper. The te was washed
three times with water. The aqueous layers were combined and extracted once with
EtOAc. The organic layers were combined, dried over Na2804 and trated. The
residue was purified on a silica gel column (heptane:EtOAc 1:0 to 9:1) to give a mixture of
methyl 4-chlorofluoroiodobenzoate and methyl 4-chlorofluorobenzoate in
approximately 1:1 ratio (1.99 g).
Step 3. Methyl 4-chlorocyanofluorobenzoate
2014/062913
Methyl 4-chlorofluoroiodobenzoate (1.99 g, 10.6 mmol) was dissolved in DMF ( 12
mL). CuCN (2.84 g, 31.7 mmol) was added and the sion was heated under
microwave at 110 °C for 18 min. EtOAc was added and the suspension was filtered
through a piece of filter paper. The filtrate was washed three times with water. The
aqueous layers were combined and extracted once with EtOAc. The organic layers were
combined, dried over NazSO4 and trated. The residue was purified on a silica gel
column (heptane:EtOAc 1:0 to 9:1) to give the product as a colorless solid (505 mg). 1H
NMR (400 MHz, CDCI3) 6 ppm 7.56 (s, 1H), 7.40 (d, 1H, J=8 Hz), 4.00 (s, 3H); 13C NMR
(100 MHz, CDCI3) 6 ppm 161.78 (d, J=58 Hz), 159.44, 139.16 (d, J=11 Hz), 129.96,
121.99, 121.74, 115.48, 114.72, 53.04.
Ste 4. Meth l4- 2-amino tetrah dro-2H- ran l ridin lc ano
fluorobenzoate
To a 2 mL microwave vial were added 5-(tetrahydro-2H-pyranyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)pyridinamine (638 mg, 1.049 mmol), methyl 4-
chlorocyanofluorobenzoate (140 mg, 0.655 mmol), Pd2(dba)3 (30.0 mg, 0.033
mmol), XPhos (31.2 mg, 0.066 mmol), NaHC03 (275 mg, 3.28 mmol), DME (3 mL) and
H20 (1.5 mL). The solution was heated under microwave at 100 °C for 15 min. Water
and EtOAc were added and the aqueous layer was extracted three times with EtOAc. The
organic layers were combined, dried over NazSO4 and concentrated. The residue was
purified on a silica gel column (heptane:EtOAc 1:0 to 1:4) to give the product as a yellow
foam (85 mg). LCMS (m/z) 356.1 (MH+), 0.58 min.
Ste 5. 4- 2-amino tetrah - ran l ridin lc anofluorobenzoic acid
To methyl 4-(2-amino(tetrahydro-2H-pyranyl)pyridinyl)cyanofluorobenzoate
(85 mg, 0.239 mmol) and lithium hydroxide drate (11.04 mg, 0.263 mmol) were
added THF (1 mL) and H20 (1.000 mL). The on was stirred at room temperature for
3 h. All solvents were evaporated to give the crude product's lithium salt as a yellow solid
(92 mg) which was used in the next step without purification. LCMS (m/z) 342.0 (MH+),
0.42 min,
Ste 6. 4- 2-amino tetrah dro-2H- ran l ridin l-N-benz lc ano
fluorobenzamide
To 4-(2-amino(tetrahydro-2H-pyranyl)pyridinyl)cyanofluorobenzoic acid
were added DCM (1 mL), followed by amine (0.017 mL, 0.153 mmol), triethylamine
(0.053 mL, 0.383 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol). After 1 h more
amine (0.017 mL, 0.153 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol)
were added and at 2 h the reaction was completed. Saturated NaHCO3 solution was
added and extracted twice with EtOAc. The organic layers were combined, dried over
Na2804 and concentrated. The residue was purified on a silica gel column
(heptane:EtOAc 1:0 to 0:1) to give the product as a colorless solid (17 mg). LCMS (m/z)
431.1 (MH+), 0.65 min. 1H NMR (400 MHz, CDCI3) ) 6 ppm 8.03 (s, 1 H), 7.74 (s, 1 H),
7.54 (d, 1 H, J 12 Hz), 7.43-7.30 (m, 4 H) 7.26 (s, 1 H), 7.23 (s, 1 H) 6.57 (br s, 1 H), 4.74
(d, J 5.53 Hz, 2 H), 4.10 -4.06 (m, 2 H), 3.55 -3.46 (m, 2 H), 2.77 -2.67 (m, 1H), 1.80 -1.70
(m, 4 H).
Example 205
S nthesis of 4- 2-amino tetrah dro-2H- ran l ridin lfluoro—N- 6-
methylpyridinyl)methyl)benzamide
Scheme 96
_QSte l Stegz
\ 0 DIEA, PdOAc2
| \JL (o—Tol)3P/DMF B0620 cat. DMAP \
+ OEt
N N/ OEt —> |
o /
81% 934 BoczN N
$2. $124
1. co Me
M6020 cone . N H/Me0H 2
1. NaH MeOH 2. :%I/H:%
M60 0\CoéngeMeZ Z
Dimethylmalonate2. 3. cat. HCI/MeOH \ 002Me
—. |
36% /
co M2 e . N
BocHN
94% (one pot) HZN
HZN l/N COZMe
m; $99 NHz SteQZ NH2
OH F o
HZSO4/toluene N \ N \
L'A'H4/THF_ Dean-Stark I NBS I 0H
/ /
’ —’ + H0
quantitative \ OH
I MeCN ‘B
790/0 I
/ OH
H2N N
o o
F O F O
4—Ste 11
NH2 OH “”2 N \
Pd(PPh3)4 H N /
NaZCO3 NI \ PyBrop, HOAt
H2N /N NI \
—> / + I —> /
DIEA, THF
0 O
Stepg Stegfl
fl NHz-OH HCI, K2003 \ Zn, ACOH \
—. I
N —> I
N/ /O / / / NH
N \OH 2
Ste 1. E -eth l3- 6-amino ridin lacr late
To a glass bomb were charged with 5-bromopyridinamine (10.0 g, 57.8 mmol), ethyl
acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144mmol) in DMF (40 mL). The mixture
was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2,89 mmol) and (o-
Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was
, and heated with 100 °C oil bath overnight. The reaction mixture was cooled down
to room temperature, and the precipitates were removed by ing through a thin layer of
Celite. The filtrate was concentrated as much as possible via p, and the residue
was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with
water (2 x 100 mL), dried over , and concentrated. A brown slid was obtained as
crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid
was collected via filtration. The filter cake was rinsed with small amount of EtOAc and
dried under vaccum as the first crop of product (5.0 g). The mother liquor from trituration
was stripped by dilute aqueous 1 N HCI (30 mL) and water (70 mL). Aqueous layer was
transferred to a clean tive funnel, basicified with 20 mL sat. Na2C03, and extracted
with EtOAc (60 mL). EtOAc layer was dried over , concentrated and provided the
second portion of product (4.0 g). The two crops of product were combined to afford 81%
yield. LCMS (m/z) 193.2 (MH+), 0.39 min.
Ste 2. E -eth l3- 6- bis tert-butox carbon lamino ridin lac late
To solution of (E)-ethyl 3-(6-aminopyridinyl)acrylate (6.6 g, 34.3 mmol) and DMAP
(0.21 g, 1.7 mmol) in THF(150 mL) was added di-tert-butyl dicarbonate (15.7 g, 71.9
mmol). The mixture was stirred ght at room temperature. The reaction was
2014/062913
concentrated and a brown solid was obtained as crude (E)-ethyl 3-(6-(bis(tert-
butoxycarbonyl)amino)pyridinyl)acrylate (12.5 g, 93%). LCMS (m/z) 237.4 (MH+) 0.98
min.
Ste 3. trimeth l2- 6- tert-butox carbon lamino ridin l ro ane-1 1 3-tricarbox late
and tetrameth l2- 6-amino ridin l ro ane-1 1 1 acarbox late
To a flame flask was charged with ous MeOH (50mL), and the content was cooled
down to 0 0C. To the flask was added sodium hydride (3.18 g, 60% in dispersion
mineraloil, 80 mmol) with gas evolution under control. The reaction mixture was stirred
at room temperature untill gas evolution ceased. To this freshly prepared NaOMe/MeOH
solution was added dimethyl malonate (10.52 g, 80 mmol), and the mixture was stirred at
room temperature for 20 min. The mixture turned into a milky slurry. The milky slurry was
diluted with 25 mL ous MeOH, and decanted to a flask with sodium hydride (12.5
g, 31.9 mmol). The reaction mixture slurry was stirred at room temperature for 15 min,
and then heated to reflux overnight. The reaction mixture was cooled down to room
temperature, and concentrated. The residue was partitioned between EtOAc/H20 (100
mL/100 mL). The EtOAc layer was washed with 1 N NaOH (3 x 30 mL), brine (30 mL),
dried over Na2804, and concentrated. A light brown oil was obtained as crude t.
The crude product was purified by flash chromatography eluting with nt
EtOAc/CH2C|2_ Two major peaks were ed and ted as trimethyl 2-(6-(tert-
butoxycarbonylamino)pyridinyl)propane-1,1,3-tricarboxylate (2.65 g, 20.3% yield) and
tetramethyl 2-(6-aminopyridinyl)propane-1,1,1,3-tetracarboxylate (1.89 g, 16% yield).
The two products were characterized and confirmed by LCMS and 1H NMR. For trimethyl
2-(6-(tert-butoxycarbonylamino)pyridinyl)propane-1,1,3-tricarboxylate. LCMS (m/z)
411.5 (MH+), 0.64 min; 1H NMR (CDCI3) 6 ppm 8.15 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.6
Hz, 1H), 7.60 - 7.52 (m, 2H), 3.90 (td, J = 9.8, 4.7 Hz, 1H), 3.76 (s, 3H), 3.56 (s, 3H),
3.55 (s, 3H), 2.92 - 2.81 (m, 1H), 2.80 - 2.69 (m, 1H), 1.53 (s, 9H). Fortetramethyl 2-(6-
aminopyridinyl)propane-1,1,1,3-tetracarboxylate: LCMS (m/z) 369.5 (MH+) 0.47 min; 1H
NMR (CDCI3) 6 ppm 8.31 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.60
(dd, J = 8.6, 2.3 Hz, 1H), 3.92 (td, J = 9.7, 4.9 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.57 (s,
3H), 3.55 (s, 3H), 2.93 - 2.82 (m, 1H), 2.81- 2.70 (m, 1H).
Ste 4. dimeth l3- 6-amino ridinl entanedioate
To a mixture of trimethyl 2-(6-(tert-butoxycarbonylamino)pyridinyl)propane-1,1,3-
tricarboxylate (2.5 g, 6.1 mmol) and tetramethyl minopyridinyl)propane-1,1,1,3-
tetracarboxylate (1.8 g, 4.9 mmol) in MeOH (30 mL) was added aqueous NaOH solution
(2.44 g NaOH in 5 mL water, 60.9 mmol). The resulting mixture was heated to relux by oil
bath for 1 hour. The reaction mixture was cooled down to room ature, and
concentrated under reduced re via rotavap. To the concentrated residue were
added water (15 mL) and conc. HCI (3 mL). The resulting mixture was heated to reflux
overnight. The reaction e was cooled down, and concentrated under reduced
pressure via rotavap, and a solid was obtained. The obtained solid residue was triturated
with methanol (100 mL) and the precipitates was removed by filtration, and a light color
filtrate was obtained. To the filtrate was added conc. HCI (200 uL) and the resulting
mixture was heated to reflux via external oil bath for 1 h. The on mixture was cooled
down, and tarted. The e was partitioned between EtOAc/sat. NaHC03 (50
mL/50 mL). Aqeous layer was extracted with EtOAc (50 mL). The EtOAc extracts were
combined, washed with brine (50 mL), dried over Na2804, and concentrated. Awhite
solid was obtained as desired dimethyl 3-(6-aminopyridinyl)pentanedioate (2.6 g, 10.31
mmol, 93.9% yield). LCMS (m/z) 253.2 (MH+) 0.38 min; 1H NMR (CDCI3) 6 ppm 7.95 (d, J
= 2.3 Hz, 1H), 7.32 (dd, J = 8.2, 2.3 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 4.37 (br. s., 2H),
3.61 (s, 6H), 3.55 (quin, J = 7.5 Hz, 1H), 2.80 -2.66 (m, 2H), 2.65- 2.51 (m, 2H).
Ste 5. 3- 6-amino ridin-3— l entane-1 5-diol
To aluminum (lll) lithium hydride/THF slurry (0.94g in 60 mL THF, 25 mmol) at 0 0C was
added dimethyl 3-(6-aminopyridinyl)pentanedioate/THF solution (2.5 g, 9.9 mmol in 30
mL THF) over ~10 min. The slurry was stirred at 0 0C for 40 min, and then at room
temperature for 45 min. The mixture was cooled down to 0 °C, and quenched by
sequential addition of water (0.96 mL) with gas evolution under control, then 15%
aqueous NaOH (0.96 mL), and water (2.9 mL). The quenched mixture was stirred at
room temperature for 30 min. The precipitates were d via filtration. The filtrate was
concentrated, and a light yellow solid (1.97 g, quantitative yield) was obtained as 3-(6-
aminopyridinyl)pentane-1,5-diol. LCMS (m/z) 197.2 (MH+) 0.22 min.
Ste 6. 5- tetrah dro-2H- ran l ridinamine
To 3-(6-aminopyridinyl)pentane-1,5-diol/toluene mixture (1.96 g, 10 mmol in 40 mL)
were added 1 mL water to help ving, and then conc. H2804 (98%, 1.6 mL, 30
mmol). The resulting mixture was heated to reflux with Dean-Stark to remove water from
reaction mixture for 1 h 20 min. The reaction e was cooled down to room
temperature, and concentrated. The residue was d with ice cold water (15 mL),
neutralized by solid Na2C03 (4 g), and extracted with EtOAc (3 x 30 mL). The EtOAc
extracts were combined, washed with brine (30mL), dried over Na2804, and
concentrated. A light yellow solid was obtained as crude 5-(tetrahydro-2H-pyran
yl)pyridinamine. LCMS (m/z) 179.2 (MH+) 0.33 min; 1H NMR (CDCI3) 6 ppm 7.95 (d, J
= 2.0 Hz, 1H), 7.32 (dd, J = 8.2, 2.3 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 4.34 (br. s., 2H),
4.11 - 3.99 (m, 2H), 3.51 (td, J = 11.2, 3.3 Hz, 2H), 2.73 -2.56 (m, 1H), 1.75 -1.69 (m,
4H).
Ste 7. o tetrah dro-2H- ran l ridinamine
To 5-(tetrahydro-2H-pyranyl)pyridinamine /acetonitrile solution (1.4 g, 7.85 mmol/30
mL) at 0-5 0C was added portionwise NBS (1.4 g, 7.85 mmol) with internal temperature
controlled below 5 oC. The resulting mixture was stirred at 0 0C for 1 hour 40 min. The
reaction mixture was concentrated under reduced pressure, and the residue was
triturated with dilute aqueous NaOH/H20(1 g/30 mL). The solid suspension was collected
via filtration. The filtercake was washed with ice cold water (~10 mL), and the tes
were combined, and extracted with EtOAc (20 mL). The EtOAc extract was washed with
brine (20 mL), dried over Na2804, and concentrated. A light yellow solid was combined
with the filter cake, and dried under high vacuum as crude 3-bromo(tetrahydro-2H-
pyranyl)pyridinamine. LCMS (m/z) 257.1/259.1 (MH+) 0.39 min. 1H NMR (CDCI3) 6
ppm 7.90 (d, J :16 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 4.80 (br. s., 1H), 4.12 -4.02 (m,
2H), 3.54 -3.44 (m, 2H), 2.71 - 2.61 (m, 1H), 1.78 -1.68 (m, 4H).
Ste 8. 4- 2-amino tetrah dro-2H- ran l ridin lfluorobenzoic acid
To a microwave vial were d with 3-bromo(tetrahydro-2H-pyranyl)pyridin
amine (500 mg, 1.95 mmol), 4-boronofluorobenzoic acid (1.07 g, 5.83 mmol), aqueous
Na2C03 (2 M, 4.86 mL) and DME (10 mL). The e was purged with argon, then
followed by addition of Pd(PPh3)4 (225 mg, 0.194 mmol). The e was purged with
argon, sealed and heated via microwave reactor at 125 0C for 20 min, and then at 130 0C
for another 40 min. The DME layer of the reaction mixture was collected, and the solid
precipitates were ated with methanol (2 x 10 mL). Methanol supernatants were
combined with DME layer, and concentrated. The obtained residue was stirred with Et20
(2 x 60 mL), and the EtZO supernatants were discarded. The solid residue was ioned
between EtOAc (20 mL) and aq. HCI (1N, 20 mL). The EtOAc layer was stripped with 1N
HCI (2 x 5 mL), and the aqueous layers were combined. The aqueous layer was
concentrated under reduced pressure, and the obtained light yellow solid was triturated
with methanol (8 mL). The supernant was isolated via filtration and concentarted. 4-(2-
Amino(tetrahydro-2H-pyranyl)pyridinyl)—2-fluorobenzoic acid (0.844 g, 2.67 mmol,
137% yield) was obtained as light yellow foam. LCMS (m/z) 317.2 (MH+) 0.46 min.
Ste 9. E meth | icolinaldeh de oxime
To 6-methylpicolinaldehyde l solution (642 mg, 5.3 mmol/2.1 mL) was added
hydroxyamine hydrochloride (368 mg, 5.3 mmol) and K2C03 aqueous solution (0.88 g/4.2
mL). The resulting solution was then heated to reflux via external oil bath for 30 min. The
reaction mixture was cooled down to 0 OC, and stirred for 30 min. The white solid
suspension was collected via filtration, and the filter cake was washed with some ld
water. The filter cake was air dried, and further dried under high vacuum as the first crop
t (0.565 g). The filtrates were combined, and concentrated to dryness. The residue
was redissolved in water (2 mL), coolded to 0 °C and stirred for 20 min. The solid product
was collected via filtration as the second crop of product (70 mg) as light yellow solid.
The two crops of product were combined to provide (E)methylpicolinaldehyde oxime
(88%). LCMS (m/z) 136.9 (MH+) 0.21 min.
Ste 10. 6-meth | ridin lmethanamine
To methylpicolinaldehyde oxime (0.635 g, 4.66 mmol)/acetic acid (267 uL, 4.66
mmol)/ethanol (10 mL) on was added portionwise zinc dust (5.19 g, 79 mmol) over
min. The resulting mixture was stirred for additional 30 min. LCMS of reaction aliquot
indicated reaction was ted. The zinc precipitates in reaction mixture was removed
by filtration, and the filtrate was concentrated. The residue was ed to pH > 12 with
excess sat. KOH (~ 7 mL), and stirred with EtZO (30 mL). The EtZO layer was collected,
dried over , and concentrated. The residue was redissolved in EtOAc(15 mL),
dried over Na2804, and concentrated. hylpyridinyl)methanamine was obtained
as a colorless oil (385 mg, 3.15 mmol, 67.6%). LCMS (m/z) 123.2 (MH+) 0.15 min.
Ste 11. 4- 2-amino tetrah - ran l ridin lfluoro-N- 6-meth l ridin-
2-yl)methyl)benzamide
To a vial were charged with 4-(2-amino(tetrahydro-2H-pyranyl)pyridinyl)—2-
fluorobenzoic acid (20 mg, 0.063 mmol), (6-methylpyridinyl)methanamine (11.6 mg,
0.095 mmol), DIEA (28 uL, 0.158 mmol), PyBOP (65.8, 0.126 mmol) and DMF (0.5 mL).
The mixture was stirred at room temperature for 10 min. The reaction e was then
ed by preparative HPLC, and product fractions were combined, frozen and
lyophilized to afford 4-(2-amino(tetrahydro-2H-pyranyl)pyridinyl)—2-fluoro-N-((6-
methylpyridinyl)methyl)benzamide as a white powder. LCMS (m/z) 421.3 (MH+) 0.41
min. 1H NMR (DMSO-d6) 6 ppm 8.99 (d, J = 3.1 Hz, 1H), 7.95 -7.83 (m, 3H), 7.79 (t, J =
7.6 Hz, 1H), 7.53 (d, J = 11.7 Hz, 2H), 7.44 (dd, J = 8.0, 1.4 Hz, 1H), 7.24 (d, J = 7.4 Hz,
2H), 4.60 (d, J = 5.5 Hz, 2H), 4.02 - 3.88 (m, 2H), 3.40 (td, J = 11.2, 2.7 Hz, 3H), 2.88 -
2.71 (m, 1H), 2.51 (br. s., 3H), 1.82 - 1.58 (m, 4H).
Example 206
S nthesis of S 2-amino1- difluorometh lmeth l-1H- razol l ridin l-
2-fluoro-N- 1- 3-fluoro fluorometh l hen lh drox eth l benzamide
Scheme 97
F 0
Ste St 2
F 0 —eL
NH2 0/
NH2 0 |
/ N
d(d(Mpnon -DCM2_
Pd(dppf)Cl2-DCM
+ \NI/g \ N Na2003'DME
B2(P|N)2, KOAc \
)‘F \
,B\ F \
o o N—N
H H
m4 F o /
Ste E
NH2 N
EDC, HOAt H
“OH (1 M)
DIEA, THF \
THF MeOH /\E?fl F
\_\ \
>¢F >’F
Ste 1. meth l4- 2-amino 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridin l
fluorobenzoate:
A mixture of methyl 4-(2-aminobromopyridinyl)f|uorobenzoate (2 g, 6.15 mmol),
B2(PIN)2 (3.12 g, 12.30 mmol), PdCl2(dppf) (0.225 g, 0.308 mmol), KOAc (1.811 g, 18.45
mmol) and dioxane (30.8 mL) was heated at oil bath overnight at 100 °C. The reaction
mixture was extracted with EtOAc. The organic layer was washed with water and brine,
dried over NazSO4, filtered off and trated in vacuo. To the crude product, ether
was added. The ble material was filtered off to provide methyl 4-(2-amino
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)fluorobenzoate as a brown
solid (79%). LCMS (m/z): 291.2 (MH+), 0.44 min (for boronic acid).
Ste 2. meth l4- 2-amino 1-meth l-1H- razol l ridin lfluorobenzoate
A mixture of crude methyl 4-(2-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridinyl)—2-fluorobenzoate (712 mg, 1.912 mmol), 1-(difluoromethyl)—4—iodo
methyl-1H-pyrazole (740 mg, 2.87 mmol), PdC|2(dppf) (70.0 mg, 0.096 mmol), DME
(7.899 mL), and 2M Na2C03 (3.95 mL) was heated at 100 °C overnight. After adding
NazSO4 followed by dilution with EtOAc, the reaction mixture was ed off and the
resulting volatile materials were concentrated in vacuo. The crude product was ed by
flash chromatography eluting with 0-100% of EtOAc in DCM. LCMS (m/z): 491.1 (MH+),
0.64 min
Ste 3. 4- 2-amino 1-meth l-1H- razol l ridin lfluorobenzoic acid
To a solution of methyl 4-(2-amino(1-(difluoromethyl)methyl-1H-pyrazolyl)pyridin-
3-yl)—2-fluorobenzoate (352 mg, 0.935 mmol) in THF (6236 uL) and MeOH (3118 uL) was
added LiOH (1 M solution) (1684 uL, 1.684 mmol). The reaction mixture was stirred at
room temperature. To the reaction mixture, 1 N HCI was added up to pH 5. The reaction
mixture was ted with EtOAc. The organic layer was dried over anhyrous sodium
e, filtered off, and concentrated in vacuo to provide crude 4-(2-amino(1-
(difluoromethyl)methyl-1H-pyrazolyl)pyridinyl)—2-fluorobenzoic acid (88%). LCMS
(m/z): 363.3 (MH+), 0.51 min.
Ste 4. S 2-amino 1-meth l-1H- razol l ridin l-N- 1- 3-chloro hen l
hydroxyethyl)—2-fluorobenzamide
To a solution of 4-(2-amino(1-(dif|uoromethyl)methyl-1 H-pyrazolyl)pyridinyl)—2—
fluorobenzoic acid (25 mg, 0.069 mmol) in DMF were added (S)—2-amino(3-fluoro
(fluoromethyl)phenyl)ethanol (15.50 mg, 0.083 mmol), EDC, HOAt, and DIEA. The
reaction mixture was stirred for 15 h. After water was added, the reaction mixture was
worked up with EtOAc. The organic layer was dried over Na2804, filtered off and
concentrated in vacuo. The crude product was ed by reverse phase prep HPLC. The
pure fractions were lyophilized to provide (S)—4-(2-amino(1-(difluoromethyl)—3-methyl-
1 zolyl)pyridinyl)—2-fluoro-N-(1-(3-fluoro(fluoromethyl)phenyl)
hydroxyethyl)benzamide as a TFA salt (50%). LCMS (m/z): 532.2 (MH+), 0.65 min; 1H
NMR (400 MHz, CD30D) 6 ppm 8.23 (m, 1H), 7.97 (m, 1H), 7.93 (m, 1H), 7.82 (m, 1H),
7.51 - 7.30 (m, 3H), 7.2 (m, 1H), 7.09 (d, J = 8 Hz, 1H), 6.98 (d, J =12 Hz, 1H), 5.30 (d, J
= 44 Hz, 2H), 5.14 (m, 1H), 3.8 (m, 2H), 2.32 (s, 3H).
8 nthesis of 4- 2-amino 1- rometh lmeth l-1H- razol | ridin l
fluorobenzoic acid
Following Steps 2 and 3 in Scheme 97, using 1,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole, 4-(2-amino(1-(difluoromethyl)methyl-1H-pyrazol
yl)pyridinyl)—2-fluorobenzoic acid was obtained. LCMS (m/z): 363.1 (MH+), 0.53 min.
8 s of 4- 2-amino 1-meth l-1H-1 2 3-triazol | ridin lfluorobenzoic
NH2 OH
ing Steps 2 and 3 in Scheme 97, using 5-iodomethyl-1H-1,2,3-triazole, 4-(2—
amino(1-methyl-1H-1,2,3-triazo|y|)pyridinyl)—2—fluorobenzoic acid was obtained.
LCMS (m/z): 314.3 (MH+), 0.38 min.
8 nthesis of 4- 2—amino—5- 1 5-dimeth l-1H- 4- | ridin | fluorobenzoic acid
Following Steps 1 and 2 in Scheme 97, using methyl 4-(2—aminobromopyridinyl)—2—
fluorobenzoate and 1,5-dimethyl(4,4,5,5-tetramethyl-1,3,2—dioxaborolan-2—yl)—1H-
pyrazole, 4-(2—amino(1,5-dimethyl-1H-pyrazolyl)pyridinyl)—2—fluorobenzoic acid
was obtained. LCMS (m/z): 327.1 (MH+), 0.45 min.
8 nthesis of 4- 2—amino 1 5-dimeth l-1H- razol | ridin | fluorobenzoic acid
Following Steps 2 and 3 in Scheme 97, using methyl 4-(2-aminobromopyridinyl)—2-
fluorobenzoate and 1,3-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-
pyrazole, 4-(2—amino(1,3-dimethyl-1H-pyrazolyl)pyridinyl)—2-fluorobenzoic acid
was obtained. LCMS (m/z): 327.2 (MH+), 0.47 min.
S nthesis of 4- 2-amino—5- 1 5-dimeth l-1H- razol l ridin l fluorobenzoic acid
Following Steps 2 and 3 in Scheme 97, using methyl 4-(2-aminobromopyridinyl)—2-
benzoate and 4-bromo—1-(difluoromethyl)methyl-1H-pyrazole, 4-(2-amino(1,3-
yl-1H-pyrazolyl)pyridinyl)—2-fluorobenzoic acid was obtained. LCMS (m/z):
341.2 (MH+), 0.47 min.
S nthesis of 38 4R 4-chlorofluoro hen lmeth l rrolidinamine
Scheme 97b
2014/062913
CI F
CI F
Steal F Stegg b Step; F
\ ? SCI
u/figOH —> + N02
3‘ ' HZN
\ Z l 2 t
0 N
N02 l (+/—) '1“ (+/—)
Ste 1. E ch|orofluoro 2-nitrovin l benzene
To a solution of 4-chlorofluorobenzaldehyde (8 g, 50.5 mmol) and ammonium e
(9.72 g, 126 mmol) in acetic acid (168 mL) was added nitromethane (8.16 mL, 151 mmol).
The reaction mixture was heated at reflux for 5 h and cooled down. Water (100 mL) was
added, and the mixture was stirred at room ature for 1 h. The solid was filtered,
washed by water, and dried under vacuum. The solid was purified by flash
chromatography (0-20% EtOAc/heptane) to yield clean t 4.2 g in 41 % yield. 1H
NMR (400 MHz, CDCI3) 8 ppm 7.92 (d, J=13.7 Hz, 1H), 7.54 (d, J=13.8 Hz, 1H), 7.49 (d,
J=7.5 Hz, 1H), 7.33 (dd, J=2.0, 9.3 Hz, 1H), 7.31 - 7.28 (m, 1H).
Ste 2. +/- - BR 48 4-chlorofluoro hen l meth lnitro rrolidine
(E)chlorofluoro(2-nitrovinyl)benzene (4.2 g, 20.84 mmol), hylamino)acetic
acid (4.64 g, 52.1 mmol), paraformaldehyde (3.75 g, 125 mmol) were mixed in dry e
(104 mL). The reaction mixture was heated at reflux using Dean-stark overnight. The
reaction mixture was partitioned between EtOAc and water. The organic was washed by
sat. NaCl, dried over NaZSO4 and concentrated. The crude material was purified by flash
chromatography to yield (+/-)-(3R,4S)(4-chlorofluorophenyl)methyl
nitropyrrolidine in 45% yield. LCMS (m/z): 259.2 (MH+), 0.52 min; 1H NMR (400 MHz,
CDCI3) 8 ppm 7.37 (t, J=8.0 Hz, 1H), 7.15 (dd, J=2.0, 10.2 Hz, 1H), 7.09 - 7.01 (m, 1H),
4.91 - 4.82 (m, 1H), 3.98 (d, J=5.1 Hz, 1H), 3.34 (dd, J=4.1, 10.8 Hz, 1H), 3.23 (t, J=8.6
Hz, 1H), 3.10 (dd, J=7.8, 10.6 Hz, 1H), 2.63 (dd, J=7.0, 9.4 Hz, 1H), 2.44 (s, 3H).
Ste 3. +/- - SS 4R 4-chlorofluoro hen lmeth l rrolidinamine
Zinc dust (5.76 g, 88 mmol) was added into a mixture of (+/-)-(3R,4S)(4-chloro
fluorophenyl)—1-methylnitropyrrolidine (2.28 g, 8.81 mmol) in MeOH (29.4 mL) and
acetic acid (30 mL, 524 mmol). The reaction mixture was stirred at room temperature for
h and filtered. Solvent was removed under vacuum. The residue was neutralized to pH
9, then extracted by Cl3 (3:7). The organic was dried over NazSO4, filtered and
concentrated. The crude product was purified by flash tography ( DCM/Methanol/
NH3 90:9:1) to obtain (3S,4R)—4-(4-chlorofluorophenyl)methy|pyrrolidinamine
in 40% yield. LCMS (m/z): 229.2 (MH+), 0.25 min.
S nthesis of +/- - 3S 4R 3-chlorofluoro hen l meth l rrolidinamine
l (+/-)
Following Scheme 97b, using 3-chlorofluorobenzaldehyde (3.92 g, 24.72 mmol), (+/-)-
(3S,4R)—4-(3-chlorofluorophenyl)methylpyrrolidinamine was obtained. LCMS
(m/z): 229.0 (MH+), 0.32 min.
Examples 207 and 208
S nthesis of trans 2-amino 1-meth l-1H- razol l ridin l-N- 3S 4R 3-
chlorofluoro hen l meth l rrolidin l fluorobenzamide and trans 2-amino
1-meth l-1H- razol l ridin l-N- 3R 4S 3-chlorofluoro hen l
meth l rrolidin lfluorobenzamide
Scheme 98
ed Step 2 in Scheme 89, using (+/-)-(3S,4R)—4-(3-chlorofluorophenyl)
methylpyrrolidinamine, 4-(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—N-
((38,4R)—4-(3-chlorofluorophenyl)methylpyrrolidinyl)—2-fluorobenzamide was
obtained in 70% yield. LCMS (m/z): 523.3 (MH+), 0.56 min. The crude racemic mixture
was resolved by chiral SFC (ChiraIPak 5mic OD column, 0 (mm), |PA+0.1%
DEA=30%, 5mL/min). For polar diastereomer (Rt = 2.37 min), LCMS (m/z): 523.2 (MH+),
0.57 min; 1H NMR (400 MHz, CD3OD) 6 ppm 8.19 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.79 -
7.73 (m, 2H), 7.63 (d, J=2.3 Hz, 1H), 7.52 (dd, J=2.3, 7.0 Hz, 1H), 7.46 - 7.29 (m, 3H),
7.26 - 7.13 (m, 1H), 4.66 (d, J=6.3 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.21 (t, J=9.0 Hz, 1H),
3.16 - 3.08 (m, 1H), 2.82 (dd, J=5.7, 10.0 Hz, 1H), 2.70 (t, J=9.2 Hz, 1H), 2.54 - 2.41 (m,
3H), 1.27 (d, J=17.6 Hz, 1H). For less polar diastereomer (Rt = 3.96 min), LCMS (m/z):
523.2 (MH+), 0.58 min; 1H NMR (400 MHz, CD3OD) 6 ppm 8.19 (d, J=2.0 Hz, 1H), 7.91
(s, 1H), 7.79 - 7.73 (m, 2H), 7.63 (d, J=2.3 Hz, 1H), 7.52 (dd, J=2.3, 7.0 Hz, 1H), 7.46 -
7.29 (m, 3H), 7.26 - 7.13 (m, 1H), 4.66 (d, J=6.3 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.21 (t,
J=9.0 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.82 (dd, J=5.7, 10.0 Hz, 1H), 2.70 (t, J=9.2 Hz, 1H),
2.54 - 2.41 (m, 3H), 1.27 (d, J=17.6 Hz, 1H).
Examples 209 and 210
S nthesis of 4- 2-amino 1-meth l-1H- razol l ridin l-N- 3S 4R 4-
chlorofluoro hen l meth l rrolidin l orobenzamide and trans 2-amino
1-meth l-1H- razol l ridin l-N- 3R 4S 4-chlorofluoro hen l
meth | rrolidin |f|uorobenzamide
Scheme 99
Following Step 2 in Scheme 86, using (3S,4R)—4-(4-chlorofluorophenyl)
methylpyrrolidinamine, (+/-)(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—N-
((38,4R)—4-(4-chlorofluorophenyl)methylpyrrolidinyl)—2-fluorobenzamide was
obtained in 79% yield. LCMS (m/z): 523.2 (MH+), 0.57 min. The crude racemic mixture
was resolved by chiral SFC (ChiralPak 5mic OD , 4.6x100 (mm), 1%
DEA=30%, 5mL/min). For polar diastereomer (Rt = 2.45 min), LCMS (m/z): 523.2 (MH+),
0.58 min; 1H NMR (400 MHz, CD3OD) 6 ppm 8.18 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.80 -
7.72 (m, 2H), 7.66 - 7.61 (m, 1H), 7.44 - 7.36 (m, 3H), 7.33 - 7.29 (m, 1H), 7.19 (dd,
J=1.8, 8.3 Hz, 1H), 4.71 - 4.62 (m, 1H), 3.90 (s, 3H), 3.44 - 3.37 (m, 1H), 3.22 (d, J=9.6
Hz, 1H), 3.12 (dd, J=7.9, 10.0 Hz, 1H), 2.86 - 2.80 (m, 1H), 2.74 - 2.67 (m, 1H), 2.51 -
2.44 (m, 3H). For less polar diastereomer (Rt = 3.92 min), LCMS (m/z): 523.2 (MH+), 0.58
min; 1H NMR (400 MHz, CD30D) 6 ppm 8.19 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.80 - 7.70
(m, 2H), 7.63 (d, J=2.2 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.30 (dd, J=2.0, 10.6 Hz, 1H), 7.19
(dd, J=1.8, 8.4 Hz, 1H), 4.66 (d, J=5.9 Hz, 1H), 3.91 (s, 3H), 3.44 - 3.36 (m, 1H), 3.19 (t,
J=9.0 Hz, 1H), 3.11 (dd, J=7.8, 10.0 Hz, 1H), 2.83 - 2.78 (m, 1H), 2.69 (dd, J=8.4, 9.5 Hz,
1H), 2.45 (s, 3H).
8 nthesis of 4- 3-aminoc clo ro l razin lfluorobenzoic acid
Scheme 100
F O Ste Ste
NH2 o/ Y H2
)2 032003 LiOH
| + ,B‘K” —> N/ —> N/
§N F I': F toluene \ MeOH/THF
90x)0 97%
Br \N
Ste 1. meth |4- 3-aminoc clo ro l razin lfluorobenzoate
To methyl 4-(3-aminobromopyrazinyl)fluorobenzoate (for synthesis see Example
34, Step 2) (300 mg, 0.920 mmol) in toluene (10 mL) and water (1 mL) was added
potassium cyclopropyl trifluoroborate (408 mg, 2.76 mmol), di(1-adamantyl)-n-
butylphosphine (66.0 mg, 0.184 mmol), cesium carbonate (1499 mg, 4.60 mmol), and
palladium(|l) e (20.65 mg, 0.092 mmol). The reaction mixture was heated in heating
block at 100 °C overnight. The reaction e was quenched with sat. NH4C| and
extracted with ethyl acetate. The organic extracts were combined, washed with brine,
dried over sodium sulfate, filtered and evaporated. The crude was purified by flash
chromatography (0 to 80% EtOAc in heptane) yielding methyl 4-(3-amino
cyclopropylpyrazinyl)fluorobenzoate (250 mg, 90%). LCMS (m/z): 288.2 (MH+),
0.756 min.
Ste 2. 4- 3-aminoc clo ro l razin lfluorobenzoic acid
To methyl 4-(3-aminocyclopropylpyrazinyl)fluorobenzoate (250 mg, 0.870 mmol)
in THF (6 mL) and MeOH (3 mL) was added 1M LiOH (1.740 mL, 1.740 mmol). The
reaction mixture was stirred at room temperature for 2 h. The pH of reaction es was
adjusted to ~4 by aqueous. 2N HCI. The reaction mixture was ioned between EtOAc
and water. The organic layer was separated, washed with brine, dried over sodium
sulfate, filtered and evaporated to yield 4-(3-aminocyclopropylpyrazinyl)
fluorobenzoic acid (230 mg, 97%) as a light yellow solid. LCMS (m/z): 274.2 (MH+), 0.621
min.
8 s of 4- 2-aminoc clo ro l ridin lfluorobenzoic acid
Following Scheme 100, using methyl 4-(2-aminobromopyridinyl)—2-fluorobenzoate,
4-(2-aminocyclopropylpyridinyl)—2-fluorobenzoic acid was obtained (80%). LCMS
(m/z): 273.0 (MH+), 0.515 min.
8 nthesis of 4- 3-aminoc clohex l razin l fluorobenzoic acid
NH2 OH
Following Steps 1, 2 and 3 in Scheme 66, using 2-(cyclohex—1-enyl)-4,4,5,5-
tetramethyl-1,3,2—dioxaborolane, minocyclohexylpyrazinyl)fluorobenzoic
acid was obtained. LCMS (m/z): 316.3 (MH+), 0.79 min.
Example 211
S nthesis of 4- 2-amino 1S 4r oxidotetrah dro-2H-thio ran l ridin l-N-
S 3-chloro hen lh drox eth lfluorobenzamide
Scheme 101
F o
F o
F 0 Step; 1 J< Ste ; J<
NH2 ’0’? —9 NH2 0
NH2 0
N\B\O 0J<
l/ Br
O\ ,O
N \ + B _, N \ NI \
I /
Br 6]
S TSte A / —fSte 5
S A
F 0 {OH
NH2 OH NH2
/OH 3
N \ 2 N \
—’ | I
/ + H2N/\© _. / CI
s_._
a 0+
8+ (3—0:
Ste 1. ut l4- 2-amino ridin lfluorobenzoate
A degassed mixture of 3-(4,4,5,5-tetramethy|—1,3,2-dioxaborolany|)pyridinamine
(2.4 g, 10.91 mmol), tert-butyl 4-bromofluorobenzoate (3.30 g, 12.00 mmol), Pd(PPh3)4
(0.63 mg, 0.0.545 mmol), 2.0 M Na2C03 s solution (10.91 mL) in n-butanol (26
mL) was microwave heated to 130 0C for 10 min. The reaction was diluted with ethyl
acetate (30 mL), and then washed with water (10 mL) and brine (10 mL). The organics
were dried over sodium e, filtered, concentrated, and then purified by flash
tography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-
aminopyridinyl)fluorobenzoate (1.35 g, 43% yield). LCMS (m/z): 289.4 (MH+), 0.67
min.
Ste 2. tert-but l4- 2-aminobromo ridin lfluorobenzoate
A solution of tert-butyl 4-(2-aminopyridinyl)—2-fluorobenzoate (700 mg, 2.43 mmol) in
acetonitrile (10 mL) was treated with NBS (453 mg, 2.55 mmol). After 10 min, the reaction
was completed. The reaction was treated with 1:1 sat. aq. NaHC03: sat.aq. Na28203 (10
mL). The e was stirred vigorously for 10 min. The mixture was diluted with ethyl
e (30 mL) and the layers were separated. The organics were washed with brine,
dried over magnesium sulfate, filtered and concentrated to provide tert-butyl mino-
-bromopyridinyl)—2-fluorobenzoate (803 mg, 90% yield). LCMS (m/z): 367.2, 369.2
(MH+), 0.75 min.
Ste 3. tert-but l4- 2-amino 3 6-dih -thio ran l ridin l
fluorobenzoate
A degassed mixture of tert-butyl 4-(2-aminobromopyridinyl)fluorobenzoate (400
mg, 1.09 mmol), -dihydro-2H-thiopyranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (296 mg, 1.31 mmol), Pd(PPh3)4 (126 mg, 0.109 mmol) in 2.0 M Na2C03
aqueous solution (1.63 mL) and n-butanol (5 mL) was microwave heated to 130 0C for 15
min. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10
mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered,
concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane
eluent) to provide tert-butyl 4-(2-amino(3,6-dihydro-2H-thiopyranyl)pyridinyl)—2-
fluorobenzoate (400 mg, 95% yield). LCMS (m/z): 387.1 (MH+), 0.87 min; 1H NMR (400
MHz, CD30D) 8 ppm 7.83 - 7.76 (m, 2H), 7.68 (d, J = 1.96 Hz, 1H), 7.37 - 7.34 (m, 1H),
7.33 - 7.29 (m, 2H), 7.28 - 7.24 (m, 2H), 7.24 - 7.18 (m, 1H), 5.10 (t, J = 5.87 Hz, 1H),
3.83 - 3.69 (m, 2H), 2.81 - 2.70 (m, 2H), 2.63 - 2.49 (m, 3H), 2.08 (dd, J = 2.74, 13.30
Hz, 2H), 1.72 (dq, J = 2.93, 12.59 Hz, 2H).
Ste 4. tert-but l4- o 1-oxido-3 6-dih dro-2H-thio ran l ridin l
fluorobenzoate
A 0 oC solution of 4-(2-amino(3,6-dihydro-2H-thiopyranyl)pyridinyl)—2-
fluorobenzoate in e (20 mL) was treated with a on of oxone (227 mg, 0.369
mmol) in water (5 mL). After 20 min, the reaction was diluted with ethyl acetate (50 mL)
and water (50 mL). The layers were separated and the aqueous layer was washed with
ethyl acetate (50 mL). The combined organics were washed with water (30 mL) and brine
(30 mL), dried over ium sulfate, filtered and concentrated to provide tert-butyl 4-
(2-amino(1-oxido-3,6-dihydro-2H-thiopyranyl)pyridinyl)—2-fluorobenzoate (220 mg,
74% yield). LCMS (m/z): 403.5 (MH+), 0.66 min.
Ste 5. tert-but l4- 2-amino 1r4r oxidotetrah dro-2H-thio ran | ridin l
fluorobenzoate
A degassed slurry of tert-butyl 4-(2-amino(1-oxido-3,6-dihydro-2H-thiopyran
yl)pyridinyl)—2-fluorobenzoate (220 mg, 0.547 mmol) in methanol (15 mL) was treated
with 1.0 N HCI s solution (0.82 mL) and 10% Pd(OH)2. The vessel was charged
with hydrogen to 250 PSI. After 2 h, the reaction was completed. The slurry was
degassed, filtered over celite and concentrated to provide tert-butyl mino((1r,4r)—
otetrahydro-2H-thiopyranyl)pyridinyl)—2-fluorobenzoate (150 mg, 68% yield).
LCMS (m/z): 405.6 (MH+), 0.63 min.
Ste 6. 4- 2-amino 1r4r oxidotetrah dro-2H-thio ran | ridin l
fluorobenzoic FA
A room temperature solution of tert-butyl 4-(2-amino((1r,4r)oxidotetrahydro-2H-
thiopyranyl)pyridinyl)f|uorobenzoate (50 mg, 0.124 mmol) in DCM (2 mL) was
treated with TFA (1 mL). After 1 h, the reaction was concentrated. The resulting material
was slurried in benzene with sonication, and then concentrated again to provide 4-(2-
amino((1r,4r)oxidotetrahydro-2H-thiopyranyl)pyridinyl)fluorobenzoic acid-
TFA (57 mg, 100% yield). LCMS (m/z): 349.2 (MH+), 0.37 min.
Ste 7. 4- 2-amino 1S 4r oxidotetrah dro-2H-thio ran | ridin l-N- S
(3-chlorophenyl )—2-hyd roxyethyl )—2-fluorobenzamide
A solution of 4-(2-amino((1r,4r)oxidotetrahydro-2H-thiopyranyl)pyridinyl)—2-
fluorobenzoic FA (57 mg, 0.123 mmol) and (S)amino(3-chlorophenyl)ethano|
(25 mg, 0.148 mmol) in DMF (1 mL) was treated with HATU (61 mg, 0.160 mmol) and
DIEA (129 uL, 0.738 mmol). After 1 h, the reaction was diluted with water (5 mL) and
extracted into ethyl acetate (2 x 10 mL). The product was present in both layers.
Therefore both the s and organic layers were trated and ed by reverse
phase prep HPLC to provide 4-(2-amino((1S,4r)—1-oxidotetrahydro-2H-thiopyran
yl)pyridinyl)—N-((S)—1-(3-chlorophenyl)hydroxyethyl)fluorobenzamide as a TFA salt
(20 mg, 26% yield). LCMS (m/z): 502.1, 504.1 (MH+), 0.57 min. 1H NMR (400 MHz,
CD3OD) 8 ppm 8.63 (dd, J = 4.11, 7.24 Hz, 1H), 7.90 (d, J = 1.96 Hz, 1H), 7.80 (t, J =
7.83 Hz, 1H), 7.76 (d, J = 1.57 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.29 -7.25 (m, 2H), 7.24 -
7.17 (m, 1H), 5.14 - 5.06 (m, 1H), 3.83 -3.70 (m, 2H), 3.06 (d, J = 12.91 Hz, 2H), 2.85 -
2.70 (m, 3H), 2.38 - 2.24 (m, 2H), 1.83 (d, J = 12.13 Hz, 2H).
Example 212
S nthesis of S 2-amino tetrah dro-2H-thio ran l ridin l-N- 1- 3-
chloro hen lh drox eth lfluorobenzamide
F 0 :/OH
I NDH
/ CI
The reaction sequence depicted in Scheme 101, steps 5, 6, and 7 was applied to tert-
butyl 4-(2-amino(3,6-dihydro-2H-thiopyranyl)pyridinyl)—2-fluorobenzoate to obtain
(S)(2-amino(tetrahydro-2H-thiopyranyl)pyridinyl)—N-(1-(3-chlorophenyl)
hydroxyethyl)fluorobenzamide. LCMS (m/z): 486.0, 488.0 (MH+), 0.73 min; 1H NMR
(400 MHz, CD30D) 8 ppm 7.83 -7.76 (m, 2H), 7.68 (d, J = 1.96 Hz, 1H), 7.37 -7.34 (m,
1H), 7.33 -7.29 (m, 2H), 7.28 - 7.24 (m, 2H), 7.24 - 7.18 (m, 1H), 5.10 (t, J = 5.87 Hz,
1H), 3.83 - 3.69 (m, 2H), 2.81 -2.70 (m, 2H), 2.63 - 2.49 (m, 3H), 2.08 (dd, J = 2.74,
13.30 Hz, 2H), 1.72 (dq, J = 2.93, 12.59 Hz, 2H).
S nthesis of 4- 2-amino 1-meth l-1H- razol-4— l ridin lmeth lbenzoic acid
Scheme 102
O Stepl 0
Br —> Br
OH K2003, Mel 0—
Step;
NH2 Stegg NH2 0
Br Q ,0 B
NI \ lB—B\ —> N \ ‘O
/ o o l
NH 0/ N/
Step4_ 2
NH2 0/ A | ,N
o o —> N/
N | oxB
N / | |
| \
Br o
NH2 0
Step g Step g ”“2 OH
—> I —> N/
\ \
LiOH
\\ /
N—N N—N
\ /
Step 1. methyl 4-bromomethylbenzoate
A stirred mixture of 4-bromomethylbenzoic acid (6 g, 27.9 mmol), iodomethane (5.21
mL, 84 mmol) and ium carbonate (11.57 g, 84 mmol) in DMF (60 mL) was stirred at
room temperature overnight. The reaction mixture was partitioned n water (250
mL) and 4:1 s:ethyl acetate (650 mL). The organic layer was washed with water
and dried over Na2804. The solvent was removed under vacuum to give 6.39 g of desired
product as an oil in 100% yield. 1H NMR (400 MHz, CD3OD) 6 ppm 7.86 - 7.65 (m, 7 H)
7.50 (br. s., 2 H) 3.88 (s, 3 H) 2.56 (s, 3 H).
Ste 2. 3- 4 4 5 5-tetrameth H 3 2-dioxaborolan l ridinamine
To a suspension of 3-bromopyridinamine (6 g, 34.7 mmol) in 1,4-dioxane (87 mL) was
added Bispin (13.21 g, 52.0 mmol) and potassium acetate (10.21 g, 104 mmol). The
e was purged with nitrogen for 10 min, and then PdCl2(dppf)-CH2C|2 adduct (2.83 g,
3.47 mmol) was added. The reaction mixture was heated to 108 °C in an oil bath for 2 - 3
h. The reaction mixture was diluted with ethyl acetate, filtered h ce|ite and
trated. The residue was used in next step Suzuki coupling without further
purification. LCMS (m/z): 139 (MH+) 0.22 min (for boronic acid).
Ste 3. meth l4- 2-amino ridin lmeth lbenzoate
To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine(7.37 g, 33.5 mmol) in
500 mL round bottom flask were added methyl 4-bromomethylbenzoate (6.390 g, 27.9
mmol), dppf)-DCM (2.041 g, 2.79 mmol), DME (209 mL) and 2 M Na2C03 solution
(69.7 mL). The on mixture was bubbled through N2 for 20 min and heated in an oil
bath at 108 °C for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water
three times, dried over NazSO4, filtered and concentrated. The crude product was purified
by flash chromatography eluting with 0-100% of EtOAc (containing 10% of
MeOH)/heptane to e crude product around 8 g which contained fair amount of
B2(P|N)2 from previous experiment. Ether was added to dissolve the crude mixture, and
then e was added to crush out the desired produt. Solid was filtered out to provide
4.2 g of desired product with high purity in 62.1 % yield. LCMS (m/z): 243.5 (MH+), 0.56
min.
Ste 4. meth l4- 2-aminobromo ridin lmeth lbenzoate
To a solution of methyl 4-(2-aminopyridinyl)—2-methylbenzoate (4.2 g, 17.34 mmol) in
acetonitrile (173 mL) was added NBS (3.15 g, 17.68 mmol) in two portions at 0 °C . The
reaction mixture was stirred at 0 °C for 20 min. LCMS showed the on completed.
After quenched with sat. Na2803 and NaHC03, the reaction mixture was d for 30
min. The on mixture was extracted with EtOAc 3 times, washed by sat NaHC03,
water and brine. The organics was dried over NazSO4, filtered and concentrated. The
crude material was triturated with ether and taken to the next step without further
purification. LCMS (m/z): 323.1 (MH+), 0.68 min.
Ste 5. meth l4- 2-amino 1-meth l-1H- razol l ridin lmeth lbenzoate
To methyl 4-(2-aminobromopyridinyl)—2-methylbenzoate (500 mg, 1.557 mmol) in 20
mL MW vial was added 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (421 mg, 2.024 mmol), PdC|2(dppf)DCM (114 mg, 0.156 mmol), DME (11.7 mL)
and 2 M Na2C03 solution (3.892 mL). The reaction mixture was heated at microwave
synthesizer (12 min, 120 °C). The reaction mixture was diluted with EtOAc and washed
with water three times, dried over NaZSO4, filtered and concentrated. The crude product
was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of
MeOH)/heptane to e crude product which was triturated with ether to provide 400
mg of pure product in 80 % yield. LCMS (m/z): 323.4 (MH+), 0.60 min.
Ste 6. 4- 2-amino 1-meth l-1H- razol l ridin lmeth lbenzoic acid
To a solution of methyl 4-(2-amino(1-methyl-1H-pyrazolyl)pyridinyl)—2-
methylbenzoate (1.20 g, 3.72 mmol) in THF/MeOH/HZO (1:1:1, 36 mL) was added LiOH-
H20 (0.234 g, 5.58 mmol). The solution was stirred at room temperature overnight. The
pH was adjusted to 3-5, optimally 4. All the organic ts were removed by reduced
re. EtOAc was added to triturate out all the impurities. Water was added and the
mixture was stirred for 30 min. Solid was ed and washed well with 50% of ether and
water. The solid was then pied on rotovap with e to provide about 800 mg of
desired acid in 69.7 % yield. LCMS (m/z): 309.2 (MH+), 0.50 min.
S nthesis of 4- 2-amino 1-eth l-1H- razol l ridin lfluorobenzoic acid
Scheme 103
Step 1 Step 2 F O
F O
isoprene OJ<
OH —. Br
. 03 + N \
cat. st04
Br 33(6) /
Step; 3,625 F o J< >1 :
Pd(dPPf)CI2, NaZCO3 NBS NH2 0 \B’O
—’ '
N \ +
00C,20min '/ N'(\g
F o
F o
—23te é NH2 oJ< SteQ 5
NH2 OH
Pd(dppf)CI2 N32C03 N/
I TFA
\ —> |
DME, 120°C, 20 min
Step 1. tert-butyl 4-bromofluorobenzoate
A slurry of 4-bromofluorobenzoic acid (20.16 g, 92 mmol) in dioxane (90 mL) and conc.
H2804 (5 mL) was cooled to 0 °C, and then bubbled through with isobutene for 2 h. The
on was allowed to gradually warm up to room temperature overnight. Solid NaHC03
(40 g) was carfully added to the reaction and the mixture was stirred for 1 h. The e
was concentrated, and then redissolved in water and ethyl e. The layers were
seperated. The aqueous phase was washed with ethyl acetate. The combined organics
were washed with sat aq NaHC03 and brine, then dried over Na2804, filtered and
concnetrated. The resulting oily tert-butyl 4-bromofluorobenzoate was used without
further purification. 1H NMR (400 MHz, MeOH-d4) 8 ppm 7.79 - 7.70 (m, 1H), 7.42 - 7.23
(m, 3H), 1.59 (s, 11H).
Step 2. tert-butyl ro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate
A slurry of tert-butyl 4-bromofluorobenzoate (5.55 g, 20.17 mmol), BISPIN (7.68 g, 30.3
mmol), PdCl2(dppf)-CH2Cl2adduct (1.153 g, 1.412 mmol) and potassium acetate (5.94 g,
60.5 mmol) in DMF (75 mL) was degassed, and then heated to 100 °C overnight. The
reaction was concentrated, then dissolved in DCM, filtered over celite, and then washed
with water and brine. The cs were filtered over celite, concentrated, and then
purified by flash tography eluting with 0 - 20% ethyl acetate/heptane to e 5.2
g of tert-butyl 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate in 80%
yield.
Ste 3. tert-but |4- 2-amino ridin |f|uorobenzoate
A slurry of tert-butyl 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate (5.1
g, 15.83 mmol), 3-bromoaminopyridine (3.01 g, 17.41 mmol) and Pd(PPh3)4 (0.732 g,
0.633 mmol) in n-butanol (50 mL) and 2.0 M Na2C03aqueous solution (19.79 mL, 39.6
mmol) was ed, and then heated to 100 °C overnight. The reaction was cooled, and
diluted with ethyl acetate. The layers were seperated, and the organics were washed with
brine, filtered over celite and concentrated. The crude was purified by flash
chromatography eluting with 10 - 50% ethyl acetae/heptane to provide 3.41 g of tert-butyl
4-(2-aminopyridiny|)fluorobenzoate in 75% yield.
Ste 4. ut l4- 2-aminobromo ridin lfluorobenzoate
NBS (2.145 g, 12.05 mmol) was added to a room temperature solution of tert-butyl 4-(2-
aminopyridinyl)f|uorobenzoate (3.31 g, 11.48 mmol) in MeCN (60 mL). The resulting
mixture was stirred for 10 min. The reaction was quenched with 1:1 of sat. aq.
Na28203:sat. aq. NaHC03 solution, and then extracted into ethyl acetate. The combined
organics were washed with brine, dried over sodium e and concentrated in vacuo
yielding utyl minobromopyridinyl)—2-f|uorobenzoate. The material was
used without further purification. LCMS (m/z): 369.0 (MH+), 0.85 min.
Ste 5. tert-but |4- 2-amino1-eth |-1H- razol | ridin |f|uorobenzoate
To tert-butyl 4-(2-aminobromopyridinyl)f|uorobenzoate (200 mg, 0.544 mmol)
(See Scheme 101, Step 2 for synthesis) in DME (3 mL) and 2 M sodium carbonate (1.5
mL, 3.0 mmol) was added 1-ethy|(4,4,5,5-tetramethyl-1,3,2-dioxaboro|anyl)-1H-
le (182 mg, 0.816 mmol) followed by PdC|2(dppf)-CH2C|2 adduct (44.5 mg, 0.054
mmol). The reaction mixture was microwave heated at 120 °C for 20 min. The reaction
mixture was partitioned between ethylacetate and water. The organic layer was
separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The
crude was purified by flash chromatography eluting with 0 -50% of EtOAc
WO 66188
(contains10%MeOH) / heptane ng tert-butyl 4-(2-amino(1-ethyl-1H-pyrazol
yl)pyridinyl)—2-fluorobenzoate (160 mg, 77%). LCMS (m/z): 383.2 (MH+), 0.782 min.
Ste 6. 4- 2-amino 1-eth l-1H- razol l ridin lfluorobenzoic acid
To tert-butyl 4-(2-amino(1-ethyl-1H-pyrazolyl)pyridinyl)—2-fluorobenzoate (160 mg,
0.418 mmol) in DCM (0.5 mL) was added TFA (2 mL, 26 mmol). The reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was co-evaporated with toluene
in The crude 4-(2-amino(1-ethyl-1H-pyrazolyl)pyridinyl)—2-fluorobenzoic
acid was used for next step. LCMS (m/z): 327.2 (MH+), 0.509 min.
Example 213
4- 2-amino 1- meth lsulfon l rrolidin l ridin lfluoro-N- S h drox
phenylethyl )benzamide
Scheme 104
Ste Ste
0‘ ,0
NHZ B H2
NQYCI NBS/ACN
+ Pd(dppf)C|2/N32003N N/
K/Nl DME/lOOUC/S—4h 94%
93% \N
3&24.
m; CF34? CFs 9 O 0‘
O CF3802\N,SOZCF3 0:S\O —
‘0 O‘B/B: B’O
ITI. O’ O
\S_,N\sl/ + / \ +
N )4 \
/ '\ /'\ N Pd(dppf)C|2/KOAC N
O 0 f0 )f0
98% >7,F): Dioxane o K
0 O K
F o
ste Stepfi StepZ
“”2 O/
Pd(dppf)CI2 3 /TFA, DCM NH2 0
/ ’
N / N / N
l DME/11OOC/20min I
\ N 60%
\ \
NwO NH
F o F o F o F o :/
NH2 0’ NH2 0/ NH2 OH NH2 N
$28 mg mm H
N/ N/ N/ N/
| | | |
\ N MeSOZCI LIOH HATU/TEA
\ N \ N \ N
DIEA/ DCM DMF
MeOH / THF
NH N\ ,,o N\ ,,o N\ ,,0
fi\ fi\ §\
0 o o
Ste 1. meth |4- 3-amino razin |f|uorobenzoate
To a mixture of 3-chloropyrazinamine (5 g, 38.6 mmol) in DME ( 160 mL) and aq. 2 M
sodium carbonate (40 mL, 80 mmol) was added methyl 2-fluoro(4,4,5,5-tetramethyl-
1,3,2-dioxaboro|any|)benzoate (12.97 g, 46.3 mmol) ed by PdC|2(dppf)-CH2CI2
adduct (3.15 g, 3.86 mmol). The reaction mixture was purged with N2 and heated in an oil
bath at 100 °C for 3 -4 h. The reaction mixture was partitioned between ethylacetate and
water. The organic layer was separated, washed with brine, dried over sodium sulfate,
filtered and evaporated. The crude was triturated with DCM. Solid observed was filtered,
washed with ether and dried under reduced pressure to provide product as an off white
solid. Filtrate was purified by flash chromatography eluting with 0% EtOAc/
heptane to provide 10.6 g of product in 93% yield. LCMS (m/z): 248.1 (MH+), 0.563 min.
Ste 2. meth |4- o razin |f|uorobenzoate
To a mixture of methyl 4-(3-aminopyrazinyl)f|uorobenzoate (8.9 g, 36.0 mmol) in
acetonitrile (300 mL) in an ice bath was added NBS (5.77 g, 32.4 mmol). The reaction
mixture was stirred at 0 °C for 1 h. NBS (0.05 equiv.) was added and the resulting mixture
was stirred for another 30 min. To the reaction mixture was added saturated sodium
bicarbonate solution. The mixture was stirred for 30 min and t was extracted with
EtOAc. The organic extracts were combined, washed with brine, dried over sodium
e, filtered and evaporated. The residue was dried under high vaccum to provide a
brown solid (12.2g, 94%). LCMS (m/z): 326.0/328.0 (MH+), 0.846 min.
Ste 3. tert-but |5- trifluorometh lsulfon lox -3 4-dih dro -1 2H -carbox late
Tert-butyl 3-oxopiperidinecarboxy|ate (1.1 g, 5.52 mmol) was taken in THF (10 mL)
and cooled to -78 °C. To that was added lithium bis(trimethylsilyl)amide (6.07 mL, 6.07
mmol) (1 M solution in THF). The reaction e was stirred at -78 °C for 20 min, and
then a solution of 1,1 ,1-trif|uoro-N-phenyl-N-((trifluoromethyl)sulfonyl)
methanesulfonamide (2.071 g, 5.80 mmol) in THF (10 mL) was added dropwise. The
reaction mixture was stirred at -78 °C for 15min, then warmed to and stirred at 0 °C for 3
h. The reaction mixture was quenched with sat. sodium onate solution and then
extracted with ethyl acetate. The combined extracts were washed with brine, dried over
sodium sulfate, filtered and evaporated.The crude was purified through a plug of neutral
alumina with 10% EtOAc in heptane. Solvent was evaporated and the residue was dried
to provide the desired product as a yellow liquid (2 g, 98%).
Ste 4. tert-but l 5- 4 4 5 5-tetrameth H 3 2-dioxaborolan l -3 4-dih dro ridine-
1(2H )—carboxylate
A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.223 g, 4.81
mmol), potassium e (1.289 g, 13.13 mmol) and PdC|2(dppf)-CH2C|2 adduct (0.107
g, 0.131 mmol) in flask was flushed with N2, and then dioxane (12 mL) was added,
followed by a solution of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-
carboxylate (1.45 g, 4.38 mmol) in dioxane (12 mL). The reaction mixture was
purged with N2 for 5 min, and then heated in oil bath at 80 °C overnight. The reaction
mixture was partitioned between ethyl acetate and water. The organic layer was
separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The
residue was purified by flash chromatography g with 0 - 30% of EtOAc / heptane to
yield the desired product as a highly viscous liquid (1.2 g, 89%). LCMS (m/z): 254.1 (MH+-
tBu), 1.21 min.
Ste 5. ut l5- 5-amino 3-fluoro methox carbon l hen l razin l-3 4-
dih dro ridine-1 2H -carbox late
To a mixture of methyl 4-(3-aminobromopyrazinyl)fluorobenzoate (240 mg, 0.70
mmol) in DME (6 mL) and 2 M sodium ate (1.0 mL, 2.0 mmol) was added tert-
butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydropyridine-1(2H)-
carboxylate(180 mg, 0.582 mmol) followed by PdCl2(dppf).CH2Cl2 adduct (14.4 mg, 17.5
umol). The reaction mixture was heated in microwave at 110 °C for 20 min. The reaction
mixture was partitioned between cetate and water. The organic layer was
separated, and washed with water and brine. The organic was dried over sodium sulfate,
filtered and evaporated. The e was purified by flash chromatography eluting with 0-
50- 80% EtOAc in heptane to yield the desired product as a yellow solid (150 mg, 60%).
LCMS (m/z): 429.2 (MH+), 1.03 min.
Ste 6. meth l4- 3-amino 1 4 5 6-tetrah dro ridin l razin-2— l fluorobenzoate
To tert-butyl 5-(5-amino(3-fluoro(methoxycarbonyl)phenyl)pyrazinyl)—3,4-
dihydropyridine-1(2H)—carboxylate (150 mg, 0.350 mmol) arable mixture) in DCM (4
mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room
ature for 30 - 45 min. The on mixture was evaporated on rotovap, and
azeotroped with toluene. The crude product was proceeded to next step without
purification. LCMS (m/z): 329.2 (MH+), 0.502 min.
Ste 7. meth l4- 3-amino i eridin l razin lfluorobenzoate
To methyl mino(1,4,5,6-tetrahydropyridinyl)pyrazinyl)fluorobenzoate
(115 mg, 0.350 mmol) in MeOH (10 mL) was added Pd/C (93 mg, 0.088 mmol). The
reaction mixture was stirred at room temperature for 24 h under H2 balloon. The reaction
mixture was filtered through Celite and washed with DCM. The filtrate was evaporated
and dried to yield the desired product. The crude product was proceeded for the next step
(115 mg, 95%). LCMS (m/z): 331.2 (MH+), 0.492 min.
Ste 8. meth l4- 3-amino 1- meth lsulfon l i eridin l razin l
fluorobenzoate
To a mixture of crude methyl 4-(3-amino(piperidinyl)pyrazinyl)fluorobenzoate
(38 mg, 0.114 mmol) in DCM (2 mL) in an ice bath was added DIEA (79 uL, 0.454 mmol)
followed by methanesulfonyl chloride (9.73 uL, 0.125 mmol). The reaction mixture was
stirred at 0 °C for 30 min. The reaction mixture was ioned n DCM and water.
The DCM layer was separated and washed with brine. The organic layer was dried over
sodium sulfate, filtered and evaporated. The crude product (50% purity) was proceeded to
next step. LCMS (m/z): 409.1 (MH+), 0.721 min.
Ste 9. 4- o 1- meth lsulfon l i eridin l razin lfluorobenzoic acid
To methyl 4-(3-amino(1-(methylsulfonyl)piperidinyl)pyrazinyl)fluorobenzoate
(60 mg, 0.147 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (400 uL,
0.400 mmol). The on mixture was stirred at room temperature overnight. The pH of
the reaction mixture was adjusted to ~3 to 4 with 2 N HCI, and the product was extracted
with ethyl acetate. The c layer was separated from water and washed with brine,
dried over sodium sulfate, filtered off, and evaporated to provide the crude product, which
was taken to the next step t further purification. LCMS (m/z): 395.1 (MH+), 0.573
min.
Ste 10. 4- 3-amino 1- meth lsulfon l i eridin l razin lfluoro-N- S
hydroxy—1-phenylethyl)benzamide
To a mixture of 4-(3-amino(1-(methylsulfonyl)piperidinyl)pyraziny|)
fluorobenzoic acid (40 mg, 0.101 mmol) in DMF (1 mL) was added (S)amino
phenylethanol (13.91 mg, 0.101 mmol) followed by HATU (57.8 mg, 0.152 mmol) and
DIEA (0.089 mL, 0.507 mmol). The reaction mixture was stirred at room ature
overnight. The reaction mixture was diluted with DMF and filtered h syringe filter,
which was then purified by prep HPLC to yield the desired product as a TFA sa|t (33.4%).
LCMS (m/z): 514.2 (MH+), 0.687 min; 1H NMR (400 MHz, CD3OD) 6 ppm7.95 (s, 1 H)
7.85 (t, J=7.83 Hz, 1 H) 7.73-7.57 (m, 2 H) 7.49-7.21 (m, 5 H) 5.22 (d, J=6.65 Hz, 1 H)
3.94-3.78 (m, 3 H) 3.71 (d, J=11.74 Hz, 1 H) 3.03-2.93 (m, 2 H) 2.87-2.74 (m, 4 H) 2.07-
1.97 (m, 1 H) 1.92 (d, J=12.13 Hz, 1 H) 1.85-1.68 (m, 1 -1.25 (m, 1 H).
e 214
meth l3- 5-amino 3-fluoro S h drox hen leth lcarbamo l hen l razin-
2- | i eridinecarbox |ate
Scheme 105
F o F o F o F 0 {OH
NH2 0/ NH2 0/ NH2 OH NH2 N
N/ Step1 N’ Step2 N/ Step3 N/
| | L'OH | HATU/TEA I
N MeC020| I
\ \ N \ N \ N
DIEA/ DCM MeOH / THF DMF
77% 83% 29%
NH NTO\ NTO\ NY0\
o o o
Ste 1. meth l3- 5-amino 3-fluoro methox carbon l hen l razin l i e-
1-carboxylate
To methyl 4-(3-amino(piperidinyl)pyrazinyl)f|uorobenzoate (55 mg, 0.166
mmol) (for synthesis, see Example 34, Step 7) in DCM (3 mL) in ice bath was added
DIEA (0.116 mL, 0.666 mmol) and methyl chloroformate (0.013 mL, 0.166 mmol) . The
reaction mixture was stirred at in ice bath for 30 min. The reaction mixture was partitioned
between DCM and water. The DCM layer was ted, washed with brine, dried over
sodium sulfate, filtered and evaporated. The residue (50 mg, 77%) was taken to the next
step without further purification. LCMS (m/z): 389.2 (MH+), 0.785 min.
Ste 2. 4- 3-amino 1- methox carbon l i eridin l razin lfluorobenzoic
To methyl 3-(5-amino(3-fluoro(methoxycarbonyl)phenyl)pyrazinyl)piperidine
carboxylate (50 mg, 0.129 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH
(0.500 mL, 0.500 mmol). The reaction mixture was d at room temperature for 4 h.
The reaction mixture pH was adjusted to ~ 3 with 2 N HCI, and product was extracted
with ethyl acetate. The EtOAc layer was separated, washed with brine, dried over sodium
sulfate, ed and evaporated. The e was proceeded to next step without
purification (40 mg, 83%). LCMS (m/z): 375.2 (MH+), 0.637 min.
Ste 3. meth l3- 5-amino 3-fluoro S h drox
hen leth lcarbamo l hen l razin l i eridinecarbox late
To a mixture of 4-(3-amino(1-(methoxycarbonyl)piperidinyl)pyrazinyl)—2-
fluorobenzoic acid (28 mg, 0.06 mmol) in DMF (1 mL) was added (S)amino
phenylethanol (12.31 mg, 0.090 mmol) followed by HATU (34.1 mg, 0.090 mmol) and
DIEA (0.052 mL, 0.299 mmol). The reaction mixture was stirred at room temperature
ght. The reaction mixture was diluted with DMF, filtered h syringe filter and
purified by prep HPLC to yield the desired product as a TFA salt (10.9 mg, 29.4%) LCMS
(m/z): 494.2 (MH+), 0.733 min. 1H NMR (400 MHz, CD3OD) 6 ppm7.82-7.72 (m, 2 H)
7.63-7.48 (m, 2 H) 7.38-7.11 (m, 5 H) 5.12 (t, J=6.06 Hz, 1 H) 4.09 (d, 1 Hz, 1 H)
3.97 (d, J=12.13 Hz, 1 H) 3.87-3.68(m, 2 H) 3.59 (s, 3 H) 3.11-2.66 (m, 3 H) 2.00-1.88 (m,
1 H) ) 1.85-1.65 (m, 2 H) 1.58-1.40 (m, 1 H)
Example 215
4- 6- 1-acet l i eridin lamino razin lfluoro-N- S h drox
phenylethyl mide
Scheme 106
F 0 :/OH
H2 NH2 N
Step1 OStep2 OHStep3 H
N / N / N /
IN MeCOCl LiOH HATU /TEA |
\ N
DIEA/ DCM MeOH /THF DMF
81% 71% 30%
NH N\n/ N\n/ N\n/
O O O
Ste 1. meth l4- 6acet l i eridin ino 2- lfluorobenzoate
To a mixture of methyl 4-(3-amino(piperidinyl)pyrazinyl)—2-fluorobenzoate (55 mg,
0.166 mmol) (for sis, see example 34, Step 7) in DCM (3 mL) in ice bath was
added DIEA (0.116 mL, 0.666 mmol) followed by acetyl chloride (0.012 mL, 0.166 mmol).
The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was partitioned
between DCM and water. The DCM layer was separated, washed with brine, dried over
sodium sulfate, filtered and evaporated. The e was proceeded to next step without
purification (50 mg, 81%). LCMS (m/z): 373.3 (MH+), 0.666 min.
Ste 2. 4- 6- 1-acet l i eridin lamino razin lfluorobenzoic acid
To a mixture of methyl 4-(6-(1-acety|piperidinyl)aminopyrazinyl)—2-fluorobenzoate
(50 mg, 0.134 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (0.500 mL,
0.500 mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of
on mixture was adjusted to ~3 with 2 N HCI, and the product was extracted with
ethyl acetate. The organic layer was separated, washed with brine, dried over sodium
sulfate, filtered and evaporated. The residue was proceeded for next step without
purification (34 mg, 70.7%). LCMS (m/z): 359.1 (MH+), 0.534min.
Ste 3. 4- 6acet l i eridin lamino razin lfluoro-N- S h drox
phenylethyl)benzamide
To a mixture of 4-(6-(1-acety|piperidinyl)—3-aminopyrazinyl)fluorobenzoic acid (34
mg, 0.076 mmol) in DMF (1.5 mL) was added (S)aminophenylethanol (15.62 mg,
0.114 mmol), ed by HATU (43.3 mg, 0.114 mmol) and DIEA (0.066 mL, 0.379
mmol). The reaction e was stirred at room temperature overnight. The reaction
mixture was diluted with DMF, ed through syringe filter and purified by prep HPLC to
yield the desired product as a TFA salt (13.9 mg, 30%). LCMS (m/z): 478.2 (MH+), 0.641
min. 1H NMR (400 MHz, CD3OD) 6 ppm 7.98-7.97 (m, 2 H) 7.73-7.58 (m, 2 H) 7.47-7.23
(m, 5 H) 5.22 (t, J=6.06 Hz, 1 H) 4.62-4.37 (m, 1 H) 4.08-3.75 (m, 3 H) 3.27-3.08 (m, 1 H)
3.03-2.71 (m, 2 H) 2.11 (d, J=11.35 Hz, 3 H) 2.04 (d, J=8.22 Hz, 1 H) 2.00-1.75 (m, 2 H)
1.73-1.46 (m, 1 H)
Example 216
meth l3- o 4- S 3-chloro hen lh drox eth l carbamo l
fluoro hen l razin l i eridinecarbox late
Scheme 107
NH2 OH /OH NH2
; H
N/ ' N/
I H2N HATU/TEA I N/\©
\ N \ N CI
CI 38%
NTO\ \fl/ \
O 0
To mino(1-(methoxycarbonyl)piperidinyl)pyrazinyl)f|uorobenzoic acid (12
mg, 0.026 mmol) (for synthesis, see Example 35, Step 2) in DMF (1 mL) was added (8)-
2-amino(3-chlorophenyl)ethanol (6.60 mg, 0.038 mmol), followed by HATU (14.63 mg,
0.038 mmol) and DIEA (0.022 mL, 0.128 mmol). The reaction mixture was d at room
temperature overnight. The reaction mixture was diluted with DMF, filtered through
syringe filter and purified by prep HPLC to yield desired product as a TFA salt (6.5 mg,
38%). LCMS (m/z): 528.1/530.1 (MH+), 0.798 min. 1H NMR (400 MHz, CD30D) 6
ppm7.96-7.80 (m, 2 H) 7.75-7.58 (m, 2 H) 7.50-7.23 (m, 4 H) 5.19 (t, J=5.87 Hz, 1 H)
4.25-4.01 (m, 2 H) 3.92-3.79 (m, 2 H) 3.68 (s, 3 H) 3.20-2.74 (m, 3 H) 2.08-1.97 (m, 1 H)
1.91-1.73 (m, 2 H) 1.67-1.51 (m, 1 H)
Example 217
F o 5/ \2 F o F 0
Step1 Step2
NH2 0 o o
~ , NH2 0 NH2 0
B I | CZH5BV’KZCOS
Pd(dppf)C|2/Na2CO3
N/ + —>N/ N/
I / I —>
+ I
N / DMF
\ DME/120 C/15mln0 \ N \ N
o=<N—N 74% 64%
0 f \ \
\ \
N—N N—NH
>/"0
F o F o F 0 {OH
NH2 ('3 NH2 OH /OH NH2
; N/\©H N/ N/ I N/
| Step3 HzN Step4 |
\ N LiOH \ N EDC-Cl/HOAt \ N
—> —>
\\ DMF
MeOH ITHF \\ 17% //
N—N N—N N-N
\_. \,. <
Ste 1. meth l4- 3-amino 1H- razol l razin l fluorobenzoate
To methyl 4-(3-aminobromopyrazinyl)fluorobenzoate (For Synthesis see Example
34, Step 2) (100 mg, 0.307 mmol) in DME (3 mL) and 2 M sodium carbonate (0.75 mL,
1.5 mmol) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazolecarboxylate (90 mg, 0.307 mmol) followed by PdC|2(dppf)-CH2C|2 adduct
(25.04 mg, 0.031 mmol). The on mixture was heated in microwave at 120 °C for
15min. The on mixture was partitioned n ethyl acetate and water. The
organic layer was separated, washed with water and brine, dried over sodium sulfate,
ed and evaporated. The residue was proceeded to next step without purification (90
mg, 74%, 80% purity). LCMS (m/z): 314.1 (MH+), 0.595 min.
Ste 2. meth l4- 3-amino1-eth l-1H- razol l razin lfluorobenzoate
To methyl 4-(3-amino(1H-pyrazolyl) pyrazinyl)fluorobenzoate (45 mg, 0.115
mmol) in DMF (2 mL) was added ium carbonate (47.6 mg, 0.345 mmol), followed
by bromoethane (0.017 mL, 0.230 mmol). The reaction mixture was stirred at room
temperature for 48 h. The reaction mixtures was partitioned between ethylacetate and
water. The organic layer was separated, washed with brine, dried over sodium e,
filtered, evaporated and purified by flash chromatography eluting with 0 - 60% of EtOAc
(contains 10% of MeOH) / heptane to yield the desired product (25mg, 64%, 80% ).
LCMS (m/z): 342.0 (MH+), 0.73 min.
Ste 3. 4- 3-amino 1-eth l-1H- razol l razin lfluorobenzoic acid
To methyl 4-(3-amino(1-ethyl-1H-pyrazolyl)pyrazinyl)fluorobenzoate (25 mg,
0.073 mmol) in MeOH (1 mL) and THF (2 mL) was added 1 M LiOH (0.220 mL, 0.2 20
mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of reaction
mixture was adjusted to ~ 4 by 2 N HCI. The product was extracted with ethyl acetate
twice. The combined organics extracts were washed with brine, dried over sodium sulfate,
ed, and evaporated. The residue was proceeded to next step t further
purification. LCMS (m/z): 328.1 (MH+), 0.607 min.
Ste 4. S 3-amino 1-eth l-1H- razol l razin lfluoro-N- 2-h drox
phenylethyl) benzamide
To 4-(3-amino(1-ethyl-1H-pyrazolyl)pyrazinyl)fluorobenzoic acid (25 mg,
0.076 mmol) in DMF (1 mL) was added EDC.HC| (21.96 mg, 0.115 mmol), followed by
HOAt (15.60 mg, 0.115 mmol), (S)aminophenylethanol (15.92 mg, 0.092 mmol) and
DIEA (0.040 mL, 0.229 mmol). The on mixture was stirred at room temperature for 6
h. The reaction mixture was diluted with DMF and filtered through syringe filter. The crude
was purified by prep HPLC to yield the d product as a TFA salt (9.1 mg, 17%).
LCMS (m/z): 447.2 (MH+), 0.699 min. 1H NMR (400 MHz, CD3OD) 6 ppm 8.67-8.41 (m, 1
H), 8.17 (s, 1 H), 8.03 (s, 1 H), 7.86 (s, 1 H), 7.78 (t, J=7.63 Hz, 1 H), 7.67-7.53 (m, 2 H),
7.40-7.09 (m, 5 H), 5.21-5.03 (m, 1 H), 4.13 (q, J=7.30 Hz, 2 H), .65 (m, 2 H), 1.39
(t, J=7.24 Hz, 3 H).
Example 218
S nthesis of 4- 2—amino 5-oxo rrolidin l ridin lfluoro-N- S h drox
phenylethyl )benzamide
Scheme 109
fial $22
\ro o
0 O o
o o s"
>I\OJJ\N/\H,OH Ki \fl yo O
TsCl N K
+ 0
O N —>
H O DMAP/DCM
\ DlEA :8 o
o 0‘ I/
F o
F o J< W Step;
NH OJ< stem
NH2 0 o
t ,O
B PdCI2(dppf)/ KOAc N / Pd(dppf)C|2-DCM
N / + E; —> I
I Nazcog, DME
\ 66.5%
B, o o
F o F 0
NHZ OH Stegg NH2 0H
l H2 N/ 3/
—> \ + HZN
Pd/C
NH NH
F 0 {OH
Step7 3
NH2 N
EDC/HOAt H
, N/l
% \
Ste 1. Tert-but l4-h drox oxo-2 5-dih dro-1H- rrolecarbox late
To Boc—Gly—OH (1 g, 5.71 mmol) in DCM (12 mL) under N2 atmosphere at 0 °C was
added DMAP (1.743 g, 14.27 mmol) and Meldrum's acid (0.987 g, 6.85 mmol). A solution
of isopropyl chloroformate (8.56 mL, 8.56 mmol) in toluene was added se. The
reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was washed with 15%
KHSO4 twice, dried over sodium sulfate, filtered and ated. The crude t was
taken in 50 mL of EtOAc and refluxed for 1 h. After le materials were evaporated,
the crude product was triturated with EtOAC and the resulting solid was filtered and dried
to provide a yellow solid (75%). LCMS (m/z): 200.1 (MH+), 0.504 min.
Ste 2. Tert-but l2-oxo tos lox -2 5-dih dro-1H- rrolecarbox late
To tert-butyl 4-hydroxyoxo-2,5-dihydro-1H-pyrrolecarboxylate (680 mg, 3.41 mmol)
in DCM (12 mL) was added DIEA (1.192 mL, 6.83 mmol) and tosyl chloride (651 mg, 3.41
mmol). The reaction e was stirred at room temperature for 6 h. The on mixture
was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer
was separated, washed with brine, dried over sodium sulfate, filtered and evaporated.
The crude product was purified by flash chromatography (0 to 50% EtOAc / heptane).
Pure fractions were combined, evaporated and dried to give desired product as a white
solid (0.98 g, 81%). LCMS (m/z): 354.1 (MH+), 0.97 min; 1H NMR (400 MHz, DMSO-d6) 6
ppm 7.99 (d, J=8.22 Hz, 2 H) 7.54 (d, J=7.83 Hz, 2 H) 5.77 (s, 1 H) 4.33 (s, 2 H) 2.43 (s,
3 H) 1.41 (s, 9 H).
Ste 3. Tert-but l 4- 2-amino 4 4 5 5-tetrameth H 3 2-dioxaborolan l 3- l -
2-fluorobenzoate
To tert-butyl 4-(2-aminobromopyridinyl)f|uorobenzoate (400 mg, 1.089 mmol) in
DME (12 mL) was added 4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) (523
mg, 2.179 mmol), potassium acetate (321 mg, 3.27 mmol) and PdCI2(dppf)-CH2C|2 (89
mg, 0.109 mmol). The reaction mixture was purged with N2 and heated in microwave vial
in g block at 110 °C for overnight. The reaction mixture was partitioned between
ethyl e and water. The organic layer was separated, washed with brine, dried over
sodium sulfate, filtered and ated. The crude was taken in ether and sonicated for
min and black solid was filtered off. The filtrate was evaporated to provide product as a
light yellow solid (300 mg, 66.5%). LCMS (m/z): 333.2 (MH+), 0.672 min (for boronic
acid).
Ste 4. Tert-but l4- 6-amino 4- tert-butox carbon lfluoro hen l ridin l
oxo-2,5-dihydro-1H-pyrrolecarboxylate
To utyl 4-(2-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)—2-
fluorobenzoate (158 mg, 0.382 mmol) in DME (3 mL) and sodium ate (0.509 mL,
1.019 mmol) was added tert-butyl 2-oxo(tosyloxy)-2,5-dihydro-1H-pyrrole
carboxylate (90 mg, 0.255 mmol) and PdCl2(dppf)-CH2Cl2 (41.6 mg, 0.051 mmol). The
reaction mixture was heated in microwave at 90 °C for 30 min. LCMS showed starting
material remained. More catalysts were added and heated again at 90 °C for 20 min. The
reaction mixture was partitioned between ethylacetate and water. The organic layer was
separated, washed with brine, dried over sodium e, filtered and evaporated. The
crude product was purified by flash torgraphy using 0-50% EtOAc (contains
%MeOH) / heptane to provide product as a yellow solid (66%). LCMS (m/z): 470.2
(MH+), 0.846 min.
Ste 5. 4- 2-amino 5-oxo-2 5-dih dro-1H- rrol l ridin l f|uorobenzoic acid
To tert-butyl 4-(6-amino(4-(tert-butoxycarbonyl)fluorophenyl)pyridinyl)—2-oxo-2,5-
dihydro-1H-pyrrolecarboxylate (158 mg, 0.337 mmol) was added TFA (2 mL, 26.0
mmol). The on mixture was stirred at room temperature for 1 h. After toluene was
added, the volatile solvents were evaporated. The crude product was used for the next
step. LCMS(m/z): 314.2 (MH+), 0.382 min.
Ste 6. 4- o 5-oxo rrolidin l ridin l f|uorobenzoic acid
To 4-(2-amino(5-oxo-2,5-dihydro-1H-pyrrolyl)pyridinyl)—2-fluorobenzoic acid (100
mg, 0.319 mmol) in MeOH (15 mL) under N2 atmosphere was added Pd-C (67.9 mg,
0.064 mmol). The reaction mixture was stirred at room temperature for 24 h under H2
balloon. The reaction mixture was filter through Celite and washed with methanol. The
filtrate was ated. The crude was proceed for next step. LCMS(m/z): 316.2 (MH+),
0.338 min.
Ste 7. +/- 2-amino 5-oxo in l ridin lfluoro-N- S h drox
phenylethyl)benzamide
To 4-(2-amino(5-oxopyrrolidinyl)pyridinyl)—2-fluorobenzoic acid (30 mg, 0.076
mmol) in DMF (1 mL) was added (S)aminophenylethanol (12.53 mg, 0.091 mmol),
EDC-HCI (21.89 mg, 0.114 mmol), HOAt (15.54 mg, 0.114 mmol) and DIEA (0.040 mL,
0.228 mmol). The on mixture was stirred at room temperature for 5 h. The reaction
mixture was d with DMF and directly purified by prep HPLC to provide (+/-)(2-
amino(5-oxopyrrolidinyl)pyridinyl)—2-f|uoro-N-((S)hydroxy
phenylethyl)benzamide as a TFA salt (20.2%). LCMS (m/z): 435.2 (MH+), 0.476 min; 1H
NMR (400 MHz, CD3OD) 6 ppm 7.88 (s, 1 H), 7.84-7.74 (m, 2 H), 7.38-7.30 (m, 4 H), 7.27
(t, J=7.43 Hz, 2 H), .13 (m, 1 H), 5.18-5.05 (m,1 H), 3.85-3.56 (m, 4 H), 3.39 -
3.26(m, 1 H), 2.62 (dd, J=16.82, 8.61 Hz, 1 H), .33 (m, 1 H).
Examples 219 and 220
S nthesis of 4- 2-amino R oxo rrolidin l ridin uoro-N- S h drox -
fluoro-N- S h drox hen leth Ibenzamide
Scheme 110
OH OH
F O :/ F O :/
NH2 N NH2 N
H H
N/ N’
\ —- \
eak1 p
NH QH
O O
(+/-)(2-amino(5-oxopyrrolidinyl)pyridinyl)—2-fluoro-N-((S)hyd roxy
phenylethyl)benzamide was resolved by chiral SFC (Chiral
Pak 5mic C10=AD-H , 4.6x100 (mm), 5mL/min, MeOH = 50%). The polar
compound (peak 1)was obtained at Rt = 1.36 min (24.5%). LCMS (m/z): 435.2 (MH+),
0.485 min. The less polar compound (peak 2) was obtained at Rt = 2.20 min (22%).
LCMS (m/z): 435.2 (MH+), 0.482 min. The absolute stereochemistry on cyclic lactam was
arbitrarily assigned.
Example 221
S nthesis of 2S 4R -meth l4- 6-amino 4- S 3-chloro hen l
h drox eth lcarbamo lfluoro hen l ridin l rrolidinecarbox late
WO 66188
Scheme 1 1 1
O=‘\ Oti
0 o
/ /
fluoro hen l ridin l-1H- rrole-1 2 2H 5H -dicarbox late
A mixture of tert-butyl 4-(2-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridin
y|)f|uorobenzoate (400 mg, 0.966 mmol), (S)—1-tert-butyl 2-methyl 4-
fluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (1.087 g, 2.90 mmol,
Pd(PPh3)4 (112 mg, 0.097 mmol) and cesium carbonate (1.258 g, 3.86 mmol) in THF (10
mL) and water (2 mL) was degassed, then microwave heated to 90 °C for 10 min. At
completion, the reaction was diluted with ethyl acetate. The organics were washed with
brine, dried over magnesium sulfate and concentrated. The crude mixture was purified by
flash chromatography over silica gel (20-90% ethyl e/heptane) to provide (S)—1-tert-
butyl 2-methyl 4-(6-amino(4-(tert-butoxycarbonyl)fluorophenyl)pyridinyl)—1 H-
pyrrole-1,2(2H,5H)-dicarboxylate (470 mg, 95%). LCMS (m/z): 514.3 (MH+), 0.92 min.
Ste 2. 2S 4R tert-but |2-meth |4- 6-amino 4- tert-butox carbon |
fluoro hen l ridin l rrolidinedicarbox late
A degassed on of tert-buty| 2-methyl 4-(6-amino(4-(tert-butoxycarbonyl)
fluorophenyl)pyridinyl)—1H-pyrrole-1,2(2H,5H)-dicarboxylate (470 mg, 0.915 mmol) in
methanol (40 mL) was treated with 10 wt.% Pd/C (3.214 g, 3.02 mmol). The system was
degassed again, then charged with 1 atm hydrogen overnight. At completion, the reaction
degassed, then treated ammonia gas then filtered over Celite. The cake was reslurried in
methanol, treated with ammonia gas, and filtred to retrieve onal product. The
process was repeated until no further product eluted from filter cake. The combined
organics were concentrated to provide (2S,4R)—1-tert—butyl 2-methyl mino(4-(tert—
butoxycarbonyl)fluorophenyl)pyridinyl)pyrrolidine-1,2-dicarboxylate (300 mg, 64%).
LCMS (m/z): 516.1 (MH+), 0.89 min.
Ste 3. 4- 2-amino 3R 58 methox carbon l rrolidin l ridin l
fluorobenzoic acid-2TFA
A solution of (2S,4R)—1-tert-butyl 2-methyl 4-(6-amino(4-(tert-butoxycarbonyl)—3-
fluorophenyl)pyridinyl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.58 mmol) in DCM (6
mL) was treated with TFA (3 mL). After 1h, the reaction was concentrated, then the
residue was slurried in benzene, sonicated, then concentrated to e mino
((3R,5S)—5-(methoxycarbonyl)pyrrolidinyl)pyridinyl)fluorobenzoic acid-2TFA (345
mg, 100% yield). LCMS (m/z): 360.2 (MH+), 0.34 min.
Ste 4. 28 4R -meth l4- 6-amino 4- S 3-chloro hen l
h drox eth lcarbamo lfluoro hen l ridin l rrolidinecarbox late
A e of mino((3R,5S)—5-(methoxycarbonyl)pyrrolidinyl)pyridinyl)—2-
fluorobenzoic acid-2TFA (35 mg, 0.060 mmol), HATU (34 mg, 0.089 mmol), and DIEA
(0.104 mL, 0.596 mmol) in DMF (2 mL) was d with (S)—2-amino-2—(3-
chlorophenyl)ethanol (51 mg, 0.348 mmol). At completion, the reaction was washed with
water and brine, then dried over MgSO4 and concentrated. The crude material was
purified by reverse phase prep HPLC to provide (2S,4R)—methyl mino(4-(((S)—1-
(3-chlorophenyl)hydroxyethyl)carbamoyl)—3-fluorophenyl)pyridinyl)pyrrolidine
carboxylate (4.2 mg, 9%). LCMS (m/z): 513.2, 515.2 (MH+), 0.58 min; 1H NMR (400 MHz,
CD3OD) 6 ppm 7.97 - 7.86 (m, 3H), 7.49 - 7.40 (m, 3H), 7.39 - 7.34 (m, 2H), 7.33 - 7.26
(m, 1H), 5.19 (t, J = 5.87 Hz, 1H), 4.62 (dd, J = 7.63, 10.76 Hz, 1H), 3.93 - 3.77 (m, 6H),
3.74 - 3.61 (m, 1H), 2.87 (td, J = 6.90, 13.21 Hz, 1H), 2.33 - 2.21 (m, 1H).
Examples 222 and 223
S nthesis of 2S 4R 6-amino 4- S 3-chloro hen l h drox eth l carbamo l -
3-fluoro hen l ridin l rrolidinecarbox lic acid and 2S 4R -meth l4- 6-amino
4- S 3-chloro hen lh drox eth lcarbamo lfluoro hen l ridin
l rrolidinecarbox late
Scheme 112
IL?9 mIf
E 12 12
_Z / i9E _2 g
\ Q <\(jg/ENE l‘%[NI _2 0:5:\/M
0 HO ‘ HN
/ ‘fio ‘QO / W0
fluoro hen l ridin l rrolidinecarbox lic acid
A solution of (2S,4R)—methyl 4-(6-amino(4-(((S)—1-(3-chlorophenyl)
hydroxyethyl)carbamoyl)fluorophenyl)pyridinyl)pyrrolidinecarboxylate (120 mg,
0.234 mmol) in MeOH (4 mL) was treated with 1.0 M LiOH aqueous on (0.468 mL),
then heated to 70 °C. After 1 h, the reaction was concentrated then dissolved in water (2
mL) and treated with 1.0 N aqueous HCI (0.468 mL). The reaction mixture was extracted
with ethyl acetate (20 mL). The organic layer was washed with water and brine, then dried
over MgSO4 and concentrated to provide the crude product (97 mg, 57%). A portion of
this material was purified by reverse phase prep HPLC yielding (2S,4R)—4-(6-amino(4-
(((S)—1-(3-chlorophenyl)hydroxyethyl)carbamoyl)fluorophenyl)pyridinyl)pyrrolidine-
2-carboxylic acid. LCMS (m/z): 501.1 (MH+), 0.49 min; 1H NMR (400 MHz, CD3OD)
8 ppm 8.56 - 8.64 (m, 1H), 7.75 - 7.87 (m, 4H), 7.31 - 7.38 (m, 4H), 7.24 - 7.29 (m, 3H),
7.17 - 7.24 (m, 1H), 5.07 - 5.14 (m, 1H), 4.36 (dd, J = 7.63, 9.98 Hz, 1H), 3.64 - 3.83 (m
4H), 3.52 - 3.62 (m, 1H), 3.27 - 3.34 (m, 1H), 2.72 - 2.81 (m, 1H), 2.56 (s, 1H), 2.15 (td, J
= 10.42, 13.21 Hz, 1H).
Ste 2. 2S 4R -meth l4- o 4- S 3-chloro hen l
h drox eth lcarbamo lfluoro hen l ridin l rrolidinecarbox late
A on of (2S,4R)—4-(6-amino(4-(((S)(3-chlorophenyl)hydroxyethyl)carbamoyl)-
3-fluorophenyl)pyridinyl)pyrrolidinecarboxylic acid (25 mg, 0.050 mmol) in THF (2
mL) and DMF (2 mL) was treated sequentially treated with a 2.0 M solution of
2014/062913
methylamine in THF (1.25 mL, 2.5 mmol), and HATU (95 mg, 0.25 mmol). After 2 h, the
reaction was d with ethyl acetate and washed with water and brine. The organics
were dried over magnesium sulfate and concentrated to provide (2S,4R)—methy| 4-(6-
amino(4-(((S)—1-(3-chlorophenyl)hydroxyethyl)carbamoyl)—3-fluorophenyl)pyridin
y|)pyrro|idinecarboxylate after purification by reverse phase prep HPLC (1.8 mg, 5%).
LCMS (m/z): 512.2, 514.2 (MH+), 0.54 min; 1H NMR (400 MHz, CD3OD) 6 ppm 8.64 -
8.73 (m, 1H), 7.84 - 7.96 (m, 2H), 7.45 (s, 1H), 7.40 - 7.44 (m, 1H), 7.35 - 7.38 (m, 1H),
7.27 - 7.34 (m, 1H), 5.16 - 5.24 (m, 1H), 4.38 (dd, J = 7.83, 10.17 Hz, 1H), 3.75 - 3.92 (m,
2H), 3.60 - 3.72 (m, 1H), 2.78 - 2.89 (m, 3H).
8 nthesis of 4- 2-amino 1-meth l-1H-imidazol l ridin l fluorobenzoic acid
Following Steps 4 and 5 in Scheme 109, using omethyl-1H-imidazole, 4-(2-
amino(1-methyI-1H-imidazoIyl)pyridiny|)f|uorobenzoic acid was obtained.
LCMS (m/z): 313.1 (MH+), 0.3 min.
8 nthesis of 4- 2-amino 1-meth l-1H- razol l ridin l fluorobenzoic acid
2014/062913
ing Steps 4 and 5 in Scheme 109, using 1-methyl(4,4,5,5-tetramethyl-1,3,2—
dioxaborolan-2—yl)—1H-pyrazole, 4-(2—amino(1-methyl-1H-pyrazolyl)pyridinyl)—2—
fluorobenzoic acid was obtained. LCMS (m/z): 313.4 (MH+), 0.44 min.
8 nthesis of 4- 2—amino 1-iso ro l-1H- razol l ridin lfluorobenzoic acid
Following Steps 4 and 5 in Scheme 109, using 1-isopropyl(4,4,5,5-tetramethyl-1,3,2—
dioxaborolan-2—yl)—1H-pyrazole, 4-(2—amino(1-isopropyl-1H-pyrazolyl)pyridinyl)—2—
fluorobenzoic acid was obtained. LCMS (m/z): 341 NH), 0.56 min.
Example 224
S nthesis of S 3-amino oxetan l razin l fluoro-N- 2—h drox
ghenylethyl )benzamide
Scheme 113
F o
F o —ES‘e l NH2 0/ _I28te Z
Pd(dppf)C|2-DCM
NH2 o/ 0‘3’0 N/ Pd(dppf)Cl2-DCM
—>KrNI + —>
o’é‘o O
N/ + KOAc,DME ,DME
\ N %Ԥ 55% ,B\ 11%
0 0
Br %—§
F o F 0 =/
NH2 0/ m; NH2 OH {OH $94—
: H
- - EDC/HOAt
N/ LIOH N/ N/ N/\©
I | + H2N I
\ N N \ N
THF,MeOH \
DIEA/DMF
11.4%
0 O O
Ste 1. Meth l4- 3-amino 4 4 5 ameth H 3 2-dioxaborolan l razin l
fluorobenzoate
To methyl 4-(3-aminobromopyrazinyl)fluorobenzoate (400 mg, 1.227 mmol) in
DME (12 mL) was added 4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane (589 mg,
2.453 mmol), potassium acetate (361 mg, 3.68 mmol) and PdC|2(dppf)-CH2Cl2 (100 mg,
0.123 mmol). The reaction mixture was purged with N2 and heated in microwave at 120°C
for 15min. The reaction mixtures was partitioned between ethylacetate and water. The
organic layer was separated, washed with brine, dried over sodium e, filtered and
evaporated. The crude product was taken in ether and sonicate for 20 min. The black
solid was filtered off. To the filtrate was added heptane. The itate was filtered and
dried to provide a light yellow solid. (250mg, 54.6%). LCMS (m/z): 292.2 (MH+), 0.47 min
(for boronic acid).
Ste 2. Meth l4- 3-amino oxetan l razin lfluorobenzoate
To methyl 4-(3-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrazinyl)
fluorobenzoate (150 mg, 0.402 mmol) in DME (6 mL) and sodium carbonate (1.5 mL, 3.0
mmol) was added 3-iodooxetane (370 mg, 2.01 mmol) and PdCl2(dppf)-CH2Cl2 (32.8 mg,
0.042 mmol). The reaction mixture was heated in microwave at 100 °C for 15 min. The
on mixture was partitioned n ethylacetate and water. The organic layer was
separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The
crude t was purified by prep HPLC to isolate the product (13.5 mg, 11.0%). LCMS
(m/z): 304.2 (MH+), 0.61 min.
Ste 3. 4- 3-amino oxetan l razin l fluorobenzoic acid
To methyl 4-(3-amino(oxetanyl)pyrazinyl)—2-fluorobenzoate (13 mg, 0.043 mmol)
in MeOH (1 mL) and THF (2 mL) was added LiOH (0.128 mL, 0.128 mmol). The reaction
mixture was stirred 2 h at room temperature. The reaction mixtures was adjusted to
acidic (pH ~3) and solvent was evaporated on rotovap. The crude was azeotrope with
toluene and proceed for next step. LCMS (m/z): 290.1 (MH+), 0.46 min.
Ste 4. S 3-amino oxetan l razin lfluoro-N- 2-h drox
phenylethyl)benzamide
To 4-(3-amino(oxetanyl)pyrazinyl)fluorobenzoic acid -crude (10 mg, 0.035
mmol) in DMF (1 mL) was added (S)—2-aminophenylethanol (14.22 mg, 0.104 mmol),
DIEA (0.030 mL, 0.173 mmol), EDC (13.25 mg, 0.069 mmol) and Bt (7.06 mg,
0.052 mmol). The reaction mixture was stirred at room temperature for overnight. The
crude was purified by prep HPLC to provide d product as a TFA salt (11.5%).
LCMS (m/z): 409.2 (MH+), 0.597 min; 1H NMR (400 MHz, CD3OD) 6 ppm 7.92-7.82 (m,
2H) 7.78-7.64 (m, 2 H) 7.48-7.32 (m, 5 H) 7.23 - 7.31-7.23 (m, 1 H) 5.28-5.17 (m, 1 H)
.03-4.90 (m, 5 H) 4.47-4.34 (m, 1 H)3.96-3.76 (m, 3 H).
Examples 225, 226, and 227
S nthesis of +/- -N- o 3-chloro hen l eth l 2-amino 1 th l-1H-
pyrazolyl)pyridinyl)—2-fluorobenzamide
WO 66188
Scheme 114
Following Steps 1 and 2 in Scheme 82, Steps 5 and 6 in Scheme 102, using (+/-)-tertbutyl
(2-amino(3-chlorophenyl)ethyl)carbamate, (+/-)-N-(2-amino(3-
chlorophenyl)ethyl)(2-amino(1,3-dimethyl-1H-pyrazolyl)pyridinyl)—2-
fluorobenzamide was obtained. LCMS (m/z): 479.3 (MH+), 0.54 min. 1H NMR (400MHz,
CDCI3) 6 ppm 8.16 (m, 2H), 7.87 (m, 1H), 7.47 - 7.18 (m, 7H), 5.23 (m, 1H), 4.58 (bs,
2H), 3.88 (s, 3H), 3.19 (m, 2H), 2.36 (s, 3H). The racemic mixture was resolved by chiral
SFC (ChiralPak 5mic AD column, 4.6x100 (mm), 5 mL/min, EtOH+0.1%, DEA = 30%).
The polar enantiomer, (S)—N-(2-amino(3-chlorophenyl)ethyl)(2-amino(1,3-
yl-1H-pyrazolyl)pyridinyl)—2-fluorobenzamide, was obtained at Rt = 2.6 min.
LCMS (m/z): 479.1 (MH+), 0.57 min. The less polar enantiomer, (R)—N-(2-amino(3-
phenyl)ethyl)(2-amino(1,3-dimethyl-1H-pyrazolyl)pyridinyl)—2-
fluorobenzamide, was obtained at Rt = 3.22 min. LCMS (m/z): 479.1 (MH+), 0.57 min. The
absolute stereomchemisty was assigned based on biochemical data and docking model.
S nthesis of 4- 3-amino 1r4r deuteridoh drox c clohex l 2- l
fluorobenzoic acid
Scheme 115
F O _r_:Ste 1 F o Stegg F o
NH2 0/ NH2 0/ NH2 OH
N/ N/ N/
I I I
\ N NaBD4 LiOH
\ N \ N
0 I5: ;OH :cis = ~4:1) D‘;OH
Ste 1. meth l4- 3-amino 1r4r deuteridoh drox c clohex l razin l
fluorobenzoate
A solution of ethyl 4-(3-amino(4-oxocyclohexyl)pyraziny|)fluorobenzoate (98 mg,
0.285 mmol) in methanol (1.903 mL), THF (0.952 mL) was cooled down to -78 °C. To this,
NaBD4 (32.4 mg, 0.856 mmol) was slowly added by a portion. The reaction mixture was
allowed to warm up to room temperature for 1 h. The on e was quenched with
NH4C| solution, then followed by Na2C03 solution and stirred for 1 h. The reaction mixture
was extracted by EtOAc. The combined organic layer was washed with water and brine,
dried over anhydrous Na2804, filtered off, and concentrated in vacuo to e crude
methyl 4-(3-amino((1r,4r)deuteridohydroxycyclohexyl)pyrazinyl)
fluorobenzoate (81.4 mg, trans:cis = ~4:1, 82%), which was used for the next step. LCMS
(m/z): 347.1 (MH+), 0.61 min (major, trans) and 0.64 min (cis).
Ste 2. 4- 3-amino 1r4r deuteridoh drox c clohex l razin l
fluorobenzoic acid
To a solution of methyl 4-(3-amino((1r,4r)deuteridohydroxycyclohexyl)pyrazin
y|)fluorobenzoate (81 mg, 0.234 mmol) in THF (1559 ul,) and MeOH (780 pl) was
added LiOH (1M solution) (421 pl, 0.421 mmol). The reaction mixture was stirred at room
ature for 1 h. After pH was adjusted to 5, the reaction mixture was extracted with
EtOAc. The combined organic layer was washed with water and brine, filtered off, and
concentrated in vacuo. The crude 4-(3-amino((1r,4r)deuterido
2014/062913
hydroxycyclohexyl)pyrazin-2—yl)fluorobenzoic acid (99%) was used for the next step
without further purification. LCMS (m/z): 333.1 (MH+), 0.47 min (major, trans) and 0.51
min (cis).
S s of S aminodeuterido 3-bromofluoro hen l ethanol
Scheme 116
Ste Ste Ste
F\EB>)10|-l D NH2
LiAlD41F\E?)ELOH—>Dess—Martin[O]2F\©/io::3F\©)\/OH
Ste 1. ofluoro hen l-1 euterido-methanol
3-Bromofluorobenzoic acid (5.3 g, 24.20 mmol) was dissolved in THF (81 mL). To this,
LiAlD4 (1.102 g, 29.0 mmol) was added at 0 OC. The reaction mixture was stirred at room
temperature overnight. After the reaction mixture was cooled down to 0 °C, 1.1 mL of
water was added, followed by 1.1 mL of 15% NaOH and 3.2 mL of water. The suspension
was stirred at room ature for 2 h, then filtered through Celite and rinsed with Et2O,
the filtrate was concentrated to yield the crude product, which was purified by flash
chromatography (0-30% EtOAc/heptane) to yield (3-bromofluorophenyl)-1,1-di-
deuterido-methanol in 64% yield. LCMS (m/z): 232.0 (MNa+), 0.69 min.
Step 2. 3-bromofluorobenzaldehyde-d1
(3-Bromofluorophenyl)-1,1-di-deuterido-methanol (3.2 g, 15.4 mmol) was dissolved in
DCM (51.5 mL) and cooled down to 0 °C. Dess—Martin periodinane (9.83 g, 23.18 mmol)
was added to the reaction mixture, which was stirred at 00C for 3 h. Saturated Na28203/
NaHC03 (8:1) solution was added to the mixture, which was stirred at room temperature
for 1 h. The reaction mixture was then extracted with DCM. The combined organic layer
was washed with water and brine, filtered off, and concentrated in vacuo. The crude
material was purified by flash chromatography to yield 3-bromofluorobenzaldehyde-d1
as white solid (2.6 g, 82%). 1H NMR (400MHz, CDCI3) 5 ppm 7.83 (s, 1H), 7.57 - 7.50 (m
2H).
Ste 3. S aminodeuterido ofluoro hen lethanol
Following Steps 4 to 9 in Scheme 74, using 3-bromo—5-fluorobenzaldehyde-d1, (S)—2-
aminodeuterido(3-bromofluorophenyl)ethanol was obtained as a HCI salt. LCMS
(m/z): 235.0/237.0 (MH+), 0.40 min.
8 nthesis of R amino 3-bromofluoro hen | -2 2-di-deuterido-ethanol
hydrochloride
Scheme 1 1 7
Step 1 Step 2
NHBoc NHBoc
Br / Br 0
RuCI3, NalO4 1. isobutyl chloroformation
a —>
2. NaBD4
F F
NHBoc m;
NHZ HCI
Br D
Br D
D HCI in dioxane D
OH OH
F F
Ste 1. R 3-bromofluoro hen l tert-butox carbon lamino acetic acid
A solution of (S)—tert—butyl (1-(3-bromofluorophenyl)a||y|)carbamate (1.235 g, 3.74
mmol) in CCI4 (4 mL), acetonitrile (4 mL) and water (6 mL) was treated with sodium
periodate (1.680 g, 7.85 mmol) and RuCI3 (16 mg, 0.075 mmol). After 1 h, the on
was complete. The reaction was partitioned between ethyl acetate and water. The
organics were washed with brine, then filtered over celite and concentrated. The crude
was redissolved in e, then ed and trated again to provide crude (R)—2-
(3-bromofluorophenyl)((tert-butoxycarbonyl)amino)acetic acid (1.30 g, 99% yield)
which was used directly. LCMS (m/z): 348.2 (MH+), 0.52 min.
Ste 2. R -tert-but | 1- 3-bromofluoro hen lh drox -2 2-deuterido-
ethyl)carbamate
A -10 °C solution of (R)(3-bromofluorophenyl)((tert-butoxycarbonyl)amino)acetic
acid (1.30 g, 3.73 mmol) in DME (6 mL) was treated with N-methyl morpholine (0.431 mL,
3.92 mmol). After 5 min, the reaction was treated with isobutyl chloroformate (0.515 mL,
2014/062913
3.92 mmol). After an additional 5 min, the reaction was filtered and the cake was washed
with DME (4 mL). The combined organics were treated with a solution of NaBD4 (0.251 g,
.97 mmol) in water (1 mL). At completion, the reaction was partitioned between ethyl
acetate and water. The cs were washed with brine, then dried over sodium sulfate
and concentrated. The crude material was purified by prep HPLC to provide the title
compound, (R)—tert—butyl (1-(3-bromofluorophenyl)hydroxy-2,2-deuteridoethyl
mate (55 mg, 4.4% yield). LCMS (m/z): 337.3 (MH+), 1.03 min.
Ste 3. R amino 3-bromofluoro hen | -2 2-di-deuterido-ethanol h drochloride
A solution of (R)—tert-butyl (1-(3-bromof|uoropheny|)hydroxy-2,2-deuterido-
carbamate (46 mg, 0.137 mmol) in 4 M HCI in dioxane (1368 ul) was stirred for
overnight. The volaitle materials were removed in vacuo. The crude product was used for
the next step without further purification. LCMS (m/z): 236/238 (MH+), 0.4 min.
8 nthesis of 4- 3-amino 4- h drox meth lc clohex | razin lfluorobenzoic
Scheme 118
$91 $2; Stegg
O l \ / \ o
/ \
HO OH O 0 O 0 1. NaH, BnBr
_ i? stOH.HZO S? L'A'H4 2. 3 N HCI
—> —> —>
O OEt OBn
O OEt OH
F o
Stepfi F O —QSte Q NH2 OMe
Bpin
1. LiHMDS,Tf2NPh NHz OMe NI \
2. (Bpin)2,PdC|2dppf,KOAc —> /N
+ N \
—> |
F 0 F 0
m5 Stepz
NHz OMe NHZ OH
N \ N \
”Z I
/N LiOH l
Pd/C
trans/cis mixture
OH OH
Ste 1. Eth l 1 4-dioxas iro 4.5 decanecarbox late
Ethyl 4-oxocyclohexanecarboxylate (15.01 g, 88.16 mmol) was combined with ethylene
glycol (21 mL, 4.27 equiv.) and enesulfonic acid monohydrate (0.2 g, 0.012 equiv.)
in anhydrous toluene (50 mL), and the mixture was stirred 14 h at room temperature. The
reaction was diluted with ether (200 mL) and was washed with H20 (2X200 mL),
saturated sodium bicarbonate (100 mL) and brine (80 mL). The organic layer was dried
(Na2804), filtered and trated under reduced pressure to yield 18.15 g ethyl 4-
lohexanecarboxylate ethylene ketal (96% yield). LCMS (m/z): 214.8 (MH+), 0.74
min.
Ste 2. 1 4-dioxas iro 4.5 decan lmethanol
LiAlH4 (2.51 g, 66.3 mmol) was ded in THF (60 mL) and then cooled in an ice-
bath. To the suspension was added Ethyl 1,4-dioxaspiro[4.5]decanecarboxylate
(11.357 9, 53.0 mmol) dissolved in THF (40 mL) dropwise and the reaction mixture was
lly warmed to room temperature over 1 h upon which LCMS indicated complete
reduction of SM. The reaction mixture was diluted with ether (200 mL) and quenched with
2.5 mL water and then 5 mL (10% NaOH) and then 7.5 mL water. To this, anhydrous
MgSO4 was added, which was then agitated for 30 min and filtered over Celite. The
filtrate was concentrated in vacuo to afford the desired product in quantitative yield.
LCMS (m/z): 173.1 (MH+), 0.41 min.
Ste 3. 4- benz lox meth lc clohexanone
1,4-dioxaspiro[4.5]decanylmethanol (1.33 g, 7.72 mmol) was ved in DMF (14
mL) and then cooled to 0 °C. To the solution was added NaH (0.402 g, 10.04 mmol) in
portions and the mixture agitated at 10 °C for 1 h and then benzyl bromide (1.194 mL,
.04 mmol) was added and the mixture agitated over 72 h. The on mixture was
quenched with water and extracted with ether and the combined organic extracts dried
), filtered and concentrated in vacuo and the crude product 8-((benzy|oxy)methy|)-
1,4-dioxaspiro[4.5]decane dissolved in acetonitrile (35 mL) and water (25 mL) and treated
with 3N HCI (13 mL) and agitated at room temperature for 20 min upon which LCMS
indicated desired product. The reaction mixture was ed with 40 mmol aqueous
NaOH and then extracted with EtOAc (200 mL) and the organic layer was washed with
water and dried (MgSO4), filtered and concentrated in vacuo and the residue purified by
flash chromatography (0-50% EtOAc/heptane) to afford 1.23 g of the desired product as a
ess syrup (73%). LCMS (m/z): 329.2 (MH+), 1.33 min.
Ste 4. 2- 4- benz lox meth l c clohexen l -4 4 5 ameth H 3 2-
dioxaborolane
1,4-dioxaspiro[4.5]decanylmethanol (1.23 g, 5.63 mmol) was dissolved in THF (22.5
mL) and cooled to -78 °C. Then LiHMDS (6.20 mL, 6.20 mmol) was added dropwise and
the mixture strred at this temperature for 1 h upon which 1,1 ,1-trifluoro-N-phenyl-N-
((trifluoromethy|)su|fony|)methanesulfonamide (2.214 g, 6.20 mmol) was added in one
portion and the reaction mixture was let to warm to room temperature and stirr overnight.
The next morning, the reaction mixture was ed with 1.0 M NaHSO4 and the
solvent evaporated in vacuo. The e was partitioned between NaOH/ether and the
organic layer was separated and washed with 1.0 M NaOH twice, and dried with brine
and then MgSO4, filtered and concentrated in vacuo to afford the desired product 4-
((benzyloxy)methyl)cyclohexeny| trifluoromethanesulfonate in quantitative yield
which was taken to the next step t any further purification. The intermdiate 4-
((benzyloxy)methyl)cyclohexenyl (1000 mg, 2.85 mmol), )2 (1087 mg, 4.28
mmol), PdCI2(dppf)-CH2C|2 (233 mg, 0.285 mmol) and KOAc (560 mg, 5.71 mmol) were
charged in a microwave vial and then dioxane (9.5 mL) was added. The mixture was
evacuated and purged with N2 and then heated to 100 °C for 22 min in microwave. The
crude mixture was diluted with ether and water and the organic layer was separated and
dried (MgSO4), filtered and concentrated in vacuo and the residue purified by flash
chromatography (0-10% EtOAc/heptanes) to afford the desired product (51%). LCMS
(m/z): 219.2 (MH+), 0.88 min.
Ste 5. Meth l4- 3-amino 4- benz lox meth lc clohexen l razin l
benzoate
Methyl 4-(3-aminobromopyrazinyl)fluorobenzoate (343 mg, 1.051 mmol), 2-(4-
((benzyloxy)methyl)cyclohexeny|)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (414 mg,
1.261 mmol) PdCl2(dppf)-CH2Cl2 adduct (86 mg, 0.105 mmol) were placed in a
microwave vial and then DME (3.5 mL) was added. Then 2.0 M Na2C03 (1261 uL, 2.52
mmol) was added and the mixture was degassed and purged with nitrogen and then
heated at 115 °C for 30 min upon which the reaction was complete. The reaction mixture
was diluted with EtOAc and washed with water and the organic layer was separated and
dried ), ed and concentrated and the residue purified by flash
chromatography (0-100% EtOAc/heptane) to afford 381 mg the desired product as a
yellow solid (81%). LCMS (m/z): 448.2 (MH+), 1.16 min.
Ste 6. Meth l4- 3-amino 4- h drox meth lc clohex l razin lfluorobenzoate
Methyl 4-(3-amino(4-((benzyloxy)methyl)cyclohexeny|)pyrazinyl)
fluorobenzoate (381 mg, 0.851 mmol) was dissolved in THF (5 mL) and then MeOH (15
mL) was added and then Pd-C (10% wet) (550 mg, 0.517 mmol) was added. The mixture
was put under vacuum and purged with hydrogen and this cycle was repeated thrice and
then finally under en overnight. After 14 h, LCMS indicated alkene saturation but
only partial benzyl deprotection, and therefore r Pd-C (10% wet) (700 mg) was
added and the mixture stirred at room temperature for another 5 h after which complete
benzyl deprotection ed. The reaction mixture was filtered and concentrated in
vacuo to afford 215.6 mg of the desired product as a mixture of romers (cis/trans
unspecified) (70%). LCMS (m/z): 360.2 (MH+), 0.71, 0.72 min.
Ste 7. S 3-amino 4- h drox meth lc clohex l razin l-N 3-
chlorophenyl)—2-hydroxyethyl)—2-fluorobenzamide
Methyl 4-(3-amino(4-(hydroxymethyl)cyclohexyl)pyrazinyl)fluorobenzoate (215.6
mg, 0.600 mmol) was dissolved in THF (3 mL) and then MeOH (3 mL) was added and
then 1.0 M LiOH (2400 uL, 2.400 mmol) was added. The reaction mixture was agitated
overnight and the next morning, LCMS ted formation of desired t. The
reaction mixture was concentrated in vacuo and then azeotroped with THF twice (10 mL
each) and then ied with 1.5 mL of 4.0 N HCI in dioxane and concentrated in vacuo.
The residue was dissolved in DMSO (5 mL) and taken to the next step as such. LCMS
(m/z): 346.2 (MH+), 0.57, 0.58 min.
S nthesis of 4- 3-amino 1s 4s oroc clohex l razin l fluorobenzoic acid
Scheme 119
F 0 Steel F o Stag; F 0 mg F o
NH2 OMe NH2 OMe NH2 0M9
NH2 OH
N \ N \
N BH Nl \ N \
| a
/N 4 K», Et3N.3HF,PBSF /N LIOH I
? Et3N
O OH F i:
Ste 1. meth l4- 3-amino 1r4r h drox c clohex l razin-2— lfluorobenzoate
Methyl 4-(3-amino(4-oxocyclohexyl)pyrazinyl)—2-fluorobenzoate (401.4 mg, 1.169
mmol) was suspended in MeOH and cooled to 0 °C. To the mixture was added NaBH4
(133 mg, 3.51 mmol) dissolved in MeOH (5 mL) and the mixture was gradually warmed to
room temperature and stirred for 30 min upon which reaction was complete. The reaction
mixture was d with EtOAc and saturated NaHC03 and the organic layer washed with
water twice and dried (MgSO4), filtered and concentrated in vacuo to afford 339.4 mg of
the desired product (84%). LCMS (m/z): 346.2 (MH+), 0.63 min.
Ste 2. Meth l4- 3-amino 1s 4s fluoroc clohex l razin lfluorobenzoate
A flask containing a solution of methyl 4-(3-amino((1r,4r)hydroxycyclohexyl)pyrazin-
2-y|)f|uorobenzoate (339.4 mg, 0.983 mmol) in itrile (3.2 mL) was cooled to 0 °C
in a ice/brine bath and orobutanesulfonyl fluoride (530 pl, 2.95 mmol) followed by
triethylamine trihydrofluoride (480 pl, 2.95 mmol) and triethylamine (1233 ul, 8.84 mmol)
was added and the resulting reaction mixture was allowed to stir at 0 °C for 90 min. After
the elapsed time, LCMS indicated a 25:1 ratio of elimination vs. desired product. The
reaction mixture was ed with water and extracted with EtOAc and the organic
extract washed with water twice and dried (MgSO4), filtered and concentrated in vacuo to
afford the crude product mixture which was carefully chromatographed (0-60%
EtOAc/heptane) to afford 67.5 mg of the desired product. (19.8%). LCMS (m/z): 348.2
(MH+), 0.86 min.
Ste 3. 4- 3-amino 1s 4s f|uoroc clohex l razin l f|uorobenzoic acid
Methyl 4-(3-amino((1s,4s)f|uorocyclohexyl)pyrazinyl)fluorobenzoate (67.5 mg,
0.194 mmol) was dissolved in THF (1 mL) and MeOH (1 mL) and then 1.0 M LiOH (0.777
mL, 0.777 mmol) was added. The reaction mixture was ed at room temperature.
After 1 h, LCMS indicated formation of desired acid. LCMS (m/z): 334.2 (MH+), 0.70 min.
S nthesis of 3-bromo 1r4r f|uoroc clohex l razinamine
Scheme 120
NH2 m1 NH2 Step g NH2
W SteE g NH2
I NS NNBF
/N I I
LiEt3BH /N Et3N.3HF, PBSF NBS
/N /N
—> —,
Et3N
o OH i 2
F F
Ste 1. 1s 4s 5-amino razin lc clohexanol
4-(5-aminopyrazinyl)cyclohexanone (1.049 g, 5.48 mmol) was dissolved in THF (10
mL) and cooled to 0 °C. ctride (12.06 mL, 12.06 mmol) was added dropwise and
the mixture d for 20 min upon which reaction complete. The reaction e was
quenched with 5 N NaOH (40 mmol) and then MeOH (5mL). The reaction mixture was
WO 66188
diluted with 2-methyl THF and the aqeous layer separated and the organic layer washed
with brine and dried (MgSO4), filtered and concentrated in vacuo to afford the desired
product in a 95:5 cis/trans ratio which was then titurated with ether to obtain 586.3 mg of
a faint yellow itate as the d product (55%). LCMS (m/z): 194.1 (MH+), 0.32
min.
Ste 2 and 3. 3-bromo 1r4r fluoroc clohex l razinamine
Following Step 2 and 3 in Scheme 119, 3-bromo((1r,4r)f|uorocyclohexyl)pyrazin
amine was obtained. LCMS (m/z): 276.0 (MH+), 0.81 min.
S nthesis of 4- 3-amino 4-c anoc clohex l razin l f|uorobenzoic acid
F O
NH2 OH
trans/cis mixture
Following Steps 4 to 7 in Scheme 118, 4-(3-amino(4-cyanocyclohexyl)pyraziny|)
fluorobenzoic acid was obtained. LCMS (m/z): 341.2 (MH+), 0.64, 0.66 min (trans, cis).
Table 5. Compounds prepared using Method 3 described above.
Structure
1H NMR (400MHz, CD30D) 5 7.88
(S)-N-(2-amino—1 - - 7.7 (m, 2 H), 7.62 (m, 1 H), 7.52
(3- (m, 1 H), 7.46 (s, 1 H), 7.36 (m, 3
chlorophenyl)ethy H), 5.4 (m, 1 H), 3.38 (m. 2 H), 2.56
|)(3-amino—6- (m, 1 H), 1.79 (m, 4 H), 1.64 (m, 1
cyclohexylpyrazin H), 1.48 - 1.33 (m, 4 H), 1.33 (m, 1
y|)-2— H).
fluorobenzamide
1H NMR (400MHz ,CD30D) 5 8.13
(S)-4—(2-amino—5- (d, J = 2.0 Hz,1 H), 8.01 (d, J = 2.0
(1 -methyI-1 H- Hz,1 H), 7.91 (t, J = 7.6 Hz,1 H),
pyrazoI 7.54 (d, J = 2.0 Hz,1 H), 7.53 -
y|)pyridinyI) 7.43 (m, 2 H), 7.43 - 7.34 (m, 1 H),
fluoro-N-(1-(3- 7.25 (d, J = 7.8 Hz,1 H), 7.17 (d, J
fluorophenyl)—2- = 10.2 Hz,1 H), 7.02 (dt, J = 2.2,
hydroxyethyl)ben 8.5 Hz,1 H), 6.51 (d, J = 2.0 Hz,1
H), 5.23 (d, J = 6.3 Hz,1 H), 3.96 -
3.89 (m, 3 H), 3.90 - 3.80 (m, 2 H)
(S)-4—(2-amino—5-
1H NMR z ,CD30D) 5 8.13
(1 -methyI-1 H-
(d, J = 2.0 Hz,1 H), 8.04 (s, 1 H),
pyrazoI
7.98 (d, J = 2.0 Hz,1 H), 7.95 -
idinyI)
7.87 (m, 2 H), 7.80 (d, J = 7.8 Hz,1
fluoro—N-(2—
H), 7.65 (t, J = 7.8 Hz,1 H), 7.53 (d,
hydroxy—1-(3-
J = 2.0 Hz, 1 H), 7.52 - 7.44 (m, 2
(methylsulfonyl)p
H), 6.50 (s, 1 H), 5.31 (d, J = 5.5
henyl)ethyl)benza
Hz,1 H), 4.00 - 3.86 (m, 5 H), 3.12
mide
(s, 3 H)
1H NMR (400MHz, CD30D) 5 ppm
(S)-4—(2-amino—5- 8.13 (d, J = 2.0 Hz,1 H), 8.03 (d, J
(1 I-1 H- = 2.3 Hz, 1 H), 7.91 (t, J = 7.8 Hz,1
pyrazoI H), 7.54 (d, J = 2.0 Hz,1 H), 7.52 -
y|)pyridinyI) 7.40 (m, 2 H), 7.28 - 7.13 (m, 3 H),
fluoro—N-(2— 7.10 (d, J = 6.7 Hz,1 H), 6.51 (d, J
hydroxy—1-(m- = 2.0 Hz, 1 H), 5.24 - 5.15 (m, 1 H),
to|y|)ethy|)benza 3.95 - 3.89 (m, 3 H), 3.89 - 3.74 (m,
mide
2 H)
Structure
H NMR (400MHz, CD30D) 8 8.13
(S)—4—(2-amino—5-
(d, J = 2.3 Hz, 1 H), 8.00 (d, J = 2.0
(1 -methyI-1 H-
Hz, 1 H), 7.91 (t, J = 7.8 Hz, 1 H),
pyrazoI
7.56 - 7.45 (m, 3 H), 7.30 (s, 1 H),
y|)pyridinyI)-N-
7.18 - 7.10 (m, 2 H), 6.50 (d, J = 2.0
(1 -(3-ch|oro—5-
Hz, 1 H), 5.18 (t, J = 5.7 Hz, 1 H),
fluorophenyl)—2-
3.91 (s, 3 H), 3.90 - 3.81 (m, 2 H).
hydroxyethyl)—2-
fluorobenzamide
1H NMR (400MHz, CD30D) 5 8.10
- 7.98 (m, 1H), 7.90 - 7.75 (m, 2H),
(S)—N-(2-amino—1 - 7.50 - 7.25 (m, 7H), 6.45 - 6.32 (m,
1H), 5.46 - 5.30 (m, 1H), 3.81 (s,
chlorophenyl)ethy
3H), 3.48 - 3.28 (m, 2H)
|)(2-amino—5-
(1 I-1 H-
pyrazoI
y|)pyridinyI)
fluorobenzamide
1H NMR (400MHz, CD30D) 8 8.87
(s, 1 H), 8.54 (d, J = 4.7 Hz, 1 H),
(S)—4—(2-amino—5-
F O {OH 8.08 (d, J = 2.0 Hz, 1 H), 7.79 (t, J
(1_methyl_1H_
: = 7.6 Hz, 1 H), 7.64 (d, J = 2.3 Hz,
imidazol_5_
”“2 N 1H), 7.57 (d, J = 1.6 Hz, 1 H), 7.43 -
12102314114113I) r.d.n_3_ I)_2_
234 N \ 450.3 049 7.32 (m, 3 H), 7.32 -7.23 (m,1 H),
/ F 7.19 - 7.12 (m, 2 H), 7.08 (d, J = 9.8
fluorophenyl)_2_
Hz, 1 H), 6.92 (dt, J = 2.0, 8.4 Hz,
yethyl)ben
/ N/ . 1H), 5.15-5.09 (m,1 H), 3.83-
zam'de
N=/ 3.71 (m, 5 H)
1H NMR (400MHz, CD30D) 8 8.97
F O _/ 1
, (s, H), 8.66 (br. s.,1 H), 8.18 (d, J
? (2'am'"°'5' = 2.0 Hz, 1 H), 7.88 (t, J = 7.8 Hz, 1
”“2 N .(1Tmethyl'1H' H), 7.72 (d, J = 2.0 Hz, 1 H), 7.67
N \ 'T'dafil': (d, J :16 Hz, H), 7.50 - 7.40 (m,
m' 'y)'I N'
235 I
/ CI 2’1)?! 466.4 0 55 3 H), 7.40-7.25 (m, 3 H), 5.20 (d, J
— 5.9 Hz, 1 H), 3.95 - 3.81 (m, 5 H)
chlorophenyl)_2_
/ N/
hydroxyethyl)—2-
N:/ fluorobenzamide
Structure
1H NMR (400MHz, CD30D) 8 8.21
4-(2-amino—5-(1 -
- 8.12 (m, 2 H), 8.05 (s, 1 H), 7.99
methyl-1 H-
(t, J = 7.8 Hz, 1 H), 7.88 (s, 1 H),
pyrazoI
7.81 (t, J = 7.6 Hz, 1 H), 7.54 - 7.44
idinyI)-N- 437.2 0.62
(m, 2 H),7.41 (d, J = 7.8 Hz, 1 H),
((6-chloropyridin-
7.37 (d, J = 7.8 Hz, 1 H), 4.71 (s, 2
2-yl)methyI)
H), 3.94 (s, 3 H).
fluorobenzamide
4-(2-amino—5-(1 -
1H NMR (400MHz, CD30D) 8 =
methyl-1 H-
8.15 (q, J = 2.2 Hz, 2 H), 8.05 (s, 1
pyrazoI
H), 7.94 - 7.87 (m, 2 H), 7.62 (s, 1
y|)pyridinyI)
H), 7.53 - 7.42 (m, 3 H), 4.46 (s, 2
fluoro-N-((1-
H), 3.93 (s, 3 H), 3.87 (s, 3 H)
methyl-1 H-
pyrazoI
y|)methy|)benzam
H NMR (400MHz, CD30D) 8 =
8.15 (d, J = 2.0 Hz, 1 H), 8.17 (d, J
= 2.3 Hz, 1 H), 8.05 (s, 1 H), 7.98 (t,
J: 7.8 Hz, 1 H), 7.88 (s, 1 H), 7.75
238 4_(2_amino_5_(1_ (d, J = 3.5 Hz, 1 H), 7.56 (d, J = 3.5
methy|_1H_ Hz, 1 H), 7.52 - 7.43 (m, 2 H), 4.92
F O pyrazoI (S. 2 H). 3-93 (S. 3 H)
NH N / idinyI)
2 H/YJ 409'2 0'49
S fluoro-N-(thiazol-
I 2-
\ ylmethyl)benzami
1H NMR (400MHz, CD30D) 8 8.15
F 0 4-(2-amino—5-(1- (d, J = 2.3 Hz, 1 H), 8.09 (s, 1 H),
NH2 Nm methyl-1H- 8.03 (s, 1 H), 7.94 - 7.84 (m, 2 H),
H pyrazoI 7.48 - 7.37 (m, 3 H), 7.31 (br. s., 1
N, s
y|)pyrIdIny|) H), 7.13 (d, J: 3.9 Hz,1 H), 4.62
239 l
\ 408.2 0.64
fluoro—N- (s, 2 H), 3.93 (s, 3 H)
hen-S-
/ ylmethyl)benzami
/ de
Structure
H NMR (400MHz, CD30D) 8 8.16
(S)(2-amino—5-
(1 -methyI-1 H- (q, J=2.1 Hz, 2H), 8.05 (s, 1H), 7.92
(t, J=7.8 Hz, 1H), 7.88 (s, 1H), 7.51
I
y|)pyridinyI) - 7.44 (m, 2H), 7.29 (s, 1H), 7.18 (d,
J=9.8 Hz, 1H), 7.07 (d, J=9.0 Hz,
fluoro-N-(1-(3-
fluoro 1H), 5.45 (s, 1H), 5.34 (s, 1H), 5.23
(fluoromethyl)phe (t, J=5.9 Hz, 1H), 3.93 (s, 3H), 3.92
- - 3.82 (m, 2H)
yethyl)ben
zamide
H NMR (400MHz, CD30D) 8 8.16
(S)(2-amino—5- (s, 2H), 8.06 (s, 1H), 7.96 - 7.90 (m,
(1 -methyI-1 H- 1H), 7.89 (s, 1H), 7.56 (dd, J=2.0,
7.0 Hz, 1H), 7.53 - 7.45 (m, 2H),
I
7.44 - 7.37 (m, 1H), 7.25
y|)pyridinyI)-N- (t, J=8.8
Hz, 1H), 5.23 - 5.15 (m, 1H), 3.94
(1 -(3-ch|oro—4-
fluorophenyl)—2- (s, 2H), 3.92 - 3.80 (m, 2H)
hydroxyethyI)
fluorobenzamide
(S)(2-amino—5-
1H NMR (400MHz, CD30D) 8 8.01
(1 ,5-dimethyI-1 H-
(d, J=2.2 Hz, 1H), 7.96 (d, J=2.1
pyrazoI
Hz, 1H), 7.95 - 7.90 (m, 1H), 7.66
y|)pyridinyI)
(s, 1H), 7.52 (d, J=1.5 Hz, 0.5H),
fluoro-N-(1-(3-
7.49 (s, 1H), 7.47 (d, J=1.7 Hz,
fluoro
0.5H), 7.30 (d, J=0.9 Hz, 1H), 7.19
(fluoromethyl)phe
(d, J=9.8 Hz, 1H), 7.09 (d, J=8.5
ny|)
Hz, 1H), 5.46 (s, 1H), 5.35 (s, 1H),
hydroxyethyl)ben
.24 (t, J=5.8 Hz, 1H), 3.95 - 3.86
zamide
(m, 2H), 3.86 (s, 3H), 2.42 (s, 3H)
(S)(2-amino—5- 1H NMR (400MHz, CD30D) 8 8.02
(1 ,3-dimethyI-1 H- (d, J=2.2 Hz, 1H), 7.97 (d, J=2.2
pyrazoI Hz, 1H), 7.94 - 7.88 (m, 1H), 7.85
y|)pyridinyI) (s, 1H), 7.51 - 7.44 (m, 2H), 7.29 (d,
fluoro-N-(1-(3- J=0.9 Hz, 1H), 7.18 (d, J=9.8 Hz,
fluoro 1H), 7.07 (d, J=8.5 Hz, 1H), 5.45 (s,
(fluoromethyl)phe 1H), 5.33 (s, 1H), 5.23 (t, J=5.9 Hz,
ny|) 1H), 3.93 - 3.86 (m, 2H), 3.86 - 3.84
hydroxyethyl)ben (m, 3H), 2.36 (s, 3H)
zamide
2014/062913
Structure
1H NMR (400MHz, CD30D) 8 8.15
(s, 2H), 8.06 (s, 1H), 7.93 - 7.85 (m,
(S)—4-(2-amino—5- 2H), 7.50 - 7.41 (m, 2H), 4.03 - 3.97
(1 -methyI-1 H- (m, 1H), 3.93 (s, 3H), 3.72 (d, J=5.1
pyrazoI Hz, 2H), 1.94 - 1.74 (m, 4H), 1.74 -
1.64 (m, 2H), 1.38 - 1.08 (m, 5H)
y|)pyridinyI)-N-
(1 -cyclohexyI
hydroxyethyl)—2-
fluorobenzamide
1H NMR (400MHz, CD30D) 8 8.19
4-(2-amino—5-(1 -
(d, J = 2.35 Hz, 1H), 7.91 (s, 1H),
methyl-1 H- 7.87 (t, J = 7.83 Hz, 1H), 7.77 (s,
pyrazoI
1H), 7.66 (d, J = 2.35 Hz, 1H), 7.58
y|)pyridinyI)-N-
(s, 1H), 7.55 (d, J = 7.04 Hz, 1H),
(3- 7.38 - 7.51 (m, 4H), 6.59 - 6.92 (m,
oromethyl)b
1H), 4.67 (s, 2H), 3.91 (s, 3H)
fluorobenzamide
1H NMR (400MHz, CD30D) 8 8.92
4-(2-amino—5-(1 - (d, J = 3.52 Hz, 1H), 8.15 (s, 2H),
methyl-1 H- 8.05 (s, 1H), 7.92 (t, J = 7.83 Hz,
pyrazoI 1H), 7.88 (s, 1H), 7.57 (s, 1H), 7.41
y|)pyridinyI)-N- - 7.51 (m, 3H), 7.37 (d, J = 7.43 Hz,
(3-bromobenzyl)- 1H), 7.21 - 7.31 (m, 1H), 4.60 (d, J
2- = 5.87 Hz, 2H), 3.93 (s, 3H)
fluorobenzamide
(S)—4-(3-amino—6-
(1 ,5-dimethyI-1 H-
pyrazoI
y|)pyrazinyI)
fluoro—N-(2-
hydroxy-1 -
phenylethyl)benz
amide
Structure
(S)—N-(2-amino—1 -
1H NMR (400MHz, CD30D) d 7.93
phenyl)ethy
- 7.77 (m, 3H), 7.60 - 7.43 (m, 2H),
|)(2-amino—5-
7.43 - 7.28 (m, 5H), 5.47 - 5.33 (m,
(1 ,5-dimethyI-1 H-
1H), 3.82 - 3.68 (m, 3H), 3.47 - 3.30
pyrazoI
(m, 2H), 2.39 - 2.24 (m, 3H)
y|)pyridinyI)
fluorobenzamide
(3-amino—6-
(1 ,3,5-trimethyl- 1H NMR (400MHz, CD30D) d 8.01
1H-pyrazoI (s, 1 H), 7.85 (m, 1 H), 7.70 (m, 1
y|)pyrazinyI) H), 7.63 (m, 1 H), 7.41 (m, 2 H),
fluoro—N-(2— 7.34 (m, 2 H), 7.27 (m, 1 H), 5.20
hydroxy-1 - (m, 1 H), 3.84 (m, 2 H), 3.79 (s, 3
phenylethyl)benz H), 2.39 (s, 3 H), 0.32 (s, 3 H)
amide
(S)—N-(2-amino—1 -
(3- 1H NMR (400MHz, CD30D) 8 7.91
chlorophenyl)ethy - 7.80 (m, 1H), 7.79 - 7.67 (m, 2H),
|)(2-amino—5- 7.49 - 7.43 (m, 1H), 7.42 - 7.25 (m,
(1 ,3,5-trimethyl- 6H), 5.45 - 5.30 (m, 1H), 3.67
1H-pyrazoI (s,3H), 3.46 - 3.30 (m, 2H), 2.17 (s,
y|)pyridinyI) 3H), 2.10 (s, 3H)
fluorobenzamide
(S)—4—(3-amino—6-
1H NMR (400MHz, CD30D) 8 7.80
cyclopropylpyrazi
-7.71 (m, 2 H), 7.56 (m, 1 H), 7.49
nyl)—2-fluoro—
(m, 1 H), 7.36 - 7.15 (m, 5 H), 5.11
N-(2-hydroxy
(m, 1 H), 3.76 (m, 2 H), 1.94 (m, 1
phenylethyl)benz
H), 0.82 (m, 4 H)
amide
Structure
(S)—N-(2-amino—1 -
1H NMR (400MHz, CD30D) 5 7.82
ethyl)—4-(3- - 7.75 (m, 2 H), 7.58 (m, 1 H), 7.49
amino
(m, 1 H), 7.43 - 7.26 (m, 5 H), 5.39
cyclopropylpyrazi
(m, 1 H), 3.36 (m, 2 H), 1.94 (m, 1
nyl)—2-
H), 0.81 (m, 4 H)
fluorobenzamide
(S)—4-(2-amino—5-
(1 -methyI-1 H- 1H NMR (400MHz, CD30D) 5 ppm
pyrazoI 8.06 (m, 1H), 7.99 (m, 1H), 7.90 (m,
y|)pyridinyI)-N- 1H), 7.79 (m, 1H), 7.38 (m, 2H),
(1 -(3- 7.26 (d, J=9.0 Hz, 1H), 7.13 (d,
(difluoromethyl)— J=8.6 Hz, 1H), 6.88 - 6.49 (t, J-56
-fluorophenyI) Hz, 1H), 5.39 (s, 2H), 5.17 (t, J=5.7
hydroxyethyl)—2- Hz, 1H), 3.83 (s, 3H), 3.82 (m, 2H)
fluorobenzamide
(S)—4-(2-amino—5-
1H NMR (400MHz, CD30D) 5 ppm
(1 -methyI-1 H-
8.77 - 8.61 (m, 1H), 8.17 - 8.08 (m,
pyrazoI
1H), 8.03 - 7.95 (m, 1H), 7.95 - 7.83
y|)pyridinyI)
(m, 1H), 7.57 - 7.35 (m, 6H), 7.35 -
fluoro-N-(1-(3-
7.26 (m, 1H), 6.54 - 6.43 (m, 1H),
(fluoromethyl)phe
.43 (s, 1H), 5.32 (s, 1H), 5.28 -
ny|)
.19 (m, 1H), 3.91 (s, 1H), 3.91 -
hydroxyethyl)ben
3.79 (m, 2 H)
zamide
....\ (S)—4-(2-amino—5-
(1 ,3-dimethyI-1 H-
IZ 1H NMR z, CD30D) 5 ppm
pyrazoI
8.69 (m, 1H), 8.02 (m, 7H), 7.97 (m,
y|)pyridinyI)
7H), 7.56 - 7.38 (m, 6H), 7.33 (m,
255 fluoro-N-(1-(3-
1H), 5.44 (s, 1H), 5.32 (s, 1H), 5.25
methyl)phe
(m, 1H), 3.96 - 3.82 (m, 2H), 3.86
ny|)
(s, 3H), 2.36 (s, 3H)
hydroxyethyl)ben
zamide
Structure
(S)(2-amino—5-
(1 ,5-dimethyI-1 H- 1H NMR (400MHz, CD30D) 5 ppm
pyrazoI 6.60 (m, 1H), 7.9 (m, 1H), 7.66 (m,
y|)pyridinyI) 1H), 7.62 (m, 1H), 7.56 (m, 1H),
fluoro-N-(1-(3- 7.43 - 7.27 (m, 5H), 7.24 (m, 1H),
(fluoromethyl)phe 5.35 (s, 1H), 5.23 (s, 1H), 5.16 (m,
ny|) 1H), 3.65 - 3.72 (m, 2H), 3.76 (s,
hydroxyethyl)ben 3H), 2.32 (s, 3H)
zamide
(S)(3-amino—6-
(tetrahydro—ZH- 1H NMR (400MHz, CD30D) 5 ppm
4- 6.69 (m, 1H), 7.66 (m, 2H), 7.73 -
y|)pyrazinyI) 7.56 (m, 2H), 7.56 - 7.36 (m, 3H),
fluoro-N-(1-(3- 7.33 (m, 1H), 5.44 (s, 1H), 5.32 (s,
(fluoromethyl)phe 1H), 5.24 (m, 1H), 4.04 (m, 2H),
ny|) 3.94 - 3.76 (m, 2H), 3.57 (m, 2H),
yethyl)ben 2.94 (m, 1H), 1.97 - 1.76 (m, 4H)
zamide
(S)(3-amino—6-
1H NMR (400MHz, CD30D) 5 ppm
(tetrahydro—ZH-
7.66 (m, 2H), 7.72 - 7.56 (m, 2H),
pyran
7.56 - 7.36 (m, 3H), 7.46 - 7.36 (m,
y|)pyrazinyI)-N
2H), 7.29 (m, 1H), 5.44 (s, 1H),
(1-(3-
.32 (s, 1H), 5.16 (m, 1H), 4.05 (m,
bromophenyI)
2H), 3.65 (m, 2H), 3.57 (m, 2H),
hydroxyethyI)
2.95 (m, 1H), 1.97 - 1.76 (m, 4H)
fluorobenzamide
(S)(3-amino—6-
1H NMR (400MHz, CD30D) 5 ppm
(tetrahydro—ZH-
7.66 (m, 2H), 7.73 - 7.60 (m, 2H),
7.56 - 7.36 (m, 3H), 7.46 (s, 1H),
y|)pyrazinyI)-N-
7.30 - 7.17 (m, 2H), 5.17 (m, 1H),
(1 -(3-bromo—5-
4.04 (m, 2H), 3.66 (m, 2H), 3.57 (m,
fluorophenyl)—2-
2H), 2.95 (m, 1H), 1.97 - 1.79 (m,
hydroxyethyI)
fluorobenzamide
Structure
(S)—4—(2-amino—5-
(difluoromethyl)—
1H NMR (400MHz, CD30D) 5 ppm
yI-1H-
7.93 (m, 1H), 7.87 - 7.77 (m, 2H),
pyrazoI
7.74 (s, 1H). 7.45 (t, J = 60 Hz, 1H),
y|)pyridinyI) 514.3 0.63
7.41 - 7.28 (m, 5H), 7.23 (m, 1H),
fluoro-N-(1-(3-
.28 (d, J = 48 Hz, 1H), 5.15 (m,
(fluoromethyl)phe
1H), 3.78 (m, 2H), 2.46 (s, 3H)
ny|)
hydroxyethyl)ben
zamide
(2-amino—5-
(1 -
(difluoromethyl)—
1H NMR (400MHz, CD30D) 5 ppm
3-methyI-1H-
8.2 (m, 1H), 7.97 (m, 1H), 7.87 -
pyrazoI
7.77 (m, 2H), 7.4 - 7.28 (m, 5H),
y|)pyridinyI)
7.32 (t, J = 60, 1H), 7.23 (m, 1H),
-N-(1-(3-
.28 (d, J = 48 Hz, 2H), 5.15 (m,
(fluoromethyl)phe
1H), 3.78 (m, 2H), 2.31 (s, 3H)
ny|)
hydroxyethyl)ben
zamide
(S)—4—(2-amino—5-
(1 -
oromethyl)—
1H NMR (400MHz, CD30D) 5 ppm
-methyI-1H-
7.93 (m, 1H), 7.87 (m, 1H), 7.81
pyrazoI
(m, 1H), 7.75 (s, 1H), 7.46 (t, J = 56
y|)pyridinyI)
Hz, m), 7.38 (m, 2H), 7.19 (m, 1H),
fluoro-N-(1-(3-
7.9 (d, J =12 Hz, 1H), 6.98 (d, J =
fluoro
8 Hz, 1H), 5.3 (d, J = 48 Hz, 2H),
(fluoromethyl)phe
.14 (m, 1H), 3.78 (m, 2H), 2.46 (s,
ny|)
hydroxyethyl)ben
zamide
(S)—4—(2-amino—5-
1H NMR (500 MHz, METHANOL-
(1 -methyI-1 H-
d4) 8 8.19 (d, J=2.35 Hz, 1 H) 7.91
pyrazoI
(s, 1 H) 7.86 (t, J=7.83 Hz,1 H)
y|)pyridinyI)-N-
7.77 (s,1 H) 7.67 (d, J=2.35 Hz,
(1 -(3-
1H) 7.49 - 7.39 (m, 3 H) 7.39 - 7.25
chlorophenyl)—2-
(m, 3 H) 5.19 (t, J=5.87 Hz, 1 H)
hydroxyethyl)—2-
4.02- 3.78 (m, 5 H).
fluorobenzamide
Structure
(S)—4-(2-amino—5-
(1 -
oromethy|)-
1H NMR (400MHz, CD30D) 5 ppm
-methyI-1H-
8.2 (m, 1H), 8.1 (m, 1H), 7.6 (m,
pyrazoI
1H), 7.55 (m, 1H), 7.48 - 7.20 (m,
yI)pyridinyl)—N-
7H), 5.32 (m, 1H), 4.03 (m, 2H),
(1 -(3-
2.54 (s, 3H)
chlorophenyl)—2-
hydroxyethyl)—2-
fluorobenzamide
(S)—4-(2-amino—5-
(1-methyI-1H- 1H NMR (400MHz, CD30D) 6 ppm
1,2,3-triazoI 8.20 (d, J=2.0 Hz, 1H), 7.96 - 7.83
yI)pyridinyl)—N- (m, 3H), 7.53 - 7.39 (m, 3H), 7.27
(1-(3- ' (d, J=8.2 Hz, 1H), 7.19 (d, J=9.8
chlorophenyl)—2- Hz, 1H), 5.17 (s, 1H), 4.13 (s, 3H),
hydroxyethyl)—2- 3.86 (dd, J=6.1, 8.0 Hz, 2H)
fluorobenzamide
(S)—4-(2-amino—5-
(1-methyI-1H- 1H NMR (400MHz, CD30D) 6 ppm
1,2,3-triazoI 8.19 (m, 1H), 7.91 (m, 1H), 7.89 (m,
yI)pyridinyl)—N- 2H), 7.61 (s, 1H), 7.53 - 7.36 (m,
(1-(3- ' 4H), 7.36 - 7.21 (m, 1H), 5.48 (s,
henyl)—2- 2H), 5.18 (t, J=5.9 Hz, 1H), 4.13 (s,
hydroxyethyl)—2- 3H), 3.86 (dd, J=5.9, 8.6 Hz, 2H)
fluorobenzamide
2014/062913
Structure
(2-amino
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 5 ppm
1,2,3-triazoI
8.20 (d, J=2.0 Hz, 1H), 7.98 - 7.83
y|)pyridinyI)
(m, 3H), 7.53 - 7.39 (m, 3H), 7.27
fluoro-N-(1-(3-
(d, J=8.2 Hz, 1H), 7.19 (d, J=9.8
fluoro
Hz, 1H), 5.17 (s, 1H), 4.13 (s, 3H),
iodophenyI)
3.88 (dd, J=6.1, 8.0 Hz, 2H).
hydroxyethyl)ben
zamide
(S)(3-amino-
1H NMR (400MHz, CD30D) 5 ppm
6-(1H-pyrazoI
8.84 (br. s., 1 H) 8.35-8.27 (m, 1 H)
y|)pyrazinyI)
8.09(s, 2 H) 7.92-7.82 (m, 1 H)
fluoro-N-(2- 419.2 0.585
7.78-7.81 (m, 2 H) 7.50-7.21 (m, 5
hydroxy
H) 5.29-5.14 (m, 1 H) 3.92-3.78 (m,
phenylethyl)benz
2 H)
amide
(S)(2-amino
1H NMR (400MHz, CD30D) 5 ppm
(1 -methyI-1 H-
8.23 -7.98 (m, 3 H), 7.88 (s, 1 H),
pyrazoI
7.58 (d, J=7.83 Hz, 1 H), 7.51 -
idinyI)-N- 428.2 0.57
7.01 (m, 7 H), 5.23 (dd, ,
(2-hydroxy
.09 Hz, 1 H), 4.07 - 3.53 (m, 5 H),
phenylethyI)
2.44 (s, 3 H)
methylbenzamide
(S)(2-amino
(1 ,3-dimethyI-1 H-
1H NMR (400MHz, CD30D) 5 8.08
pyrazoI
- 7.78 (m, 4H), 7.53 - 7.42 (m, 3H),
y|)pyridinyI)-N-
7.35 (d, J=9.8 Hz, 1H), 7.23 (d,
(1 -(3-
514.1 0.65 J=8.6 Hz, 1H), 8.97 - 8.58 (t, J=56
(difluoromethy|)-
Hz, 1H), 5.48 (s, 2H), 5.28 (t, J=5.7
-fluorophenyI)
Hz, 1H), 3.89 (m, 2H), 3.85 (s, 3H),
hydroxyethyI)
2.38 (s, 3H)
fluorobenzamide
Structure
(S)—4-(2-amino—5-
(1 ,5-dimethyI-1 H- 1H NMR (400MHz, CD30D) 5 ppm
pyrazoI 8.03 - 7.85 (m, 3H), 7.64 (s, 1H),
y|)pyridinyI)-N- 7.55 - 7.41 (m, 3H), 7.35 (d, J=9.4
(1 -(3- Hz, 1H), 7.23 (d, J=8.6 Hz, 1H),
(difluoromethyl)— 6.99 - 6.56 (t, J=56 Hz, 1H), 5.48
-fluorophenyI) (s, 2H), 5.26 (t, J=5.7 Hz, 1H), 3.91
hydroxyethyl)—2- (m, 2H), 3.84 (s, 3H), 2.40 (s, 3H)
fluorobenzamide
(S)—4-(2-amino—5-
(1 -methyI-1 H-
1H NMR z, CD30D) 8 8.20
1,2,3-triazoI
(d, J=2.0 Hz, 1H), 7.95 - 7.82 (m,
y|)pyridinyI)-N-
3H), 7.54 - 7.42 (m, 3H), 7.34 (d,
(1 -(3-
J=9.4 Hz, 1H), 7.22 (d, J=8.6 Hz,
(difluoromethyl)—
1H), 5.25 (t, J=5.9 Hz, 1H), 4.13 (s,
-fluorophenyI)
3H), 3.97 - 3.80 (m, 2H)
hydroxyethyl)—2-
fluorobenzamide
(S)—4-(2-amino—5-
F 0 {OH
= (1-
F 1H NMR 400MHz,( C
. D3OD 5ppm)
””2 N éflfigflefiy')‘ 7.94 (m, 1H), 7.85 - 7.76 (m, 2H),
N/ 7.74 (s, 1H), 7.65
| - 7.25 (t, J=60
pyrazol_4_
\ _
273 F F y1l)pélridinyI)-N- 550.1 0.73 :12ggfif,fiffifirg’fifli?
\\ ( .'( '
Hz, 1H), 6.89-6.49 (t, J=56 Hz,
N‘N>,F (d'fluoromethy')'
1H), 5.21 - 5.08 (m, 1H), 3.89 - 3.70
-fluorophenyI)
F (m, 2H), 2.46 (s, 3H)
yethyl)_2_
fluorobenzamide
(S)—4-(2-amino—5-
F o r (1-
' F
NH2 N (difluoromethyl)— 1H NMR (400MHz, CD30D) 6 ppm
H 3-methyI-1H- 8.28 (s, 1H), 8.07 (d, J=2.0 Hz, 1H),
| pyrazoI 7.98- 7.81 (m, 2H), 7.61 -7.45 (m,
274 F F y|)pyridinyI)-N- 550.1 0.73 4H), 7.36 (m, 1H), 7.26 (m, 1H),
\ (1-(3- 6.97 - 6.60 (t, J=56 Hz, 1H), 5.25 (t,
N—N (difluoromethy|)- J=5.7 Hz, 1H), 4.01 - 3.77 (m, 2H),
>’F rophenyI) 2.40 (s, 3H)
hydroxyethyl)—2-
fluorobenzamide
2014/062913
Structure
(S)-4—(2-amino—5-
(1 -
(difluoromethyl)- 1H NMR (400MHz, CD30D) 5 ppm
-methyI-1H- 8.86 - 8.73 (m, 1H), 8.10 - 7.98 (m,
pyrazoI 2H), 7.96 - 7.83 (m, 2H), 7.73 - 7.55
y|)pyridinyI)-N- (m, 3H), 7.55 - 7.41 (m, 5H), 6.98 -
(1 -(3- 6.61 (m, 1H), 5.36 -5.22 (m, 1H),
(difluoromethyl)p 4.01 - 3.77 (m, 2H), 2.65 - 2.51 (m,
henyI) 3H)
hydroxyethyI)
fluorobenzamide
(S)-4—(2-amino—5-
(1 ,5-dimethyI-1 H-
pyrazoI 1H NMR (400MHz, CD30D) 5 ppm
idinyI)-N- 8.85 - 8.74 (m, 1H), 8.06 - 7.87 (m,
(1 -(3- 3H), 7.73 - 7.57 (m, 3H), 7.55 - 7.42
(difluoromethyl)p (m, 4H), 6.98 - 6.62 (m, 1H), 5.39 -
henyI) 5.22 (m, 1H), 4.00 - 3.81 (m, 5H),
hydroxyethyI) 2.48 - 2.36 (m, 3H)
fluorobenzamide
(S)-4—(2-amino—5-
(1 ,3-dimethyI-1 H- 1H NMR (400MHz, CD30D) 5 ppm
I 8.81 (d, J=4.1 Hz, 1H), 8.10 - 7.97
y|)pyridinyI)-N- (m, 2H), 7.97 - 7.83 (m, 2H), 7.70 -
(1 -(3- 7.57 (m, 2H), 7.56 - 7.43 (m, 3H),
(difluoromethyl)p 6.98 - 6.63 (m, 1H), 5.37 - 5.23 (m,
henyI) 1H), 3.99 - 3.80 (m, 5H), 2.44 - 2.33
hydroxyethyI) (m, 3H)
fluorobenzamide
(R)(2-amino—5-
(1 -
(difluoromethyl)- 1H NMR (400MHz, CD30D) 5 ppm
-methyI-1H- 9.03 (d, J=6.3 Hz, 1H), 8.11 - 7.94
pyrazoI (m, 2H), 7.93 - 7.77 (m, 3H), 7.74 -
y|)pyridinyI) 562.1 0] 7.64 (m, 1H), 7.61 - 7.54 (m, 1H),
fluoro-N-(1-(3- 7.53 - 7.42 (m, 2H), 5.36 (t, J=6.9
fluoro Hz, 1H), 3.19 (s, 3H), 2.65 - 2.51
lsulfonyl)p (m, 3H), 1.64 (d, J=6.9 Hz, 3H)
henyl)ethyl)benza
mide
Structure
(S)—4—(3-amino—6- 1H-NMR (400MHz, CD30D) 8 7.85
(tetrahydro—ZH- - 7.70 (m, 2 H), 7.66 - 7.50 (m, 2
pyran H), 7.34 - 7.22 (m, 1 H), 7.19 - 7.12
y|)pyrazinyI) (m, 1 H), 7.12- 7.04 (m,1 H), 6.98
fluoro-N-(1-(3- -6.83 (m, 1 H), 5.18 - 5.04 (m, 1
fluorophenyl)—2- H), 4.03 - 3.87 (m, 2 H), 3.83 - 3.67
hydroxyethyl)ben (m, 2 H), 3.54 - 3.40 (m, 2 H), 2.92
zamide -2.78 (m, 1 H), 1.89- 1.66 (m, 4 H)
(S)—4—(3-amino—6-
(1 -methyI-1 H-
pyrazoI
y|)pyrazinyI)
451.1 0.66
fluoro-N-(1-(3-
fluorophenyl)—2-
yethyl)ben
zamide
(S)—4—(3-amino—6-
ropylpyrazi 1H NMR z, CD30D) 8 8.05
nyl)—2-fluoro— (m, 1 H), 7.91 - 7.87 (m, 2 H), 7.87
N-(2-hydroxy - 7.78 (m, 2 H), 7.68 - 7.64 (m, 2
471.2 0.63
(3- H), 7.64 - 7.57 (m, 1 H), 5.30 (m, 1
(methylsulfonyl)p H), 3.91 (m, 2 H), 3.12 (s, 3 H),
henyl)ethyl)benza 2.05 (m, 1 H), 0.93 (m, 2 H).
mide
(S)—4—(2-amino—5-
1H NMR (400MHz, CD30D) 8 8.60
(1 ,3-dimethyI-1 H-
(m, 1 H), 7.92 (m, 1 H), 7.87 (m, 1
pyrazoI
H), 7.81 (m 1 H), 7.76 (m, 2 H),
y|)pyridinyI)
464.1 0.60 7.37 (m, 2 H), 7.28 (m, 1 H), 7.15
fluoro-N-(1-(3-
(m, 1 H), 7.08 (m, 1 H), 6.92 (m, 1
fluorophenyl)—2-
H), 5.12 (m, 1 H), 3.84 - 3.69 (m, 2
hydroxyethyl)ben
H), 3.76 (s, 3 H), 2.26 (s, 3 H)
zamide
Structure
(S)(2-amino
1H NMR (400MHz, CD30D) 8 8.52
(1 ,3-dimethyI-1 H-
(m, 1 H), 7.92 (m, 1 H), 7.87 (m 1
pyrazoI
H), 7.81 (m, 1 H), 7.76 (m, 1 H),
y|)pyridinyI)
7.36 (m, 2 H), 7.22 - 7.08 (m, 3 H),
fluoro-N-(2-
7.01 (m, 1 H), 5.1 (m, 1 H), 3.82-
hydroxy—1-(m-
3.68 (m, 2 H), 3.76 (s, 3 H), 2.26 (s,
tolyl)ethy|)benza
3 H), 2.25 (s, 3 H).
mide
(S)(2-amino
(1 ethyI-1 H- 1H NMR (400MHz, CD30D) 8 8.74
pyrazoI (m, 1 H), 7.95 (m, 1 H), 7.92 (m, 1
y|)pyridinyI) H), 7.87 (m 1 H), 7.81 (m, 2 H),
fluoro-N-(2- 7.76 (m, 1 H), 7.71 (m,1 H), 7.56
hydroxy—1-(3- (m, 1 H), 7.38 (m, 2 H), 5.21 (m, 1
(methylsulfonyl)p H), 3.84 (m, 2 H), 3.76 (s, 3 H),
henyl)ethyl)benza 3.03 (s, 3 H), 2.26 (s, 3 H).
mide
4-(3-amino
cyclopropylpyrazi 1H NMR (400MHz, CD30D) 8 7.93
nyI)-N-(3- - 7.84 (m, 3 H), 7.87 (m 1 H), 7.76
chloro 4 . . (m, 1 H), 7.67 (m, 1 H), 7.59 (m, 1
(methylsulfonyl)b H), 4.09 (m, 2 H), 3.15 (s, 3 H),
enzyI) 2.05 (m, 1 H), 0.92 (s, 4 H).
fluorobenzamide
4-(3-amino
1H NMR (400MHz, CD30D) 8 7.91
cyclopropylpyrazi
- 7.84 (m, 2 H), 7.83 (m 1
H), 7.70 - nyI)fluoro-
459.2 0.75 7.57 (m, 3 H), 7.51 (m,1 H), 4.71
N-(3-fluoro
(m, 2 H), 3.16 (s, 3 H), 2.04 (m, 1
(methylsulfonyl)b
H), 0.91 (s, 4 H)
enzyl)benzamide
(R)(3-amino-6—
1H NMR (400MHz, CD30D) 8 7.90-
ropylpyrazi
7.82 (m, 2 H) 7.80-7.72 (m, 1 H)
nyI)fluoro-
7.68-7.51 (m, 4 H) 5.32 (q, J=7.04
N-(1-(3-fluoro 473.3 0.775
Hz,1 H) 3.16 (s, 3 H) .99 (m,
(methylsulfonyl)p
1 H) 1.61 (d, J=7.04 Hz, 3 -
henyl)ethyl)benza
0.87 (m, 4 H)
mide
WO 66188
Rt NMR
(min)
1H NMR (400MHz CD30D))5ppm
8.97 (d, J:828Hz 1H 7.(87s 1
(R)(2-amino
H), 7.80 (t, J:7.83 Hz,1 H), 7.72
cyclopropylpyridi
(dd, J=11.93, 2.15 Hz, 2 H) 7.83
nyI)fluoro-
(dt, J=7.83, 1.78 Hz, 1 H), 7.55 (d,
N-(1-(3-fluoro 472.3 0.682
J:9.39 Hz, 1 H), 7.45-7.35 (m, 2 H),
(methylsulfonyl)p
.40-5.25 (m, 1 H), 3.18 (s, 3 H),
henyl)ethyl)benza
2.03-1.88 (m, 1 H), 1.81 (d, J=7.04
mide
Hz, 3 H), 1.07-0.97 (m, 2 H), 0.80-
0.89 (m, 2 H)
(S)(2-amino
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 8 8.18
pyrazoI
(m, 2 H), 8.05 (s, 1 H), 7.88 (m 2
y|)pyridiny|)-N-4 H), 7.48 (m, 2 H), 7.31 (s, 1 H),
(1 -(3-chloro
fluorophenyI) I6:
7.14 (m, 2 H), 5.12 (m, 1 H), 3.93
(s, 3 H), 3.87 (m, 2 H).
hydroxyethy|)
fluorobenzamide
(S)(2-amino
(1 H-pyrazoI
-N-(2-y|)pyridiny|)4
hydroxy-1 -
phenylethyl)benz
amide I53 1H NMR (400MHz, CD30D) 8 ppm8.24-8.15 (m, 2 H) 8.08 (s, 2 H)7.91 (t, J=7.83 Hz, 1 H) 7.54-7.22(m, 7 H) 5.22 (t, J=8.08 Hz, 1 H)3.98-3.77 (m, 2 H)
Structure
(S)(2-amino
(1-isopropyI-1H-
1H NMR (400MHz, CD30D) 5 ppm
I
8.17 (s, 3 H) 8.04 (s, 1 H) 7.98-7.88
y|)pyridinyI)
(m, 3 H) 7.80 (d, J=7.83 Hz, 1 H)
fluoro-N-(2-
7.70-7.81 (m, 1 H) .42 (m, 2
hydroxy(3- 538.3 0.601
H) 5.31 (t, J=5.67Hz, 1 H) 4.58 (dt,
(methylsulfonyl)p
J=13.30, 8.85 Hz, 1 H) 4.08-3.74
henyl)ethy|)benza
(m, 2 H) 3.12 (s, 4 H) 1.52 (d,
mide
J=6.65 Hz, 8 H)
1H NMR (400MHz, CD30D) 5 ppm
(S)(2-amino 8.08 (d, J=2.35 Hz, 1 H) 8.05 (s,1
(1-isopropyI-1H- H) 8.00 (br. s., 1 H) 7.87-7.72 (m, 2
pyrazoI H) 7.42-7.35 (m, 2 H) 7.33-7.23 (m,
idinyI) 478.2 0.698 1 H) 7.18 (d, J=7.43 Hz, 1 H) 7.09
fluoro-N-(1-(3- (d, J=10.17 Hz, 1 H) 8.93 (t,J=8.41
fluorophenyI) Hz,1 H)4.48 (quin, J=6.65 Hz,1 H)
hydroxyethyl)ben 5.13 (t, J=5.87 Hz, 1 H) .58
zamide (m, 2 H) 1.42 (d, J=6.65 Hz, 8 H)
1H NMR (400 MHz, CD30D) 8 ppm
7.88 - 7.82 (m, 2H), 7.71 - 7.85 (m,
(S)(3-amino-6—
1H), 7.83 - 7.58 (m, 1H), 4.10 - 4.01
(tetrahydro-ZH-
(m, 2H), 4.01 - 3.94 (m, 1H), 3.72
pyran
(d, J=5.1 Hz, 2H), 3.58 (dt, J=2.5,
azinyI)-N-
11.4 Hz, 2H), 3.01 - 2.90 (m, 1H),
(1 -cyclohexyI
1.97 - 1.75 (m, 9H), 1.75 - 1.84 (m,
hydroxyethyI)
2H), 1.38 - 1.09 (m, 5H)
fluorobenzamide
(S)(2-amino
(1-isopropyI-1H- 1H NMR (400MHz, CD30D) 8 ppm
pyrazoI 8.85-8.47 (m, 1 H) 8.13-8.02 (m, 3
y|)pyridinyI) H) 7.89-7.71 (m, 2 H) 7.47-7.10 (m,
fluoro-N-(2- 7H) 5.23-5.05 (m, 1 H) 4.47 (spt,
hydroxy J=6.65 Hz, 1 H) 3.92-3.88 (m, 2 H)
phenylethyl)benz 1.43 (d, J=6.65 Hz, 8 H)
amide
Structure
(S)(2-amino 1H NMR (400MHz, CD30D) 5 ppm
(1 ,5-dimethyI-1 H- 8.00 (d, J=2.35 Hz, 1 H) 7.96 - 7.86
pyrazoI (m, 2 H) 7.65 (s, 1 H) 7.53 - 7.43
idinyI) (m, 2 H) 7.42 - 7.33 (m, 1 H) 7.25
fluoro-N-(1-(3- (d, J=7.83 Hz, 1 H) 7.17 (d,
fluorophenyI) J=10.17 Hz, 1 H) 7.02 (td, ,
hydroxyethyl)ben 1.96 Hz, 1 H) 5.22 (t, J=5.87 Hz, 1
zamide H) 3.84 (s, 5 H) 2.40 (s, 3 H)
(S)(2-amino-
1H NMR (400MHz, CD30D) 5 ppm
-(1-ethyI-1H-
8.20-8.15 (m, 2 H) 8.12 (s, 1 H)
pyrazoI
8.04 (s, 1 H) 7.96-7.87 (m, 3 H)
y|)pyridinyI)
7.80 (d, J=7.83 Hz, 1 H) 7.70-7.60
fluoro-N-(2-
(m, 1 H) 7.54-7.42 (m, 2 H) 5.31 (t,
hydroxy—1-(3-
J=5.48 Hz, 1 H) ) 4.22 (q, J=7.30
(methylsulfonyl)p
Hz, 2 H) 4.05-3.77 (m, 2 H) 3.12 (s,
henyl)ethy|)benza
3 H) 1.48 (t, J=7.24 Hz, 3 H)
mide
(S)(2-amino
1H NMR (400MHz, CD30D) 5 ppm
(1 -ethyI-1 H-
8.08 (s, 2 H) 8.03 (s, 1 H) 7.89-7.76
pyrazoI 480.3 (m, 2 H) 7.47-7.33 (m, 3 H) 7.31-
y|)pyridinyI)-N-
/482. 0.687 7.13 (m,3 H) 5.11 (t, J=5.87 Hz, 1
(1 -(3-
H) 4.14 (q, J=7.30 Hz, 2 H) 3.93-
chlorophenyI)
3.58 (m, 2 H) 1.40 (t, J=7.43 Hz, 3
hydroxyethyl)
fluorobenzamide
1H NMR (400MHz, CD30D) 5 ppm
(2-amino 8.19-8.14 (m, 2 H) 8.12 (s, 1 H)
(1 -ethyI-1 H- .87 (m, 2 H) 7.52-7.44 (m, 2
pyrazoI H) 7.38 (td, , 5.87 Hz, 1 H)
y|)pyridinyI) 7.25 (d, J=7.83 Hz, 1 H) 7.18 (d,
fluoro-N-(1-(3- J=10.17 Hz, 1 H) 7.02 (td,J=8.41,
fluorophenyI) 1.96 Hz, 1 H) 5.22 (t, J=5.87 Hz, 1
hydroxyethyl) H) 4.22 (q, J=7.43 Hz, 2 H) 4.01-
benzamide 3.67 (m, 2 H) 1.48 (t, J=7.43 Hz, 3
Structure
(2-amino
1H NMR (400MHz, CD30D) 5 ppm
(1-ethyI-1H-
8.06 (s, 2 H) 8.02 (s, 1 H) 7.94 (s, 1
pyrazoI
H) .65 (m, 4 H) 7.60-7.50
yI)pyridinyI) 508.3 0.624
(m, 1 H) 7.42-7.32 (m, 2 H) 5.26 (q,
-N-(1-(3-
J=6.52 Hz, 1 H) 4.12 (q, J=7.04 Hz,
(methylsulfonyl)
2 H) 3.03 (s, 3 H) .47 (m, 3
phenyl)ethyl)
H) 1.43-1.32 (m, 3 H)
benzamide
(S)(2-amino
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 8 ppm
1,2,3-triazoI
8.2 (m,1 H), 7.95-7.81 (m, 3 H),
y|)pyridinyI)-N- 467.2 0.61
7.48 (m, 3 H), 7.35 - 7.25 (m, 3 H),
(1 -(3-
.19 (m, 1 H), 4.13 (s, 3 H), 3.86
chlorophenyI)
(m, 2 H)
hydroxyethyI)
fluorobenzamide
4-(3-amino
((1r,4S) 1H NMR (400MHz, CD30D) 5 ppm
hydroxycyclohexy 8.85 - 8.72 (m, 1H), 8.23 (d, J=1.6
|)pyrazinyI)-N- Hz, 1H), 7.99 (d, J=1.6 Hz, 1H),
((S)(3- 7.96 - 7.87 (m, 3H), 7.71 - 7.57 (m,
(difluoromethy|)- 2H), 7.57 - 7.43 (m, 4H), 6.97 - 6.62
-fluorophenyI) (m, 1H), 5.35 - 5.22 (m, 1H), 4.22 -
hydroxyethyI) 4.10 (m, 3H), 4.01 - 3.82 (m, 2H)
fluorobenzamide
(S)(2-amino
(1 -methyI-1 H-
1,2,3-triazoI 1H NMR (400MHz, CD30D) 8 8.72
y|)pyridinyI)-N- (m, 1 H), 8.21 (m, 1 H), 7.80 (m, 3
(1 -(3-chloro H), 7.48 (m, 2 H), 7.3 (s, 1 H), 7.15
fluorophenyI) (m, 2 H), 5.19 (m,1 H), 7.41 (s, 3
hydroxyethyI) H), 3.87 (m, 2 H).
fluorobenzamide
Structure
(R)—4-(2-amino—5-
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 8 8.7
1,2,3-triazoI
(m, 1 H), 8.11 (m, 1 H), 7.79 (m, 2
y|)pyridinyI)-N- 451.2 0.71
H), 7.71 (m, 1 H), 7.35 (m, 3 H),
(1-(3-
7.29 - 7.12 (m, 3 H), 5.15 (m, 1 H),
phenyl)ethy
4.03 (s, 3 H), 1.47 (m, 3 H).
|)
fluorobenzamide
(S)—4-(2-amino—5-
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 8 8.62
1,2,3-triazoI
(m, 1 H), 8.2 (m, 1 H), 7.89 (m, 3
y|)pyridinyI) 433.3 1.642
H), 7.5 - 7.39 (m 4 H), 7.39 - 7.22
—N-(2—
(m, 2 H), 5.23 (m, 1 H), 4.13 (s, 3
hydroxy-1 -
H), 3.87 (m, 2 H)
phenylethyl)benz
amide
(S)—4-(2-amino—5-
(1 -methyI-1 H- 1H NMR (400MHz, CD30D) 5 8.67
1,2,3-triazoI (m, 1 H), 8.2 (m, 1 H), 7.87 (m, 3
y|)pyridinyI) 451.1 0.45 H), 7.45 (m, 2 H), 7.38 (m,1 H),
fluoro-N-(1-(3- 7.30 - 7.20 (m, 2 H), 7.02 (m, 1 H),
fluorophenyl)—2- 5.22 (m, 1 H), 4.12 (s, 3 H), 3.86
hydroxyethyl)ben (m, 2 H
zamide
(S)—4-(2-amino—5-
(1 -methyI-1 H-
1H NMR (400MHz, CD30D) 8 8.58
1,2,3-triazoI
(m, 1 H), 8.19 (m, 1 H), 7.85 (m, 3
y|)pyridinyI) 447.1 0.58
H), 7.46 (m, 2 H), 7.24 (m, 3 H),
—N-(2—
7.21 (m, 1 H), 5.19 (m, 1 H), 4.12
hydroxy—1-(m-
(s, 3 H), 3.84 (m, 2 H), 2.35 (s, 3 H)
tolyl)ethy|)benza
mide
WO 66188
Structure
N-(2-amino(3-
phenyl)ethy 1H NMR (400MHz, CD30D) 5 8.07
|)(2-amino (m, 1 H), 8.02 (s, 1 H), 7.95 (s, 1
(1-methyI-1H- ' '
H), 7.85 (m, 1 H), 7.78 (s,1 H),
pyrazoI 7.47 (m, 1 H), 7.35 (m, 5 H), 5.4 (m,
y|)pyridiny|) 1 H), 3.84 (s, 3 H), 3.38 (m, 2 H)
fluorobenzamide
8831;531:1331? 1H NMR (400MHz, CD30D) 5 ppm
8.05 (s, 1 H) 7.94-7.76 (m, 4 H)
pyran_4_
7.73-7.58 (m, 3 H) 5.35-5.25 (m, 1
yl)pyrazin_2_yl)_2_
515.3 0.575 H) 4.05 (dd, J=11.54, 2.15 Hz, 2 H)
fluoro-N-(2-
33-84 (m, 2 H) 3.64-3.49 (m, 2
h(r11ethdroxlysulfon(3-
H) 3'13 (S! 3 H) -33 (m, 1 H)
y yI) p
1.97-1.75 (m, 4 H) 1.15 (d, J=5.87
henyl)ethyl)benza
- Hz, 1 H)
mide
(S)(3-amino-6— 1H NMR (400MHz, CD30D) ) 5
(tetrahydro-2H- ppm 7.83-7.68 (m, 2 H) .42
pyran (m, 2 H) 7.20-7.07 (m, 3 H) 7.00 (d,
yI)pyrazinyI) 451 1 0.695 J=7.04 Hz, 1 H) 5.08 (t, J=6.06 Hz,
fluoro-N-(2- 1 H) 4.07-3.88 (m, 2 H) 3.83-3.64
hydroxy(m- (m, 2 H) 3.48 (td, J=11.44, 2.54 Hz,
tolyl)ethy|)benza 2 H) 2.96-2.74 (m, 1 H) 2.25 (s, 3
mide H) 1.89-1.63 (m, 4 H)
mino 1H NMR (400MHz, CD30D) ) 5
(tetrahydro-2H- ppm 7.98-7.80 (m, 3 H) 7.71 (dd,
pyran J=8.02, 1.37 Hz, 1 H) 7.67-7.59 (m,
yI)pyrazinyI) 503 2 0.6822 H) 7.51 (d, J=9.00 Hz, 1 H) 4.71
fluoro-N-(3- (s, 2 H) 4.10-3.99 (m, 2 H) 3.57 (td,
fluoro J=11.44, 2.54 Hz, 2 H) 3.15 (s, 3 H)
(methylsulfonyl)b 3.01-2.87 (m, 1 H) 1.98-1.74 (m, 5
enzyl)benzamide H)
Structure
4-(3-amino
(tetrahydro-ZH- 1H NMR (400MHz, CD30D) 5 ppm
pyran 7.95 - 7.84(m, 4 H) 7.79 — 7.57(m,
y|)pyrazinyI)-N- 519.3 0.736 3 H) 4.70 (s, 2 H) 4.09 - 3.98 (m, 2
(3-chloro H) 3.57 (td, J=11.64, 2.54 Hz, 2 H)
(methylsulfonyl)b 3.15 (s, 3 H) 3.00 — 2.87 (m, 1 H)
enzyI) 1.97— 1.76 (m, 4 H)
fluorobenzamide
(S)(3-amino 1H NMR z, CD30D) 5 ppm
(1-isopropyI-1H- 8.17 (s, 1 H) 8.07 (s, 1 H) 7.87 (s, 1
pyrazoI H) 7.83-7.75 (m, 1 H) 7.67-7.54 (m,
y|)pyrazinyI) 461 .3 0.75 2 H) 7.38-7.31 (m, 2 H) 7.27 (t,
fluoro-N-(2- J=7.63 Hz, 2 H) .14(m,1 H)
hydroxy-1 - 5.13 (t, J=6.06 Hz, 1 H) 4.47 (spt,
phenylethyl)benz J=6.72 Hz, 1 H) 3.85-3.69 (m, 2 H)
amide 1.43 (d, J=6.65 Hz, 6 H)
(R)(2-amino 1H NMR (400MHz, CD30D) 5 ppm
(1 -ethyI-1 H- 8.99 (d, J=6.26 Hz, 1 H), 8.16 (s, 2
pyrazoI H) 8.12 (s, 1 H) 7.94-7.78 (m, 3 H)
idinyI) 7.63 (dt, J=7.83, 1.76 Hz, 1 H) 7.56
526.30.653
fluoro-N-(1-(3- (d, J=9.39 Hz, 1 H) 7.51-7.42 (m, 2
fluoro H) 5.40-5.26 (m, 1 H) 4.22 (q,
(methylsulfonyl)p J=7.17 Hz, 2 H) 3.16 (s, 3 H) 1.62
henyl)ethy|)benza (d, J=7.04 Hz, 3 H) .41 (m, 3
mide H)
(S)(2-amino-
-(1-ethyI-1H- 1H NMR (400MHz, CD30D) 5 ppm
pyrazoI 8.10-8.05 (m, 2 H) 8.03 (s, 1 H)
y|)pyridinyI) 446.3 0.616 7.87-7.73 (m, 2 H) 7.44-7.10 (m,
fluoro-N-(2- 7H) 5.30-4.94 (m, 1 H) 4.13 (q,
hydroxy-1 - J=7.17 Hz, 2 H) 3.89-3.54 (m, 2 H)
phenylethyl)benz 1.39 (t, J=7.24 Hz, 3 H)
amide
Structure
1H NMR (400MHz, METHANOL-
N-((S)amino d4) 6 ppm 7.61 (s, 1H), 7.77 - 7.65
(3-fluoro (m, 1H), 7.65 - 7.46 (m, 3H), 7.36
iodophenyl)ethyl) (d, J=7.6 Hz, 1H), 7.11 (d, J=9.6
(3-amino Hz, 1H), 5.02 (t, J=6.6 Hz, 1H),
((1R,3R,4R) 4.44 - 4.09 (m, 1H), 3.67 - 3.45 (m,
fluoro 1H), 2.99 - 2.65 (m, 2H), 2.75 (t,
ycyclohexy J=11.5 Hz, 1H), 2.26 - 2.06 (m, 1H),
|)pyrazinyI) 2.06 - 1.66 (m, 1H), 1.67 - 1.64 (m,
fluorobenzamide 2H), 1.56 (dq, J=3.3, 13.0 Hz, 1H),
1.46- 1.29 (m, 1H)
1H NMR (400MHz ,CD30D) 6 7.97
4-(2-amino(5- (d, J=2.35 Hz, 1 H), 7.93-7.63 (m, 2
oxopyrrolidin-S- H), 7.49-7.31 (m, 6 H), 22
y|)pyridinyI)-N- (m, 1 H),4.64-4.57 (m, 2 H), 3.62-
benzyI-Z- 3.66 (m, 2 H),3.46-3.36 (m, 1 H),
fluorobenzamide .65 (m, 1 H), 2.56-2.44 (m, 1
4-(2-amino 1H NMR (400MHz ,CD30D) 6 6.61
(tetrahydro-ZH- (d, J = 5.1 Hz, 1H), 6.06 (t, J = 7.6
pyran Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H),
y|)pyridinyI) 7.60 (d, J = 2.0 Hz, 1H), 7.41 - 7.50
fluoro-N-((4- (m, 2H), 7.30 (d, J = 5.1 Hz, 1H),
methylpyrimidin- 4.76 - 4.62 (m, 2H), 4.05 (dd, J =
2- 11.2, 2.9 Hz, 2H), 3.55 (td, J = 11.4,
y|)methy|)benzam 2.5 Hz, 2H), 2.61 - 2.95 (m, 1H),
ide 2.55 (s, 3H), 1.69 - 1.69 (m, 4H)
4-(2-amino 1H NMR (400MHz, DMSO-d6) 6
(tetrahydro-ZH- 9.26 - 9.11 (m, 2 H), 9.06 - 6.96 (m,
pyran 1 H), 7.96 - 7.76 (m, 3 H), 7.69 -
y|)pyridinyI) 408.2 0.42 7.44 (m, 3 H), 7.40 (dd, J = 1.4, 6.0
fluoro-N- Hz, 1 H), 4.54 (d, J = 5.9 Hz, 2 H),
azin 4.02 - 3.77 (m, 3 H), 3.37 (dt, J =
ylmethyl)benzami 27,113 Hz, 2 H), 2.77 (s,1 H),
de 1.76 - 1.54 (m, 4 H)
Structure
1H NMR (400MHz ,CD30D) 8 7.95
4-(3-amino—6— (t, J = 7.8 Hz, 1H), 7.87 (s, 1H),
(tetrahydro—ZH- 7.70 (dd, J = 78,16 Hz, 1H), 7.61
pyran (dd, J =11.9, 1.4 Hz, 1H), 4.05 (dd,
y|)pyrazinyI) J =11.3,2.3 Hz, 3H), 3.57 (td, J =
fluorobenzamide 11.5, 2.7 Hz, 3H), 2.89 - 3.01 (m,
1H), 1.77 - 1.97 (m, 6H)
4-(3-amino—6— 1H NMR (400MHz ,CD30D) 8 7.83
(tetrahydro—ZH- - 7.91 (m, 2H), 7.68 (dd, J = 8014
pyran Hz, 1H), 7.60 (dd, J =11.7, 1.6 Hz,
azinyI) 1H), 4.05 (dd, J = 11.3, 2.3 Hz, 2H),
fluoro—N- 3.57 (td, J =11.5,2.7 Hz, 2H), 2.88
methylbenzamide - 3.01 (m,4H), 1.74 - 1.96 (m, 4H)
1H NMR (400 MHz, d6—DMSO) ) 5
(S)—4-(3-amino—6— ppm 0.47 - 0.55 (m, 2 H) 0.64 -
(tetrahydro—ZH- 0.73 (m, 2 H) 1.21 - 1.30 (m, 1 H)
pyran 1.62 - 1.73 (m, 4 H) 2.72 - 2.86 (m,
y|)pyrazinyI)-N-425.1 0.64 1 H) 3.30 - 3.41 (m, 2 H) 3.45 (d,
(4-cyclopropyI J=6.26 Hz, 3 H) 3.87 (d, 6
ybutyn- Hz, 2 H) 4.66 (q, J=6.65 Hz, 1 H)
2-y|) 7.52 (d, J=11.74 Hz, 1 H) 7.55 -
fluorobenzamide 7.59 (m, 1 H) 7.61 - 7.68 (m,1 H)
7.87 (s, 1 H) 8.35- 8.42 (m, 1 H)
1H NMR (400MHz ,CD30D) 5 7.77
- 7.88 (m, 3H), 7.59 (d, J = 8.2 Hz,
(S)—(4-(3-amino—
2H), 7.54 (br. s., 1H), 7.41 (t, J =
NH2 6-(tetrahydro—2H-
7.6 Hz, 2H), 7.28 - 7.36 (m, 1H),
322 N \ 4.54 (d, J = 11.3 Hz, 1H), 3.95 -
| y|)pyrazin
4.11 (m, 3H), 3.88 (br. s., 1H), 3.68
y|)pheny|)(3-
(t, J = 11.5 Hz, 1H), 3.56 (td, J =
phenylmorpholino
11.4, 2.5 Hz, 2H), 3.34 - 3.41 (m,
)methanone
1H), 2.85 - 3.01 (m, 1H), 1.73 - 1.99
(m, 4H)
Structure
1H NMR (400MHz ) 8 8.03
4-(3-amino—6-
(d, J = 8.2 Hz, 2H), 7.98 (s, 1H),
(tetrahydro—ZH-
7.83 - 7.91 (m, 3H), 7.80 (s, 1H),
pyran
7.75 (d, J = 7.8 Hz, 1H), 7.59 - 7.67
y|)pyrazinyI)-N-
(m, 1H), 4.71 (s, 2H), 3.99 -4.10
(m, 2H), 3.57 (td, J = 11.3, 2.7 Hz,
lsulfonyl)b
2H), 3.12 (s, 3H), 2.90 - 3.03 (m,
enzyl)benzamide
1H), 1.78 - 1.99 (m, 4H)
1H NMR (400MHz, DMSO-d6)
4-(3-amino—6-
88.86 (s,1 H), 7.90 (s, 1 H), 7.76-
(tetrahydro—ZH-
7.51 (m, 2 H), 7.32 (m, 4 H), 7.23
pyran
(m, 1 H), 6.11 (s, 1 H), 4.47 (m, 1
y|)pyrazinyI)-NH
), 3.91 (m, 2 H), 3.40 (m, 2 H),
benzyI-Z-
3.26 (m, 1H), 2.78 (m, 1 H), 1.71
fluorobenzamide
(m, 4 H)
(S)—4—(3-amino—6-
(tetrahydro—ZH-
1H NMR (400MHz, DMSO-d6)
pyran
88.61 (s,1 H), 7.92 (s, 1 H), 7.78-
y|)pyrazinyI) 473.2 0.61
7.51 (m, 5 H), 6.12 (s, 1 H), 4.95
fluoro—N-(2—
(m, 1 H), 3.92 (m, 2 H), 3.66 (m, 2
hydroxy-1 -
H), 3.4 (m, 2 H), 1.73 (m, 4 H)
phenylethyl)benz
amide
1H NMR (400MHz ) 8 7.90
(s, 1 H), 7.82 (t, J = 7.6 Hz, 1 H),
(S)—N-(2-amino—1 -
7.70 (dd, J = 1.4, 8.0 Hz, 1 H), 7.63
phenylethyl)—4—(3-
(dd, J :12, 11.7 Hz, 1 H), 7.49 - amino
7.36 (m, 4 H), 7.32 (d, J = 7.4 Hz, 1
(tetrahydro—ZH-
H), 5.20 (t, J = 6.8 Hz, 1 H), 4.05
pyran
(dd, J = 2.9, 11.2 Hz, 2 H), 3.58 (dt,
y|)pyrazinyI)
J = 23,117 Hz, 2 H), 3.08 (d, J =
fluorobenzamide
7.4 Hz, 2 H), 2.94 (s, 1 H), 2.00 -
1.77 (m, 4 H).
Structure
1H NMR z ,CD30D) 8 7.92
(S)—4-(3-amino—6— (d, J = 8.6 Hz, 2 H), 7.75 (d, J = 9.8
(tetrahydro—ZH- Hz, 3 H), 7.40 - 7.32 (m, 2 H), 7.29
pyran (t, J = 7.4 Hz, 2 H), 7.26 - 7.18 (m,
y|)pyrazinyI)-N- 1 H), 5.41 (dd, J = 7.4, 15.7 Hz, 1
(2-fluoro—1 - H), 4.71 - 4.66 (m, 1 H), 4.62 -4.53
phenylethyl)benz (m, 1 H), 4.00 - 3.89 (m, 2 H), 3.48
amide (dt, J = 27,115 Hz, 2 H), 2.92 -
2.74 (m, 1 H), 1.88 - 1.68 (m, 4 H).
4-(3-amino—6—
1H NMR (400MHz, DMSO-d6)
(tetrahydro—ZH-
88.35 (m, 1 H), 7.90 (s, 1 H), 7.70-
pyran
4 0.77 7.51 (m, 3 H), 7.35 -7.12 (m, 4 H),
y|)pyrazinyI)
6.10 (s, 1 H), 3.92 (m, 2 H), 3.53 -
3.35 (m, 4 H), 2.82 (m, 2 H), 1.72
phenethylbenzam
(m, 4 H)
(S)—4-(3-amino—6— 1H NMR (400MHz, CD30D) 8 7.91
(tetrahydro—ZH- - 7.84 (m, 2H), 7.70 (dd, J=1.6, 7.8
pyran Hz, 1H), 7.65 (dd, J=1.2, 11.7 Hz,
y|)pyrazinyI) 1H), 7.30 (s, 1H), 7.20 (d, J=9.8 Hz,
fluoro-N-(1-(3- 487 2 0.67 1H), 7.08 (d, J=9.0 Hz, 1H), 5.46 (s,
fluoro 1H), 5.35 (s, 1H), 5.23 (t, J=5.7 Hz,
(fluoromethyl)phe 1H), 4.06 (dd, J=2.3, 11.3 Hz, 2H),
ny|) 3.93 - 3.82 (m, 2H), 3.58 (dt, J=2.5,
hydroxyethyl)ben 11.4 Hz, 2H), 3.00 - 2.90 (m, 1H),
zamide 1.98 - 1.79 (m, 4H).
(S)—4-(3-amino—6—
hydro—ZH- 1H NMR (400MHz, CD30D) 8 8.21
pyran (m, 1H), 7.94 (m, 1H), 7.75 (m, 1H),
y|)pyrazinyI)-N- 489.1 0.74 7.63 (m, 2H), 7.21 (m, 1H), 7.05 (m,
(1 -(3-ch|oro—5- 2H), 5.20 (m, 1H), 4.09 (m, 4H),
fluorophenyl)—2- 3.56 (m, 2H), 2.93 (m, 1H), 1.88 (m,
hydroxyethyl)—2- 4H)
fluorobenzamide
Structure
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6-
8.72 (br. s., 1H), 7.94 - 7.77 (m,
(tetrahydro—ZH-
2H), 7.74 - 7.59 (m, 2H), 7.48 (s,
1H), 7.42 - 7.23 (m, 3H), 5.06 - 4.95
y|)pyrazinyI)-N-485.1 0.76
(m, 1H), 4.14 (quin, J=6.2 Hz, 1H),
((18,2R)—1-(3-
4.05 (dd, J=3.6, 11.5 Hz, 2H), 3.66
chlorophenyl)—2-
- 3.51 (m, 2H), 2.95 (ddd, J=3.5,
hydroxypropyl)—2-
79,154 Hz, 1H), 2.02 - 1.75 (m,
fluorobenzamide
4H),1.30 - 1.13 (m, 3H)
mino—5-(1 -
1H NMR (400MHz, CD30D) 5 ppm
methyl-1 H-
8.14 (d, J=1.6 Hz, 2H), 8.05 (s, 1H),
pyrazoI
7.94 - 7.80 (m, 2H), 7.55 - 7.40 (m,
y|)pyridinyI)-N- 480.1 0.66
3H), 7.39 - 7.23 (m, 3H), 5.48 (s,
((18,2R)—1-(3-
1H), 4.99 (d, J=5.9 Hz, 1H), 4.21 - chlorophenyl)—2-
4.07 (m, 1H), 3.93 (s, 3H), 1.29 -
hydroxypropyl)—2-
1.11 (m, 3H)
enzamide
(S)—4-(3-amino—6-
1H NMR (400MHz, DMSO-
(tetrahydro—ZH-
16 (m, 1 H), 7.90 (s, 1 H),
pyran
7.76 - 7.53 (m, 3 H), 7.48 - 7.20 (m,
y|)pyrazinyI) 437.2 0.61
6 H), 6.11 (s, 2 H), 5.54 (d, J = 4
fluoro—N-(2-
Hz, 1 H), 4.75 (m, 1 H), 3.92 (m, 2
hydroxy—Z-
H), 3.58 - 3.28 (m, 4 H), 2.82 (m, 1
phenylethyl)benz
H), 1.71 (m, 4 H)
amide
4-(3-amino—6-
(tetrahydro—ZH- 1H NMR (400MHz, DMSO-d6)
pyran 87.96 (m, 1 H), 7.91 (s, 1 H), 7.79
y|)pyrazinyI) 422.2 0.46 (m, 1 H), 7.70 - 7.57 (m, 2 H), 7.38
fluoro-N-((6- (m, 2 H), 4.62 (m, 2 H), 3.90 (m, 2
methylpyridin-Z- H), 3.4 (m, 2 H), 2.55 (s, 3 H), 1.72
y|)methy|)benzam (m, 4 H)
Structure
(S)—4—(3-amino—6- 1H NMR (400MHz, CD30D) 5 ppm
(tetrahydro—ZH- 7.95 - 7.79 (m, 2H), 7.77 - 7.58 (m,
4- 2H), 7.47 (s, 1H), 7.35 (d, J=9.8 Hz,
y|)pyrazinyI)-N 1H), 7.22 (d, J=8.6 Hz, 1H), 6.98 -
(1 -(3- 6.58 (t, J=56 Hz, 1H), 5.48 (s, 2H),
(difluoromethyl)— 5.25 (t, J=5.9 Hz, 1H), 4.12 - 3.97
-fluorophenyl)—2— (m, 2H), 3.95 - 3.76 (m, 2H), 3.57
yethyl)—2- (dt, J=2.3, 11.5 Hz, 2H), 2.94 (m,
fluorobenzamide 1H), 2.00 - 1.75 (m, 4H)
(S)—4—(3-amino—6- 1H NMR z, CD30D) 5 ppm
(tetrahydro—ZH- 7.98 - 7.90 (m, 1H), 7.89 - 7.80 (m,
pyran 1H), 7.73 (d, J=8.2 Hz, 1H), 7.66 (d,
y|)pyrazinyI)-N- J=11.7 Hz, 1H), 7.39 - 7.31 (m, 1H),
(1 -(3-ch|oro—5- 7.26 - 7.11 (m, 2H), 5.33 (dd, J=5.2,
fluorophenyl)—2- 9.0 Hz, 1H), 4.15 - 4.01 (m, 2H),
(methylamino)eth 3.60 (dt, J=2.2, 11.7 Hz, 2H), 3.14 -
y|) 2.86 (m, 3H), 2.54 - 2.43 (m, 3H),
fluorobenzamide 1.99 - 1.79 (m, 4H)
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6-
8.76 (br. s., 1H), 7.92 - 7.78 (m,
((1r,4S)—4—
2H), 7.74 - 7.56 (m, 2H), 7.47 (s,
hydroxycyclohexy
1H), 7.35 (d, J=9.0 Hz, 1H), 7.22 (d,
|)pyrazin-2—yI)-N-
J=8.6 Hz, 1H), 6.99 - 6.59 (t, J=56
((S)(3-
Hz, 1H), 5.26 (m, 2H), 4.10 (q,
(difluoromethyl)—
J=7.0 Hz, 8H), 3.89 (m, 2H), 3.63
-fluorophenyl)—2—
(m, 1H), 2.64 (t, J=12.1 Hz, 1H),
hydroxyethyl)—2-
2.12 - 1.88 (m, 4H), 1.75 - 1.56 (m,
fluorobenzamide
2H), 1.50 - 1.32 (m, 2H).
1H NMR (400MHz, CD30D) d =
N-((S)—2-amino—1 - 7.96 - 7.82 (m, 2H), 7.76 - 7.59 (m,
(3-bromo—5- 2H), 7.59 - 7.48 (m, 1H), 7.41 (d,
fluorophenyl)ethy| J=8.2 Hz, 1H), 7.29 (d, J=9.4 Hz,
)(3-amino—6- 1H), 5.48 (t, J=7.2 Hz, 1H), 4.51 -
((1R,3R,4R)—3- 4.24 (m, 1H), 3.74 - 3.55 (m, 1H),
fluoro 3.53 - 3.38 (m, 2H), 2.84 (t, J=11.9
hydroxycyclohexy Hz, 1H), 2.27 (td, J=3.1, 6.0 Hz,
|)pyrazinyI) 1H), 2.14 - 1.96 (m, 1H), 1.96 - 1.73
fluorobenzamide (m, 2H), 1.64 (dq, J=2.9, 13.0 Hz,
1H),1.56 - 1.39 (m, 1H)
4-(3-amino—6-
1H NMR (400MHz, CD30D) 5 ppm
((1r,4S)—4—
7.64 - 7.69 (m, 1H), 7.63 - 7.44 (m,
hydroxycyclohexy
2H), 7.43 - 7.31 (m, 1H), 6.91 - 6.44
|)pyrazin-2—yI)-N-
(t, J = 56 Hz, 1H), 5.25 - 5.10 (m,
((S)(3-
1H), 3.66 - 3.66 (m, 2H), 3.60 - 3.42
(difluoromethyl)p
(m, 1H), 2.67 - 2.43 (m, 1H), 2.03 -
henyl)—2-
1.76 (m, 4H), 1.66 - 1.44 (m, 2H),
hydroxyethyl)—2-
1.42 - 1.25 (m, 2H)
fluorobenzamide
1H NMR (400MHz, CD30D) 6 ppm
mino—6-
6.66 (br. s., 1H), 7.93 - 7.63 (m,
((1r,4S)—4—
2H), 7.79 (s, 1H), 7.74 - 7.67 (m,
ycyclohexy
2H), 7.66 - 7.54 (m, 3H), 5.30 (t,
|)pyrazinyI)
J=5.8 Hz, 1H), 4.01 - 3.62 (m, 2H),
fluoro-N-((S)—2-
3.71 - 3.55 (m, 1H), 2.77 - 2.60 (m,
hydroxy—1-(3-
1H), 2.16 - 2.05 (m, 2H), 2.02 - 1.69
(trifluoromethyl)p
(m, 2H), 1.60 - 1.60 (m, 2H), 1.51 - ethy|)benza
1.34 (m, 2H)
mide
4-(3-amino—6- 1H NMR (400MHz, CD30D) 6 ppm
((1s,4R)—4— 8.86(br.s.,1H),7.93 - 7.63 (m,
hydroxycyclohexy 2H), 7.62 - 7.71 (m, 2H), 7.70 - 7.56
|)pyrazinyI) (m, 3H), 5.36 - 5.24 (m, 1H), 4.04
fluoro-N-((S)—2- (br. s., 2H), 3.96 - 3.61 (m, 1H),
hydroxy—1-(3- 2.60 - 2.66 (m, 1H), 2.14 - 2.00 (m,
(trifluoromethyl)p 2H), 1.90 (d, J=10.7 Hz, 2H), 1.77 -
henyl)ethy|)benza 1.65 (m, 4H)
mide
1H NMR (400MHz, CD30D) 5 ppm
7.95 - 7.64 (m, 2H), 7.71 (dd, J=1.6,
N-((S)—2-amino—1 -
6.0 Hz, 1H), 7.63 (dd, J=1.5, 12.0
(3-bromo—5-
Hz, 1H), 7.55 (s, 1H), 7.41 (td,
fluorophenyl)ethy|
J=2.1, 6.2 Hz, 1H), 7.33 - 7.23 (m,
)(3-amino—6-
1H), 5.55 - 5.40 (m, 1H), 3.67 - 3.53
((1r,4S)—4—
(m, 1H), 3.52 - 3.39 (m, 2H), 2.72 -
hydroxycyclohexy
2.54 (m, 2H), 2.06 (d, J=9.7 Hz,
|)pyrazinyI)
2H), 1.99 - 1.67 (m, 2H), 1.76 - 1.56
fluorobenzamide
(m, 2H), 1.49 - 1.31 (m, 2H)
+ Rt NMR
Structure
N-((S)—2-amino—1 -
iodophenyl)ethyl)
(3-amino—6-
((1r,4S)—4—
hydroxycyclohexy
|)pyrazinyI)
fluorobenzamide576-
4-(3-amino—6- 1H NMR (400MHz, CD30D) 5 ppm
((1r,4S)—4— 8.76 (br. s., 1H), 7.92 - 7.80 (m,
2H), 7.73 - 7.55 (m, 3H), 7.45 (d,
|)pyrazinyI) J=7.9 Hz, 1H), 7.22 (d, J=9.5 Hz,
fluoro—N-((S)—1 - 1H), 5.49 (m, 1H), 5.23 - 5.11 (m,
(3-fluoro—5- 1H), 3.94 - 3.76 (m, 2H), 3.69 - 3.53
enyl)—2— (m, 1H), 2.72 - 2.57 (m, 1H), 2.07
hydroxyethyl)ben (m, 2H), 1.97 (m, 2H), 1.97 (m, 2H),
zamide 1.44 (m, 2H).
4-(3-amino—6-
1H NMR (400MHz, CD30D) 5 ppm
((1s,4R)—4—
8.75 (br. s., 1H), 7.95 - 7.79 (m,
2H), 7.77 - 7.58 (m, 3H), 7.44 (d,
|)pyrazinyI)
J=6.9 Hz, 1H), 7.22 (d, J=9.5 Hz,
fluoro—N-((S)—1 -
1H), 5.49 (m, 1H), 5.15 (m, 1H),
(3-fluoro—5-
4.02 (br. s., 1H), 3.85 (m, 2H), 2.71
enyl)—2—
(m, 1H), 2.03 (m, 2H), 1.88 (m, 2H),
hydroxyethyl)ben
1.77 - 1.59 (m, 4H)
zamide
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6-
8.73 (br. s., 1H), 7.92 - 7.77 (m,
((1r,4S)—4—
3H), 7.71 - 7.56 (m, 3H), 7.44 (d,
J=7.6 Hz, 1H), 7.15 (t, J=7.7 Hz,
zinyI)
1H), 5.5 (m, 1H), 5.15 (m, 1H), 3.85
fluoro-N-((S)—2-
(m, 2H), 3.61 (m, 1H), 2.65 (m, 1H),
hydroxy—1-(3-
2.07 (m, 2H), 1.97 (m, 2H), 1.68 (m,
iodophenyl)ethyl)
2H), 1.46 (m, 2H).
benzamide
Structure
4-(3-amino—6- 1H NMR (400MHz, CD30D) 5 ppm
R)-4— 8.74 (br. s., 1H), 7.91 - 7.76 (m,
hydroxycyclohexy 3H), 7.76 - 7.56 (m, 3H), 7.44 (d,
|)pyrazinyI) 577.4 0.76 J=7.6 Hz, 1H), 7.15 (t, J=7.9 Hz,
fluoro-N-((S)— 1H), 5.49 (m, 1H), 5.15 (m, 1H),
hydroxy( 4.02 (br. s., 1H), 3.84 (m, 2H), 2.74
iodophenyl)ethyl) (m, 1H), 1.99 (m, 2H), 1.88 (m, 2H),
benzamide 1.72 (m, 4H)
4-(3-amino—6-
1H NMR (500MHz, CD30D) 5 ppm
((1r,4S)—4—
7.93 - 7.79 (m, 2H), 7.73 - 7.57 (m,
deuterido—4-
2H), 7.47 (s, 1H), 7.34 - 7.14 (m,
ycyclohexy
548 1 0 71 2H), 5.18 (t, J = 5.7 Hz, 1H), 3.93 - |)pyrazin-2—yI)-N- '
3.78 (m, 2H), 2.70 - 2.55 (m, 1H),
((S)(3-bromo—
2.06 (d, J = 12.3 Hz, 2H), 1.95 (d, J
-fluorophenyI)
=12.3 Hz, 2H), 1.76 - 1.58 (m, 2H),
hydroxyethyI)
1.48 - 1.35 (m, 2H)
fluorobenzamide
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6-
8.72 - 8.56 (m, 1H), 7.84 - 7.67 (m,
((1r,4S)-4—
2H), 7.67 - 7.45 (m, 2H), 7.37 (s,
hydroxycyclohexy 549-1
1H), 7.23 - 7.03 (m, 2H), 5.07 (d,
|)pyrazin-2—yI)-N-
l551 J=5.1 Hz, 1H), 3.82 - 3.68 (m,
((S)(3-bromo—
0 0.15H), 3.59 - 3.41 (m, 1H), 2.67 -
rophenyI)
2.44 (m, 1H), 2.05 - 1.79 (m, 2H),
hydroxy, 2,2-di-
1.57 (dq, J=2.7, 13.0 Hz, 2H), 1.39
deuteridoethyI)
- 1.24 (m, 2H)
fluorobenzamide
Structure
4-(3-amino—6—
1H NMR z, CD30D) 5 ppm
((1r,4S)—4—
8.64 (br. s., 1H), 7.82 - 7.68 (m,
deuterido—4-
2H), 7.63 - 7.47 (m, 2H), 7.37 (s,
hydroxycyclohexy 550.0
/552. 0.71 1H), 7.22 - 7.03 (m, 2H), 5.07 (d,
|)pyrazin-2—yI)-N-
J=7.4 Hz, 1H), 3.81 - 3.66 (m,
((S)—1-(3-bromo—
0.15H), 2.63 - 2.45 (m, 1H), 2.05 -
-fluorophenyl)—
1.78 (m, 2H), 1.66 - 1.46 (m, 2H),
oxy, 2,2—di-
1.39 - 1.20 (m, 2H)
deuteridoethyl)—2-
fluorobenzamide
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6— 7.87 (s, 1H), 7.84 (t, J=7.8 Hz, 1H),
S)—4— 7.68 (d, J=8.2 Hz, 1H), 7.62 (d,
hydroxycyclohexy 548.1 J=11.7 Hz, 1H), 7.46 (s, 1H), 7.27
|)pyrazin-2—yI)-N- (d, J=8.2 Hz, 1H), 7.20 (d, J=9.4
((S)—1-(3-bromo— Hz, 1H), 3.85 (d, J=5.1 Hz, 2H),
-fluorophenyl)—2— 3.60 (t, J=11.2 Hz, 1H), 2.63 (t,
hydroxy, 1- J=11.9 Hz, 1H), 2.06 (d, J=12.1 Hz,
deuteridoethyl)—2- 2H), 1.95 (d, J=12.9 Hz, 2H), 1.73 -
fluorobenzamide 1.60 (m, 2H), 1.48 - 1.36 (m, 2H)
4-(3-amino—6— 1H NMR (400MHz, CD30D) 5 ppm
((1r,4S)—4— 8.76 (br. s., 1H), 7.92 - 7.80 (m,
deuterido—4- 2H), 7.73 - 7.55 (m, 3H), 7.45 (d,
ycyclohexy 549.1 J=7.9 Hz, 1H), 7.22 (d, J=9.5 Hz,
|)pyrazin-2—yI)-N- /551. 1H), 5.49 (m, 1H), 5.23 - 5.11 (m,
((S)—1-(3-bromo— 1H), 3.94 - 3.76 (m, 2H), 3.69 - 3.53
-fluorophenyl)—2— (m, 1H), 2.72 - 2.57 (m, 1H), 2.07
hydroxy, 1- (m, 2H), 1.97 (m, 2H), 1.97 (m, 2H),
deuteridoethyl)—2- 1.44 (m, 2H).
fluorobenzamide
N-((S)—2-amino—1 - 1H NMR (400MHz, CD30D) 5 ppm
(3-bromo—5- 7.97 - 7.82 (m, 2H), 7.77 - 7.58 (m,
fluorophenyl)ethy| 2H), 7.59 - 7.47 (m, 1H), 7.44 - 7.35
-amino—6— (m, 1H), 7.29 (d, J=9.4 Hz, 1H),
.48 - 3.56
absolute stereochemistry ((1R,SS,4R) (t, J=7.2 Hz, 1H), 3.77
assigned aritrari/y fluoro (m, 1H), 3.53 - 3.38 (m, 3H), 3.10 -
hydroxycyclohexy 2.94 (m, 1H), 2.31 -2.14 (m, 1H),
|)pyrazinyI) 2.09 -1.78(m,4H), 1.77 - 1.60 (m,
fluorobenzamide 1H)
Structure
1H NMR (400MHz, CD30D) 6 ppm
N-((S)—2-amino—1 -
7.65 - 7.74 (m, 2H), 7.62 (dd, J=1.4,
(3-bromo—5-
6.0 Hz, 1H), 7.55 (dd, J=1.2, 11.7
fluorophenyl)ethy|
Hz, 1H), 7.45 (s, 1H), 7.36 - 7.26
)(3-amino—6-
(m, 1H), 7.20 (d, J=9.4 Hz, 1H),
((18,3R,4S)—3-
absolute stereochemistry 5.39 (t, J=7.2 Hz, 1H), 3.66 - 3.46
assigned aritrarily fluoro
(m, 1H), 3.44 - 3.32 (m, 2H), 2.96 -
hydroxycyclohexy
2.62 (m, 1H), 2.21 - 2.05 (m, 1H),
|)pyrazinyI)
1.97 - 1.70 (m, 4H), 1.69 - 1.49 (m,
fluorobenzamide
4-(3-amino—6— 1H NMR (400MHz, CD30D) 6 ppm
((1R,38,4R)—3- 7.66 - 7.69 (m, 3H), 7.62 (dd, J=1.6,
fluoro 6.2 Hz, 1H), 7.59 - 7.50 (m, 1H),
hydroxycyclohexy 7.47 (s, 1H), 7.36 - 7.26 (m,
578/5
|)pyrazin-2—yI)-N- 1H),7.23 (dd, J=9.0, 14.9 Hz, 2H),
80'1
absolute stereochemistry ((S)—1-(3-bromo— 5.46 (t, J=7.2 Hz, 1H), 3.67 - 3.49
assigned ri/y
-fluorophenyl)—2— (m, 1H), 3.49 - 3.39 (m, 2H), 3.00 -
(methylamino)eth 2.65 (m, 1H), 2.72 (s, 3H), 2.14 (dt,
y|) J=3.9, 10.6 Hz, 1H), 1.99 - 1.71 (m,
fluorobenzamide 4H),1.70 - 1.49 (m, 1H)
4-(3-amino—6— 1H NMR (400MHz, CD30D) 6 ppm
((18,3R,4S)—3- 7.67 - 7.74 (m, 2H), 7.62 (dd, J=1.6,
fluoro 6.2 Hz, 1H), 7.55 (dd, J=1.2, 12.1
hydroxycyclohexy Hz, 1H), 7.47 (s, 1H), 7.32 (td,
578/5
|)pyrazin-2—yI)-N- J=1.8, 6.2 Hz, 1H), 7.21 (d, J=9.4
80.2
absolute stereochemistry ((S)—1-(3-bromo— Hz, 1H), 5.55 - 5.40 (m, 1H), 3.67 -
assigned aritrari/y rophenyl)—2— 3.50 (m, 1H), 3.46 - 3.37 (m, 2H),
(methylamino)eth 2.99 - 2.64 (m, 1H), 2.72 (s, 3H),
y|) 2.20 - 2.06 (m, 1H),1.97 - 1.69 (m,
enzamide 66 - 1.50 (m, 1H)
4-(3-amino—6— 1H NMR (400MHz, CD30D) 6 ppm
((1S,38,4S)—3- 7.67 - 7.76 (m, 2H), 7.69 - 7.60 (m,
fluoro 2H), 7.59 - 7.51 (m, 1H), 7.49 (d,
hydroxycyclohexy J=7.4 Hz, 1H), 7.22 (d, J=9.4 Hz,
357 |)pyrazinyI) 626.1 0.68 1H), 5.45 (t, J=7.2 Hz, 1H), 4.43 -
fluoro—N-((S)—1 - 4.14 (m, 1H), 3.62 - 3.49 (m, 1H),
(3-fluoro—5- 3.45 (d, J=7.4 Hz, 2H), 2.61 - 2.66
enyl)-2— (m, 4H), 2.25 - 2.09 (m, 1H), 2.04 -
lamino)eth 1.66 (m, 1H), 1.67 - 1.63 (m, 2H),
y|)benzamide 1.64 - 1.30 (m, 2H)
Structure
4-(3-amino 1H NMR (400MHz, CD30D) 5 ppm
((1R,3R,4R) 7.98 - 7.84 (m, 2H), 7.77 - 7.88 (m,
fluoro 2H), 7.88 - 7.53 (m, 2H), 7.49 (d,
hydroxycyclohexy J=8.2 Hz, 1H), 7.43 - 7.33 (m, 1H),
zinyI) 626.1 0.67 5.58 (dd, J=5.5, 9.0 Hz, 1H), 4.50 -
-N-((S) 4.25 (m, 1H), 3.72 - 3.59 (m, 1H),
(3-fluoro 3.80 - 3.48 (m, 2H), 2.89 - 2.74 (m,
iodophenyI) 4H), 2.33 - 2.19 (m, 1H), 2.05 (br.
(methylamino)eth s., 1H), 1.98 - 1.73 (m, 2H), 1.73 -
y|)benzamide 1.58 (m, 1H), 1.55 - 1.40 (m, 1H)
4-(3-amino 1H NMR (400MHz, CD30D) 5 ppm
((1R,3R,4R) 8.00 - 7.85 (m, 2H), 7.78 - 7.88 (m,
fluoro 2H), 7.88 - 7.53 (m,2H), 7.49 (d,
hydroxycyclohexy 560.2 J=8.2 Hz, 1H), 7.43 - 7.32 (m, 1H),
|)pyrazinyI)-N- /562. 0.64 5.58 (dd, J=5.5, 9.0 Hz, 1H), 4.51 -
((S)(3- 2 4.24 (m, 1H), 3.74 - 3.80 (m, 1H),
bromophenyI) 3.59 - 3.49 (m, 2H), 2.87 - 2.74 (m,
(methylamino)eth 4H), 2.34 -2.19 (m, 1H), 2.14 - 1.97
y|) (m, 1H), 1.98 - 1.75 (m, 2H), 1.73 -
fluorobenzamide 1.40 (m, 2H)
1H NMR z, CD30D) 5 ppm
4-(3-amino
7.87 (s, 1H), 7.81 (t, J=7.8 Hz, 1H),
((1r,4S)
.71 (m, 3H), 7.42-7.49 (m,
hydroxycyclohexy
1H), 7.21 (d, J=9.4 Hz, 1H), 5.25
|)pyrazinyI)
608.1 0.68 (dd, J=8.6, 5.1 Hz, 1H), 3.52-3.71
fluoro-N-((S)
(m, 1H), 2.88-3.08 (m, 2H), 2.82 (tt,
(3-fluoro
J=12.1, 3.4 Hz, 1H), 2.44 (s, 3H),
iodophenyI)
2.08 (d, J=9.8 Hz, 2H), 1.95 (d,
(methylamino)eth
J=12.9 Hz, 2H), 1.88 (qd, J=13.0,
y|)benzamide
2.9 Hz, 2H), 1.32-1.50 (m, 2H)
1H NMR (400MHz, METHANOL-
4-(3-amino—6-
d4) d = 7.88 - 7.75 (m, 2H), 7.69 -
((1R,3R,4R)—3-
7.51 (m, 2H), 7.47 (s, 1H), 7.37 -
fluoro—4-
7.27 (m, 1H), 7.21 (d, J=9.0 Hz,
hydroxycyclohexy 578.2
1H), 5.48 (t, J=7.2 Hz, 1H), 4.43 -
|)pyrazinyI)-N- /580. 0.65
4.13 (m, 1H), 3.64 - 3.50 (m, 1H),
((S)—1-(3-bromo—
3.46 (d, J=7.4 Hz, 2H), 2.80 - 2.65
-fluorophenyI)
(m, 4H), 2.17 (br. s., 1H), 2.05 -
(methylamino)eth
1.89 (m, 1H), 1.86 - 1.64 (m, 2H),
y|)
1.65 - 1.46 (m, 1H), 1.46 - 1.29 (m,
enzamide
4-(3-amino—6- 1H NMR (500MHz, METHANOL-
((18,3R)—3- d4) 5 ppm 8.01 - 7.88 (m, 2H), 7.84
hydroxycyclohexy - 7.65 (m, 2H), 7.59 (s, 1H), 7.45 (d,
|)pyrazinyI)-N- 560/5 J=8.2 Hz, 1H), 7.34 (d, J=9.1 Hz,
-(3-bromo— 1H),5.73 - 5.49 (m, 1H), 3.81 - 3.64
-fluorophenyI) (m, 1H), 3.57 (s, 2H), 2.84 (s, 3H),
(methylamino)eth 2.80 - 2.71 (m, 1H), 2.24 - 2.09 (m,
single enantiomer,‘
cis on cyc/ohexyl group; y|) 1H), 2.08 - 1.76 (m, 3H), 1.63 - 1.39
absolute stereochemistry
fluorobenzamide
assigned arbitrarily (m,3H),1.39 - 1.16 (m, 1H)
4-(3-amino—6-
((1 R,38)—3- 1H NMR (500MHz, METHANOL-
hydroxycyclohexy d4) 5 ppm 8.01 - 7.86 (m, 2H), 7.81
|)pyrazinyI)-N- 560/5 - 7.55 (m, 3H), 7.44 (d, J=8.2 Hz,
((S)—1-(3-bromo— 1H), 7.38 - 7.25 (m, 1H), 5.71 - 5.51
-fluorophenyI) (m, 1H), 3.80 - 3.46 (m, 3H), 2.84
(methylamino)eth (s, 4H), 1.91 ,4H),1.63 - 1.37
single enantiomer;
cis on cyclohexyl group; y|) (m, 3H), 1.35- 1.13 (m, 1H)
absolute stereochemislry
fluorobenzamide
assigned arbitrarily
Structure
4-(3-amino( 1H NMR (500MHz, METHANOL-
hydroxycyclohexy d4) 5 ppm 8.01 - 7.86 (m, 2H), 7.60
|)pyrazinyI)-N- (s, 3H), 7.48 (s, 3H), 5.72 - 5.46 (m
((S)(3- 1H), 3.79 - 3.64 (m, 1H), 3.65 - 3.49
chlorophenyl)—2- (m, 2H), 2.84 (s, 4H), 2.16 (d,
(methylamino)eth J=12.0 Hz, 1H), 2.08 - 1.80 (m, 3H)
y|) 1.63 - 1.39 (m, 3H), 1.33 - 1.19 (m
single enantiomer;
cis on cyclohexyl group; fluorobenzamide 1H)
absolute stereochemistry unknown
(S)(3-amino
1H NMR (500MHz, METHANOL-
(tetrahydro-ZH-
d4) 5 ppm 7.99 - 7.79 (m, 2H), 7.77
pyran
- 7.57 (m, 2H), 7.50 (s, 1H), 7.37 -
azinyI)-N- 546/5
7.07 (m, 2H), 5.41 - 5.21 (m, 1H),
(1 omo
4.07 (dd, J=3.8, 11.0 Hz, 2H), 3.68
henyl)—2-
- 3.54 (m, 2H), 2.98 (d, J=5.4 Hz,
(methylamino)eth
3H), 2.48 (s, 3H), 1.99 - 1.66 (m
y|)
fluorobenzamide
1H NMR (500MHz, METHANOL-
d4) 5 ppm 7.90 (s, 2H), 7.74 (dd,
4-(3-amino(3-
J=1.4, 8.0 Hz, 1H), 7.67 (dd, J=1.4,
hydroxycyclohexy
11.8 Hz, 1H), 7.60 (s, 1H), 7.50 -
366 23:28? y') N' - - - -
/N 0| 7.41 (m, 3H), 5.69 - 5.47 (m, 1H),
498 2 0 67I
3.70 (tt, J=4.2, 11.0 HZ, 1H), 3.64 -
ChIOFO hen |)_2_
3.51 (m, 2H), 2.84 (s, 3H), 2.81 -
0H (meth fiamiri'omhV
2.72 (m, 1H), 2.20 -2.11 (m, 1H),
yI)_2_
single enantlomer; 2.03 (d, J=12.6 HZ, 1H), 1.96 - 1.79
fluorObenzam'de, cis on cyclohexylgroup;
1 61 _ 1 42 (m
absolute stereochemistry unknown (m’ 2H) ’ ' ' ’ 3H)
1 34 _
’ '
1.24 (m, 1H)
F o {NHQ
N/q/éj/KHHD= 1H NMR(500MHz L-d4)
NH N 211(8) 2 ammo. ’
_ _ _ _ 1 _
ppm 8.01 - 7.82 (m, 2H), 7.78 -
7.64 (m, 2H), 7.61 - 7.56 (m, 1H),
367 /N 0' Shiogghrfimfiihum 3 0 61 7.52 - 7.35 (m, 3H), 5.65 - 5.42 (m
' 1H),3.77 - 3.66 (m, 1H), 3.55 - 3.42
(m, 2H), 2.84 - 2.73 (m, 1H), 2.16
hydroxycyclohexy
(d, J=12.0 Hz, 1H), 2.03 (d, J=12.0
|)pyrazinyI)
single omer;
Hz, 1H), 1.97 - 1.83 (m, 2H), 1.62 -
cis on cyclohexyl group; fluorobenzamide
absolute stereochemistry unknown 1.41 (m, 3H), 1.34 - 1.22 (m, 1H)
WO 66188 2014/062913
N-((S)amino 1H NMR (500MHz, METHANOL-
(3- d4) 5 ppm 7.89 (s, 2H), 7.80 - 7.70
chlorophenyl)ethy (m, 1H), 7.58 (s, 2H), 7.47 (s, 3H),
|)(3-amino 5.62 - 5.43 (m, 1H), 3.80 - 3.64 (m
(3- 1H), 3.59 - 3.40 (m, 2H), 2.77 (br.
hydroxycyclohexy s., 1H), 2.16 (d, J=12.0 Hz, 1H),
|)pyrazinyI) 2.07 - 1.77 (m, 3H), 1.65 - 1.40 (m
single enantiomer;
cis on cyclohexyl group; fluorobenzamide 3H), 1.36 - 1.16 (m, 1H)
absolute stereochemlstry unknown
4-(3-amino(
hydroxycyclohexy 1H NMR (500MHz, METHANOL-
|)pyrazin-2—yI)-N- d4) 5 ppm 7.89 (s, 2H), 7.80 - 7.71
((S)(3- (m, 1H), 7.70 - 7.62 (m, 1H), 7.61 -
chlorophenyl)—2- 7.54 (m, 1H), 7.48 (s, 3H), 5.67 -
(methylamino)eth 5.50 (m, 1H), 4.18 (br. s, 1H), 3.65 -
y|) 3.51 (m, 2H), 3.21 - 3.07 (m, 1H),
fluorobenzamide 2.84 (s, 3H), 2.02 - 1.74 (m, 5H),
single enantiomer;
1.70 - 1.46 (m, 3H)
trans on cyclohexyl group;
absolute stereochemistry unknown
amino 1H NMR (500MHz, METHANOL-
(3- d4) 5 ppm 7.97 - 7.84 (m, 2H), 7.74
chlorophenyl)ethy (d, J=0.9 Hz, 1H), 7.68 - 7.62 (m
|)(3-amino 1H), 7.58 (s, 1H), 7.50 - 7.37 (m,
(3- 3H), 5.62 - 5.44 (m, 1H), 4.27 - 4.13
hydroxycyclohexy (m, 1H), 3.57 - 3.42 (m, 2H), 3.17
single enantiomer; |)pyrazinyI) (br. s., 1H), 2.05 - 1.72 (m, 5H),
trans on cyclohexyl group; fluorobenzamide 1.68 - 1.53 (m, 3H)
absolute stereochemistry unknown
(S)-4—(3-amino 1H NMR (400MHz, METHANOL-
(tetrahydro-ZH- d4) 5 ppm 7.87 - 7.71 (m, 2H), 7.67
pyran - 7.53 (m, 1H), 7.46 (d, J=7.8 Hz,
y|)pyrazinyI)-N- 560, 1H), 7.40 - 7.27 (m, 2H), 7.25 - 7.15
(1 -(3-bromo (m, 1H), 5.52 - 5.36 (m, 1H), 4.01 -
fluorophenyl)—2- 3.82 (m, 2H), 3.54 - 3.36 (m, 4H),
(ethylamino)ethyl 3.36 - 3.27 (m, 1H), 3.13 - 3.00 (m
) 2H), 2.84 (s, 1H), 1.73 (br. s., 3H),
fluorobenzamide 1.31 - 1.18 (m, 3H)
N-((S)amino—1 -
(3- 1H NMR (500MHz, METHANOL-
chlorophenyl)ethy d4) 6 ppm 7.88 (s, 2H), 7.74 (s,
|)(3-amino—6- 1H), 7.66 (dd, J=1.3, 11.7 Hz, 1H),
7.58 (s, 1H), 7.49 - 7.40 (m, 3H),
.59 - 5.43 (m, 1H), 4.18 (d, J=2.8
|)pyrazinyI) Hz, 1H), 3.56 - 3.42 (m, 2H), 3.22 -
single enantiomer,’ fluorobenzamide 3.12 (m, 1H), 2.00 - 1.76 (m, 5H),
trans on cyclohexyl group;
absolute stereochemistry unknown 1.69 - 1.55 (m, 3H)
amino—1 -
(3-fluoro—5- 1H NMR (400MHz, METHANOL-
iodophenyl)ethyl) d4) 5 ppm 7.92 - 7.81 (m, 2H), 7.78
(3-amino—6- - 7.67 (m, 2H), 7.66 - 7.47 (m, 2H),
((1r,4S)—4- 7.30 (d, J=9.4 Hz, 1H), 5.50 - 5.38
hydroxycyclohexy (m, 1H), 3.68 - 3.53 (m, 1H), 3.50 -
|)pyrazinyI) 3.40 (m, 2H), 2.69 - 2.54 (m, 1H),
fluorobenzamide 2.14 - 1.86 (m, 4H), 1.66 (dq, J=2.9,
13.0 Hz, 2H), 1.50 - 1.33 (m, 2H)
4-(3-amino—6-
((1r,4S) 1H NMR (500MHz, METHANOL-
methoxycyclohex d4) 5 ppm 7.91 (s, 2H), 7.76 - 7.56
y|)pyrazinyI)-N- (m, 2H), 7.54 - 7.47 (m, 1H), 7.36 -
((S)(3-bromo— 7.27 (m, 1H), 7.27 - 7.13 (m, 1H),
ropheny|) 5.36 - 5.25 (m, 1H), 3.41 (s, 3H),
(methylamino)eth 3.12 - 2.89 (m, 2H), 2.76 - 2.59 (m,
y|) 1H), 2.49 (s, 3H), 2.32 - 2.14 (m,
fluorobenzamide 2H), 2.06 - 1.96 (m, 2H), 1.79 - 1.61
(m, 2H), 1.44 - 1.23 (m, 2H)
Structure
4-(3-amino—6-
1H NMR (400MHz, METHANOL-
((1r,4S)—4-
d4) 5 ppm 7.99 - 7.63 (m, 2H), 7.76
methoxycyclohex
- 7.67 (m, 2H), 7.65 - 7.44 (m, 3H),
aziny|)-N-
7.42 - 7.32 (m, 1H), 5.63 - 5.49 (m,
((S)(3-
1H), 3.64 - 3.46 (m, 2H), 3.37 (s,
bromophenyl)—2-
3H), 3.26 (s, 1H), 2.61 (s, 3H), 2.71
(methylamino)eth
- 2.57 (m, 1H), 2.20 (d, J=9.8 Hz,
y|)
2H), 2.05 - 1.94 (m, 2H), 1.65 (dq,
fluorobenzamide
J=2.9, 13.0 Hz, 2H), 1.44 -1.25(m,
mino—6-
((1r,4S)—4- 1H NMR (500MHz, METHANOL-
hydroxycyclohexy d4) 5 ppm 7.97 - 7.63 (m, 2H), 7.79
|)pyraziny|)—N- - 7.57 (m, 2H), 7.50 (s, 1H), 7.36 -
NHz fi/UF ((S)—1-(3-bromo- 560/5 7.29 (m, 1H), 7.27 - 7.16 (m, 1H),
0 64 '
NI \ 5-f|uoropheny|)—2- 62 5.39 - 5.28 (m, 1H), 3.63 (s, 1H),
/N Br (methylamino)eth 3.13 - 2.91 (m, 2H), 2.66 (s, 1H),
y|) 2.49 (s, 3H), 2.15 - 1.88 (m, 4H),
fluorobenzamide 1.69 (d, J=12.6 Hz, 2H), 1.44 (d,
5H J=13.6 Hz, 2H)
’3‘ I g i
9. ‘r’ 5' ‘r’
H ,2: 3 $2 3 1H NMR (400MHz, METHANOL-
F O _/N\ g g ‘5 5- d4) 6 ppm 7.93 - 7.90 (m, 1H), 7.88
3 5' 8 E g, (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.63
““2 fl ‘2’ g §é (d, J=12.1 Hz, 1H), 7.57(s, 1H),
377 N \ E 57—, g i 7.49 - 7.39 (m, 3H), 5.57 (dd, J=5.3,
b” CI ‘5 'P ‘3’ 57/3 512.4 0.74 9.2 Hz, 1H), 3.61 - 3.50 (m, 2H),
E é—h g 4P 3.37 (s, 3H), 3.28 - 3.22 (m, 1H),
Q 3 3 2.81 (s, 3H), 2.70 - 2.60 (m, 1H),
g f: 2.20 (d, J=10.2 Hz, 2H), 1.98 (d,
O E} ‘17 J=12.9 Hz, 2H), 1.65 (d, J=14.9 Hz,
\ 3 : 2H), 1.47 - 1.23 (m, 2H)
% ‘4’
H (S)—4-(3-amino—6- 1H NMR z, METHANOL-
F 0 g/ V (tetrahydro—2H- d4) 6 ppm 7.98 - 7.90 (m, 2H), 7.75
378 NH2 ” pyran (d, J=1.6 Hz, 2H), 7.71 - 7.65 (m,
y|)pyrazinyI)-N-542/5 1H), 7.62 - 7.57 (m, 1H), 7.52 (s,
N \ 0 69 '
/N Br (1-(3- 44 1H), 7.42(s, 1H), 5.65 - 5.45 (m,
bromophenyl)—2- 1H), 4.11 - 3.99 (m, 2H), 3.69 - 3.50
(ethylamino)ethy| (m, 4H), 3.26 - 3.16 (m, 3H), 3.05 -
o ) 2.87 (m, 1H), 1.85 (br. s., 4H), 1.38
fluorobenzamide (t, J=7.3 Hz,3H)
Structure
4-(3-amino—6- 1H NMR (500MHz, METHANOL-
((1r,4S)—4- d4) 5 ppm 7.90 (s, 2H), 7.77 - 7.72
(m, 2H), 7.69 - 7.63 (m, 1H), 7.62 -
|)pyrazin-2—yI)-N- 7.56 (m, 1H), 7.55 - 7.51 (m, 1H),
((S)(3- 7.42 (s,1 H), 5.67 - 5.49 (m, 1H),
henyl)—2- 3.66 - 3.52 (m, 3H), 3.47 (t, J=1.6
(ethylamino)ethyl Hz, 1H), 3.23 - 3.16 (m, 3H), 2.71 -
)—2— 2.62 (m, 1H), 2.09 (d, J=9.1 Hz,
fluorobenzamide 2H), 1.97 (d, J=13.6 , 1.66
(d, J=15.4 Hz, 2H), 1.44 (d, J=12.6
Hz, 2H), 1.36 (t, J=7.4 Hz, 3H)
(S)—4-(3-amino—6-
(tetrahydro—ZH-
pyran 1H NMR (400MHz, METHANOL-
y|)pyrazinyI)-N- d4) 5 ppm 7.66 (s, 2H), 7.77 - 7.45
(1-(3- (m, 5H), 7.43 - 7.29 (m, 1H), 5.63 -
bromophenyl)—2- 5.47 (m, 1H), 4.04 (dd, J=2.7, 11.3
(methylamino)eth Hz, 2H), 3.66 -3.46 (m, 4H), 3.04 -
y|) 2.66 (m, 1H), 2.61 (s, 3H), 1.97 -
fluorobenzamide 1.74 (m, 4H)
4-(3-amino—6-
((1r,4S)—4- 1H NMR (400MHz, METHANOL-
hydroxycyclohexy d4) 5 ppm 7.69 - 7.74 (m, 2H), 7.64
|)pyrazin-2—yI)-N- (d, J=1.6 Hz, 2H), 7.56 - 7.45 (m,
-(3- 542/5 2H), 7.40 (s, 1H), 7.31 (d, J=7.8 Hz,
381 0.65
bromophenyl)—2- 44 1H), 5.46 (dd,J=5.1, 9.4 Hz, 1H),
(methylamino)eth 3.60 - 3.41 (m, 3H), 2.73 (s, 3H),
y|) 2.61 - 2.43 (m, 1H), 2.05 - 1.76 (m,
fluorobenzamide 4H), 1.57 (dq, J=2.9, 13.0 Hz, 2H),
1.33 (d, J=13.7 Hz, 2H)
Structure
N-((S)—2-amino—1 -
1H NMR (400MHz, METHANOL-
Séiuirgfl'mh d4) 6 ppm 7.94 - 7.81 (m, 2H), 7.77
F o {NHz 4_(3Fjamir3:o_6_y - 7.51 (m, 4H), 7.37 - 7.21 (m, 1H),
F 5.59-5.32 (m, 1H), 3.49 -3.40 (m,
382 NH2 N{U ((1r4s)_4_ 608
methox C clohex 2H), 3.37 (S, 3H),3.27 - 3.20 (m.
KIN/ 1 I) raz3i/nE12- 1H), 2.73 -2.55 (m, 1H), 2.20 (d,
|)
; gugzobenzaéide J=9.4 Hz, 2H), 2.04 - 1.89 (m, 2H),
1.65 (dd, J=2.7, 12.5 , 1.33
(d, J=13.7 Hz, 2H)
0.77
N-((S)—2-amino—1-
F O {NHZ (3-
NH2 N bromophenyl)eth
383 y|)(3-am|no
N \ 542/5
b,“ 0.73
B, ((1r,4S)—4-
44 NA
g methoxycyclohex
y|)pyrazinyI)
enzamide
F 0 {OH
F 1H NMR (400MHz, DMSO d6) 5
NHZ N _
H 4_(3_amino_6_(3_
ppm 8.76 - 8.55 (m, 1H), 7.88 (s,
N \ hydroxycyclohexy
/N Br 1H), 7.77 - 7.53 (m, 3H), 7.47 (s,
(g_1_(3_br:mo_I) razin_2_ I)_N_ 547/5
384 0.77 2H), 7.27 (d, J=9.8 Hz, 1H), 5.05 (q,
J=6.5 , 3.58 - 3.37 (m, 3H),
-fluoro'0henVI)_2_
OH 2.72 - 2.56 (m, 1H), 1.98 (d, J=11.7
hydroxyethyl)—2-
single enantiomer; Hz, 1H), 1.90 - 1.64 (m, 3H), 1.49 -
cis on cyclohexane ring; fluorobenzamide
absolute stereochemistry unknown 1.24 (m, 3H), 1.17 - 0.97 (m, 1H)
1H NMR (400MHz, DMSO-d6) 5
4-(3-amino—6-(
ppm 8.76 - 8.59 (m, 1H), 7.88 (s,
ycyclohexy
1H), 7.76 - 7.53 (m, 4H), 7.50 - 7.21
|)pyraziny|)—N- 529/5
(m, 3H), 5.03 (q, J=6.7 Hz, 1H),
((S)(3-
3.80 - 3.68 (m, 4H), 2.75 - 2.57 (m
bromophenyl)—2-
1H), 1.98 (d, J=11.7 Hz, 1H), 1.89 -
hydroxyethyl)—2-
sing/e enantiomer; 1.62 (m, 3H), 1.47 - 1.21 (m, 3H),
fluorobenzamide
cis on cyo/ohexane ring; 1.16 - 0.96 (m, 1H)
absolute stereocnemistry unknown
H NMR (400MHz, DMSO-d6) 5
ppm 8.76 - 8.55 (m, 1H), 7.83 (s,
1H), 7.73 - 7.50 (m, 3H), 7.45 - 7.32
|)pyraziny|)—N- (m, 2H), 7.22 (d, J=9.4 Hz, 1H),
((S)—1-(3-bromo— 5.00 (q, J=6.5 Hz, 1H), 3.48 - 3.35
-f|uoropheny|)—2- (m, 2H), 2.68 - 2.52 (m, 1H), 1.93
hydroxyethyl)—2- (d, J=11.7 Hz, 1H), 1.86 - 1.60 (m
single enantiomer;
cis on cyclohexane ring; fluorobenzamide 3H), 1.41 - 1.18 (m, 3H), 1.12 - 0.93
te stereochemistry unknown (m, 1H)
(S)—4-(3-amino—6-
(tetrahydro—2H-
1H NMR (400MHz, DMSO-d6) 5
pyran
ppm 8.70 - 8.58 (m, 1H), 7.92 (s,
y|)pyraziny|)—2-
1H), 7.76 - 7.52 (m, 3H), 7.37 - 7.21
fluoro—N-(2-
(m, 2H), 7.18 - 7.04 (m, 2H), 5.09 -
y—1-(3-
4.92 (m, 1H), 3.99 - 3.87 (m, 2H),
(methylthio)phen
3.64 (d, J=6.7 Hz, 2H), 3.50 - 3.29
y|)ethy|)benzamid
(m, 2H), 2.94 - 2.75 (m, 1H), 1.83 -
1.62 (m, 4H)
4-(3-amino—6-
((1r,4S)—4-
1H NMR (400MHz, DMSO-d6) 5
F 0 :/OH hydroxycyclohexy
ppm 8.69 - 8.56 (m, 1H), 7.88 (s,
|)pyraziny|)
388 NH2 N
H 1H), 7.76 - 7.49 (m, 3H), 7.34 - 7.20
fluoro-N-((S)—2-
N \ 497 0.69 (m, 2H), 7.18 - 7.02 (m, 2H), 5.02
I hydroxy—1-(3-
/N s\ (q, J=6.7 Hz, 1H), 3.64 (d, J=6.3
(methylthio)phen
Hz, 2H), 3.49 - 3.29 (m, 1H), 2.46
y|)ethy|)benzamid
(s, 3H), 2.02 - 1.76 (m, 4H), 1.59 -
1.43 (m, 2H), 1.35 - 1.12 (m, 2H)
Structure
1H NMR (400MHz, 6) 5
ppm 8.78 - 8.55 (m, 1H), 7.88 (s,
4-(3-amino—6-(
1H), 7.76 - 7.67 (m, 1H), 7.66 - 7.55
hydroxycyclohexy
529/5 (m, 3H), 7.48 - 7.35 (m, 2H), 7.34 -
|)pyraziny|)-N-
7.24 (m, 1H), 5.03 (d, J=7.4 Hz,
((S)(3-
1H), 3.55 - 3.24 (m, 1H), 2.79 - 2.56
bromophenyI)
(m, 1H), 1.98 (d, J=12.1 Hz, 1H),
hydroxyethy|)
1.85 (d, J=12.1 Hz, 1H), 1.79 - 1.65
single enantiomer; fluorobenzamide
cis on cyclohexane ring; (m,2H), 1.48 -1.22 (m, 3H), 1.09
absolute stereochemistry unknown (d, J=11.3 Hz, 1H)
(S)(3-amino—6- 1H NMR (400MHz, DMSO-d6) 5
(tetrahydro—2H- ppm 8.79 - 8.55 (m, 1H), 7.92 (s,
pyran 1H), 7.78 - 7.48 (m, 3H), 7.31 (s,
aziny|)-N- 1H), 7.19 (t, J=10.0 Hz, 2H), 6.13
(1 -(3- (s, 1H), 5.13 - 4.95 (m, 1H), 4.82 -
(chloromethyI) 4.66 (m, 1H), 3.92 (d, J=11.0 Hz,
fluorophenyl)—2- 2H), 3.66 (t, J=5.9 Hz, 2H), 3.42
hydroxyethy|) (dd, J=2.7, 5.9 Hz, 2H), 2.84 (s,
fluorobenzamide 1H), 1.78 - 1.64 (m, 4H)
1H NMR (500 MHz, METHANOL-
4-(3-amino—6-(
d4) 5 ppm 8.06- 7.82 (m, 2 H) 7.77
hydroxycyclohexy
-7.58 (m, 2 H) 7.49 (s,1 H) 7.46-
|)pyraziny|)-N-
7.13 (m, 3 H) 5.30 -5.13 (m,1 H)
((S)(3-
4.19 (br. s., 1 H) 3.88 (dd, J=8.98,
chlorophenyl)—2-
6.15 Hz, 2 H) 3.18 (d, J=4.41 Hz,1
hydroxyethy|)
sing/e enantiomer; H) 2.08 -1.74 (m, 5 H) 1.71 -1.50
enzamide
trans on cyclohexane ring; (m, 3 H)
absolute stereochemistry unknown
F 0 {NH2 1H NMR (500 MHz, METHANOL-
N-((S)amino—1 -
NH N d4) 5 ppm 7.90 (s, 2 H) 7.75- 7.71
H (3-
(m, 1 H) 7.65 (dd, J=11.98, 1.26
392 N \ chlorophenyl)ethy
I Hz,1 H) 7.58 (s,1 H) 7.47 (s, 3 H)
/N CI |)(3-amino—6-
.63 -5.42 (m, 1 H) 3.67 -3.58 (m,
((1r,4S)
1 H) 3.54 - 3.42 (m, 2 H) 2.70- 2.62
hydroxycyclohexy
(m, 1 H) 2.09 (d, J=9.46 Hz, 2 H)
|)pyrazinyI)
1.97 (d, 2 Hz, 2 H) 1.74-
fluorobenzamide
1.63 (m, 2 H) 1.50 - 1.39 (m, 2 H)
Structure
1H NMR (500 MHz, METHANOL-
4-(3-amino(
d4) 5 ppm 8.00- 7.81 (m, 2 H)
hydroxycyclohexy
7.75- 7.57 (m, 2 H) 7.57 -7.47 (m,
zinyI)-N-
1 H) 7.42-7.13 (m, 3 H) 5.22 (s,1
((S)(3-
H) 4.19 (br.s.,1 H) 3.88 (dd,
chlorophenyI)
J=8.83, 5.99 Hz, 2 H) 3.23- 3.07
hydroxyethyI)
sing/e enantiomer; (m,1 H) 2.12- 1.75 (m,5 H) 1.71-
fluorobenzamide
trans on cyclohexane ring; 1.49 (m, 3 H)
absolute chemistry unknown
(S)(2-amino
(1 ,3-dimethyI-1 H-
pyrazoI 1H NMR (500 MHz, DMSO-d6) 5
y|)pyridinyI) ppm 8.74 (d, J=7.88 Hz, 1 H) 8.16
fluoro-N-(1-(3- - 7.74 (m, 4 H) 7.61- 7.33 (m, 2 H)
fluoro 7.19 -6.86 (m, 3 H) 5.19- 4.97 (m,
(methylthio)phen 1 H) 3.79 (s, 3 H) 3.71 -3.64 (m, 2
y|) H) 2.29 (s, 3 H)
hydroxyethyl)ben
zamide
(S)(3-amino
(tetrahydro-ZH- 1H NMR (500 MHz, DMSO-d6) 5
pyran ppm 8.71 (d, J=7.88 Hz, 1 H) 7.95
y|)pyrazinyI) (s, 1 H) 7.79-7.44 (m, 3 H) 7.17-
fluoro-N-(1-(3- 6.91 (m, 3 H) , J=6.83 Hz, 1
fluoro H) 3.97- 3.87 (m, 4 H) 3.67 (d,
(methylthio)phen J=6.31 Hz, 3 H) 3.44 (br. s., 2 H)
y|) .75 (m, 1 H) .68 (m,
hydroxyethyl)ben 4 H)
zamide
4-(3-amino
1H NMR (500 MHz, DMSO-d6) 5
((1r,4S)
ppm 8.70 (d, J=8.20 Hz, 1 H) 7.91
(s, 1 H) 7.77- 7.46 (m, 3 H) 7.14 (s,
|)pyrazinyI)
1 H) 7.01 (t, J=10.25 Hz, 2 H) 5.05
fluoro-N-((S)
(d, J=7.57 Hz,1 H) 3.50-3.33 (m,
(3-fluoro
1 H) 2.60-2.53 (m,1 H) 2.47-2.42
(methylthio)phen
(m, 1 H) 2.02 -1.80 (m, 4 H) 1.5 5
y|)
(d, J=15.13 Hz, 2 H) 1.28 (d,
hydroxyethyl)ben
J=13.24 Hz, 2 H)
zamide
2014/062913
Structure
(S)(3-amino—6- 1H NMR (400 MHz, METHANOL-
(4- d4) 5 ppm 7.83 - 7.70 (m, 2 H)
oxocyclohexyl)py 7.65- 7.45 1 H)
545/5 (m, 2 H) 7.37 (s,
razinyI)-N-(1- 7.22 - 7.00 (m, 2 H) 5.08 (t, J=5.67
(3-bromo—5- Hz, 1 H) 3.76 (t, J=5.67 Hz, 2 H)
fluorophenyl)—2- 2.74- 2.58 (m, 1 H)2.04 (d, J=12.13
hydroxyethy|) Hz, 2 H) ) 1.80 -1.58 (m, 4 H) 1.41
fluorobenzamide (td, J=13.11,4.30 Hz, 2 H)
1H NMR (400 MHz, METHANOL-
d4) 5 ppm 8.73 - 8.63 (m, 1 H) 7.88
4-(3-amino—6-
-7.77 (m, 2 H) 7.70 -7.56 (m, 2 H)
((1r,4S)
7.47 (s,1 H) 7.40-7.23 (m, 3 H)
hydroxycyclohexy
.03-4.94 (m, 1 H) 4.13 (quin,
ziny|)-N- 499.1 0.69
J=6.26 Hz, 1 H) 3.66 -3.54 (m, 1
R)(3-
H) 2.74 -2.57 (m, 1 H) 2.06 (d,
chlorophenyl)—2-
J=9.78 Hz, 2 H) 1.96 (d, J=12.91
hydroxypropy|)
Hz, 2 H) 1.74 - 1.58 (m, 2 H) 1.51-
fluorobenzamide
1.35 (m, 2 H) 1.20 (d, J=6.26 Hz, 3
F 0 1H NMR (400MHz, CD30D) 6 7.94
NH2 N \ 4-(3-amino—6- (t, J=7.6 Hz, 1H), 7.85 - 7.76 (m,
H I
N / ((1r,4r) 2H), 7.69 (dd, J=1.6, 8.2 Hz, 1H),
hydroxycyclohexy 7.62 (dd, J=1.2, 11.7 Hz, 1H), 7.42
399 N CI 4982 0'63
;/ |)pyraziny|)-N- (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.69
((6-chloropyridin- (s, 2H), 3.67 - 3.54 (m, 1H), 2.72 -
2-y|)methy|) 2.58 (m, 1H), 2.07 (d, J=9.4 Hz,
enzamide
OH 2H), 1.96 (d, J=12.9 Hz, 2H), 1.74 -
1.56 (m, 2H), 1.50 - 1.35 (m, 2H)
F 0 1H NMR (400MHz, CD30D) 6 7.93
NHZ N \ 4-(3-amino—6- (t, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.80
H I
N / ((1s,4s) (t, J=7.8 Hz, 1H), 7.71 (dd, J=1.6,
400 /N CI hydroxycyclohexy498-2 0.65 8.2 Hz, 1H), 7.65 (dd, J=1.4, 11.9
|)pyraziny|)-N- Hz, 1H), 7.41 (d, J=7.4 Hz, 1H),
((6-chloropyridin- 7.35 (d, J=8.2 Hz, 1H), 4.69 (s, 2H),
2-y|)methy|) 4.01 (br. s., 1H), 2.79 - 2.68 (m,
fluorobenzamide 1H), 2.11 - 1.96 (m, 2H), 1.93 - 1.83
(m, 2H), 1.77 - 1.64 (m, 4H)
Structure
1H NMR (500MHz, METHANOL-
d4) 5 ppm 7.90 (s, 1H), 7.84 (t,
4-(3-amino—6— J=7.7 Hz, 1H), 7.70 (dd, J=1.4, 8.0
((1r,4S)—4- Hz, 1H), 7.63 (dd, J=1.3, 11.7 Hz,
hydroxycyclohexy 1H), 7.49 (s, 1H), 7.40 (d, J=5.0 Hz,
|)pyrazin-2—yI)-N- 2H), 7.38 - 7.29 (m, 1H), 5.34 (dd,
-(3- J=5.4, 8.8 Hz, 1H), 3.68 - 3.57 (m,
chlorophenyl)—2- 1H), 3.07 (dd, J=9.0, 12.8 Hz, 1H),
(methylamino)eth 2.97 (dd, J=5.4, 12.6 Hz, 1H), 2.71
y|) - 2.59 (m, 1H), 2.48 (s, 3H), 2.13 -
fluorobenzamide 2.04 (m, 2H), 2.03 - 1.90 (m, 2H),
1.76 - 1.61 (m, 2H), 1.51 - 1.37 (m,
1H NMR (400MHz, CD30D) 5 ppm
4-(3-amino—6— 7.89 - 7.75 (m, 2H), 7.71 - 7.64 (m,
((1r,4S)—4— 1H), 7.61 (d, J=12.6 Hz, 1H), 7.53 -
hydroxycyclohexy 7.45 (m, 1H), 7.46 - 7.27 (m, 3H),
|)pyrazin-2—yI)-N- 510.2 0.83 5.43 - 5.28 (m, 1H), 3.74 (d, J=6.7
((S)—2-azido—1-(3- Hz, 2H), 3.68 - 3.50 (m, 1H), 2.64
chlorophenyl)ethy (tt, J=3.6, 12.2 Hz, 1H), 2.14 - 1.99
|) (m, 2H), 1.96 (d, J=12.9 Hz, 2H),
fluorobenzamide 1.77 - 1.56 (m, 2H), 1.51 - 1.31 (m,
4-(3-amino—6— 1H NMR (400MHz, CD30D) 5 ppm
R)—4— 7.88 (s, 1H), 7.83 - 7.74 (m, 1H),
hydroxycyclohexy 7.73 - 7.66 (m, 1H), 7.64 (d, J=11.4
|)pyrazin-2—yI)-N- 510.2 0.86 Hz, 1H), 7.50 (s, 1H), 7.43 - 7.27
((S)—2-azido—1-(3- (m, 3H), 5.44 - 5.30 (m, 1H), 3.80 -
chlorophenyl)ethy 3.67 (m, 4H), 2.79 - 2.64 (m, 1H),
|) 2.11 - 1.93 (m, 2H), 1.76 -1.61 (m,
fluorobenzamide 5H)
Structure
1H NMR (400MHz, CD30D) 5 ppm
(S)—4-(3-amino—6-
7.94 - 7.75 (m, 2H), 7.75 - 7.58 (m,
(tetrahydro—ZH-
2H), 7.50 (s, 1H), 7.43 - 7.26 (m,
pyran
3H), 5.35 (t, J=6.5 Hz, 1H), 4.13 -
y|)pyrazinyI)-N-496.2 0.93
3.96 (m, 2H), 3.74 (d, J=6.7 Hz,
(2-azido—1-(3-
2H), 3.57 (dt, J=2.3, 11.5 Hz, 2H),
chlorophenyl)ethy
3.02 - 2.85 (m, 1H), 2.00 - 1.71 (m,
|)
fluorobenzamide 4H)
—2- 1H NMR (400MHz, CD30D) 5 ppm
acetamido—1-(3- 8.85 (br. s., 1H), 7.89 - 7.76 (m,
chlorophenyl)ethy 2H), 7.71 - 7.55 (m, 2H), 7.45 (s,
|)(3-amino—6- 1H), 7.40 - 7.24 (m, 3H), 5.26 (br.
((1r,4S)—4- s., 1H), 3.71 - 3.51 (m, 3H), 2.75 -
hydroxycyclohexy 2.53 (m, 1H), 2.06 (d, J=9.8 Hz,
|)pyrazinyI) 2H), 2.00 - 1.86 (m, 5H), 1.78 - 1.56
fluorobenzamide (m, 2H), 1.53 - 1.31 (m, 2H)
N-((S)—2- 1H NMR (400MHz, CD30D) 5 ppm
acetamido—1-(3- 7.93 - 7.79 (m, 2H), 7.73 - 7.57 (m,
chlorophenyl)ethy 2H), 7.47 (s, 1H), 7.34 - 7.14 (m,
|)(3-amino—6- 2H), 5.18 (t, J = 5.7 Hz, 1H), 3.93 -
((1r,4S)—4- 3.78 (m, 2H), 2.70 - 2.55 (m, 1H),
methoxycyclohex 2.06 (d, J = 12.3 Hz, 2H), 1.95 (d, J
azinyI) =12.3 Hz, 2H), 1.76 - 1.58 (m, 2H),
fluorobenzamide 1.48 - 1.35 (m, 2H)
2014/062913
Structure
(S)-methyl (2-(4-
1H NMR (500MHz, METHANOL-
(3-amino—6-
d4) 5 ppm 7.90 (s, 1H), 7.85 (t,
(tetrahydro—ZH-
J=7.7 Hz, 1H), 7.72 (d, J=7.9 Hz,
pyran
1H), 7.66 (d, J=11.3 Hz, 1H), 7.48
y|)pyrazinyI)
(s, 1H), 7.44 - 7.36 (m, 2H), 7.36 -
enzamido)
7.22 (m, 1H), 5.28 (d, J=7.3 Hz,
_2_(3_
1H), 4.07 (dd, J=3.8, 11.0 Hz, 2H),
chlorophenyl)ethy
3.67 (s, 3H), 3.60 (dt, J=2.0, 11.7
I)carbamate
Hz, 2H), 3.54 (d, J=6.9 Hz, 2H),
2.97 (s, 1H), 2.02 - 1.81 (m, 4H)
1H NMR (500MHz, OL-
(S)—N-(2-
d4) 5 8.92 (br. s., 1H), 8.31 (br. s.,
acetamido—1-(3-
1H), 7.88 (s, 1H), 7.83 (t, J=7.7 Hz,
bromo—5-
1H), 7.70 (d, J=7.9 Hz, 1H), 7.65 (d,
fluorophenyl)ethy|
J=12.9 Hz, 1H), 7.46 (s, 1H), 7.30
)(3-amino—6-
(d, J=8.2 Hz, 1H), 7.20 (d, J=10.1
(tetrahydro—ZH-
Hz, 1H), 5.26 (d, J=6.6 Hz, 1H),
pyran
4.05 (dd, J=3.5, 11.0 Hz, 2H), 3.66
y|)pyrazinyI)
- 3.53 (m, 4H), 3.01 - 2.88 (m, 1H),
fluorobenzamide
1.95 (s, 3H), 1.94 - 1.80 (m, 4H)
(S)-methyl (2-(4-
1H NMR (400MHz, CD30D) 5 ppm
(3-amino—6-
7.89 (s, 1H), 7.86 - 7.78 (m, 1H),
(tetrahydro—ZH-
7.74 - 7.67 (m, 1H), 7.67 - 7.57 (m,
pyran
2H), 7.49 - 7.38 (m, 2H), 7.34 - 7.25
y|)pyrazinyI)
(m, 1H), 5.25 (d, J=7.4 Hz, 1H),
fluorobenzamido)
4.12 - 3.98 (m, 2H), 3.65 (s, 3H),
_2_(3_
3.62 - 3.49 (m, 4H), 2.99 - 2.89 (m,
bromophenyl)eth
1H), 1.97 - 1.78 (m, 4H)
yl)carbamate
(S)-methyl (2-(4- 1H NMR (400MHz, CD30D) 5 ppm
(3-amino—6- 7.89 (s, 1H), 7.88 - 7.80 (m, 1H),
(tetrahydro—ZH- 7.76 - 7.68 (m, 1H), 7.64 (d, J=11.7
pyran Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.2
y|)pyrazinyI) Hz, 1H), 7.19 (d, J=9.4 Hz, 1H),
fluorobenzamido) 5.31 -5.19 (m, 1H),4.13 -4.01 (m,
(3-bromo—5- 2H), 3.65 (s, 3H), 3.62 - 3.46 (m,
fluorophenyl)ethy| 4H), 3.01 - 2.87 (m, 1H), 1.98 - 1.77
)carbamate (m, 4H)
Structure
(S)(3-amino 1H NMR (400MHz, CD30D) 5 ppm
(tetrahydro-ZH- 7.99 - 7.88 (m, 2H), 7.75 (dd, J=1.4,
pyran 8.0 Hz, 1H), 7.72 - 7.63 (m, 1H),
azin-2—yI)-N- 578.2 7.58 (s, 1H), 7.43 (d, J=8.2 Hz, 1H),
(1 -(3-bromo 7.32 (d, J=9.4 Hz, 1H), 5.61 (dd,
fluorophenyI) J=5.5, 9.0 Hz, 1H), 4.74 (t, J=4.3
((2- Hz, 1H), 4.05 (dd, J=3.1, 11.0 Hz,
fluoroethy|)amino 2H), 3.72 - 3.53 (m, 5H), 3.53 - 3.45
)ethy|) (m, 1H), 3.04 - 2.86 (m, 1H), 2.01 -
fluorobenzamide 1.72 (m, 4H)
4-(3-amino 1H NMR (400MHz, CD30D) 5 ppm
((1r,4S) 7.99 - 7.87 (m, 2H), 7.77 - 7.70 (m,
hydroxycyclohexy 1H), 7.65 (d, J=12.1 Hz, 1H), 7.58
|)pyrazinyI)-N- (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.32
((S)(3-bromo- (d, J=9.4 Hz, 1H), 5.61 (dd, J=5.9,
-fluorophenyI) 8.6 Hz, 1H), 4.74 (t, J=4.3 Hz, 1H),
((2- 3.73 - 3.49 (m, 6H), 2.70 - 2.53 (m,
fluoroethy|)amino 1H), 2.07 (d, J=9.8 Hz, 2H), 1.95 (d,
) J=12.9 Hz, 2H), 1.76 - 1.58 (m, 2H),
fluorobenzamide 1.52 - 1.34 (m, 2H)
1H NMR (400 MHz, DMSO-d6) 8
4-(3-amino 8.81-8.94 (m, 1H), 7.89 (s, 1H),
(1 ,4- 7.69-7.80 (m, 1H), 7.52-7.67 (m,
dioxaspiro[4.5]de 463.3 0.82 2H), 7.33 (d, J=4.3 Hz, 4H), 7.18-
canyl)pyrazin- 7.27 (m, 1H), 6.09 (s, 2H), 4.49 (d,
2—yl)—N-benzyI J=5.9 Hz, 2H), 3.85 (s, 4H), 2.61-
fluorobenzamide 2.70 (m, 1H), 1.67-1.84 (m, 6H),
1.48-1.65 (m, 2H)
1H NMR (400 MHz, CD30D ) 5 7.97
(2-amino - 7.85 (m, 2H), 7.75 - 7.69 (m, 2H),
(3- 7.65 (dd, J=1.2, 11.7 Hz, 1H), 7.57
bromophenyl)eth (d, J=8.2 Hz, 1H), 7.48 (d, J=7.8
y|)(3-amino 5511:: 0.64 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H),
(tetrahydro-ZH- 5.48 (dd, J=5.9, 8.6 Hz, 1H), 4.04
pyran (dd, J=3.1, 11.3 Hz, 2H), 3.57 (dt,
y|)pyrazinyI) J=2.2, 11.6 Hz, 2H), 3.52 - 3.39 (m,
fluorobenzamide 3H), 2.99 - 2.87 (m, 1H), 1.97 -1.76
(m, 4H)
WO 66188
Structure
1H NMR (400 MHz, CD30D) 6 7.61
(s, 1H), 7.71-7.79 (m, 1H), 7.65 (dd,
4-(3-amino
J=8.0, 1.4 Hz, 1H), 7.59 (dd,
((1r,4R)
J=11.3, 1.2 Hz, 1H), 7.45 (s, 1H),
hydroxycyclohexy
7.31-7.36 (m, 2H), 7.23-7.29 (m,
|)pyrazinyI)-N- 469.2 0.79
1H), 5.23 (q, J=6.8 Hz, 1H), 3.54-
-(3-
3.67 (m, 1H), 2.65 (tt, J=12.1, 3.5
chlorophenyl)ethy
Hz, 1H), 2.07 (d, J=9.4 Hz, 2H),
|)
1.97 (d, J=12.9 Hz, 2H), 1.66 (qd,
fluorobenzamide
J=13.0, 2.9 Hz, 2H), 1.56 (d, J=7.0
Hz, 3H), 1.32-1.49 (m, 2H)
1H NMR (400 MHz, CD30D) 6 7.75
mino
(s, 1H), 7.64-7.71 (m, 1H), 7.55-
((1s,4S)
7.60 (m, 1H), 7.47-7.54 (m, 1H),
hydroxycyclohexy
7.35 (s, 1H), 7.21-7.26 (m, 2H),
|)pyrazinyI)-N- 469.3 0.82
7.13-7.19 (m, 1H), .19 (m,
((R)(3-
1H), 3.92 (br. s., 1H), 2.59-2.70 (m,
chlorophenyl)ethy
1H), 1.66-2.00 (m, 2H), 1.71-1.62
|)
(m, 2H), 1.61 (d, J=12.1 Hz, 4H),
fluorobenzamide
1.47 (d, J=7.0 Hz, 3H)
1H NMR (400 MHz, CD30D) 5 7.77
mino (t, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.46-
((1r,4S) 7.61 (m, 2H), 7.37 (s, 1H), 7.23-
hydroxycyclohexy 7.30 (m, 2H), 7.15-7.22 (m, 1H),
|)pyrazinyI)-N- 485.3 0.66 5.10 (t, J=6.1 Hz, 1H), 3.69-3.85
((S)(3- (m, 2H), 3.45-3.56 (m, 1H), 2.56 (tt,
chlorophenyI) J=12.1, 3.4 Hz,1H),1.97(d,J=9.4
hydroxyethyI) Hz, 2H), 1.62-1.92 (m, 2H), 1.57
fluorobenzamide (qd, J=12.9, 2.7 Hz, 2H), 1.25-1.41
(m, 2H)
mino 1H NMR (400 MHz, CD30D) 6
((1s,4R) 7.70-7.65 (m, 2H), 7.50-7.64 (m,
hydroxycyclohexy 2H), 7.37 (s, 1H), 7.22-7.30 (m,
|)pyrazinyI)-N- 485.3 0.69 2H), 7.15-7.22 (m, 1H), 5.10 (t,
((S)(3- J=5.9 Hz, 1H), 3.92 (br. s., 1H),
chlorophenyI) 3.65-3.63 (m, 2H), 2.59-2.75 (m,
hydroxyethyI) 1H), 1.66-2.07 (m, 2H), 1.72-1.62
OH fluorobenzamide (m, 2H), 1.62 (d, J=12.1 Hz, 4H)
Structure
4-(3-amino
1H NMR (400 MHz, CD30D) 8 7.88
((1r,4R)
(s, 1H), 7.83 (s, 1H), 7.74-7.81 (m,
ycyclohexy
1H), 7.52-7.69 (m, 4H), 5.33 (q,
|)pyrazinyI)
J=7.0 Hz, 1H), 3.54-3.67 (m, 1H),
fluoro-N-((R)
3.16 (s, 3H), 2.59-2.71 (m, 1H),
(3-fluoro
2.07 (d, J=9.4 Hz, 2H), 1.91-2.01
(methylsulfonyl)p
(m, 2H), 1.63-1.74 (m, 2H), 1.61 (d,
ethyl)benza
J=7.0 Hz, 3H), 1.33-1.50 (m, 2H)
mide
4-(3-amino 1H NMR (400 MHz, CD30D) 8
((1s,4S) 7.82-7.90 (m, 2H), 7.74-7.81 (m,
hydroxycyclohexy 1H), 7.68 (dd, J=8.0, 1.4 Hz, 1H),
|)pyrazinyI) 7.59-7.66 (m, 2H), 7.56 (d, J=9.4
-N-((R) Hz, 1H), 5.33 (t, J=7.0 Hz, 1H),
(3-fluoro 4.01 (br. s., 1H), 3.16 (s, 3H), 2.73
(methylsulfonyl)p (tt, J=11.2, 3.3 Hz, 1H), 1.96-2.10
henyl)ethyl)benza (m, 2H), 1.81-1.93 (m, 2H), 1.64-
mide 1.78 (m, 4H), 1.61 (d, J=7.0 Hz, 3H)
1H NMR (400 MHz, CD30D) 8 7.76
(t, J=7.6 Hz, 1H), 7.71 (s, 1H), 7.57
(dd, J=8.0, 1.4 Hz, 1H), 7.49 (dd,
4-(3-amino
J=11.5, 1.4 Hz, 1H), 7.21-7.32 (m,
cyclohexylpyrazin 405.3 0.97
4H), 7.12-7.20 (m, 1H), 4.52 (s,
-N-benzy|—2-
2H), 2.50-2.67 (m, 1H), 1.73-1.89
fluorobenzamide
(m, 4H), 1.66 (d, J=12.5 Hz, 1H),
1.27-1.55 (m, 4H), 1.12-1.27 (m,
1H NMR (400 MHz, CD30D) 8 7.77
(t, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.58
(S)(3-amino
(dd, J=8.0, 1.4 Hz, 1H), 7.47-7.55
cyclohexylpyrazin
(m, 1H), 7.37 (s, 1H), 7.23-7.30 (m,
y|)-N-(1-(3-
2H), 7.15-7.22 (m, 1H), 5.10 (t,
chlorophenyI)
J=5.9 Hz, 1H), 3.69-3.86 (m, 2H),
hydroxyethyI)
.65 (m, 1H), 1.73-1.93 (m,
fluorobenzamide
4H), 1.67 (d, J=12.5 Hz, 1H), 1.28-
1.57 (m, 4H), 1.12-1.27 (m, 1H)
Structure
1H NMR (400 MHz, CD30D) 5 7.87
(R)(3-amino (s, 1H), 7.63 (s, 1H), 7.74-7.60 (m,
cyclohexylpyrazin 1H), 7.67 (dd, J=8.0, 1.4 Hz, 1H),
y|)f|uoro-N- 7.50-7.65 (m, 3H), 5.27-5.36 (m,
(1 -(3-f|uoro 1H), 3.16 (s, 3H), .71 (m,
(methylsulfonyl)p 1H), 1.62-1.97 (m, 4H), 1.76 (d,
henyl)ethyl)benza J=12.5 Hz, 1H), 1.61 (d, J=7.0 Hz,
mide 3H), 1.37-1.56 (m, 4H), 1.23-1.37
(m, 1H)
1H NMR (400 MHz, CD30D) 6 7.96
(s, 1H), 7.70-7.79 (m, 1H), 7.61 (dd,
4-(3-amino
J=8.2, 1.6 Hz, 1H), 7.53 (dd,
(cyclohexen
J=11.9, 1.4 Hz, 1H), 7.21-7.35 (m,
y|)pyrazinyI)-N-
4H), 7.06-7.20 (m, 1H), 6.36-6.48
benzyI-Z-
(m, 1H), 4.52 (s, 2H), 2.39 (d, J=2.0
enzamide
Hz, 2H), 2.10-2.19 (m, 2H), 1.65-
1.74 (m, 2H), 1.54-1.63 (m, 2H)
1H NMR (400 MHz, CD30D) 6 7.96
(s, 1H), 7.71-7.60 (m, 1H), 7.62 (dd,
(S)(3-amino
J=8.0,1.4 Hz, 1H), 7.55 (d, J=11.7
(cyclohexen
Hz, 1H), 7.37 (s, 1H), 7.26 (d, J=6.7
y|)pyrazinyI)-N-
Hz, 2H), 7.14-7.21 (m, 1H), 6.44
(1 -(3-
(br. s., 1H), 5.09 (t, J=6.1 Hz, 1H),
chlorophenyI)
3.76 (t, J=5.9 Hz, 2H), 2.39 (d,
hydroxyethyI)
J=2.0 Hz, 2H), .21 (m, 2H),
fluorobenzamide
1.65-1.76 (m, 3H), 1.54-1.64 (m,
1H NMR (400 MHz, CD30D) 6 7.96
(R)(3-amino
(s, 1H), 7.76 (s, 1H), 7.64-7.70 (m,
hexen
1H), 7.58-7.63 (m, 1H), 7.50-7.57
y|)pyrazinyI)
(m, 2H), 7.46 (d, J=9.4 Hz, 1H),
fluoro-N-(1-(3- 513.2 0.92
6.41-6.46 (m, 1H), 5.23 (q, J=7.0
fluoro
Hz, 1H), 3.06 (s, 3H), 2.34-2.44 (m,
(methylsulfonyl)p
2H), 2.15 (dd, J=6.3, 23 Hz, 2H),
:Tenyl)ethyl)benza
.75 (m, 2H), 1.54-1.64 (m,
mide
426 3H), 1.51 (d, J=7.0 Hz, 3H)
WO 66188 PCT/USZOl4/062913
Structure
F 0 1H NMR (400 MHz, CD30D) 6 7.99
NHZ NAG 4-(3-amino—6- (s, 1H), 7.73-7.79 (m, 1H), 7.61 (dd,
N/ (3,6-dihydro—2H- J=8.0, 1.4 Hz, 1H), 7.53 (dd,
427 \ 'N pyran 405.2 0.79 J=11.7, 1.2 Hz, 1H), 7.21-7.34 (m,
y|)pyrazinyI)-N- 4H), 7.10-7.19 (m, 1H), 6.49 (br. s.,
\ benzyI 1H), 4.52 (s, 2H), 4.23 (d, J=2.7 Hz,
fluorobenzamide 2H), 3.82 (t, J=5.5 Hz, 2H), 2.49 (d,
J=1.6 Hz, 2H)
1H NMR (400 MHz, CD30D) 6 6.01
F 0 {OH (Sgtf'zm'nzolf' (s, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.62
' £1644?
428 . . . .
N\/ lN
”D m, , s, Edd’ffif'i’st‘?Hi’H‘fl’Sfi'SSf, m,
0'77
c1 {10fgiaz'n'2'yn'N'469'1 2H), 7.14-7.22 (m, 1H), 6.49 (br. s.,
1H), 5.10 (t, J=5.9 Hz, 1H), 4.23 (d,
chlorophenyl)_2_
\ J=2.7 Hz, 2H), 3.63 (t, J=5.5 Hz,
hydroxyethyl)_2_
2H), 3.76 (t, J=6.3 Hz, 2H), 2.50 (d,
0 fluorobenzamide
J=2.0 Hz, 2H)
(R)—4-(3-amino—6- 1H NMR (400 MHz, CD30D) 6 6.09
F O ihydro—2H- (s, 1H), 7.67 (s, 1H), 7.74-7.61 (m,
F 1H), 7.66-7.73 (m, 1H), 7.59-7.67
NH2 N p);ran H y| pyrazinyI) 2- - (m, 2H), 7.56 (d,J=9.4 Hz, 1H),
429 Ag 515'1 0'75
1 fluoro—N-(1-(3- 6.59 (br. s., 1H), 5.33 (q,J=7.0 Hz,
\ N O=f=o fluoro—5- 1H),4.32 (d, J=2.7 Hz, 2H), 3.92 (t,
\ (methylsulfonyl)p J=5.5 Hz, 2H), 3.16 (s, 3H), 2.59 (d,
henyl)ethyl)benza J=2.0 Hz, 2H), 1.61 (d, J=7.0 Hz,
mide 3H)
F 0 {OH
? 4-(3-amino—6- 1H NMR (400 MHz, CD30D) 6
NH2 ((1r,4S)—4-(2- 7.70-7.82 (m, 2H), 7.59 (dd, J=8.0,
N/ methoxyacetamid 1.4 Hz, 1H), 7.53 (d, J=11.7 Hz,
\ IN
(:1 o)cyclohexyl)pyra 1H), 7.37 (s, 1H), 7.22-7.30 (m,
556 3 0 71
ziny|)-N-((S) ' '
2H), .22 (m, 1H), 5.10 (t,
(3-chlorophenyl)— J=5.9 Hz, 1H), .85 (m, 5H),
2-hydroxyethyl)— 3.32 (s, 3H), 2.52-2.65 (m, 1H),
Hi 2- 1.91
, (d, J=11.3 Hz, 4H), 1.55-1.70
r0 fluorobenzamide (m, 2H), 1.33-1.48 (m, 2H)
WO 66188
Structure
1H NMR (400 MHz, CD30D) 6
4-(3-amino 7.79-7.91 (m, 2H), 7.66 (dd, J=8.0,
((1r,4S)(3- 1.4 Hz, 1H), 7.62 (d, J=11.7 Hz,
methoxypropana 1H), 7.46 (s, 1H), 7.33-7.40 (m,
yclohexyl) 2H), 7.26-7.31 (m, 1H), 5.19 (t,
pyrazin-Z-yI)-N- J=5.9 Hz, 1H), 3.60-3.92 (m, 2H),
((S)(3- 3.67-3.76 (m, 1H), 3.63 (t, J=6.1
chlorophenyI) Hz, 2H), 3.33 (s, 3H), 2.66 (t,
hydroxyethyI) J=12.1 Hz, 1H), 2.41 (t, J=6.1 Hz,
fluorobenzamide 2H), 2.01 (t, J=15.1 Hz, 4H), 1.62-
1.60 (m, 2H), 1.33-1.46 (m, 2H)
1H NMR (400 MHz, CD30D) 6
4-(6-((1s,4R) 7.75-7.63 (m, 2H), 7.56 (d, J=7.8
acetamidocycloh Hz, 1H), 7.54 (d, J=11.7 Hz, 1H),
exyI) 7.37 (s, 1H), 7.23-7.31 (m, 2H),
aminopyrazin-Z- 526.3 0.69 7.16-7.22 (m, 1H), 5.10 (t, J=5.9
y|)-N-((S)(3- Hz, 1H), 3.93 (d, J=3.5 Hz, 1H),
chlorophenyI) 3.69-3.64 (m, 2H), 2.64-2.76 (m,
hydroxyethyI) 1H), 1.66 (s, 3H), 1.76-1.65 (m,
fluorobenzamide 2H), 1.66-1.77 (m, 4H), 1.55-1.67
(m, 2H)
4-(3-amino
1H NMR (400 MHz, CD30D) 6
((1s,4R)
7.72-7.64 (m, 2H), 7.49-7.64 (m,
(methylsulfonami
2H), 7.37 (s, 1H), 7.22-7.30 (m,
do)cyclohexyl)pyr
562.3 0.72 2H), 7.15-7.22 (m, 1H), 5.04-5.15
-yI)-N-((S)-
(m, 1H), 3.70-3.64 (m, 2H), 3.57
1-(3-
(br. s., 1H), 2.66 (s, 3H), 2.62-2.76
chlorophenyI)
(m, 1H), 1.76-1.96 (m, 4H), 1.55-
yethyI)
1.75 (m, 4H)
fluorobenzamide
Structure
methyl ((1R,4s)-
4-(5-amino(4- 1H NMR (400 MHz, CD30D) 5 7.81
(((S)(3- (s, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.47-
chlorophenyI) 7.63 (m, 2H), 7.37 (s, 1H), 7.22-
yethyl)carb 542.3 0.76 7.31 (m, 2H), 7.12-7.22 (m, 1H),
amoyI) 5.04-5.15 (m, 1H), 3.74-3.62 (m,
fluorophenyl)pyra 2H), 3.71 (d, J=5.5 Hz, 1H), 3.53 (s,
zin 3H), 2.62-2.74 (m, 1H), 1.53-1.92
y|)cyc|ohexyl)car (m, 8H)
bamate
(S)(3-amino-6— 1H NMR (400 MHz, CD30D) 6
(4,4- 7.79-7.92 (m, 2H), 7.66 (dd, J=8.0,
difluorocyclohexyl 1.4 Hz, 1H), 7.56-7.65 (m, 1H),
)pyrazin-Z-yI)-N- 505.2 0.87 7.46 (s, 1H), 7.32-7.40 (m, 2H),
(1 -(3- .32 (m, 1H), 5.19 (t, J=5.9
chlorophenyI) Hz, 1H), 3.76-3.94 (m, 2H), 2.77-
hydroxyethyI) 2.66 (m, 1H), 2.06-2.23 (m, 2H),
fluorobenzamide 1.76-2.05 (m, 6H)
1H NMR (400 MHz, CD30D) 6
4-(3-amino
7.66-7.62 (m, 2H), 7.47-7.62 (m,
S)
3H), 7.34 (dd, J=12.9, 7.6 Hz, 2H),
hydroxycyclohexy 529.2
7.10-7.27 (m, 1H), 5.09 (t, J=5.7
|)pyrazinyI)-N- /531.
Hz, 1H), 3.69-3.60 (m, 2H), 3.44-
((S)(3-
3.57 (m, 1H), 2.50-2.62 (m, 1H),
bromophenyI)
1.97 (d, J=9.8 Hz, 2H), 1.67 (d,
hydroxyethyI)
J=12.5 Hz, 2H), 1.46-1.66 (m, 2H),
fluorobenzamide
1.21-1.41 (m, 2H)
4-(3-amino 1H NMR (400 MHz, CD30D) 6
((1s,4R) 7.79-7.91 (m, 2H), 7.60-7.75 (m,
hydroxycyclohexy 547.1 2H), 7.46 (s, 1H), 7.27 (d, J=8.2 Hz,
437 zinyI)-N- /549. 0.71 1H), 7.20 (d, J=9.4 Hz, 1H), 5.16 (d,
((S)(3-bromo- 1 J=5.1 Hz, 1H), 4.01 (br. s., 1H),
-fluorophenyI) 3.66 (t, J=5.5 Hz, 2H), .60
hydroxyethyI) (m, 1H), 1.95-2.11 (m, 2H), 1.79-
fluorobenzamide 1.92 (m, 2H), 1.61-1.76 (m, 4H)
Structure
(S)—4-(3-amino—6-
(tetrahydro—ZH- 1H NMR (400MHz, DMSO-d6) 8
pyran 8.69 (m, 1 H), 7.92 (s,1 H), 7.78 -
y|)pyrazin-2—yI)-N-471 .1 0.7 7.54 (m, 3 H), 7.45 (s,1 H), 7.44 -
(1 -(3- 7.21 (m, 3 H), 6.13 (m, 1 H), 5.01
chlorophenyl)—2- (m, 1 H), 3.92 (m, 2 H), 3.65 (m, 2
hydroxyethyl)—2- H), 3.43 (m, 2 H), 1.74 (m, 4 H)
fluorobenzamide
1H NMR (400 MHz, CD30D) 8 ppm
6-(2-amino—5-
1.59 - 1.80 (m, 4 H) 2.70 - 2.85 (m,
(tetrahydro—ZH-
1 H) 2.98 (t, J=6.65 Hz, 2 H) 3.40 -
pyran
3.54 (m, 4 H) 3.95 (dd, J=11.15,
yl)pyridinyl)—
3.33 Hz, 2 H) 7.35 (s, 1 H) 7.36 -
3,4-
7.42 (m, 1 H) 7.68 (d, J=1.96 Hz, 1
dihydroisoquinoli
H) 7.82 (d, J=2.35 Hz, 1 H) 7.99 (d,
n-1(2H)—one
J=7.83 Hz, 1 H)
4-(2—amino—5-
((1s,4R)—4- 1H NMR (400 MHz, CD30D) 8 ppm
hydroxycyclohexy 7 7.75 - 7.86 (m, 2 H) 7.68 (d,
dinyI)-N- 484.2 0.67 J=1.96 Hz, 1 H) 7.14 - 7.40 (m, 6 H)
((S)(3- 5.10 (t, J=5.87 Hz, 1 H) 3.95 (br. s.,
chlorophenyl)—2- 1 H)3.65 - 3.83 (m, 2 H) 2.34 - 2.65
hydroxyethyl)—2- (m, 1 H) 1.49-1.91 (m,8 H)
fluorobenzamide
Methyl ((1S,4r)—4-
(5-amino—6-(4- 1H NMR (400 MHz, CD30D) 8 ppm
(((S)—1-(3-bromo— 7.79 - 7.92 (m, 1 H) 7.57 - 7.71 (m,
-fluorophenyl)—2— 1 H) 7.46 (s,1 H)7.14-7.31(m,2
441 hydroxyethyl)carb 606.1 0.83 H) 5.17 (t, J=5.87 Hz, 1 H) 3.83 -
amoyl)—3- 3.98 (m, 2 H) 3.62 (s, 3 H) 3.39 -
fluorophenyl)pyra 3.50 (m, 1 H) 2.65 (t, J=12.13 Hz, 1
zin H) .14 (m, 4 H) 1.61 - 1.79
y|)cyc|ohexyl)car (m, 2 H) 1.25 - 1.52 (m, 2 H).
bamate
WO 66188
Structure
1H NMR (400 MHz, CD30D) 8 ppm
4-(2-amino—5- 7.77 - 7.85 (m, 2 H) 7.69 (d, J=1.96
((1r,4S)—4- Hz, 1 H) 7.18 - 7.38 (m, 6 H) 5.10
hydroxycyclohexy (t, J=5.87 Hz, 1 H) 3.70 - 3.86 (m,
|)pyridinyI)-N- 484.2 0.63 2H) 3.45 - 3.60 (m, 1 H) 2.40 - 2.54
((S)(3- (m, 1 H) 1.97 (d, J=9.78 Hz, 2 H)
chlorophenyl)—2- 1.85 (d, J=12.52 Hz, 2 H) 1.40 -
hydroxyethyl)—2- 1.57 (m, 2 H) 1.23 - 1.39 (m, 2 H)
fluorobenzamide
1H NMR (400 MHz, CD30D) 8 ppm
4-(2-amino—5- 7.85 - 7.91 (m, 2 H) 7.81 (t, J=7.83
((1r,4R)—4- Hz,1 H) 7.77 (d, J=1.96 Hz,1 H)
hydroxycyclohexy 7.63 (d, J=7.83 Hz, 1 H) 7.55
|)pyridiny|)—2- (d,J=9.39 Hz, 1 H) 7.37 - 7.45 (m, 2
fluoro—N-((R)—1- H) 5.33 (q, J=7.04 Hz, 1 H) 3.54 -
(3-fluoro—5- 3.74 (m, 1 H) 3.16 (s, 3 H) 2.48 -
(methylsulfonyl)p 2.63 (m, 1 H) 2.06 (d, J=9.78 Hz, 2
henyl)ethy|)benza H) 1.94 (d, J=12.52 Hz, 2 H) 1.61
mide (d, J=7.43 Hz, 3 H) 1.49 - 1.58 (m,
2 H) 1.34- 1.48 (m, 2 H).
1H NMR (400 MHz, CD30D) 8 ppm
(S)—4-(3-amino—6— 7.79 - 7.91 (m, 2 H) 7.58 - 7.71 (m,
(4- 2 H) 7.46 (s,1 H) 7.24 - 7.40 (m, 3
(hydroxymethyl)c H) 5.19 (t, J=5.87 Hz, 1 H) 3.76 -
yclohexyl)pyrazin 499.1 0.74 3.98 (m, 2 H) 3.41 (d, J=6.26 Hz, 2
-N-(1-(3- H) 2.56 -2.75 (m, 1 H) 1.88 - 2.14
single reomer; chlorophenyl)—2- (m, 4 H) 0.99 - 1.81 (m, 6 H)
trans or cis hydroxyethyl)—2-
fluorobenzamide
(S)—4-(3-amino—6—
1H NMR (400 MHz, CD30D) 8 ppm
7.69 - 7.82 (m, 1 H) 7.50 - 7.62 (m,
(hydroxymethyl)c
1 H) 7.37 (s,1 H)7.15-7.31 (m, 3
CI yclohexyl)pyrazin 499.1 0.75
H) 5.10 (t, J=5.87 Hz, 1 H) 3.68 -
y|)-N-(1-(3-
3.86 (m, 2 H) 3.47 (d, J=7.04 Hz, 1
chlorophenyl)—2-
1 H)
single diastereomer,‘ H) 2.74 (td, J=8.71,4.50 Hz,
yethyl)—2-
trans or cis 1.46- 1.97 (m, 11 H).
fluorobenzamide
Structure
1H NMR (400 MHz, CD30D) 8 ppm
(S)—4-(3-amino—6—
7.79 - 7.91 (m, 2 H) 7.58 - 7.71 (m,
2 H) 7.46 (s,1 H) 7.24 - 7.40 (m, 3
(hydroxymethyl)c
H) 5.19 (t, J=5.87 Hz, 1 H) 3.76 -
yclohexyl)pyrazin 561/5
3.98 (m, 2 H) 3.41 (d, J=6.26 Hz, 2
y|)-N-(1-(3-
H) 2.56 -2.75 (m, 1 H) 1.88 - 2.14
sing/e diastereomer; bromo—5-
trans or ois (m, 4 H) 0.99 - 1.81 (m, 6 H)
fluorophenyl)—2-
hydroxyethyl)—2-
fluorobenzamide
(S)—4-(3-amino—6—
(4- 1H NMR (400 MHz, CD30D) 8 ppm
(hydroxymethyl)c 7.69 - 7.82 (m, 1 H) 7.50 - 7.62 (m,
yclohexyl)pyrazin 561/5 1 H) 7.37 (s,1 H)7.15-7.31 (m, 3
-N-(1-(3- H) 5.10 (t, J=5.87 Hz, 1 H) 3.68 -
sing/e diastereomer; bromo—5- 3.86 (m, 2 H) 3.47 (d, J=7.04 Hz, 1
trans or 01's fluorophenyl)—2- H) 2.74 (td, J=8.71,4.50 Hz, 1 H)
hydroxyethyl)—2- 1.46- 1.97 (m, 11 H).
fluorobenzamide
4-(3-amino—6—
1H NMR (400 MHz, CD30D) 8 ppm
R)—4-
7.77 (t, J=7.63 Hz, 1 H) 7.72 (s, 1
fluorocyclohexyl)
H) 7.50 - 7.63 (m, 2 H) 7.37 (s, 1 H)
pyrazin-Z-yI)-N-
7.17 - 7.33 (m, 3 H) 5.10 (t,
((S)(3-
J=5.87Hz,1 H) 3.65 - 3.85 (m, 2 H)
phenyl)—2-
2.68 (t, J=11.74 Hz, 1 H) 1.96 -
hydroxyethyl)—2-
2.13 (m, 2 H) 1.46 - 1.90 (m, 7 H).
fluorobenzamide
Structure
F O :/OH
4-(3-amino—6- 1H NMR (400 MHz, CD30D) 5 ppm
NH2 N
H ((1r,4S) 7.80 - 7.90 (m, 2 H) 7.55 - 7.71 (m,
N \ Dfluorocyclohexyl) 2 H) 7.46 (s, 1 H) 7.20 - 7.41 (m, 3
449 Kw CI pyrazinyI)-N- 487.2 0.88 H) 5.19 (t, J=5.87 Hz, 1 H) 4.42 -
E ((S)(3- 4.71 (m, 1 H) 3.76 - 3.96 (m, 2 H)
E? chlorophenyl)—2- 2.57 - 2.82 (m, 1 H) 2.19 (d, J=5.87
hydroxyethy|) Hz, 2 H) 2.00 (d, J=11.74 Hz, 2 H)
fluorobenzamide 1.50 - 1.79 (m, 4 H)
F 0 :/OH
NHZ (0FN E:}'4'(3'am'"°'6'. 1H NMR (400 MHz, CD30D) 8 ppm
7.80 - 7.95 (m, 2 H) 7.59 - 7.72 (m,
N) \ Cyan9°y°'°hexy') 556/5 2 H) 7.46 (s,1 H) 7.14 -7.30 (m, 2
450 ’N Br p1yraszg'2'yl)'5N' 0 85'
58.0 H) 5.17 (t, J=5.87 Hz, 1 H) 3.74 -
3.97 (m, 2 H) 3.14 (d, J=3.13 Hz, 1
trans/olsmlxture. . gu'érépLoemn:[)_é_
H) 2.67 - 2.85 (m, 1 H) 1.68 - 2.18
hydroxyethy|)
(m, 9 H)
CN fluorobenzamide
F 0 :/OH .
NHZ N (3'am'"°'6' 1H NMR (400 MHz, CD30D) 8 ppm
7.80 — 7.95 (m, 2 H) 7.59 - 7.72 (m,
I (U yclohexyl) 556/5 2 H) 7.46 (s,1 H) 7.14 -7.30 (m, 2
451 /N Br pyrazin_2_yl)_N_ 0.84
58.0 H) 5.17 (t, J=5.87 Hz, 1 H) 3.74 -
(1_(3_br0m0_5_
3.97 (m, 2 H) 3.14 (d, J=3.13 Hz, 1
trans/01s e. . fluorophenyl)_2_
H) 2.67 - 2.85 (m, 1 H) 1.68 - 2.18
hydroxyethy|)
(m, 9 H)
CN fluorobenzamide
1H NMR (400 MHz, CDch), 8 ppm
1.76 (s, 2 H) 2.15 (s, 3 H) 3.34 -
4-(3-amin0 3.57 (m, 3 H) 3.74 - 3.96 (m, 4 H)
((1S.SS) 4.39 (d, J=5.48 Hz, 2 H) 5.12 (d,
F 0 (OH hydroxycycIOPent J=6.65Hz, 1 H) 7.22 (dd, J=9.78,
F y|)pyraziny|) 1.96 Hz, 1 H) 7.48 (dd, J=8.22, 1.56
452 NH2 3 fluorO-N-((S) 581.0 0.73 Hz,1 H) 7.56- 7.72 (m, 4 H) 7.81
N’ (3-fluor0 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) I
RN | iodophenyI)
3 hydroxyethy|)ben
’0. zamide
2014/062913
Structure
1H NMR (400 MHz, CD3CN), 8 ppm
mino—6- 1.56 - 1.82 (m, 2 H) 2.01 - 2.30 (m,
((1 R,3R)—3- 3 H) 3.47 (t, J=8.61 Hz, 1 H) 3.73-
hydroxycyclopent 3.92 (m, 3 H) 4.32 - 4.45 (m, 2 H)
y|)pyrazinyI) 5.05 - 5.19 (m, 1 H) 7.16 - 7.27 (m,
fluoro—N-((S)—1 - 1 H) 7.48 (dt, J=8.12, 1.81 Hz, 1 H)
(3-fluoro—5- 7.56 - 7.71 (m, 4 H) 7.74 - 7.81 (m,
iodophenyl)—2- 1 H) 7.97 (t, J=7.83 Hz, 1 H
hydroxyethyl)ben
zamide
4-(3-amino—6- 1H NMR (400 MHz, CD3CN), 8 ppm
((1 R,38)—3- 1.65 - 1.91 (m, 4 H) 2.03 - 2.39 (m,
hydroxycyclopent 3 H) 3.33 (t, J=7.24 Hz, 1 H) 3.70 -
y|)pyrazinyI) 3.92 (m, 2 H) 4.30 (br. s.,1 H) 5.03
fluoro—N-((S)—1 - -5.19 (m, 2 H) 7.22 (d, J=9.78 Hz, 1
(3-fluoro—5- H) 7.40 - 7.71 (m, 5 H) 7.81 - 7.90
iodophenyl)—2- (m, 1 H) 7.97 (td, J=7.83, 1.96 Hz,
hydroxyethyl)ben 1 H)
zamide
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 8 ppm
((1S,3R)—3- 1.67 - 1.92 (m, 4 H) 2.02 - 2.17 (m,
hydroxycyclopent 2 H) 2.22 - 2.43 (m, 1 H) 3.33 (t,
y|)pyrazinyI) J=7.63 Hz, 1 H) 3.69 - 3.92 (m, 2
fluoro—N-((S)—1 - H)4.24 - 4.34 (m, 1 H) 5.03 - 5.18
(3-fluoro—5- (m, 3 H) 7.22 (dt, J=9.78, 1.96 Hz,
iodophenyl)—2- 1 H) 7.44 - 7.53 (m, 1 H) 7.57 - 7.70
hydroxyethyl)ben (m, 4 H) 7.84 (s,1 H) 7.92 - 8.04
zamide (m, 1 H)
mino—6- 1H NMR (400 MHz, DMSO), 8 ppm
((1S,4S)—3,3- 1.46 - 1.69 (m, 2 H) 1.71 - 2.26 (m,
difluoro—4- 4 H) 2.79 - 3.02 (m, 1 H) 3.58 - 3.83
hydroxycyclohexy (m, 2 H) 4.94 - 5.15 (m, 2 H) 5.25 -
|)pyrazinyI) 5.45 (m, 1 H) 6.11 - 6.26 (m, 1 H)
fluoro—N-((S)—1 - 7.19 - 7.34 (m, 1 H) 7.46 - 7.56 (m,
(3-fluoro—5- 1 H) 7.56 - 7.66 (m, 2 H) 7.66 - 7.77
iodophenyl)—2- (m,1 H) 7.95 (s,1 H) 8.66- 8.79
hydroxyethyl)ben (m, 1H)
zamide
2014/062913
Structure
4-(3-amino—6- 1H NMR (400 MHz, DMSO), 6 ppm
((1R,4R)-3,3- 1.15- 1.30 (m, 1 H) 1.46- 1.69 (m,
difluoro—4— 2 H) 1.72 - 2.25 (m, 5 H) 2.77 - 2.97
hydroxycyclohexy (m, 2 H) 3.57 - 3.64 (m, 3 H) 4.92 -
|)pyrazinyI) 5.14 (m, 2 H) 5.27 - 5.42 (m, 1 H)
fluoro—N-((S)—1 - 6.10 - 6.24 (m, 2 H) 7.16 - 7.34 (m,
(3-fluoro—5- 1 H) 7.46 - 7.57 (m, 1 H) 7.57 - 7.67
iodophenyI) (m, 2 H) 7.67 - 7.77 (m, 1 H) 7.95
hydroxyethyl)ben (s,1H)8.63-8.80(m,1 H)
zamide
4-(3-amino—6- 1H NMR (400 MHz, DMSO) 6 ppm
S)-3,3- 1.56 (d, J=10.56 Hz, 2 H) 1.76 -
difluoro—4— 1.94 (m, 2 H) 1.96 - 2.26 (m, 2 H)
hydroxycyclohexy 2.63 (t, J=5.28 Hz, 3 H) 2.66 (br. s.,
|)pyrazinyI) 1 H)3.33 - 3.41 (m, 4 H) 3.66 (d,
fluoro—N-((S)—1 - J=4.30 Hz, 3 H) 5.44 (d, J=7.82 Hz,
(3-fluoro—5- 1 H) 6.07 - 6.30 (m, 2 H) 7.26 - 7.40
iodophenyI) (m, 1 H) 7.50 - 7.64 (m, 5 H) 7.97
aminoethyl (s, 1 H)6.45 - 6.70 (m, 2 H) 6.96 (d,
)benzamide J=8.22 Hz, 1 H)
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 5 ppm
F O {OH ((1R,4R)-3,3- 1.58 - 1.77 (m, 2 H) 1.85 - 2.12 (m,
? difluoro—4— 3 H) 2.27 - 2.37 (m, 1 H) 2.88 - 3.05
NH2 H/\©/N hydroxycyclohexy (m, 1 H) 3.40 (br. s., 2H) 3.70-3.94
459 I |)pyraziny|) (m, 3 H) 5.08 - 5.22 (m, 2 H) 7.21
585'0 0'73
\ N Br fluoro—N-((S)—1- (d, J=9.78 Hz, 1 H) 7.30 (d, J=8.61
(3-fluoro—5- Hz, 1 H) 7.46 (s, 1 H) 7.59 - 7.76
henyI) (m, 3 H) 7.86 - 8.00 (m, 2H).
; hydroxyethyl)ben
6H zamide
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 5 ppm
F O {OH ((1S,4S)-3,3- 1.45 - 1.66 (m, 2 H) 1.71 - 1.87 (m,
? difluoro—4— 3 H) 1.87 - 1.97 (m, 2 H) 2.13 - 2.30
NH2 {UN hydroxycyclohexy (m, 2 H) 2.69 (t, J=11.35 Hz, 1 H)
460 I |)pyraziny|) 3.11 - 3.37 (m, 2 H) 3.61 - 3.83 (m,
585'0 0'73
\_ N Br fluoro—N-((S)—1- 3 H) 4.96 - 5.14 (m, 3 H) 7.10 (d,
: (3-fluoro—5- J=9.78 Hz, 1 H) 7.20 (dt, J=8.31,
bromophenyI) 1.71 Hz, 1 H) 7.36 (s, 1 H) 7.46 -
hydroxyethyl)ben 7.64 (m, 3 H) 7.78 - 7.92 (m, 2 H)
OH zamide
Structure
4-(3-amino—6-
((1R,3R,4R)—3,4-
oxycyclohe 1H NMR (400 MHz, CD30D) 8 ppm
xyl)pyrazinyl)— 1.35- 1.55 (m, 1 H) 1.57 - 1.74 (m,
2-fluoro—N-((S)—1 - 2 H) 1.84 - 1.98 (m, 1 H) 1.98 - 2.23
(3-fluoro—5- (m, 2 H) 2.72-2.91 (m, 1 H) 3.34-
iodophenyl)—2- 3.54 (m, 3 H) 3.74 - 3.93 (m, 2 H)
hydroxyethyl)ben 5.06 - 5.23 (m, 1 H) 7.10 - 7.30 (m,
zamide 1 H) 7.36- 7.52 (m,1 H) 7.64 (s, 3
H) 7.78 - 7.95 (m, 2 H)
4-(3-amino—6-
((1R,3R,4S)—3,4-
dihydroxycyclohe 1H NMR (400 MHz, CD30D) 8 ppm
xyl)pyrazinyl)— 1.53 - 1.75 (m, 2 H) 1.78 - 2.09 (m,
2-fluoro—N-((S)—1 - 5 H) 2.71 - 2.89 (m, 1 H) 3.64 - 3.77
(3-fluoro—5- (m, 1 H) 3.84 (s, 2 H) 3.91 - 4.04(m,
iodophenyl)—2- 1 H) 5.06 - 5.23 (m, 1 H) 7.10 - 7.27
hydroxyethyl)ben (m,1 H) 7.36- 7.51 (m, 1 H) 7.57-
zamide 7.74 (m, 3 H) 7.84 (s, 2 H)
4-(3-amino—6-
((1S,SS,4S)-3,4-
dihydroxycyclohe 1H NMR (400 MHz, CD30D) 8 ppm
razinyl)— 1.37 - 1.73 (m, 4 H) 1.83 - 1.96 (m,
2-fluoro—N-((S) 611.1 0.67 1 H) 1.98-2.21 (m, 2 H) 2.71 -2.91
(3-fluoro—5- (m, 1 H) 3.34 - 3.55 (m, 3 H) 3.85(s,
iodophenyl)—2- 2 H) 5.05 - 5.26 (m, 1 H) 7.08 - 7.28
hydroxyethyl)ben (m,1 H) 7.34- 7.51 (m, 1 H) 7.64
zamide (s, 3 H) 7.84 (s, 2 H)
4-(3-amino—6- 1H NMR (400 MHz, DMSO) 8 ppm
((1S,38,4R)—3,4- 0.72 - 0.91 (m, 2 H) 0.96 - 1.25 (m,
dihydroxycyclohe 5 H) 1.89 - 2.05 (m, 1 H) 2.81 - 2.95
xyl)pyrazinyl)— (m, 1 H) 3.03 (s, 2 H) 3.09 - 3.21
2-fluoro—N-((S)—1 - (m,1 H)4.25 -4.42 (m, 1 H) 6.30 -
464 (3-fluoro—5- 611.1 0.67 6.47 (m, 1 H) 6.55 - 6.69 (m, 1 H)
enyl)—2- 6.77 - 6.94 (m, 3 H) 7.03 (s, 2 H)
hydroxyethyl)ben
zamide
Structure
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 8 ppm
((1R,3R,4R)—3,4- 1.19 - 1.59 (m, 3 H) 1.68 - 2.07 (m,
dihydroxycyclohe 4 H) 3.13 - 3.39 (m, 4 H) 3.62 - 3.88
xyl)pyrazinyl)— (m, 3 H)4.95-5.14(m,1 H) 7.10
2-fluoro—N-((S)—1 - (d, J=9.78 Hz, 1 H) 7.20 (dt,
ro—5- J=8.31, 1.91 Hz, 1 H) 7.29- 7.74
henyl)—2- (m, 5 H) 7.86 (t, J=8.02 Hz, 1 H)
hydroxyethyl)ben
zamide
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 8 ppm
((1S,38,4R)—3,4- 1.42 - 1.95 (m, 7 H) 3.48 - 3.86 (m,
dihydroxycyclohe 5 H)4.97-5.12 (m, 1 H) 7.10 (d,
xyl)pyrazinyl)— J=9.78 Hz, 1 H) 7.20 (d,J=8.22 Hz,
2-fluoro—N-((S)—1 - 1 H) 7.36 (s,1 H) 7.44 -7.60 (m, 3
(3-fluoro—5- H) 7.68 (d, J=5.09 Hz, 1 H) 7.86 (t,
bromophenyl)—2- J=7.83 Hz, 1 H)
hydroxyethyl)ben
zamide
4-(3-amino—6- 1H NMR (400 MHz, CD3CN) 8 ppm
((1S,SS,4S)-3,4- 1.19 - 1.58 (m, 4 H) 1.69 - 2.08 (m,
dihydroxycyclohe 5 H) 2.65 - 2.79 (m, 5 H) 3.12 - 3.36
xyl)pyrazinyl)— (m, 5 H) 3.63 - 3.87 (m,3 H) 4.94 -
2-fluoro—N-((S)—1 - 5.14 (m, 1 H) 7.10 (d, J=9.39 Hz, 1
(3-fluoro—5- H) 7.15- 7.26 (m, 1 H) 7.36 (s, 1 H)
bromophenyl)—2- 7.42 - 7.70 (m, 3 H) 7.79 - 7.95 (m,
hydroxyethyl)ben 1 H)
zamide
mino—6- 1H NMR (400 MHz, CD3CN) 8 ppm
((1R,3R,4S)—3,4- 1.49 - 2.02 (m, 7 H) 3.55 - 3.94 (m,
dihydroxycyclohe 4 H) 5.04 - 5.26 (m, 1 H) 7.21 (d,
xyl)pyrazinyl)— J=9.00 Hz, 1 H) 7.30 (d,J=7.83 Hz,
2-fluoro—N-((S)—1 - 1 H) 7.46 (s,1 H) 7.54 -8.03 (m,4
(3-fluoro—5- H)
bromophenyl)—2-
hydroxyethyl)ben
zamide
Structure
4-(3-amino—6— 1H NMR (400 MHz, CD3CN) 8 ppm
((1S,38,4S)—3- 1.18- 1.35 (m, 2 H) 1.49 - 1.68 (m,
hydroxy,4- 3 H) 1.86 - 2.00 (m, 5 H) 2.04 - 2.15
methoxylcyclohex (m, 3 H) 2.17 - 2.25 (m,3 H) 2.72 -
y|)pyrazinyI) 2.89 (m, 2 H) 2.94 - 3.08 (m, 2 H)
fluoro—N-((S)—1 - 3.41 (d, J=1.17 Hz, 3 H) 3.46 - 3.60
(3-fluoro—5- (m, 1 H) 3.72 - 3.91 (m, 2 H) 4.01 -
bromophenyl)—2- 4.14 (m, 1 H) 4.70 (t, J=8.22Hz, 1
hydroxyethyl)ben H) 5.03 - 5.24 (m, 2 H) 7.14 - 7.26
zamide (m,1 H) 7.27- 7.35 (m, 1 H) 7.47
(s, 1 H) 7.56 - 7.74 (m, 2 H) 7.82 -
8.03 (m, 2 H)
4-(3-amino—6— 1H NMR (400 MHz, CD30D) 8 ppm
R)—4,4- 1.16- 1.28 (m, 1 H) 1.75 - 1.98 (m,
difluoro—S- 4 H) 2.07 - 2.28 (m, 2 H) 2.83 - 3.06
ycyclohexy (m, 2 H) 3.86 (s, 3 H) 4.03 - 4.19(m,
|)pyrazinyI)-N- 521.1 0.76 1 H) 5.11 -5.27 (m, 1 H) 7.21 - 7.32
((S)(3- (m, 1 H) 7.35 (d, J=6.26 Hz, 2 H)
chlorophenyl)—2- 7.42 - 7.49 (m, 1 H) 7.57 - 7.65 (m,
hydroxyethyl)—2- 1 H) 7.66 - 7.73 (m, 1 H) 7.79 - 7.88
enzamide (m,1 H) 7.90 (s,1 H)
4-(3-amino—6— 1H NMR (400 MHz, CD30D) 8 ppm
((1R,3R)-4,4- 1.07 - 1.37 (m, 3 H) 1.74 - 2.12 (m,
difluoro—S- 6 H) 2.12 - 2.41 (m, 3 H) 3.04 - 3.24
hydroxycyclohexy (m, 3 H) 3.75 - 3.90 (m, 2 H) 3.92 -
|)pyrazinyI)-N- 521.1 0.76 4.05 (m, 2 H) 5.10 - 5.27 (m, 2 H)
((S)(3- 7.35 (d, J=6.65 Hz, 3 H) 7.40 - 7.52
chlorophenyl)—2- (m, 1 H) 7.56 - 7.75 (m, 2 H) 7.78 -
hydroxyethyl)—2- 7.99 (m, 2 H)
fluorobenzamide
4-(3-amino—6— 1H NMR (400 MHz, CD30D) 8 ppm
((1R,38)—4,4- 1.23 (s, 2 H) 1.71 - 2.04 (m, 5 H)
difluoro—S- 2.06 - 2.24 (m, 2 H) 2.26 - 2.46 (m,
hydroxycyclohexy 1 H) 2.82 - 3.05 (m, 2 H) 3.86 (t,
472 zinyI)-N- 521.1 0.76 J=5.67Hz, 3 H) 4.01 - 4.18 (m, 1 H)
((S)(3- 5.19 (s, 2 H) 7.18 - 7.41 (m, 3 H)
chlorophenyl)—2- 7.46 (s, 1 H) 7.70 (d, J=0.78 Hz, 2
hydroxyethyl)—2- H) 7.77 - 7.99 (m, 2 H)
fluorobenzamide
1H NMR (500 MHz,
(S)—4-(3-amino—6-
(morpholine—4- ACETONITRILE-dS) 5 ppm 3.56 -
carbonyl)pyrazin- 3.99 (m, 13 H) 5.06 - 5.23 (m, 1 H)
.78 - 6.13 (m, 2 H) 7.22 (d, J=8.20
2-yl)—N-(1-(3-
Hz, 1 H) 7.27 -7.36 (m, 1 H) 7.41 bromo—5- -
fluorophenyl)—2- 7.79 (m, 5 H) 7.89 - 8.05 (m, 1 H)
8.25 - 8.43 (m, 1 H)
hydroxyethyl)—2-
fluorobenzamide
1H NMR (500 MHz,
(S)—4-(2-amino—5- ACETONITRILE-dS) 5 ppm 3.49 -
(morpholine—4- 3.74 (m, 7 H) 3.77 - 3.94 (m, 2 H)
carbonyl)pyridin- 5.15 (br. s., 1 H) 7.15 -7.52 (m, 5
3-y|)-N-(1-(3- H) 7.62 - 7.83 (m, 2H) 7.92 - 8.07
- (m, 2 H)
fluorophenyl)—2-
hydroxyethyl)—2-
fluorobenzamide
1H NMR (500 MHz,
(S)—4-(3-amino—6-
ACETONITRILE-dS) 5 ppm 1.12 -
1.36 (m, 2 H) 1.60 - 1.87 (m, 4 H)
(hydroxymethy|)pi
2.71 - 2.92 (m, 2 H) 2.98 - 3.22 (m,
peridine—1 -
1 H) 3.39 (d, J=5.99 Hz, 2 H) 3.85
carbonyl)pyrazin-
(dd, J=18.29, 5.36 Hz, 2 H) 4.12 -
2-yl)—N-(1-(3-
4.36 (m, 1 H) 4.48 -4.68 (m, 1 H)
bromo—5-
.04 - 5.25 (m, 1 H) 5.58 - 5.82 (m,
fluorophenyl)—2-
2 H) 7.15 - 7.26 (m, 1 H) 7.31 (s,1
hydroxyethyl)—2-
fluorobenzamide H) 7.47 (s,1 H) 7.54 - 7.73 (m, 3 H)
7.97 (s, 1 H) 8.23- 8.38 (m, 1 H)
1H NMR (500 MHz,
(S)—4-(3-amino—6- ITRILE-dS) 5 ppm 3.74 -
(3- 3.99 (m, 3 H) 4.25 - 4.44 (m, 2 H)
hydroxyazetidine— 4.58 (ddd, , 4.10, 2.52 Hz, 1
1- H) 4.81 (d, J=7.25Hz, 1 H) 5.16 (d,
carbonyl)pyrazin-
476 549.9 0.66 J=5.04 Hz, 1 H) 5.89 (br. s., 2 H)
2-yl)—N-(1-(3- 7.22 (d, J=9.77 Hz, 1 H) 7.32 (dt,
bromo—5- J=8.20, 2.05 Hz, 1 H) 7.48 (d,
fluorophenyl)—2- J=1.26 Hz, 1 H) 7.58 - 7.77 (m,
hydroxyethyl)—2-
fluorobenzamide 3 H) 7.91 - 8.05 (m, 1 H) 8.49 - 8.74
(m.1 H)
(S)—4-(2—amino—5- 1H NMR (500 MHZ.
(4- ACETONITRILE-dS) 6 ppm 1.32 -
hydroxypiperidine 1-57 (m, 2 H) 1-74 ' 1-39 (m, 3 H)
3.29 (ddd, J=13.16, 9.54, 3.15 HZ,
carbonyl)pyridin- 2 H) 3.73 - 3.91 (m, 3H) 3.91 - 4.17
3-yl)—N-(1-(3- (m, 1 H) 5.15 (d, J=5.67 Hz, 1 H)
bromo—5- 7.12 - 7.52 (m, 4 H) 7.68 (br. s., 1
heny|)_2_ H) 7.80 (d, J=1.89 Hz, 1 H) 7.91 -
hydroxyethyl)—2— 8-08 (m, 2 H)
fluorobenzamide
Example 453
S nthesis of 4- 3-amino 1R 3R h drox 0 do ent | razin-2— Ifluoro-N- S
3-fluoroiodo hen Ih drox eth Ibenzamide
F O
F O
NH2 0J< Pd (tri-t-butyl-Ph)2
TBAC N \
N \ —’
+ |
RFNI /
N-cyclohexyl-N—methyl
cyclohexanamine
Br 40%
F o J< F o
F o J< J<
m2 0
NH2 0 Step 3 NH2 0 NH2
H2 N \
NaBH4 NI \ NI \
| /N /N
Pd/C, MeOH 100%
58.1 %
OH "OH
O (+/-)
(+/.)
F o 0
NH2 0 _eE_St 5 NH2 OH
Ste §
_l25te A N \ nane NI \ Amide coupling
—.I —>
/N ,N —.
100 A’D 45%
Chiral separation
-.,0H 6H
F O {OH
WN/OH: F
:I /;N |
Step 1. tert-butyl 4-(3-amino(3-oxocyclopentenyl)pyrazinyl)—2-fluorobenzoate:
A mixture of tert—butyl minobromopyrazinyl)fluorobenzoate (1 g, 2.72
mmol), cyclopent—2-enone (0.892 g, 10.86 mmol), N-cyclohexyl-N-
methylcyclohexanamine (1.061 g, 5.43 mmol), i-t—butylphosphine)palladium(0)
(0.069 g, 0.136 mmol), TBAC (0.075 g, 0.272 mmol) in dioxane (7 mL) was microwaved
at 1350C for 25 min. After cooling, the mixture was concentrated and the residue was
diluted with 10 ml of DCM, sonicated for 5 min, ed and the solid was washed with 3ml
of DCM. The combined DCM solution was directly applied for ISCO silica column
separation. (40 gram column, 10 to 90% EtOAc in Heptane). 400 mg of the desired
product was obtained as a light yellow solid. LCMS (m/z): (MH+) 370.0, 0.903 min. 1H
NMR (400 MHz, DMSO) 6 ppm 1.12 - 1.26 (m, 5 H) 1.55 (s, 10 H) 1.59 - 1.72 (m, 5 H)
2.41 (dt, J=5.09, 2.15 Hz, 3 H) 2.48 (dt, J=3.62, 1.91Hz, 3 H) 3.00 (dd, J=5.09, 2.35 Hz, 2
H) 3.30 (s, 3 H)6.66 (t, J=1.76 Hz, 1 H)7.09 (s, H) 7.55-7.69 (m, H)7.83-7.95 (m, 1
H) 8.57 (s, 1 H).
Step 2: tert-butyl 4-(3-amino(3-oxocyclopentyl)pyrazinyl)fluorobenzoate: To tertbutyl
mino(3-oxocyclopent—1-enyl)pyrazinyl)fluorobenzoate (650 mg,
1.760 mmol) in MeOH (15 ml) was added 15 ml of DCM under stirring until a clear
solution was obtained. The solution was purged by nitrogen for 5 min, then Pd/C (300
mg, 10%, Degussa type) was added, and the resultant mixture was degassed by N2
stream for 15 min. After equipped with en gas balloon, the reaction mixture was
stirred at room temperature for 16 h. The on mixture was filtered, and the ted
solution was concentrated, and the crude material was purified by ISCO. (24 g silica gel,
to 80% EtOAc in heptane) to afford 380 mg of the desired product as a light yellow
solid. 58.1 % yield. LC-MS (m/z): (MH+) 372.1, 0.829 min.
Step 3: (+/-) tert-butyl 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)pyrazinyl)
fluorobenzoate and (+/-)tert-butyl 4-(3-amino((1R,3S)hydroxycyclopentyl)pyrazin
f|uorobenzoate: To a on of tert-butyl 4-(3-amino(3-oxocyclopentyl)pyrazin-
2-yl)fluorobenzoate (200 mg, 0.538 mmol) in MeOH ( 4 mL) at -780C was added
NaBH4 (61.1 mg, 1.615 mmol). The reaction mixture was stirred at -78 °C for 1 hr -
. At
780C, the reaction mixture was quenched with sat NH4C| ( 4 ml), and the cooling bath was
removed, and the mixture was gradually warmed to RT, then sat NaHC03 solution ( 4 ml)
was added. The reaction mixture was extracted with EtOAc ( 30 ml x2). The c layer
was washed with water and brine, dried over sodium sulfate, filtered off and concentrated
in vacuo. About 210 mg of the crude product was obtained. The crude product was
dissolved into 4 ml of DMSO, filtered and purified by prep HPLC. The more polar
compound is trans ( desired, came out earlier), the less polar compound is cis, came out
later. After netrilized with 1N NaOH, tran and cis compound were obtained as free base
compounds.
(+/-) tert-butyl 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)pyraziny|)fluorobenzoate
: 40 mg, 19.9 % , trans. LC-MS (m/z): (MH+) 374.1, 0.81 min, NMR (400 MHz,
CD3CN) 6 ppm 1.61 (s, 9 H) 1.69 - 1.82 (m, 1 H) 1.88 - 2.25 (m, 6 H) 2.59 - 2.77 (m, 1 H)
3.32 - 3.56 (m, 1 H) 4.31 - 4.48(m, 1 H) 5.07 (br. s., 2 H) 7.59 (dd, J=12.13, 1.56 Hz, 1 H)
7.66 (dd, J=8.02, 1.76 Hz, 1 H) 7.88 - 8.03 (m, 2 H).
(+/-) tert-butyl 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)pyrazinyl)fluorobenzoate
: 150 mg, 74.6 % yield, cis. LC-MS (m/z): (MH+) 374.1, 0.81 min. 1H NMR (400 MHz,
CD3CN) 6 ppm: 1.55 - 1.67 (m, 9 H) 1.69 - 1.89 (m, 2 H) 1.91 - 2.03 (m, 4 H) 2.05 - 2.13
(m, 1 H) 2.21 -2.33 (m, 1 H) 3.21 -3.41 (m, 1 H) 3.99 (s, 1 H)4.20 -4.34 (m, 1 H) 5.04 -
.23 (m, 2 H) 7.50 - 7.58 (m, 1 H) 7.58 - 7.67 (m, 1 H) 7.90 - 8.05 (m, 2 H).
fluorobenzoate: The two trans isomers (160 mg total) were separated by chiral column:
OJ column (21 X250 mm), SFC = 100 ml/min, CO2/EtOH = 85/15, loading: 70 mg/7ml
EtOH, 274 bar. 80 mg of each enantiomer was ed.
tert-butyl 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)pyrazinyl)fluorobenzoate:
NMR (400 MHz, DMSO) 6 ppm: 1.04 (t, J=6.85 Hz, 1 H) 1.47 - 1.73 (m, 11 H) 1.75 - 1.86
(m, 2 H) 1.89 - 2.18 (m, 2 H) 3.15 (s, 1 H) 3.30 (s, 4H) 3.97 - 4.16 (m, 1 H) 4.19 - 4.39 (m,
1 H) 4.44 - 4.59 (m, 1 H) 6.10 (s, 2 H) 7.57 (d, J=12.13 Hz, 1 H) 7.63 (dd, J=8.02, 1.76
Hz, 1 H) 7.77 - 8.01 (m, 2 H).
tert-butyl 4-(3-amino((1S,3S)hydroxycyclopentyl)pyrazinyl)fluorobenzoate:
NMR (400 MHz, DMSO) 6 ppm: 1.04 (t, J=6.85 Hz, 1 H) 1.14 - 1.28 (m, 1 H) 1.50 - 1.57
(m, 10 H) 1.59 - 1.71 (m, 1 H) 1.75 - 1.87 (m, 2 H)1.89 - 2.14 (m, 2 H) 3.15 (s, 1 H) 3.30
(s, 4 H) 4.18 - 4.37 (m, 1 H) 4.42 - 4.55 (m, 1 H) 6.10 (s, 2 H) 7.51 - 7.60 (m, 1 H) 7.63
(dd, J=8.02, 1.76 Hz,1 H) 7.81 - 7.95 (m, 2 H).
Step 5. mino((1R,3R)—3-hydroxycyclopentyl)pyrazinyl)fluorobenzoic acid
Procedure: To a solution of tert-butyl 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)-
pyrazinyl)fluorobenzoate (7 mg, 0.019 mmol) in DCM (2 mL) at RT was added TFA
(0.361 mL, 4.69 mmol). The resultant solution was stirred at RT for 2 h. The solution was
concentrated, and further dried by high vacumm to afford the d product as a TFA
slat, which was used at the next step directly. (6 mg, 100 % yield) LC-MS (m/z): 318.1
(MH+), 0.46 min.
Step 6: 4-(3-amino((1R,3R)—3-hydroxycyclopentyl)pyrazinyl)fluoro-N-((S)—1-(3-
fluoroiodophenyl)hydroxyethyl)benzamide: To a mixture of (4-(3-amino((1R,3R)—
3-hydroxycyclopentyl)pyrazinyl)fluorobenzoic acid) ( 6 mg, 0.019 mmol), (S)—2-
amino(3-fluoroiodophenyl)ethanol (8.96 mg, 0.028 mmol), HOAt (5.15 mg, 0.038
mmol) and EDC (7.25 mg, 0.038 mmol) in DMF (1ml) was added DIEA (0.036 ml, 0.208
mmol). The resultant e was stirred over night at RT. The mixture was diluted with
EtOAc, washed with water three times and brine, dried with , filtered and
concentrated to afford the crude product as a light yellow viscous liquid. This crude was
purified by prep HPLC to afford desired product (6 mg, 45.2 % yield) as a light yellow
solid, a TFA salt. LC-MS: (MH+) 581.0 at 0.726 min. 1H NMR (400 MHz, CD3CN) 6 ppm
1.56 - 1.82 (m, 2 H) 2.01 - 2.30 (m, 3 H) 3.47 (t, J=8.61 Hz, 1 H) 3.73 - 3.92 (m, 3 H) 4.32
-4.45 (m, 2 H) 5.05 - 5.19 (m, 1 H) 7.16 - 7.27 (m, 1 H) 7.48 (dt, J=8.12, 1.81 Hz, 1 H)
7.56 - 7.71 (m, 4 H) 7.74 - 7.81 (m, 1 H) 7.97 (t, J=7.83 Hz, 1 H).
Example 456
F O J<
F O J<
OTf N/ /
O N
tnfluoromethanesulfomc 013/0 \ lN step 2
anhydride
\ N step4
—’ —’ Br
O —> —>a77A)
O step1 52%
step3, 51%
two steps
F O F O
Bno \ ,Bcc J< BeeNBocwk film1 Boo\ 800
N 0 0 N OOJ<
N/ / N’
| XtalFlour-E
step5
\ N —. \ N
Pd-C, H2 :
step7 87%
41% Gig—0 0 step 6,41%
IN T, O ...\
I 2mg \i
2[\z
N / TFA / DCM |
I \z _Im 12
N r 2
\ N —’ _<
step 8, 100%
step 9, 89%
F FF
BZF OBZ
step 10,100% NWNiEP/F
—> K/N
step 11
chiral separation
Step 1: 3-oxocyclohexenyl trifluoromethanesulfonate: To a solution of cyclohexane-
1,3-dione (8 g, 71.3 mmol) in CH2C|2 ( 120 ml) at 00C ( ice water bath) under nitrogen was
added sodium carbonate (8.32 g, 78 mmol). The resultant mixture was stirred at 00C for
min. A on of trifluoromethanesulfonic anhydride (12.05 mi, 71.3 mmol) in 35 ml
of DCM was added dropwise over 1h . The mixture was d at 00C for 1.5 h. The
mixture was ed through fritted glass , and 60 ml of saturated NaHC03 was
added . Organic layer was then separated and washed with 40ml of brine, dried
over NazSO4, filtered and concentrated to e 9 g ( 52 % yield) ofdesired product as
a light yellow liquid. LC-MS (m/z): (MH+) 244.9, 0.72 min.
Step 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohexenone, (3-oxocyclohex—
1-enyl)boronic acid: A mixture of 3-oxocyclohexenyl trifluoromethanesulfonate (9
g, 36.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (14.04 g, 55.3
mmol), potassium acetate (10.85 g, 111 mmol) and Pd(dppf)Cl2.DCM (0.808 g, 1.106
mmol) in dioxane (80 mL) was flushed with nitrogen for 5 min and then heated at 90 °C
overnight. After cooling, the mixture was filtered, and the solid was washed with
3x20mL warm dioxane. The combined solution was concentrated until about 70 ml of
dioxan was left. This product ( in dioxane) was used directly at the next step. LCMS (
m/z): MH+=140.8 (Boronic acid), 0.284 min.
Step 3: Tert-butyl 4-(3-amino(3-oxocyclohexenyl)pyrazinyl)fluorobenzoate:
A 250 ml RB was charged with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohex
enone (7.00 g, 31.5 mmol) ( in about 70 ml e), tert-butyl 4-(3-amino
bromopyrazinyl)f|uorobenzoate (5.8 g, 15.75 mmol)), Pd(dppf)C|2.DCM (0.576 g,
0.788 mmol), and then Saturated Na2C03 (25 mL). The resultant e was flushed
with nitrogen for 15min. DME (10 mL) was then added. The e was stirred at
1000C overnight. Ethyl acetate ( 150 ml) and water( 50 ml) were added, and the
resultant mixture was stirred for 30 min. Organics was separated and the aqueous layer
was extracted with ethyl acetate ( 30 ml x3). Organic layers were combined and dried
over NazSO4, filtered and ated to provide crude desired material as a sticky dark
color semi solid. This solid was taken to about 30 ml of ether, sonicated for 10 min, and
the precipitaed yellow solid was filtered, and washed with cold ether( 5m| x3), dried under
high vacumm to afford the desired product (3.1 g 51.3%
, ) as a yellow solid. LC-MS
(m/z): (MH+) 384.2, 0.92 min.
Step 4: tert-butyl 4-(3-(bis(tert-butoxycarbonyl)amino)(3-oxocyclohexen
y|)pyrazinyl)fluorobenzoate: To a sion of tert-butyl 4-(3-amino(3-
oxocyclohex—1-enyl)pyraziny|)fluorobenzoate (3 g, 7.82 mmol) in itrile ( 25
mL) at RT was added DMAP (0.048 g, 0.391 mmol) followed by Boc—anhydride (6.36 mL,
27.4 mmol). The resultant mixture was stirred at RT for 25 min. The solution was diluted
with EtOAc, washed with sat NaHC03 and water, dried and concentrated. The crude
product was purified by ISCO separation ( 80 g silica, 30 min, 5 to 60% EtOAc in
Heptane). The desired product was obtained as a light yellow sticky liquid, which
solidified upon standing over night. (3.5 g, 6.00 mmol, 77 % yield). LC-MS ( m/z): (MH+)
584.2, 1.286 min. 1H NMR (400 MHz, ACETONITRILE-d3) 5 ppm 0.91 (s, 1 H) 1.31 (s,
16 H) 1.61 (s, 7 H) 1.88 - 2.03 (m, 1 H) 2.16 (s, 2 H) 2.50 (d, J=7.04 Hz, 2H) 2.85 - 3.09
(m, 2 H) 6.90 (s, 1 H) 7.51 - 7.71 (m, 2 H) 7.91 - 8.11 (m, 1 H) 8.92 (s, 1 H).
Step 5: tert-butyl 4-(3-(bis—(tert-butoxycarbonyl)amino)(3-oxocyclohexyl)pyraziny|)-
2-fluorobenzoate: To a solution of tert-butyl 4-(3-(bis(tert-butoxycarbonyl)amino)(3-
oxocyclohex—1-enyl)pyraziny|)fluorobenzoate (3g, 5.14 mmol) in MeOH (15 mL)
and DCM (10 mL) at RT was added Pd-C (10%, degauss, 1.094 g, 1.028 mmol). The
resultant mixture was d with hydrogen for 10 min, then stirred at RT for 5 hours
under hydrogen atmosphere. The suspension was filtered and the solution was
concentrated. ISCO silica column separation ( 80 g silica, 30 min, 5 to 60% EtOAc in
Heptane) afforded the desired product as a light yellow sticky liquid, which solidified upon
ng over night. (1.485 g, 2.54 mmol, 49.3 % yield). LC-MS (m/z): (MH+) 586.3, 1.17
min.
Step 6: tert-butyl (1S,4S)—4-(benzoyloxy)—3-oxocyclohexyl)(bis(tertbutoxycarbonyl
)amino)pyrazinyl)fluorobenzoate and tert-butyl 4-(6-((1R,4R)
(benzoyloxy)—3-oxocyclohexyl)(bis(tert-butoxycarbonyl)amino)pyrazinyl)—2-
fluorobenzoate:
A: Prep of the free base catalyst: 300 mg of -methoxyquinolin
y|)((1S,2R,4S,5R)vinquuinuclidinyl)methanamine ( tri.HCl salt) was dissolved into
ml of DCM, then neutrilzed with 1N NaOH (5 ml), the organic layer was ted,
washed with brine ( 5ml x2) and water( 5ml x2), dried, filtered and concentrated to afford
the product as a free base. (200 mg free base amine in 4 ml of dioxane).
B: A 10 mL microwave vial, equipped with a magnetic stirring bar, was charged with tert-
butyl 4-(3-(bis-(tert-butoxycarbonyl)amino)(3-oxocyclohexy|)pyraziny|)
fluorobenzoate (1.485 g, 2.54 mmol), BHT (Butylated hydroxyltoluene, 0.067 g, 0.304
mmol), (S)—(6-methoxyquinolinyl)((1S,2R,4S,5R)—5-vinquuinuclidinyl)methanamine
(0.098 g, 0.304 mmol) ( in 2 ml of Dioxane) and trichloroacetic acid (0.050 g, 0.304
mmol). Dioxane ( 1ml) was then added, and the resultnat mixture was stirred for 5 min
before benzoic peroxyanhydride (0.983 g, 4.06 mmol) was added. The reaction mixture
was stirred at 30 °C for 16 h. The reaction mixture was diluted with dichloromethane,
treated with a saturated aqueous on of , washed with brine, dried over
Na2804, filtered, concentrated to approx. 3 ml of DCM. The crude ( in 3 ml of DCM) was
purified by ISCO flash column chromatography eluting with a EtOAc in Heptane ( 10 to
45% EtOAc in Heptane, 120 g silica gel column, 35 min). The enantioselectivity could not
be ined at this stage by chiral-phase HPLC analysis. No separations were
observed by all the columns/methods available. This product was directly used in the next
step reaction. (730 mg, 40.8 % yield) LC-MS (m/z): (MH+) 706.3 at 1.38 min. 1H NMR
(400 MHz, CDCI3) 6 ppm 1.26 - 1.41 (m, 19 H) 1.46 - 1.67 (m, 11 H) 2.08 - 2.22 (m, 1 H)
2.26 - 2.42 (m, 2 H) 2.50 - 2.67 (m, 1 H) 2.70- 2.91 (m, 1 H) 3.08 (s, 1 H) 3.26 - 3.49 (m, 1
H) 4.03 - 4.19 (m, 1 H) 5.49 - 5.67 (m, 1 H) 7.26 (d, J=0.78 Hz, 2 H) 7.40 - 7.66 (m, 5 H)
7.97 (t,J=7.83 Hz, 1 H) 8.07 - 8.19 (m, 2 H) 8.41 (s, 1 H).
Step 7: tert-butyl 4-(6-(4-(benzoyloxy)-3,3-dif|uorocyc|ohexy|)(bis(tertbutoxycarbonyl
)amino)pyrazinyl)fluorobenzoate: To a solution of utyl 4-(6-
((1S,4S)(benzoyloxy)oxocyc|ohexy|)(bis(tert-butoxycarbony|)amino)pyraziny|)-
2-fluorobenzoate (730 mg, 1.034 mmol) in DCM (7 mL) at RT was added XtalFlour-E
(939 mg, 4.14 mmol) followed by triethylamine rofluoride (0.674 mL, 4.14 mmol).
The resultant mixture was stirred at RT for 5 hours. The mixture was filtered and the
ed solution was directly applied for ISCO separation: 24 g silica gel, 0 to 70% EtOAc
in Heptane, 30 min. A light yellow solid (670 mg, 0.902 mmol, 87 % yield) was obtained.
LC-MS (m/z): (MH+) 728.0 at 0.95 min ( lar MS method). 1H NMR (400 MHz,
CDCI3) 6 ppm 0.88 (s, 2 H) 1.19 - 1.39 (m, 21 H) 1.48 - 1.68 (m, 11 H) 1.86 - 2.08 (m, 2
H) 2.08 - 2.21 (m, 1 H) 2.26 - 2.47(m, 2 H) 2.47 - 2.63 (m, 1 H) 3.21 - 3.44 (m, 1 H) 5.22 -
.51 (m, 1 H) 7.41 - 7.55 (m, 4 H) 7.60 (s, 1 H) 7.96 (d, J=7.82 Hz, 1 H) 8.06 - 8.19 (m,
2H) 8.42 (s, 1 H).
Step 8: 4-(3-amino(4-(benzoyloxy)—3,3-difluorocyclohexyl)pyrazinyl)fluorobenzoic
acid: To a solution of tert-butyl 4-(benzoyloxy)-3,3-difluorocyclohexyl)(bis(tert-
butoxycarbonyl)amino)pyrazinyl)fluorobenzoate (670 mg, 0.921 mmol) in DCM (12
mL) at RT was added TFA (4.96 mL, 64.4 mmol). The resultant mixture was stirred at
RT for 2 hours. The mixture was concentrated, diluted with EtOAc, neutrized with
NaHC03 twice, then brine, the organic layer was separated, dried and concentrated to
afford the crude product, which was used at the next step directly. (434 mg, 0.921 mmol,
100 % yield). LC-MS (m/z): (MH+) 472.1, at 0.942 min. 1H NMR (400 MHz, DMSO) 6
ppm: 1.07 (t, J=7.04 Hz, 2 H) 1.83 (t, J=10.17 Hz, 2 H) 2.16 (d, J=5.09 Hz, 1 H) 2.29 -
2.45 (m, 2 H) 3.02 (br. s., 1H) 3.16 - 3.44 (m, 9 H) 5.22 - 5.52 (m, 1 H) 5.73 (s, 1 H) 6.24
(s, 2 H) 7.44 - 7.75 (m, 5 H) 7.89 (t, J=7.83 Hz, 1 H) 7.94 - 8.07 (m, 3 H).
Step 9: 4-(5-amino(3-fluoro(((S)(3-fluoroiodophenyl)
hydroxyethyl)carbamoyl)phenyl)pyrazinyl)-2,2-difluorocyclohexyl te, 4-(5-amino-
6-(3-fluoro(((S)(3-fluoroiodophenyl)hydroxyethyl)carbamoyl)phenyl)pyrazin
y|)-2,2-difluorocyclohexyl benzoate: To a mixture of 4-(3-amino(4-(benzoyloxy)—3,3-
difluorocyclohexyl)pyrazinyl)fluorobenzoic acid (434 mg, 0.92 mmol) (4-(3-amino
((4R)(benzoyloxy)-3,3-difluorocyclohexyl)pyrazinyl)fluorobenzoic acid), (S)—2-
amino(3-fluoroiodophenyl)ethanol (320 mg, 1.012 mmol),HOAt (250 mg, 1.840
mmol) and EDC (353 mg, 1.840 mmol) in DMF (5 mL) was added DIEA (1.607 mL, 9.20
mmol) . The ant mixture was stirred over night at RT. The mixture was diluted with
EtOAc, washed with water three times and brine, dried, concentrated to afford the crude
product as a light yellow viscous liquid.
After ISCO cation (24 g silica, 10 to 80% EtOAc in heptane, 35 min), the d
product was obtained as a light yellow liquid, which containes two possible isomers. (601
mg, 0.818 mmol, 89 % yield) LC-MS ( m/z): (MH+) 735.0 at 1.09 min. 1H NMR (400 MHz,
CDCI3) 6 ppm 1.71 (br. s., 1 H) 1.80 - 2.00 (m, 2 H) 2.18 - 2.39 (m, 2 H) 2.39 - 2.52 (m, 1
H) 2.53 - 2.70 (m, 1 H) 3.13 (br. s.,1 H) 3.82 - 4.07 (m, 2 H) 4.78 (s, 2 H) 5.23 (d, J=5.09
Hz, 2 H) 7.02 - 7.16 (m, 1 H) 7.31 - 7.39 (m, 1 H) 7.41 - 7.50 (m, 2 H) 7.50 - 7.76 (m, 5 H)
7.87 - 8.03 (m, 2 H) 8.07 - 8.23 (m, 3 H).
Step 10: 4-(3-amino(3,3-difluorohydroxycyclohexyl)pyrazinyl)fluoro-N-((S)
(3-fluoroiodophenyl)hydroxyethyl)benzamide: To 4-(5-amino(3-fluoro(((S)(3-
fluoroiodophenyl)—2-hydroxyethyl)carbamoyl)phenyl)pyraziny|)-2,2-difluorocyclohexyl
benzoate (600 mg, 0.817 mmol) in MeOH (8 ml), THF (8 ml) and Water ( 8 ml) at RT was
added LiOH.H20 (206 mg, 4.90 mmol). The resultant e was stirred at 250C for 2
hours. The reaction e was concentrated and to the residue was added 30 ml of
EtOAc, washed with water (10 ml x3), dried, filtered, and concentrated to afford the crude
product as a light yellow sticky liquid, which became an off white solid after overnight
standing. (515 mg, 100 % yield) . LC-MS (m/z): (MH+) 631.1 at 0.771 min.
Step 1 1: 4-(3-amino((1S,4S)—3,3-difluorohydroxycyclohexyl)pyrazinyl)—2-fluoro-N-
((S)—1-(3-fluoroiodophenyl)hydroxyethyl)benzamide: The compound obtained from
step 10 was purified by chiral separation column (OJ column (21 X250 mm), SFC = 100
ml/min, CO2/EtOH = 85/15, g: 70 mg/7ml EtOH, 274 bar) to afford two chiral pure
compounds: 4-(3-amino((1S,4S)—3,3-difluorohydroxycyclohexyl)pyrazinyl)
fluoro-N-((S)(3-fluoroiodophenyl)hydroxyethyl)benzamide (255 mg, 27.8 %
. 1H NMR (400 MHz, DMSO) 6 ppm 1.46 - 1.69 (m, 2 H) 1.71 - 2.26 (m, 4 H) 2.79 -
3.02 (m, 1 H) 3.58 - 3.83 (m, 2 H) 4.94 - 5.15 (m, 2 H) 5.25 -5.45 (m, 1 H) 6.11 - 6.26 (m,
1 H) 7.19 - 7.34 (m, 1 H) 7.46 - 7.56 (m, 1 H) 7.56 - 7.66 (m, 2 H) 7.66 - 7.77 (m, 1 H)
7.95 (s, 1 H) 8.66 - 8.79 (m, 1H).
4-(3-amino((1R,4R)—3,3-difluorohydroxycyclohexyl)pyrazinyl)f|uoro-N-((S)(3-
fluoroiodophenyl)hydroxyethyl)benzamide (53 mg, 5.77 % yield). 1H NMR (400
MHz, DMSO) 6 ppm 1.15 - 1.30 (m, 1 H) 1.48 - 1.69 (m, 2 H) 1.72 - 2.25 (m, 5 H) 2.77 -
2.97 (m, 2 H) 3.57 - 3.84 (m, 3 H) 4.92 -5.14 (m, 2 H) 5.27 - 5.42 (m, 1 H) 6.10 - 6.24 (m,
2 H) 7.16 - 7.34 (m, 1 H) 7.46 - 7.57 (m, 1 H) 7.57 - 7.67 (m, 2 H) 7.67 - 7.77 (m, 1 H)
7.95 (s, 1H) 8.63 - 8.80 (m, 1 H).
Example 473
S nthesis of S 3-amino mor holinecarbon l razin l -N- 1- 3-bromo
fluoro hen lh drox eth lfluorobenzamide
WO 66188
Step1
N / N2\|r Step 2, 74%
(:OA%\ 'N CH3CN i“ F o
78% 0 o/\
F O
NH2 OH
Step 4, 84%
Step 3 N /
N / |
\N TFA in] {OH
100% ' F
O O/\ H2N (S)
oto“ /\©/
F 0 :/OH
= N
F (S)
NH2 ” (S) Step5 100%
I LiOH / MeOH
\ N Br OOH
0 o/\
N(S)
Step6 25%
HN/W00 0
Step 1: Ethyl 5-aminobromopyrazinecarboxylate: To a solution of ethyl 5-
yrazinecarboxylate (880 mg, 5.26 mmol) in acetonitrile ( 20 mL) at RT was
added NBS (984 mg, 5.53 mmol), the resultant solution was stirred at RT for 1 hour. The
reaction mixture was diluted with EtOAc, washed with sat NaHC03, brine and water,
dried, filtered, and concentrated to afford the crude product, which was purified by ISCO (
24 g silica gel column, 0 to 50% EtOAc in Heptane, 30 min). 1.01 g, 78 % yield. LC-MS
(m/z): 247.9 ( MH+), 0.51 min.
Step 2: Ethyl 5-amino(4-(tert-butoxycarbonyl)fluorophenyl)pyrazinecarboxylate: A
mixture of ethyl 5-aminobromopyrazinecarboxylate (210 mg, 0.853 mmol), tert-butyl
2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate (357 mg, 1.109 mmol),
PdC|2(dppf).CH2C|2 adduct (69.7 mg, 0.085 mmol) and Na2C03 (362 mg, 3.41 mmol) (2M
solution was used) in DME ( 5 mL) was placed into a 20 ml vial and sealed. The mixture
was microwaved for 15 min at 1100C. The mixture was diluted with EtOAc, washed with
water twice and brine, dried, filtered, and concentrated to afford the crude as a light
yellow solid. The crude product was purified by ISCO ( 12 g, 10 -55 % EtOAc in e,
min) to afford 228 mg (74 % yield) of light yellow solid. LC-MS (m/z): 362.1 ( MH+),
0.89 min.
Step 3: 4-(3-amino(ethoxycarbonyl)pyrazinyl)fluorobenzoic acid: To a solution of
ethyl 5-amino(4-(tert-butoxycarbonyl)fluorophenyl)pyrazinecarboxylate (0.253 g,
0.7 mmol) in DCM (4 mL) at RT was added TFA (2.157 mL, 28.0 mmol). The resultant
solution was stirred at RT for 2 hours. The reaction solution was concentrated and r
dried to afford the crude desired product as a TFA salt. This product was ly used at
the next step. 0.214 g (100 % yield) of light sticky liquid was obtained. LC-MS (m/z):
306.1 (MH+), 0.563 min.
Step 4: (S)-ethy| 5-amino(4-((1-(3-bromofluorophenyl)hydroxyethyl)carbamoyl)
fluorophenyl)pyrazinecarboxylate: To a mixture of 4-(3-amino
(ethoxycarbonyl)pyrazinyl)fluorobenzoic acid (0.214 g, 0.7 mmol) , (S)amino(3-
bromofluorophenyl)ethanol (272 mg, 1.009 mmol),HOAt (187 mg, 1.376 mmol) and
EDC (264 mg, 1.376 mmol) in DMF ( 2.5 mL) was added DIEA (0.961 mL, 5.50 mmol).
The resultant mixture was stirred over night at RT. The mixture was diluted with EtOAc,
washed with water three times and brine, dried, concentrated to afford the crude product
as a light yellow viscous liquid. ISCO purification ( 12 g silica, 10 to 90% EtOAc in
heptane, 30 min) provided the desired product (200 mg, 84 % yield) as a light yellow
liquid. LC-MS (m/z): 522.9 ( MH+), 0.787 min.
Step 5: amino(4-((1-(3-bromofluorophenyl)hydroxyethyl)carbamoyl)
fluorophenyl)pyrazinecarboxylic acid: A mixture of (S)-ethy| 5-amino(4-((1-(3-bromo-
-fluorophenyl)hydroxyethyl)carbamoyl)fluorophenyl)pyrazinecarboxylate (220
mg, 0.422 mmol) and 2O (142 mg, 3.38 mmol) in MeOH ( 2ml), THF (2mL) and
Water ( 2mL) was stirred for 3 hours at RT. The mixture was trated, to the residue
was added 2ml of water, 3N HCI was then added under stirring until the final pH was
about 4. The resultant mixture was then concentrated and further dried to afford the
crude product was a light yellow solid. (208 mg, 0.422 mmol, 100 % yield). LC-MS (m/z):
494.9 ( MH+), 0.653 min.
Step 6: (S)(3-amino(morpholinecarbonyl)pyrazinyl)—N-(1-(3-bromo
fluorophenyl)hydroxyethyl)fluorobenzamide: To a mixture of (S)amino(4-((1-
(3-bromofluorophenyl)hydroxyethyl)carbamoyl)fluorophenyl)pyrazinecarboxylic
acid (40 mg, 0.081 mmol), morpholine (28.3 mg, 0.324 mmol),HOAt (33.1 mg, 0.243
mmol) and EDC (46.6 mg, 0.243 mmol) in DMF ( 0.5 mL) was added DIEA (0.170 mL,
0.973 mmol). The resultant mixture was stirred over night at RT. The mixture was d
with EtOAc, washed with water three times and brine, dried, concentrated to afford the
crude product as a light yellow viscous liquid. The crude product was dissolved into 1.5 ml
of DMSO, filtered, and was purified by prep HPLC. (14 mg, 25.3 % yield). LC-MS (m/z):
563.9 ( MH+), 0.707 min. 1H NMR (500 MHz, ACETONITRILE-d3) 6 ppm 3.56 - 3.99 (m
13 H) 5.06 - 5.23 (m, 1 H) 5.78 - 6.13 (m, 2 H) 7.22 (d, J=8.20 Hz, 1 H) 7.27 -7.36 (m, 1
H) 7.41 - 7.79 (m, 5 H) 7.89 - 8.05 (m, 1 H) 8.25 - 8.43 (m, 1 H).
Example 478a and 478b
4- o R oxo i eridin l 2- lfluoro-N- S 3-fluoro
iodo hen lh drox eth lbenzamide Exam le 478a and 4- 3-amino S
oxo i eridin l razin lfluoro-N- S 3-fluoroiodo hen l
h drox eth l benzamide Exam le 478b .
/O£10KZCO3,TBAII:LO 1. L-Selectride 1. ICI, MeOH
2. DMAP, TFAA, DIEA 2. cat. TFA
acetone, rt, ON
¢fiwN99“—»PdClzdppf, NaZCO3 I
N,\ Iw-OMSmay“
”(gm TQM
F o 0
NH 2 OH
F O z/OH F 0 {OH
N \ F :
I OH NH N
/N :/ 2 NH2 m
+ F m
H2N ChiralSeparation NI \ H/\©/ + NI \
.HCI DMF /N | /N I
HN E
Example478a HN
Example478b
O o
1- 4-methox benz / i eridine-2 6-dione: Glutarimide (5 g, 44.2 mmol) was suspended in
acetone (Volume: 100 mL) and then K2C03 (12.22 g, 88 mmol), Bu4Nl (3.27 g, 8.84
mmol) and 4-methoxybenzyl chloride (6.02 mL, 44.2 mmol) were added. The mixture
was agitated at room temperature ght and filtered through celite and then
trated in vacuo and the residue purified by flash tography (0-50%
EtOAc/heptane) to afford 8.99 g of the desired product as a colorless solid. LCMS (m/z):
(MH+), 234.2, 0.66 min.
1-(4-methoxybenzyl)—3,4-dihydropyridin-2( 1 H )—one: 1-(4-methoxybenzyl)piperidine-2,6-
dione (8.99 g, 38.5 mmol) was dissolved in Toluene (Volume: 128 ml) and cooled to -78
°C. L-Selectride (42.4 mi, 42.4 mmol) was added dropwise and the mixture agitated for 1
h. After 1 h, thick slurry along with itate observed. Reaction mixture was briefly
pulled outside cooling bath to nize the mixture. Then DMAP (0.047 g, 0.385
mmol) was added in one portion and then DIEA (38.4 ml, 220 mmol) was added and then
TFAA (6.53 ml, 46.2 mmol) was added. Then the cooling flask was removed and the
mixture agitated at room temperature for 2 h and then quenched with water and the
product extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered
and concentrated in vacuo to afford crude residue which was purified by flash
chromatography to afford 7.66g of the desired product as a yellow syrup. LCMS (m/z):
(MH+), 234.2, 0.73 min.
-iodo(4-methoxybenzyl)—3,4-dihydropyridin-2(1H)—one: ethoxybenzyl)—3,4-
opyridin-2(1H)-one (2 g, 9.21 mmol) was dissolved in MeOH (90 mL) and cooled to
-78 °C. lCl (13.81 mi, 13.81 mmol) was added slowly and the mixture ed for 1 h
and then Sat'd Na28203 was added and the mixture was agitated until room temperature
was observed. The solvent was evaporated in vacuo. The residue was dissolved in DCM
and washed with Sat'd Na28203 and then with water and dried (MgSO4), filtered and
concentrated in vacuo. The residue was dissolved in toluene (40 mL) and treated with
Trifluoroacetic acid (100 uL) and heated immediately to 145 °C for 15 min and then
cooled to 0 °C and ET3N (5 mL) was added. The mixture was agitated for 1 h and
concentrated in vacuo and then the residue purified by flash chromatography (0-20%
EtOAc/heptane) to afford the desired product as a gummy syrup. LCMS (m/z): (MH+),
344.1, 0.88 min.
Meth l4- 3-amino 1- 4-methox benz l oxo-1 4 5 6-tetrah dro ridin l razin
yl)—2-fluorobenzoate: (4-methoxybenzyl)—3,4-dihydropyridin-2(1H)-one (630 mg,
1.836 mmol), PdC|2(dppf).CH2C|2 adduct (150 mg, 0.184 mmol), methyl 4-(3-amino
bromopyrazinyl)fluorobenzoate (1028 mg, 2.75 mmol) and Na2C03 (2754 ul, 5.51
mmol) were combined in a flask and then DME (Volume: 6120 ul) was added. The
mixture was degassed and purged with nitrogen and then finally heated at 90 °C for 2 h
upon which complete consumption of starting al was observed. The reaction
mixture was diluted with EtOAc and water and the organic layer was separated and dried
(MgSO4), filtered and concentrated in vacuo and the residue purified by flash
chromatography (0-60% EtOAc/DCM) to afford 361 mg of the d product as a yellow
solid. LCMS (m/z): (MH+), 463.1, 0.88 min.
Meth l4- 3-amino 6-oxo i eridin | razin lfluorobenzoate: Methyl 4-(3-
amino(1-(4-methoxybenzyl)oxo-1,4,5,6-tetrahydropyridinyl)pyrazinyl)—2-
fluorobenzoate (361 mg, 0.781 mmol) was ved in MeOH (Volume: 7 mL) and then
Pd-C (400 mg, 3.76 mmol) was added. The mixture was evacuated and purged with
en thrice and finally, the mixture was agitated under 1 atm of hydrogen overnight.
The next g, desired product along with over-reduced amino-pyrazine was obtained.
The mixture was filter over celite and the filtrate trated in vacuo and the residue
dissolved in DCM and agitated under airfor 1 day and then conentrated and purified by
flash chromatography (0-50% DCM/EtOAc) to afford 144 mg the desired product as a
yellow solid. LCMS (m/z): (MH+), 465.1, 0.81 min.
4- 3-Amino 6-oxo i eridin | razin lfluorobenzoic acid: Methyl 4-(3-amino-
xopiperidinyl)pyrazinyl)—2-f|uorobenzoate (144 mg, 0.310 mmol) was dissolved
in TFA (Volume: 3 mL) and heated at 150 °C for 30 min in microwave The solvent was
evaporated in vacuo and the residue was azeotroped with toluene thrice to afford the
crude debenzylated lactam. This crude product was dissolved in THF (Volume: 3 mL,
Ratio: 3) and MeOH (Volume: 1.500 mL, Ratio: 1.5) and to the e was added LiOH
(0.037 g, 1.550 mmol) dissolved in Water (Volume: 1.500 mL, Ratio: 1.5). The mixture
was agitated at room temperature for 30 min and concentrated in vacuo and the residue
neutralized with 2 mL (4.0 N HCI) and the solvent evaporated. The e was
oped once with THF and once with toluene to afford the crude acid which was
taken to the next step (assuming quantitative yield) without any further purification.
LCMS (m/z): (MH+), 331.2, 0.44 min.
4-(3-Amino(6-oxopiperidinyl)pyraziny|)f|uoro-N-((S)(3-f|uoroiodopheny|)-
2-hydroxyethyl)benzamide: 4-(3-Amino(6-oxopiperidinyl)pyrazinyl)—2-
fluorobenzoic acid (41.0 mg, 0.124 mmol), DIEA (0.108 mL, 0.620 mmol) and HATU (94
mg, 0.248 mmol) were combined in DMF (1.0 mL) and then (S)amino(3-fluoro
iodophenyl)ethanol (39.4 mg, 0.124 mmol) was added. The mixture was agitated at
room temperature for 1 h and then subjected directly to purification by e-phase
HPLC to afford the title compound as TFA adduct. The solid obtained upon llization
was dissolved in MeOH and passed through basic carbonate containing silica catridge
and the te was concentrated in vacuo to afford 28.5 mg of the mixture of
diastereomer. The residue was purified by chiral SFC to provide the two diastereomers:
Diasteromer1 (Example 478a): 4-(3-amino((R)—6-oxopiperidinyl)pyrazinyl)—2-
fluoro-N-((S)(3-fluoroiodophenyl)hydroxyethyl)benzamide (8.8 mg). 1H NMR
(CD3OD): 7.88 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.48-7.64 (m, 3H), 7.34 (d, J=7.4 Hz, 1H),
7.11 (d, J=9.8 Hz, 1H), 5.05 (t, J=5.7 , 3.67-3.83 (m, 2H), 3.43 (d, J=7.8 Hz, 2H),
3.00-3.15 (m, 1H), 2.28-2.46 (m, 2H), 1.88-2.16 (m, 2H); LCMS (m/z): (MH+), 594.1, 0.71
min.
Diasteromer 2 (Example 478b): 4-(3-amino((R)—6-oxopiperidinyl)pyrazinyl)—2-
fluoro-N-((S)(3-fluoroiodophenyl)hydroxyethyl)benzamide (8.2 mg) 1H NMR
(CD3OD): 7.89 (s, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.50-7.65 (m, 3H), 7.35 (d, J=7.8 Hz, 1H),
7.12 (d, J=9.8 Hz, 1H), 5.06 (t, J=5.7 Hz,1H), 3.65-3.89 (m, 2H), 3.37-3.53 (m, 2H), 2.96-
3.16 (m, 1H), 2.31-2.59 (m, 2H), 1.88-2.20 (m, 2H); LCMS (m/z): (MH+), 594.1, 0.71 min.
ical Activity
Inhibition of ERK1 and ERK2 was measured using the following methods.
Activated ERK2 (20 pM) Kinase Assay:
Compound potency against activated ERK2 was determined using a kinase assay
that measures ERK2-catalyzed phosphorylation of biotinylated ERKtide peptide substrate
([Biotin] -AHA-K-R-E-L-V-E-P-L-T-P-S-G-E-A-P-N-Q-A—L-L-R- [NH2], the peptide
ce derived from EGF receptor: SEQ ID NO:1). The assay was carried out in 20
mM HEPES [pH 7.5], 5 mM MgCl2, 1 mM DTT, 0.01% Tween-20, 0.05% BSA using 0.02
nM ERK2, 400 nM e peptide and 35 uM ATP (all concentrations are final in the
reaction) in a total volume of 10.25 uL. A 16-point, half-log dilution series of compounds
at 41x final concentration was used for ting |C50 curves. Compound on
series were prepared in 100% DMSO. ERK2 was preincubated with compounds for 30
minutes at ambient temperature. Reaction was initiated by addition of a substrate cocktail
of e peptide and ATP and was allowed to proceed for 4 hours at ambient
temperature. on was terminated by addition of 10 uL of a 2x stop buffer consisting
of 100 mM Tris-Cl [pH 7.5], 25 mM EDTA, 0.01 % Tween 20, 20 ug/mL of AlphaScreen
Protein A or Beads, 20 ug/mL of Streptavidin Donor Beads (PerkinElmer,
Waltham, MA), and 1:1000 dilution phospho-EGF Receptor (Thr669) antibody (Cat#
8808, Cell Signaling Technology, Danvers, MA). Terminated reactions were read, after
overnight incubation in the dark, on an EnVision Multilabel Plate Reader (PerkinElmer,
Waltham, MA), with excitation and emission wavelengths set to 680 nm and 570 nm,
respectively. IC50 values were determined using a four-parameter fit.
The following assay conditions (ERK2 New) were used for some nds in
the following Table, and provide substantially similar lC50s to the assay described above,
for IC50 about 0.1 uM or above. When the limitation of this assay was reached, the
assay described above was used.
Compound potency against activated ERK2 is determined using a kinase assay
that measures ERK2-catalyzed phosphorylation of ylated ERKtide peptide ate
([Biotin] -AHA-K-R-E-L-V-E-P-L-T-P-S-G-E-A—P-N-Q-A—L-L-R- [NH2], the peptide
sequence derived from EGF receptor: SEQ ID NO:1). The assay is carried out in 50 mM
HEPES [pH 7.5], 5 mM MgCl2, 1 mM DTT, 0.01% 20, 0.05% BSA using 0.25 nM
ERK2, 200 nM e e and 35 uM ATP (all concentrations are final in the
reaction) in a total volume of 10.25 uL. A 16-point, half-log on series of compounds
at 41x final concentration is used for generating IC50 curves. Compound dilution series
are prepared in 100% DMSO. ERK2 is preincubated with compounds for 30 minutes at
ambient temperature. Reaction is initiated by addition of a substrate cocktail of e
peptide and ATP and is allowed to proceed for 2-3 hours at ambient
temperature. Reaction is terminated by addition of 10 uL of a 2x stop buffer consisting of
100 mM Tris-Cl [pH 7.5], 25 mM EDTA, 0.01% Tween 20, 10 ug/mL of AlphaScreen
Protein A Acceptor Beads, 10 ug/mL of Streptavidin Donor Beads (PerkinElmer,
Waltham, MA), and 1.4 ug/mL phospho-EGF Receptor (Thr669) antibody (Cat # 3056,
Cell Signaling Technology, Danvers, MA). Terminated reactions are read, after overnight
incubation in the dark, on an EnVision Multilabel Plate Reader nElmer, Waltham,
MA), with excitation and emission ngths set to 680 nm and 570 nm,
respectively. |C50 values are determined using a four-parameter fit.
Activated ERK1 Kinase Assay:
Compound potency against activated ERK1 was determined using a kinase assay
that measures ERK1-catalyzed phosphorylation of biotinylated e peptide substrate
([Biotin] -AHA—K-R-E-L-V-E-P-L-T-P-S-G-E-A—P-N-Q-A—L-L-R- [NH2], the peptide
sequence derived from EGF receptor: SEQ ID NO:1). The assay was d out in 20
mM HEPES [pH 7.5], 5 mM MgCl2, 1 mM DTT, 0.01% Tween-20, 0.05% BSA using 0.2
nM ERK1, 200 nM ERKtide peptide and 45 uM ATP (all concentrations are final in the
reaction) in a total volume of 10.25 uL. A 16-point, half-log dilution series of compounds
at 41x final concentration was used for generating |C50 . Compound dilution
series were prepared in 100% DMSO. ERK1 was ubated with compounds for 30
minutes at ambient temperature. Reaction was ted by addition of a substrate cocktail
of ERKtide peptide and ATP and was d to d for 4 hours at ambient
temperature. Reaction was terminated by addition of 10 uL of a 2x stop buffer consisting
of 100 mM Tris-Cl [pH 7.5], 25 mM EDTA, 0.01 % Tween 20, 10 ug/mL of AlphaScreen
Protein A Acceptor Beads, 10 ug/mL of Streptavidin Donor Beads (PerkinElmer,
Waltham, MA), and 1.4 ug/mL phospho-EGF Receptor (Thr669) antibody (Cat # 3056,
Cell Signaling Technology, Danvers, MA). Terminated reactions were read, after
overnight incubation in the dark, on an EnVision Multilabel Plate Reader (PerkinElmer,
Waltham, MA), with excitation and emission wavelengths set to 680 nm and 570 nm,
respectively. |C50 values were determined using a four-parameter fit.
All |C50s are presented in scientific notation where ‘E’ indicates the power of 10;
for example, 1.63E-03 ents 1.63 x 103, or 0.00163.
ERK2
ERK2 (20pM) creen
Example ERK2 New (pM) (pM) (pM)
1 1.63E-03 1.06E-03
2 1.92E-01
3 1.23E+01
4 3.15E-01
s ———
6 ———
7 ———
s ———
9 ———
1o ———
11 ———
12 ———
1s ———
14 ———
1s ———
16 2.06E-01 1.97E-01
17 ---
1s ———
19 ———
1.09E+00
21 2.67E+00
22 5.81E-01
23 3.93E-01
24 4.53E-01
04
26 3.27E-03
27 4.10E-03 1.87E-03
28 2.55E-03 1.20E-03
29 7.52E-02
6.95E-02 2.25E-02
31 7.40E-02 3.20E-02
32 2.43E-02
33 1.82E-02 02
34 03 3.98E-03
1.09E-03
36 1.60E-03
37 1.05E-03
38 8.09E-03
39 2.48E-03 1.30E-03
40 2.46E-03 1.26E-03
41 5.10E-02
42 5.44E-03
4s ———
44 ———
45 3.61E-03
46 4.79E+00
2014/062913
47 ———
45 ———
45 ———
5o ———
54 ———
52 ———
55 ———
54 ———
55 ———
55 ———
57 ———
58 3.61E-03
59 ---
5o ———
54 ———
62 6.41 E-02
63 2.33E-02
64 03 3.64E-03
65 6.84E-04 1.84E-03
66 4.18E-02 5.53E-02
67 6.77E-02 8.55E-02
68 3.14E-01 2.14E-01
69 1.00E-02 1.60E-02
70 01 5.74E-01
71 8.78E-03 1.72E-02
72 1 .77E-01
73 1.29E-03 3.08E-03
74 2.03E-02 3.76E-02
75 00 00
76 3.04E-03 5.24E-03
77 5.08E-02 9.76E-02
78 1 .72E-01
79 3.24E-02 3.33E-02
80 5.10E-04 5.84E-04
81 4.87E-04 1.63E-04 1.66E-04
82 9.00E-04 2.13E-03
83 7.52E-04 5.74E-04
84 2.05E-03 9.64E-03
85 — 1.31E-03 2.06E-02
86 — 3.75E-03 4.78E-03
87 2.09E-01 2.66E-01
88 7.05E-02 8.14E-02
99 ———
99 ———
91 ———
92 ———
99 ———
94 ———
99 ———
99 ———
97 ———
99 ———
99 ———
100 7.76E-03
192 ———
199 ———
104 1.91 E-01
105 2.56E-03
106 1.28E-03
107 1.16E-03
108 9.77E-03
109 5.81 E-03
1 10 1 .00E+00
11 1 3.08E-02
1 12 1 .41 E-01
113 7.80E-01
114 1.24E-01
115 2.74E-01
116 1.89E-02 9.42E-03
117 4.79E-03
118 1.76E-02
119 5.49E-04
120 1.35E-03 04
121 3.40E-04 2.17E-04
122 7.38E-03 1.10E-02
123 04
124 6.26E-02
125 2.23E+00
126 1.69E-01
127 ———
129 ———
129 2.02E-03
130 1 .66E-03
131 ———
132 ———
133 ———
134 ———
133 ———
133 ———
137 ———
133 ———
133 ———
14o ———
141 ———
142 2.10E-04 2.01E-04
144 ———
146 3—.39E-03_.33E-03 ——
147 02
148 1.90E-03
149 1.49E-04
150 9.37E-05
151 1.15E-04 2.33E-05
152 1.45E-04 4.10E-05
153 3.60E-04
154 2.88E-04
155 1.69E-03
156 3.32E-03
157 4.16E-04
158 634504
159 314503
160 6.53E-04
161 5.76E-03
162 4.87E-04
163 514503
164 1.40E-03
165 3.90E-01
166 -05
167 9.98E-04
168 5.13E-03
133 ———
17o ———
171 1.09E-03
172 1.58E-04 7.85E-05
178 ———
174 ———
178 ———
178 ———
177 ———
178 ———
178 ———
18o ———
181 ———
182 ———
188 ———
184 2.61E-05
188 ———
187 ———
188 4.69E-05
189 1.39E-05
190 1.76E-05
191 4.53E-03 1.49E-03
192 8.04E-03 4.93E-03
193 1.19E-03 04
194 2.60E-04 9.55E-05
195 04 1.02E-04
196 04 3.63E-04
197 2.10E-03 7.51E-04
197 4.00E-05
198 2.23E-04
199 3.00E-04
200 2.07E-04 8.42E-05 1.83E-04
201 6.42E-02
202 1.52E-04
203 7.33E-03
204 5.46E-02
205 8.02E-02
206 1.04E-05
207 4.30E-01
208 7.44E+00
209 3.28E+00
21o ———
211 ———
212 3.97E-04
213 1.19E-02
214 ———
21s ———
216 ———
217 ———
218 ———
219 ———
22o ———
221 ———
222 ———
22s ———
224 ———
225 9.01E-05
227 ———
228 ———
229 1.07E-03
230 8.99E-04
231 2.17E-04
232 2.57E-04
233 2.09E-05
234 1.47E-03
235 3.26E-04
236 5.66E-02
237 2.61E+00
238 3.52E-01
239 02
240 1.99E-05
241 9.44E-04
242 8.75E-06
243 1.21E-05
244 1.57E-01
245 2.67E-03
246 1.52E-03
247 7.30E-04
248 3.64E-05
249 3.71E-03
250 3.64E-05
251 7.04E-03
252 ———
252 ———
254 05
255 2.87E-05
255 ———
257 ———
255 ———
255 ———
255 ———
251 ———
252 ———
255 ———
254 ———
255 ———
255 ———
267 05
255 ———
275 ———
271 3.08E-05
272 6.19E-05
273 4.82E-05
274 3.12E-05
275 7.45E-05
276 3.71E-05
277 05
278 1.46E-04
279 5.18E-04 4.29E-04
280 1.66E-03
281 1.79E-03
282 1.20E-03
283 1.69E-04 3.78E-05
284 2.96E-04
285 2.66E-02
286 3.90E-03
287 7.94E-04
288 2.03E-03
289 1.92E-04 8.14E-05
290 1.74E-03
291 1.48E-03
292 03
293 2.65E-02
254 ———
255 ———
296 1.08E-03
297 1.53E-04 7.15E-05
233 ———
233 ———
3oo ———
331 ———
332 ———
3o3 ———
334 ———
333 ———
333 ———
337 ———
333 ———
309 1.04E-04 2.63E-05
311———
312 ———
313 6.17E-04
314 1.48E-03
315 5.00E-06
316 3.30E-01
317 1.34E+00
318 3.81E-01 3.11E-01
319 1.51E-01
320 3.54E-01
321 8.49E-02
322 02
323 3.29E-03
324 03 6.17E-03
325 5.93E-04 5.44E-04
326 2.53E-04
327 5.42E-02
328 8.29E-03 7.64E-03
329 05
330 2.22E-05
331 6.45E-05
332 8.15E-04
333 3.46E-02 3.38E-02
334 2.52E-02 1 .94E-02
335 2.08E-05
333 ———
337 ———
338 1.39E-05
339 1.05E-04
s40 ———
s41 ———
s42 ———
s43 ———
s44 ———
s45 ———
s46 ———
s47 ———
s48 ———
s49 ———
sso ———
351 2.25E-05
353 ———
354 ———
355 2.30E-05
356 3.17E-05
357 1.43E-05
358 2.05E-05
359 7.60E-05
360 06
361 1.04E-04
362 2.91E-05
363 5.57E-05
364 2.05E-04
365 2.08E-05
366 1.27E-04
367 1.50E-04
368 8.95E-05
369 2.13E-04
370 1.38E-04
371 05
372 4.00E-05
373 8.37E-06
374 2.05E-05
375 4.01E-05
376 1.83E-05
377 7.00E-05
s78 ———
s79 ———
380 9.70E-06
381 2.09E-05
332 ———
333 ———
334 ———
333 ———
333 ———
337 ———
333 ———
333 ———
33o ———
331 ———
332 ———
393 7.52E-05
333 ———
333 ———
397 3.60E-05
398 2.81E-04
399 2.10E-02
400 1.59E-01
401 05
402 4.36E-04
403 5.81E-03
404 1.15E-04
405 2.38E-04
406 04
407 3.33E-04
408 2.01E-05
409 2.25E-04
410 9.43E-05
411 7.43E-05
412 3.74E-04
413 2.04E-01
414 2.00E-05
415 03
416 5.68E-03
417 6.90E-04 9.28E-05
418 1.28E-03
419 8.53E-04
423 ———
421———
422 1.87E-04 6.51 E-05
423 1.47E-04 6.14E-05
WO 66188
424 ———
423 ———
423 ———
427 ———
423 ———
423 ———
43o ———
432 ———
433 ———
434 ———
433 ———
436 4.85E-05
433 ———
440 7.01E-05
441 5.59E-05
442 3.39E-04
443 3.45E-04
444 2.15E-04
445 5.31E-04
446 4.64E-05
447 1.63E-04
448 3.71E-04
449 1.84E-04
450 1.50E-03
451 4.42E-05
452 0.00003
453 0.0000684
454 0.0000403
455 0.000144
456 872
457 0.0000581
458 0.0000823
459 0.0000261
460 0.0000397
461 0.00000431
462 0.000135
433 ———
434 ———
465 0.0000187
466 0.000218
2014/062913
467 ———
468 ———
469 ———
470 ———
471 ———
472 ———
473 ———
474 ———
475 ———
476 ———
477 ———
478a 0.000009
478b 0.000039
Claims (12)
1. A compound of a (I): or a pharmaceutically acceptable salt f, wherein: R1 is an optionally substituted group selected from C3-8 cycloalkyl, 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring s, phenyl, -SO2-phenyl, -C(O)-phenyl, -C(R8)2-phenyl, and 5-6 membered heteroaryl ring, n said heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from N, O and S as ring members, and wherein the optional substituents for R1 are 1-3 groups independently selected from D, halo, hydroxy, amino, -N(R8)2, CN, C1-4 alkyl, C1-4 alkoxy, -S(C1-4 alkyl), C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, oxo (except on aromatic rings), COOR8, CON(R8)2, (O)R8, -NR8-C(O)OR8 -SO2R8, -NR8SO2R8, and SO2N(R8)2, where each R8 is ndently H or C1-4 alkyl; L is wherein R” is methyl or ethyl, and is optionally substituted with fluoro, amino, hydroxy, methylamino, ethylamino, ylamino, -OP(O)(OH)2, methoxy or ethoxy; X and Y are independently selected from H, D, halo, CN, amino, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R2 is H, C1-4 alkyl, or aryl-C1alkyl-, wherein the aryl and C1-4 alkyl are ally substituted with halo, CN, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, or C1-4 alkylsulfonyl; or R2 and L are linked together to form a cyclic group selected from morpholine, piperidine, thiomorpholine, piperazine, and pyrrolidine that is attached to R1 and is also optionally substituted with one or two groups independently selected from C1-4 alkyl, C1-4 alkoxy, oxo, CN, COOR7, CON(R7)2, and -SO2R7, where each R7 is independently H or C1-4 alkyl; Z is N or CR4; R4 is H, D, halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy; R5 is selected from R5a and R5a ; wherein R5a is an optionally substituted C3-8 cycloalkyl, C3-8 cycloalkenyl, saturated or unsaturated 3-8 ed heterocyclic ring containing 1-2 heteroatoms selected from N, O and S, phenyl, or 5-6 ed heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the optional substituents for R5 are 1-4 groups independently ed from D, halo, hydroxy, amino, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, oxo (except on aromatic rings), -COOR9, -C(O)R9, )2, -NR9C(O)R 9, - NR 9CO 9, 2R -SO2R9, -NR9SO 9, 2R and -SO2N(R 9) 2, where each R9 is independently H or C1-4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH 5 2, NHMe and NMe2; and two substituents on the same or adjacent carbon atoms of R can optionally be taken together to form a 5-6 membered ring that can be saturated or aromatic and contains 1-2 heteroatoms selected from N, O and S and can optionally be substituted with 1-2 groups independently selected from D, Me, halo, OH, oxo, O(C1-4 alkyl), NH2, C1-4 mino, 4 alkyl)amino; and R6 is H, D, halo, C1-4 alkyl, or C1-4 haloalkyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is N.
3. The compound according to claim 1 or claim 2 or a ceutically acceptable salt thereof, wherein R2 is H or Me.
4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R6 is H.
5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, n R5 is ed from –C(O)-R5a and R5a ; wherein R5a is selected from C3-8 cycloalkyl, 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl, and is optionally substituted with 1-3 groups independently selected from D, halo, CN, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy, -SO2R’, -NR’-C(O)-R’, and – SO 2NR’ 2, where each R’ is independently H or C1-4 alkyl.
6. The nd according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from –C(O)-R5a and R5a ; n R5a is selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, ydropyran, dihydropyran, tetrahydrofuran, oxetane, azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrothiopyran (thiacyclohexane), and tetrahydrothiofuran (thiacyclopentane), each of which is optionally substituted with 1-3 groups independently selected from halo, D, CN, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 kyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy, oxo, COOR9, CON(R9)2, -NHC(O)R9, -NHCOOR9, -NHSO2R9, and -SO2R9, where each R9 is independently H or C1-4 alkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl and is ally substituted with one to three groups ndently selected from halo, D, CN, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2R’, -N(R’)2, -NR’-C(O)-R’, and –SO2NR’ 2, where each R’ is independently H or C1-4 alkyl.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Y is H, methyl, or halo.
9. The compound of claim 1, which is of the a IB: (IB) wherein R5 is a 4-7 membered cyclic ether or C5-6 cycloalkyl, and R5 can be substituted with up to four groups independently selected from D, F, Cl, CN, amino, -CH2OH, - NHC(O)Me, Me, -NHSO2Me, Me, OMe, OH, oxo, Et, iPr, OEt, and CF3; Y is H, F, Cl, or Me; R10 is –CH2-R*, where R* is H, -OH, F, -NH2, -NHMe, -OP(O)(OH)2, -NMe2, or – OMe; and R1 is phenyl, optionally substituted with 1-2 groups ndently selected from halo, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, COOR8, CON(R8)2, and -SO2R8, where each R8 is independently H or C1-4 alkyl; or a pharmaceutically acceptable salt f.
10. The compound of any one of claims 1-4 or 9, wherein R5 is cyclohexyl substituted with 1-3 groups groups independently selected from D, F, Cl, CN, amino, Me, NHSO2Me, NHCOMe, OMe, OH, Et, CN, -CH2OH, and CF3.
11. The compound of claim 1, wherein R1 is phenyl substituted with 0, 1 or 2 groups independently selected from F, Cl, Br, I, SMe, SO2Me, and CH3.
12. The compound of claim 1, or a pharmaceutically able salt thereof selected from the group consisting of: F o 5 I NDH /N CI F 0 {OH F o {OH NH2 N NH2 N H H N \ N \ I ' / CI / Cl N o OH OH F o g F o 1 NH2 N NH2 N H H N \ N \ l I / CI / CI w 0 (N10 F o g F o 3 Z/:M IZ Z/IM IZ Z Z 471471 OH OH F O F O NH2 N NH2 N H H N N Cl Cl N N O O F O NH2 N NH2 N NH2 N H H N\ N\ l/ Cl l/ Cl 0 0 F o 3/ NH N 2 H/\© F o {0 NH2 N \ Cl o \ 473473 E F O Z/OH NH2 N NH2 H N/ ”w \ I o‘?°o NH2 N/\©H {OH N \ F o I f /N NH2 N N \ F /N CI :/ F O E NH2 N® NH2 N H H N/ N/ I w \ N \ N CI N N 0% o‘s\‘o F 0 {OH NH2 N 474474 F O :/ N/l N/\©H \ N CI 0%0/ F O {OH OH , F O / : NH2 N N CI N \ HQ \ 0 0% F O _/ O _/OH NH2 NH/\© N/ H \' NI \ / F 0:3\ /\0 O O _/OH 475475 0 / : CI 0 {OH N \ pg N \ “Q / ‘ O O F F /OH o KOH F O NH2 N NH2 N H H \ N \ / \\<0 0 (OH NHZO 0 ;/ N/ E/\© N \ N/\© CI \ o O o 0 g :/OH NHZ NH2 H N/\© N \ him N‘ \ | / //S\\ O O O 476476 F O {OH _/OH \ um N \ fig / I /S\ / O ;/ (OH m “Q N \ N \ / / / / l | \ \ N N F 0 {OH NH2 N F O ?/ _/OH N / HQ ‘U ‘ N \ \ / E J \ o N/ 477477 o Z/OH F O {OH NH2 N N I C' OH F O ,/ F o :/ : N NH2 N H NI \ CI {OH 0 0 r0“ N \ N/\© N \ F Em I/ ‘/ o \ 0 _/OH N \ N/\©H 0%0/ 478478 NH2 N N\ H/\© ‘/ CI F O 3 NH2 N '/ CI N o OH F 0 (OH NH2 RED NH2 N N \ N \ l/ ‘/ CI 0 N o 0 {0H N/ m© 479479 F o { /0H NH2 N I N/ N“ \ N—N N-N \ \ F o _/OH F o {OH NH2 N /N CI 0 (OH NH2 jH D D D D 480480 0 :/OH 0 {OH NH2 N NH2 H HN/\© N \ N \ ' ' /N /N 0 Q 0 /OH E/OH NH2 N H N / N/\© | \ IN O /N—N {OH F O F {OH N/ mg N/ m | \ IN Nfl /N
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361898761P | 2013-11-01 | 2013-11-01 | |
US61/898,761 | 2013-11-01 | ||
CN2014088409 | 2014-10-11 | ||
CNPCT/CN2014/088409 | 2014-10-11 | ||
PCT/US2014/062913 WO2015066188A1 (en) | 2013-11-01 | 2014-10-29 | Aminoheteroaryl benzamides as kinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ717223A NZ717223A (en) | 2021-05-28 |
NZ717223B2 true NZ717223B2 (en) | 2021-08-31 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10660888B2 (en) | Aminoheteroaryl benzamides as kinase inhibitors | |
TWI804003B (en) | Tlr7/8 antagonists and uses thereof | |
EP3286172B1 (en) | Lsd1 inhibitors and uses thereof | |
AU2011205302B2 (en) | Voltage-gated sodium channel blockers | |
JP6577479B2 (en) | Heterocyclic compounds and their use as NAV channel inhibitors | |
CA3165168A1 (en) | Compounds and methods for the targeted degradation of androgen receptor | |
CA3199074A1 (en) | Compounds and methods for the targeted degradation of androgen receptor protein | |
BR112020004800A2 (en) | saramere-activating bisamide compounds and their uses | |
TW200838517A (en) | Compounds useful as protein kinases inhibitors | |
BR112020014516A2 (en) | Aminopyrrolotriazines as kinase inhibitors | |
ES2925473T3 (en) | Pyridinyl pyrazoles as modulators of RORyt | |
AU2016366546A1 (en) | Inhibitors of bruton's tyrosine kinase and methods of their use | |
KR20230035049A (en) | Compounds, Compositions and Methods | |
NZ717223B2 (en) | Aminoheteroaryl benzamides as kinase inhibitors | |
TWI810547B (en) | Pd-l1 antagonist compound | |
JP2024526192A (en) | Cereblon-binding compounds, compositions thereof and methods of treatment therewith |