CA2359510C - .omega.-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents
.omega.-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Download PDFInfo
- Publication number
- CA2359510C CA2359510C CA002359510A CA2359510A CA2359510C CA 2359510 C CA2359510 C CA 2359510C CA 002359510 A CA002359510 A CA 002359510A CA 2359510 A CA2359510 A CA 2359510A CA 2359510 C CA2359510 C CA 2359510C
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- trifluoromethyl
- chloro
- urea
- pyridyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 diphenyl ureas Chemical class 0.000 title claims abstract description 99
- 102000009929 raf Kinases Human genes 0.000 title claims description 17
- 108010077182 raf Kinases Proteins 0.000 title claims description 17
- 235000013877 carbamide Nutrition 0.000 title abstract description 158
- 239000004305 biphenyl Substances 0.000 title description 3
- 235000010290 biphenyl Nutrition 0.000 title description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title description 3
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 230000001404 mediated effect Effects 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 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 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- WINHEDROZCCEOE-UHFFFAOYSA-N 4-[4-[[4-bromo-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Br)=CC=3)C(F)(F)F)=CC=2)=C1 WINHEDROZCCEOE-UHFFFAOYSA-N 0.000 claims description 5
- UAEWBZYTKIMYRQ-UHFFFAOYSA-N 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyridine-2-carboxamide Chemical compound C1=NC(C(=O)N)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 UAEWBZYTKIMYRQ-UHFFFAOYSA-N 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- NPGKFYOSHPOSFZ-UHFFFAOYSA-N 4-[3-chloro-4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(Cl)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 NPGKFYOSHPOSFZ-UHFFFAOYSA-N 0.000 claims description 3
- PAFWNASGEYHRSQ-UHFFFAOYSA-N 4-[4-[[4-chloro-2-methoxy-5-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C(=CC(Cl)=C(C=3)C(F)(F)F)OC)=CC=2)=C1 PAFWNASGEYHRSQ-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 230000010261 cell growth Effects 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- WZXCMMDJRYMKQT-UHFFFAOYSA-N 4-[3-[[4-bromo-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(NC(=O)NC=3C=C(C(Br)=CC=3)C(F)(F)F)C=CC=2)=C1 WZXCMMDJRYMKQT-UHFFFAOYSA-N 0.000 claims description 2
- YOISALVSHLULBC-UHFFFAOYSA-N 4-[3-[[4-bromo-3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]sulfanyl-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(SC=2C=C(NC(=O)NC=3C=C(C(Br)=CC=3)C(F)(F)F)C=CC=2)=C1 YOISALVSHLULBC-UHFFFAOYSA-N 0.000 claims description 2
- RSDXTEAFHPMIAZ-UHFFFAOYSA-N 4-[3-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)C=CC=2)=C1 RSDXTEAFHPMIAZ-UHFFFAOYSA-N 0.000 claims description 2
- HRLTXHASHFPQAJ-UHFFFAOYSA-N 4-[3-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyridine-2-carboxamide Chemical compound C1=NC(C(=O)N)=CC(OC=2C=C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)C=CC=2)=C1 HRLTXHASHFPQAJ-UHFFFAOYSA-N 0.000 claims description 2
- WWQRKFRUJIHXLV-UHFFFAOYSA-N 4-[4-[[4-bromo-3-(trifluoromethyl)phenyl]carbamoylamino]-2-chlorophenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C(=CC(NC(=O)NC=3C=C(C(Br)=CC=3)C(F)(F)F)=CC=2)Cl)=C1 WWQRKFRUJIHXLV-UHFFFAOYSA-N 0.000 claims description 2
- DHMDTRVWYXIDFX-UHFFFAOYSA-N 4-[4-[[4-bromo-3-(trifluoromethyl)phenyl]carbamoylamino]-3-chlorophenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(Cl)C(NC(=O)NC=3C=C(C(Br)=CC=3)C(F)(F)F)=CC=2)=C1 DHMDTRVWYXIDFX-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 206010048832 Colon adenoma Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 208000025113 myeloid leukemia Diseases 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 210000001685 thyroid gland Anatomy 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- SITFWSXSQYZWRX-UHFFFAOYSA-N 4-[3-chloro-4-[[4-chloro-2-methoxy-5-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(Cl)C(NC(=O)NC=3C(=CC(Cl)=C(C=3)C(F)(F)F)OC)=CC=2)=C1 SITFWSXSQYZWRX-UHFFFAOYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- YMLYEIUEWVJFQU-UHFFFAOYSA-N 2-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methyl-1h-pyridine-2-carboxamide Chemical compound C=1C=C(NC(=O)NC=2C=C(C(Cl)=CC=2)C(F)(F)F)C=CC=1OC1(C(=O)NC)NC=CC=C1 YMLYEIUEWVJFQU-UHFFFAOYSA-N 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 235000011087 fumaric acid Nutrition 0.000 claims 1
- 201000005296 lung carcinoma Diseases 0.000 claims 1
- 239000001117 sulphuric acid Substances 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 391
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 388
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 210
- 235000019439 ethyl acetate Nutrition 0.000 description 194
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 180
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- 238000003786 synthesis reaction Methods 0.000 description 109
- 230000002829 reductive effect Effects 0.000 description 101
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- 238000004128 high performance liquid chromatography Methods 0.000 description 76
- 239000007787 solid Substances 0.000 description 72
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
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- 238000004809 thin layer chromatography Methods 0.000 description 41
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 37
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 35
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- 238000006243 chemical reaction Methods 0.000 description 34
- YMQVJIXUIXHEGG-UHFFFAOYSA-N 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene Chemical compound COC1=CC=C(C(F)(F)F)C=C1N=C=O YMQVJIXUIXHEGG-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
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- 229920006395 saturated elastomer Polymers 0.000 description 30
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 description 29
- 238000007429 general method Methods 0.000 description 29
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- BGVBBMZMEKXUTR-UHFFFAOYSA-N 4-chloro-n-methylpyridine-2-carboxamide Chemical compound CNC(=O)C1=CC(Cl)=CC=N1 BGVBBMZMEKXUTR-UHFFFAOYSA-N 0.000 description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 23
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- 125000005554 pyridyloxy group Chemical group 0.000 description 22
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- 150000003672 ureas Chemical class 0.000 description 17
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
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- 239000012074 organic phase Substances 0.000 description 11
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
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- NTQCONSUJVLCLR-UHFFFAOYSA-N 5-(4-aminophenoxy)isoindole-1,3-dione Chemical compound C1=CC(N)=CC=C1OC1=CC=C(C(=O)NC2=O)C2=C1 NTQCONSUJVLCLR-UHFFFAOYSA-N 0.000 description 10
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- 230000000875 corresponding effect Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- BILJMVTZCRRVSV-UHFFFAOYSA-N 4-chloro-2-methoxy-5-(trifluoromethyl)aniline Chemical compound COC1=CC(Cl)=C(C(F)(F)F)C=C1N BILJMVTZCRRVSV-UHFFFAOYSA-N 0.000 description 9
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- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
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- AEXDMFVPDVVSQJ-UHFFFAOYSA-N trifluoro(trifluoromethylsulfonyl)methane Chemical compound FC(F)(F)S(=O)(=O)C(F)(F)F AEXDMFVPDVVSQJ-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- IARSSOVWSJAVSZ-UHFFFAOYSA-N tris(dimethylamino)sulfanium Chemical compound CN(C)[S+](N(C)C)N(C)C IARSSOVWSJAVSZ-UHFFFAOYSA-N 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Description
~-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Field of the Invention This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Background of the Invention The p2lras oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep.
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al.
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see:
Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol.
Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.
Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).
Summary of the Invention 1o The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the enzyme is a downstream effector of p21'as, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., 2o myeloid leukemia) or adenomas (e.g., villous colon adenoma).
The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically acceptable salt thereof.
°'-D-B (I) ~o In forn~ula I, D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L ~
)q , .
where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting to of -SOZRx, -C(O)RX and -C(NRy) RZ, RY is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, RZ is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
RX is RZ or NRaRb where Ra and Rb are a) independently hydrogen, 2o a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or -OSi(Rf)3 where R,~ is hydrogen or a carbon based moiety of up to 24 carbon ?5 atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a S-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a C~-CS divalent alkylene group or a substituted C,-CS divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted Cl-CS divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to to 24 carbon atoms, which optionally contain heteroatoms selected from N, S
and O and are optionally substituted by halogen;
where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -COZR', -C(O)NR'R', -C(O)-R', -NOz, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R', -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -COzR', -C(O)R', -C(O)NR'R', -OR', -SR', -2o NR'R', -NOz, -NR'C(O)R', -NR'C(O)OR' and halogen up to per-halo; with each R' independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R')-, -(CHz)m , -C(O)-, -CH(OH)-, -(CHz)m0-, -(CHz)mS-, -(CHz)mN(R')-, -O(CHz)m- CHXa-, -CXaz-, -S-(CHz)m and -N(R')(CHz)m , where m=
1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z",, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -COzR', -C(O)RD, -C(O)NR-R .
',~IO~, -OR'. - SR' -NR'R', -NR'C(O)OR', -NR'C(O)R', and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO~R', -COR', -C(O)NR'R', -OR', -SR', -N02, -NR'R', -NR'C(O)R', and -NR'C(O)OR', with R' as def ned above.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,.4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -S-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, S-or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-2o benzisothiazolyl, 2-, 4-, 5-, 6- or 7-bent-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, I-Z5 methyl-3-pyrryl, 1-methyl-3-pyrazolyl, S-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-y1.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc.
throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
;rr Suitable aryl groups which do not contain heteroatoms include, for example. phcnvl and 1- an~i _'-naphthvl.
The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C9 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.
The term "cycloalkyl", as used herein also includes saturated heterocyclic groups.
Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
The invention also relates to compounds per se, of formula I.
The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, furmaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li+, Na+ or K+), alkaline earth cations (e . g. , Mg+2, Ca+2 or Ba+2) , the ammonium canon, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium rations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]under-7-ene (DBU).
According to another aspect of the present invention, there is provided a compound selected from the group consisting of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl) phenyl) -N'- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3 (trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-6a methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.
6b General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available.
Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.
Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3'd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and HZ or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)).
Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne.
Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH
Publishers: New York ( 1991 )), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3'd Ed.;
John Wiley: New York (1985). Larock. Comprehensive Organic Transformations;
VCH
Publishers: New York (1989)).
H21 catalyst (eg. Ni, Pd, Pt) ArN02 ~H ~ ArNH2 M(0) (eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO:, or an alternative NO,' source. Nitroaryls may be further elaborated prior to reduction. Thus.
nitroaryls substituted with Ar-H ArN02 potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide.
Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).
OzN
ArSH
\~F
base 1 02N \
R j ~ S-Ar Br-Ar j~SH
R Cu0 / base Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stifle reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
02N ~ ~ ArB(OR')2 02N
R j~X Pd(0) j- Ar R
Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol ( 10), for example with zinc amalgum. Reaction of thiol 10 with CHC1F~ in the presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.
Zh. Org. Khim. 1970, 6; (568).
SOZCI
R ~ ; R 7 KF \ Zn(H9) R 8 ~ ~ R 10 (Me2N)3S Me3SiF2 CHCIF2 Me3SiCF3 base R 9 v R 11 [O]
Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be syntnesizea from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or !o N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid ( 17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.
Are-NH2 13 H2N-Ar2 O
Are-NCO. --~. Ar~~N~N.Ar~
O O
Ar~~X Ar~~OH
Scheme IV Selected Methods of Non-Symmetrical Urea Formation 5 Finally, ureas may be further manipulated using methods familiar to those skilled in the art.
The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
to The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or. more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable 'u preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be, for example, inert diluents, such as calcium carbonate, sodium IU
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption 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 may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active to ingredient is mixed with an inert solid diluent, for example, 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.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation 2o products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the :u addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be to preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurnng phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irntating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formula I, the daily ural ~iosa~~r regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily ~iosa~~e for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), e.g., through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below. The following examples 13a are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at to approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 - 1.0 mmHg.
All temperatures are- reported uncorrected in degrees Celsius (°C).
Unless otherwise indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification.
N
cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification.
Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491 ) have previously been described.
3o Thin-layer chromatography (TLC) was performed using Whatman~ pre-coated glass-backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4=dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using s 230-400 mesh EM Science~ silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
to Proton (tH) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or residual protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard.
Carbon (~3C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution 15 mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with 2o electron energy of 70 eV and a trap current of 300 ~tA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas ( 1 x 10-4 torr to 2.5x 10~ torr). The direct insertion desorption chemical ionization (DCI) probe 25 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at l0.amps until all traces of the sample disappeared ( ~l-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrosprav _'~0 ionization. Spectra were scanned from 120-800 amu using a variable ion time accor~lin~~ to the number of ions in the source. Gas chromatography - ion selective mass spectra 1 CJ(~-~1S ~
l5 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.
List of Abbreviations and Acronyms:
1o AcOH acetic acid anh anhydrous atm atmospheres) BOC tent-butoxycarbonyl CDI l,l'-carbonyl diimidazole t 5 conc concentrated d days) dec decomposition DMAC N,N dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2o DMF N,N dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate 25 EtOH ethanol ( 100%) EtZQ diethyl ether Et3N triethylamine h hours) HOBT 1-hydroxybenzotriazole o nr-CPBA 3-chloroperoxybenzoic acid YIeOH methanol pct. ether petroleum ether (boiling range 30-60 C) temp. temperature THF tetrahydrofuran TFA trifluoroAcOH
Tf trifluoromethanesulfonyl S
A. General Methods for Synthesis of Substituted Anilines Al. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.
i C02Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and KZC03 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp.
I S overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCI
solution (100 mL), dried (MgS04), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil ( 10.30 g): ~ H
NMR (DMSO-db) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J--8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J--8.09 Hz, 1H), 7.84 (d, J--8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
i OMe Step 2. 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH ( 100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 3 ,.-l mmol ).
?a The mixture was heated at the reflux temp. for 3 h, cooled to room temp., and magic ardnr with a 10°,'o citric acid solution. The resulting solution was extracted with EtO.-~r 1 ~ v 1 m ~
mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgS04) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'H-NMR (DMSO-db) 8 3.88 (s, 3H), 7.34-7.41 (m, ZH), 7.49-7.54 (m, 1H), 7.83 (d, J--8.09 Hz, 1 H), 7.91 (d, J--8.09 Hz, 1 H), 8.19 (s, 1 H), 12.83 (br s, 1 H).
I~
i I OII
H ~O I W
OMe Step 3. 2-(N (Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6 mmol) in anh toluene ~ (70 mL) was stirred at room temp. for 15 min., then treated with a to solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol)~was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%):
'H-NMR
(DMSO-db) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, SH), 7.72-7.75 (m, 2H), 8.20 (s, 1 H), 8.76 (s, 1 H).
I~
i OMe Step 4. 2-Amino-3-methoxynaphthalene A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a HZ atm (balloon) at room temp.
overnight. The resulting mixture was filtered through Celite~' and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (?..10 85%): 'H-NMR (DMSO-db) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J--8.0 Hz, 1H), 7.56 (d, J--8.0 Hz, 1H); EI-MS m/z 173 (M+).
A2. Synthesis of ~-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline O
CI ~ NHMe ~N
Step la. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide via the Menisci reaction to Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N methylformamide (250 mL) at room temp. was added conc.
HZS04 (3.55 mL) to generate an exotherm. To this mixture was added H202 (30%
wt in HzO, 17 mL) followed by FeS04~7H20 (0.56 g) to generate another exothenm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 °C.
When bubbling had subsided, the reaction was heated at 60 °C for 16 h.
The resulting opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH
solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCI solution (3 x 150 mL), then they were combined, dried (MgS04) and filtered through a pad of silica gel with the aid of EtOAc. The 2o resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50%
hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-N methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50%
EtOAc/50%
hexane) Rf 0.50; 'H NMR (CDC13) 8 3.04 (d, J--S.1 Hz, 3H), 7.43 (dd, J--5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J--5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).
O
CI ~ CI
I
~ N HCI
Step 1 b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 40°
and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SOZ evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HC1 salt as a yellow-orange solid (92.0 g, 89%).
O
CI
home ~ N HCI
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HC1 salt Anh DMF (10.0 mL) was slowly added to SOC12 (300 mL) at 40-48 °C. The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous SOZ
evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (S00 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (SO mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HCl salt as an off white solid (27.2 g, 16%). This material was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 °C. The contents were stirred at room temp. for 45 min., cooled to S °C and treated with Et20 (200. mL) dropwise. The resulting solids were filtered, washed with Et~O (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 °C; 'H-NMR (DMSO-db) 8 3.88 (s, 3H); 7.82 (dd, J--5.5, 2.2 Hz, 1H); 8.08 (d, J--2.2 Hz, 1H); 8.68 (d, J--S.5 Hz, IH);
Background of the Invention The p2lras oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep.
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al.
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see:
Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol.
Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.
Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).
Summary of the Invention 1o The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the enzyme is a downstream effector of p21'as, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., 2o myeloid leukemia) or adenomas (e.g., villous colon adenoma).
The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically acceptable salt thereof.
°'-D-B (I) ~o In forn~ula I, D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L ~
)q , .
where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting to of -SOZRx, -C(O)RX and -C(NRy) RZ, RY is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, RZ is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
RX is RZ or NRaRb where Ra and Rb are a) independently hydrogen, 2o a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or -OSi(Rf)3 where R,~ is hydrogen or a carbon based moiety of up to 24 carbon ?5 atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a S-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a C~-CS divalent alkylene group or a substituted C,-CS divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted Cl-CS divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to to 24 carbon atoms, which optionally contain heteroatoms selected from N, S
and O and are optionally substituted by halogen;
where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -COZR', -C(O)NR'R', -C(O)-R', -NOz, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R', -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -COzR', -C(O)R', -C(O)NR'R', -OR', -SR', -2o NR'R', -NOz, -NR'C(O)R', -NR'C(O)OR' and halogen up to per-halo; with each R' independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R')-, -(CHz)m , -C(O)-, -CH(OH)-, -(CHz)m0-, -(CHz)mS-, -(CHz)mN(R')-, -O(CHz)m- CHXa-, -CXaz-, -S-(CHz)m and -N(R')(CHz)m , where m=
1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z",, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -COzR', -C(O)RD, -C(O)NR-R .
',~IO~, -OR'. - SR' -NR'R', -NR'C(O)OR', -NR'C(O)R', and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO~R', -COR', -C(O)NR'R', -OR', -SR', -N02, -NR'R', -NR'C(O)R', and -NR'C(O)OR', with R' as def ned above.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,.4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -S-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, S-or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-2o benzisothiazolyl, 2-, 4-, 5-, 6- or 7-bent-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, I-Z5 methyl-3-pyrryl, 1-methyl-3-pyrazolyl, S-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-y1.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc.
throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
;rr Suitable aryl groups which do not contain heteroatoms include, for example. phcnvl and 1- an~i _'-naphthvl.
The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C9 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.
The term "cycloalkyl", as used herein also includes saturated heterocyclic groups.
Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
The invention also relates to compounds per se, of formula I.
The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, furmaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li+, Na+ or K+), alkaline earth cations (e . g. , Mg+2, Ca+2 or Ba+2) , the ammonium canon, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium rations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]under-7-ene (DBU).
According to another aspect of the present invention, there is provided a compound selected from the group consisting of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl) phenyl) -N'- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3 (trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-6a methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.
6b General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available.
Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.
Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3'd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and HZ or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)).
Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne.
Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH
Publishers: New York ( 1991 )), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3'd Ed.;
John Wiley: New York (1985). Larock. Comprehensive Organic Transformations;
VCH
Publishers: New York (1989)).
H21 catalyst (eg. Ni, Pd, Pt) ArN02 ~H ~ ArNH2 M(0) (eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO:, or an alternative NO,' source. Nitroaryls may be further elaborated prior to reduction. Thus.
nitroaryls substituted with Ar-H ArN02 potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide.
Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).
OzN
ArSH
\~F
base 1 02N \
R j ~ S-Ar Br-Ar j~SH
R Cu0 / base Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stifle reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
02N ~ ~ ArB(OR')2 02N
R j~X Pd(0) j- Ar R
Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol ( 10), for example with zinc amalgum. Reaction of thiol 10 with CHC1F~ in the presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.
Zh. Org. Khim. 1970, 6; (568).
SOZCI
R ~ ; R 7 KF \ Zn(H9) R 8 ~ ~ R 10 (Me2N)3S Me3SiF2 CHCIF2 Me3SiCF3 base R 9 v R 11 [O]
Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be syntnesizea from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or !o N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid ( 17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.
Are-NH2 13 H2N-Ar2 O
Are-NCO. --~. Ar~~N~N.Ar~
O O
Ar~~X Ar~~OH
Scheme IV Selected Methods of Non-Symmetrical Urea Formation 5 Finally, ureas may be further manipulated using methods familiar to those skilled in the art.
The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
to The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or. more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable 'u preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be, for example, inert diluents, such as calcium carbonate, sodium IU
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption 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 may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active to ingredient is mixed with an inert solid diluent, for example, 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.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation 2o products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the :u addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be to preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurnng phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irntating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formula I, the daily ural ~iosa~~r regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily ~iosa~~e for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), e.g., through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below. The following examples 13a are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at to approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 - 1.0 mmHg.
All temperatures are- reported uncorrected in degrees Celsius (°C).
Unless otherwise indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification.
N
cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification.
Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491 ) have previously been described.
3o Thin-layer chromatography (TLC) was performed using Whatman~ pre-coated glass-backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4=dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using s 230-400 mesh EM Science~ silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
to Proton (tH) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or residual protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard.
Carbon (~3C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution 15 mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with 2o electron energy of 70 eV and a trap current of 300 ~tA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas ( 1 x 10-4 torr to 2.5x 10~ torr). The direct insertion desorption chemical ionization (DCI) probe 25 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at l0.amps until all traces of the sample disappeared ( ~l-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrosprav _'~0 ionization. Spectra were scanned from 120-800 amu using a variable ion time accor~lin~~ to the number of ions in the source. Gas chromatography - ion selective mass spectra 1 CJ(~-~1S ~
l5 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.
List of Abbreviations and Acronyms:
1o AcOH acetic acid anh anhydrous atm atmospheres) BOC tent-butoxycarbonyl CDI l,l'-carbonyl diimidazole t 5 conc concentrated d days) dec decomposition DMAC N,N dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2o DMF N,N dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate 25 EtOH ethanol ( 100%) EtZQ diethyl ether Et3N triethylamine h hours) HOBT 1-hydroxybenzotriazole o nr-CPBA 3-chloroperoxybenzoic acid YIeOH methanol pct. ether petroleum ether (boiling range 30-60 C) temp. temperature THF tetrahydrofuran TFA trifluoroAcOH
Tf trifluoromethanesulfonyl S
A. General Methods for Synthesis of Substituted Anilines Al. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.
i C02Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and KZC03 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp.
I S overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCI
solution (100 mL), dried (MgS04), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil ( 10.30 g): ~ H
NMR (DMSO-db) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J--8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J--8.09 Hz, 1H), 7.84 (d, J--8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
i OMe Step 2. 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH ( 100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 3 ,.-l mmol ).
?a The mixture was heated at the reflux temp. for 3 h, cooled to room temp., and magic ardnr with a 10°,'o citric acid solution. The resulting solution was extracted with EtO.-~r 1 ~ v 1 m ~
mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgS04) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'H-NMR (DMSO-db) 8 3.88 (s, 3H), 7.34-7.41 (m, ZH), 7.49-7.54 (m, 1H), 7.83 (d, J--8.09 Hz, 1 H), 7.91 (d, J--8.09 Hz, 1 H), 8.19 (s, 1 H), 12.83 (br s, 1 H).
I~
i I OII
H ~O I W
OMe Step 3. 2-(N (Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6 mmol) in anh toluene ~ (70 mL) was stirred at room temp. for 15 min., then treated with a to solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol)~was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%):
'H-NMR
(DMSO-db) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, SH), 7.72-7.75 (m, 2H), 8.20 (s, 1 H), 8.76 (s, 1 H).
I~
i OMe Step 4. 2-Amino-3-methoxynaphthalene A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a HZ atm (balloon) at room temp.
overnight. The resulting mixture was filtered through Celite~' and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (?..10 85%): 'H-NMR (DMSO-db) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J--8.0 Hz, 1H), 7.56 (d, J--8.0 Hz, 1H); EI-MS m/z 173 (M+).
A2. Synthesis of ~-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline O
CI ~ NHMe ~N
Step la. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide via the Menisci reaction to Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N methylformamide (250 mL) at room temp. was added conc.
HZS04 (3.55 mL) to generate an exotherm. To this mixture was added H202 (30%
wt in HzO, 17 mL) followed by FeS04~7H20 (0.56 g) to generate another exothenm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 °C.
When bubbling had subsided, the reaction was heated at 60 °C for 16 h.
The resulting opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH
solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCI solution (3 x 150 mL), then they were combined, dried (MgS04) and filtered through a pad of silica gel with the aid of EtOAc. The 2o resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50%
hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-N methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50%
EtOAc/50%
hexane) Rf 0.50; 'H NMR (CDC13) 8 3.04 (d, J--S.1 Hz, 3H), 7.43 (dd, J--5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J--5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).
O
CI ~ CI
I
~ N HCI
Step 1 b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 40°
and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SOZ evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HC1 salt as a yellow-orange solid (92.0 g, 89%).
O
CI
home ~ N HCI
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HC1 salt Anh DMF (10.0 mL) was slowly added to SOC12 (300 mL) at 40-48 °C. The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous SOZ
evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (S00 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (SO mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HCl salt as an off white solid (27.2 g, 16%). This material was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 °C. The contents were stirred at room temp. for 45 min., cooled to S °C and treated with Et20 (200. mL) dropwise. The resulting solids were filtered, washed with Et~O (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 °C; 'H-NMR (DMSO-db) 8 3.88 (s, 3H); 7.82 (dd, J--5.5, 2.2 Hz, 1H); 8.08 (d, J--2.2 Hz, 1H); 8.68 (d, J--S.5 Hz, IH);
10.68 (br s, 1H); HPLC ES-MS m/z 172 ((M+H)+).
O
NHMe ~N
Step 3a. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in s MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF ( 1 L) at a rate which kept the internal temp. below S °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc ( 1 L) and filtered. The filtrate was washed with a saturated NaCI solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-N methyl-2-to pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; ~H-NMR (DMSO-db) 8 2.81 (s, 3H), 7.74 (dd, J 5.1, 2.2 Hz, 1 H), 8.00 (d, J 2.2, 1 H), 8.61 (d, J--5.1 Hz, 1 H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)+).
O
CI
~NHMe ~N
Step 3b. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from 4-15 chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered.
The filtrate 2o was washed with a saturated NaCI solution (2 x 100 mL), dried (NazS04) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.
O
O
NHMe Step 4. Synthesis of 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline 2s A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 mL) was treated with potassium tent-butoxide ( 10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at 2t room temp. for 2 h. The contents were treated with 4-chloro-N methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and KZC03 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (S00 mL) and a saturated NaCI solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI
solution (4 x 1000 mL), dried (NaZS04) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J--8.4 Hz, 4H), 7.06 (dd, J--5.5, 2.5 Hz, l0 1H), 7.33 (d, J--2.5 Hz, 1H), 8.44 (d, J--S.5 Hz, 1H), 8.73 (br d, 1H);
HPLC ES-MS m/z 244 ((M+H)+).
A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-Aminophenoxy)isoindoline-1,3-dione O
'N H
HO
O
Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated 2o at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%):
~H NMR
(DMSO-db) 8 7.00-7.03 (m, 2H), 7.56 (d, J--9.3Hz, 1 H).
02N ~ O
NH
O
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione To a stirnng slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C
was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise.
The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1 fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted slowly with water ( 150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30%
EtOAc/70%
hexane) Rf 0.28; 1H NMR (DMSO-db) 8 7.32 (d, J--12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, J--7.8 Hz, 1H), 8.29 (d, J--9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).
i ~ i H2N ~ O
NH
O
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give S-(4-2o aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC
(5O%
EtOAc/50% hexane) Rf0.27; iH NMR (DMSO-db) 8 5.14 (br s, 2H), 6.62 (d, J--8.7 Hz, 2H), 6.84 (d, J--8.7 Hz, 2H), 7.03 (d, J 2.1 Hz, 1 H), 7.23 (dd, 1 H), 7.75 (d, J
8.4 Hz, 1 H), 11.02 (s, 1 H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline N
Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (O.ImL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CHZC12 (10 mL) and sequentially washed with a 1 N HCl solution ( 15 mL), a 1 N NaOH solution ( 15 mL) and a saturated NaCI
solution (lSmL), dried ( MgS04) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g Si02;
gradient from 6%
to EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85%
hexane) Rf 0.67; ~H NMR (CDC13) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J--2.4 Hz, 1H); CI-MS mlz 273 ((M+H)+, 50%).
N
Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (SO mL) under an HZ atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite°. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf0.43; ~H NMR (CDC13) 8 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
A5. General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N
Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt O
NHMe HZN / . ~ N
HCI
Me A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with 1o water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (MgSO~) and concentrated under reduced pressure. The residual black oil was treated with Et~O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et20; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 °C
prior to use: ' H NMR
(DMSO-d6) b 2.41 (s, 3H), 2.78 (d, J--4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J--8.5, 2.6 Hz, 1H), 7.23 (dd, J--5.5, 2.6 Hz, 1H), 7.26 (d, J 2.6 Hz, 1H), 7.55 (d, J--2.6 Hz, 1H), 7.64 (d, J--8.8 Hz, 1,H), 8.55 (d, J--5.9 Hz, 1 H), 8.99 (q, J--4.8 Hz, 1 H).
2o A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N-Protection, Nucleophilic Aromatric Substitution and Deprotectioa.
Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline O ~ OH
F3C~H
CI
Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)pheno!
?5 Iron (3.24 ~, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added ?-chloro--t-nitrophenol ( 10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This ~~rav slum was stirred at room temp. for 6 d. The iron was filtered from solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCOz solution (SO mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCI solution (125 mL), dried (MgS04) and concentrated under reduced pressure. The 'H NMR (DMSO-db) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material 1o was taken on to the next step without further purification.
O
NHMe ~N
CI
Step 2: Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in t s dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into 20 cold water ( 100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40%
EtOAc/pet.
ether) to yield 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
O
O ~ NHMe i I ~N
Step 3. Synthesis of 4-(2-(N-h~tethylcarbamoyl)-4-pyridyloxy)-2-chloroaniline A solution of crude 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1N
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR
(DMSO-d6) 8 2.77 (d, J--4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J--8.5, 2.6 Hz, 1H), 6.76 (d, J--2.6 Hz, 1H), 7.03 (d, J--8.5 Hz, 1H), 7.07 (dd, J--5.5, 2.6, Hz, 1H), 7.27 (d, J--2.6 Hz, 1H), 8.46 (d, J--5.5 Hz, 1H), 8.75 (q, J--4.8, 1H).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline CI
OMe A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for 1 h. The resulting solution was allowed to cool to room temp. during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHC03 solution until the solution was basic. The organic layer was extracted with CHZC12 (3 x 50 mL). The combined organics were dried (MgSOa) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 'H
NMR (DMSO-db) b 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of w-Alkoxy-c~-carboxyphenyl Anilines.
Synthesis of 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline.
O
O OMe i OZN OMe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:
To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5- .
dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step l, 12 mmol) in acetone (50 mL) was added KzC03 (S g) and dimethyl sulfate (3.5 mL).
The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and s filtered through a pad of Celite~. The resulting solution was concentrated under reduced pressure, absorbed onto Si02, and purified by column chromatography (50% EtOAc i 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118 °C.
O
O OH
I
OZN OMe 1o Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp.
and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous 15 mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was ~ dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
O
O NHMe 02N OMe Step 3. 4-(3-(lV Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:
2o To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CHzCIZ ( 12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CHZCIz (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 ?, mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH~CI~ (25 mL).
The organic layer was dried (NazS04) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).
O
O
NHMe H2N OMe Step 4. 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline:
A slurry of 4-(3-(N methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of Hz (balloon) for 2.5 d, then was filtered through a pad of Celite~. The resulting solution was concentrated under reduced pressure to afford 4-(3-(N methylcarbamoly)-4-methoxyphenoxy)aniline as an off white solid (0.68 g, 96%): TLC (0.I% Et3N/99.9% EtOAc) Rf0.36.
A9. General Method for Preparation of w-Alkylphthalimide-containing Anilines. Synthesis of 5-(4-Aminopheuoxy)-2-methylisoindoline-1,3-dione O
O
N-Me O
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp.
overnight, then was cooled to °C and treated with water ( 10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
O
O
~ N-Me O
Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C
(0.10 g) in MeOH was stirred under 1 atm of HZ (balloon) overnight.' The resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure.
The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si02 (60%
EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
A10. General Method for Synthesis of w-Carbamoylaryl Anilines Through 1o Reaction of w-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline O
CI
~O
~ N N~N
Step 1. Synthesis of 4-Chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine ~s To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (SO
mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to 2o afford 4-chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf0.50.
O
O
~ N N~.N
Step 2. Synthesis of 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-s chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and KZC03 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C
overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCI solution (2s mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCI solution (3 x 25 mL) and concentrated under reduced pressure.
1o The resulting brown solids were purified by column chromatography (58 g;
gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf0.32.
A11. General Method for the Reduction of Nitroarenes to Arylamines.
15 Synthesis of 4-(3-Carboxyphenoxy)aniline.
O
O OH
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10%
Pd/C (0.50 g) in MeOH (120 mL) was stirred under an Hz atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite~, then concentrated under reduced pressure to 2o afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90%
CHzCIz) Rf 0.44 (streaking).
A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.
Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline.
HO
'NH
O
Step 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25%
MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf0.17;
HPLC ES-MS m/z 150 ((M+H)+).
I \ I NH
02N \\
O
1o Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp.
and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf0.35.
~ I NH
O
Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C
(0.20 g) in EtOH (50 mL) was stirred under an HZ atmosphere (balloon) for 4 h, then filtered through a pad of Celite~. The filtrate was concentrated under reduced pressure to afford 4-( 1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC ( 100% EtOAc} Rf 0.15.
A13. General Method for the Synthesis of c~-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-N Methylcarbamoylphenoxy)aniline.
O
O ~ OEt Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and KZC03 (41 g, 300 mmol) in DNiF (125 mL) was heated at the reflux temp.
overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NazS04) and concentrated under reduced pressure. The residue was purified by column chromatography 1o (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
O
O ~ OH
~ i Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH~HZO (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at SO °C
overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 2o solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
O
NHMe ~ i Step 3. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI~HC1 (3.63 g, 18.6 mmol), N methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CHZC12 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCI solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x SO mL). The combined organic phases were washed with a saturated NaCI
solution (50 mL), dried (NaZSOa), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
O
O ~ NHMe i Step 4. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)aniline A slurry of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an Hz atm (balloon) overnight. The a 5 resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95%
CHZCIZ).
The resulting oil solidified under vacuum overnight to give 4-(3-(N
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
2o A14. General Method for the Synthesis of w-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline O
O ~ I OMe 2, Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl S-hvdroxvnicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc ( 100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
O
O ~ OMe HZN N
Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an HZ atmosphere (balloon) for 72 h.
The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90%
hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H NMR (CDC13) 8 3.92 (s, 3H), 6.71 (d, ~ 5 2H), 6.89 (d, 2H), 7.73 (, 1 H), 8.51 (d, 1 H), 8.87 (d, 1 H).
A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
O~ ,O
S~NHMe Step 1. Synthesis of N methyl-3-bromobenzenesulfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL).
The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases 1o were sequentially washed with water (2 x 25 mL) and a saturated NaCI
solution (25 mL), dried (MgS04) and concentrated under reduced pressure to give N methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
O ,O
~ O , I S~NHMe Step 2. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)benzene To a slurry of phenol (1.9 g, 20 mmol), KZC03 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N methyl-3-bromobenzenesulfonamide (2.5 g, l Ommol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially 2o washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).
O~ ,O
O , I S~NHMe OzN
Step 3. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene To a solution of 4-(3-(N methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaN02 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCI solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carned on to the next step without further purification.
OSO
NHMe Step 4. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)aniline A slurry of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10%
Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an HZ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite~. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30%
EtOAc/70%
hexane) to give 4-(3-(N methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of w-ketones. Synthesis of 4-(4-(1-(N
methoxy)iininoethyl)phenoxyaniline HCI salt.
N.O~
HCI
O
To a slurry of 4-(4-acetylphenoxy)aniline HC1 salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine ( 1.0 mL) was added O-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and 3a concentrated under reduced pressure. The resulting solids were triturated with water ( 10 mL) and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt as a yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf0.78; ~H NMR (DMSO-d6) 8 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)+).
A17. Synthesis of N (w-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
O
CI , N~O.Si \ N
Step 1. 4-Chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide To a solution of 4-chloro-N (2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added to triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water ( 10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgS04), and concentrated under reduced pressure to afford 4-chloro-2-(N (2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.
O
\ O ~ N~O'Si N
Step 2. 4-(4-(2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyriidyloxyaniline To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added 2o potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2 triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by KZC03 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. T'he mixture was cooled to 0 °C with an ice/water bath, then water (approx.
1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL).
The~combined organic layers were washed with a saturated NaCI solution (20 mL), dried (MgS04) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiOz; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).
A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-Methylpyridines. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.
~ o i Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
A mixture of S-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), KZC03 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCI solution ((100 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
O
I / ~ I oMe O
2o Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH ( 100 mL). The solution was treated with a conc HCI solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure.
The residue was separated between EtOAc (50 mL) and a 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).
W
OMe H2N N.
O
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.
A slurry of 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a HZ
atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite'~, to and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 70% EtOAc/30% hexane) to give 4-(S-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of w-Sulfonylphenyl Anilines. Synthesis of 4-(4-Methylsulfonylphenyoxy)aniline.
O
i ,Me 02N O S~O
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CHZCIz (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
z5 Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-nitrobenzene was reduced to the aniline in a manner analogous to that described Wlethod -~ 1 S, strp 3.
B. Synthesis of Urea Precursors B1. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.
Br NH2~HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution (1 M in Et20; 300 mL) dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g , l0 98%).
Br i NCO
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CHZCIZ (500 mL), then concentrated under reduced pressure. The CHZCIz treatment/concentration protocol was repeated and resulting 2o amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea CI ~ I 0 ~ I O I w NHMe ~N
N N
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CHZCIz (35 mL) was added dropwise to a suspension of 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CHzCl2 (35 mL) at 0 °C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CHZCIZ (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off white solid (28.5 g, 93%): mp 207-209 °C; ~H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J--2.5 Hz, t o 1 H), 7.62 (m, 4H), 8.11 (d, .l--2. S Hz, 1 H), 8.49 (d, J--S .S Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea Br / I O / I O I ~ NHMe W ~ ~ iN
N N
H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2;
8.0 g, 30.1 mmol) in CHzCIz (80 mL) was added dropwise to a solution of 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CHZC12 (40 mL) at 0 °C. The 2o resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CHZC12 (2 x 50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40 °C to afford N (4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid ( 13.2 g, 90%): mp 203-205 °C; 'H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J--2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J--8.8 Hz, 1H), 8.11 (d, J--2.5 Hz, 1 H), 8..19 (ci, ,l=>.s Hz; 1 H), 8.77 (br d, I H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/_ 509 ((:~~t~H )~ 1 Clc. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) Urea CI w O ~ O ~ NHMe N~N ~ I ~ , N
H H Me A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CHZCIz (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (S mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgS04) 1o and concentrated under reduced pressure to yield N (4-chloro-3-(trifluoromethyl)phenyl)-N' (2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 'H NMR (DMSO-db) 8 2.27 (s, 3H), 2.77 (d, J--4.8 Hz, 3H), 7.03 (dd, J--8.5, 2.6 Hz, 1H), 7.11 (d, J--2.9 Hz, 1H), 7.15 (dd, J--5.5, 2.6, Hz, 1H), 7.38 (d, J--2.6 Hz, 1H), 7.62 (app d, J--2.6 Hz, 2H), 7.84 (d, J--8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J--5.5 Hz, 1H), 8.78 (q, J--5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) Urea CI ~ O , NH2 I
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CHZCIz (308 rizL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CHZC12 ( 100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc ( 110 mL) and MeOH ( 1 SmL), and the clear solution was washed with a 0.05 ' HCl solution. The organic layer was concentrated under reduced pressure to afford impure N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (3.3 g): TLC ( 100°ro EtOAc) Rj 0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate s with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N' (4-ethoxycarbonylphenyl) Urea CI I ~ O ~ I OEt N~N
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CHZCIZ (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at to room temp. overnight. The resulting slurry was diluted with CHZC12 (50 mL) and filtered to afford N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea as a white solid (s.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 1s with an Aniline. Synthesis ofN (4-Chloro-3-(trifluoromethyl)phenyl)-N' (3-carboxyphenyl) Urea CI I ~ O , I O I ~ OH
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CHZCIZ
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the 2o resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.
The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea as an off white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with lV,:'V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N
methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O I ~ O I ~ NHMe W ~ ~ ~N
N N
OMe H H
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CHZCIz (15 mL) at 0 °C
was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N
methylcarbamoyl)-4 pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H20 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCI
solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67%
hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N (2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) Rf 0.62; 'H NMR (DMSO-db) 8 2.76 (d, J--4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11 H), 8.75 (d, J--4.8 Hz, 1 H), 9.55 (s, 1 H); FAB-MS
m/z 461 ((M+H)+)~
Zo C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,/V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O O
MeHN ~ ~ O ~ I O I ~ O I ~ NHMe N ~ ~ ~ ~ ~N
N N
H H
To a stirnng solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CHZCIz ( 15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp.
over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCI solution (100 ml), dried (MgS04) and concentrated under reduced pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N
methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf0.50;'H NMR (DMSO-db) b 2.76 (d, J--5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J--5.4 Hz, 1H), 8:75 (d, J--4.8 Hz, 2H),, 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)+).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea O
~N N ~O
OMe H H NH
O
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CHZC12 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CHZC12 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1 N HCl solution ( 15 mL) and a saturated NaCI solution ( 1 S
mL), dried (MgS04) and concentrated under reduced pressure to afford N (2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf0.50;'H NMR (DMSO-db) 8 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 1 I .27 (br s, 1 H); HPLC ES-MS 472.0 ((M+H)r, 100%).
-t6 C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O i I 0 I ~ NHMe / ~ ~ iN
~N N
N H H
To a stirring solution of CDI (0.21g, 1.30 mmol) in CHZCIz (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmo1) was then added in one portion. The resulting 1o mixture was heated at 36 °C overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N
solution ( lSmL), dried (MgSOa), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40%
EtOAc/60% hexane) Rf 0.24; 'H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J--4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J--5.4Hz, 1H), 8.57 (d, J--2.1 Hz, 1 H), 8.80 (br s, 1 H); HPLC ES-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of biphenyl Ureas Using 2o Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M).
This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial z5 was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.). followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.
C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O ~ O ~ NHMe i ~ w I ~ ~N
~N N
OMe H H
To a stirnng solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CHZC12 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2;
0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHC03 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCI
solution, combined, dried (MgS04), and concentrated under reduced pressure. The resulting prok-2o brown residue was dissolved in MeOH and absorbed onto Si02 (100 g). Column chromatography (300 g Si02; gradient from 1% Et3N/33% EtOAc/66% hexane to 1%
Et3N/99% EtOAc to 1 % Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with hexane ( 10 mL) to slowly form crystals of N (2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC ( 1 % Et3N/99%
EtOAc) Rf 0.40.
D. Interconversion of Ureas Dla. Conversion of w-Aminophenyl Ureas into w-(Aroylamino)phenyl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) Urea CI ~ O , N ~ I OMe I / ~ W I O O
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT~Hz0 (0.41 g, 3.03 mmol) and N methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI ~HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp.
overnight;
to diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80%
EtOAc/20% hexane) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC
(80%
EtOAc/20% hexane) Rf 0.75.
Dlb. Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) Urea CI ~ O , N w I NHMe N~N ~ I H O
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT~HZO (0.14 g, 1.07 mmol), and N-methylmorpholine (O.SmL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI~HC1 (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water ( l OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10%
MeOH/90% EtOAc) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%):
mp 225 229; TLC ( 100% EtOAc) Rf 0.23.
Dlc. Combinatorial Approach to the Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-1o pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea CI ~ O , N W I N ~N
~ ~ ~ I H o I ~
N N
H H
A mixture of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and N cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane ( 1 mL) was treated with a solution of 3-aminopyridine in CHZC12 ( 1 M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight.
Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was 2o stirred at 36 °C for 72 h, then cooled ~to room temp. and filtered.
The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%
EtOAc/30%
hexane) Rf 0.12.
D2. Conversion of w-Carboalkoxyaryl Ureas into w-Carbamoylaryl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) Urea CI ~ O ~ N w I NHMe i ~ ~ ( O O
N N
H H
To a sample of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC ( 100%
EtOAc) Rf0.35.
D3. Conversion of w-Carboalkoxyaryl Ureas into w-Carboxyaryl Ureas.
to Synthesis ofN=(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) Urea CI I ~ O / I OH
N~N
H H
To a slurry of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH
solution ~ 5 (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCI solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) urea as a white solid (5.0S g, 92%).
2o D4. General Method for the Conversion of cu-Alkoxy Esters into w-Alkyl Amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea CI \ I ~ I j O \ I OH
N N N
H H
Step 1. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) Urea N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting 1o precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).
CI \ I O I j O , I H~N~
N N N
H H
Step 2. Synthesis of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea A mixture of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N
dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N methylmorpholine (0.035 g, 0.28 mmol), 2o and EDCI~HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp.
overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL).
The organic phase was washed with water (35 mL), dried (MgS04) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2C12 (approximately 2 mL). The resulting solution was treated with Et20 dropwise to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%:'H NMR (DMSO-db) b 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1 H), 8.90 (s, 1 H), 9.14 (s, 1 H); HPLC ES-MS m/z 522 ((M+H)+).
D5. General Method for the Deprotection of N (w-Silyloxyalkyl)amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CI / O \ O / I N~O~gi \ N H
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method C 1 a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 to mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; gradient from 100%
hexane to 40% EtOAc/60% hexane) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above:
Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4-(3-N Methylcarbamoylphenoxy)aniline was prepared according to Method A13.
According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N Methylcarbamoylphenoxy)aniline to afford the urea.
Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI, followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-N Methylcarbamoylphenoxy)aniline, prepared according to Method A 13, was reacted with the isocyanate according to Method C 1 a to afford the urea.
1o Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to Method A3.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 5 (4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 7: 4-(1-Oxoisoindolin-S-yloxy)aniline was synthesized according to Method A12.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4 (1-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-N Methylcarbamoylphenoxy)aniline was synthesized according to Method AI3. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI
followed by 4-(3-N methylcarbamoylphenoxy)aniline to afford the urea.
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-S-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea.
Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford ~ 4-(4-acetylphenoxy)aniline: According to Method C3, S-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 11: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using to DMAC in place of DMF to give 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 13: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-o pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step :1 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to ~letho~l C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 1S: According to Method C2d, S-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 16: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method AS. 5-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method C 1 c to afford the urea.
Entry 17: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized ~ 5 according to Method A6. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
2o Entry 18: According to Method A2, Step 4, S-amino-2-methylphenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was 25 reacted with 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C 1 a to afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted 3o with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method 1 o C 1 a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline.
According to Method C 1 a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method C 1 a, S-(trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-carbamoylphenoxy)aniline to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method C 1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according 3o to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give .1-t ~-~.~'..~'-dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 25: 4-(I-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(I-(N methoxy)iminoethyl)phenoxyaniline HCI salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(1-(N methoxy)iminoethyl)phenoxyaniline HC1 salt to Method C 1 a to afford the urea.
Entry 27: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 2o A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to Method C 1 a to afford the urea.
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Vlethocl A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to :~lethocl A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-pyridinecarboxamide .was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline was to converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method t5 A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, 2o and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2.
Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-25 methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(S-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 3o to afford the amide.
Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N,N dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
1o Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. S
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N (5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 3 t 5 aminopyridine according to Method D 1 c.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-20 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (S-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N
(4-fluorophenyl)piperazine according to Method Dlc.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
25 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Dlc.
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
~-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl ~o isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according to Method Dlc.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-to (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method D 1 c.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method D 1 c.
2o Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N
(2-pyridyl)piperazine according to Method D 1 c.
Entry 41: 4-(3-(N Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A 13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4-(3-(N Methylcarbamoyl)phenoxy)aniline to afford the urea.
Entry 42: 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 45: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to 2o Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N methylcarbamoyl)-pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized ,o according to Method A5. According to Method Clc, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 48: 4-(3-N Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 49: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
to Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl 2o isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A 19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced 3o according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -1-j.l-methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N methyl-4-bromobenzenesulfonamide. N Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N methylsulfamoyl)phenoxy)benzene. 4-(4-(N
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N
methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N
Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford the urea.
to Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoXycarbonyl)pyridyloxy)-1-nitrobenzene.
The t5 nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C 1 a to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The rriethylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea.
The methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-5-pyridyloxy)phenyl) urea.
:o Entry ~7: lV-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford the urea.
Entry 58: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford N
(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.
According to Method D2, N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.
1o Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N
dimethylcarbamoyl)-4 ts pyridyloxy)aniline to afford the urea.
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was 2o converted to the 4-(4-(1-(N methoxy)iminoethyl) phenoxyaniline HCl salt according to Method A 16. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, 25 Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was . coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N (2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N (2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-o (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.
1o Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, 2o Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N ((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 65: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 3o A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -l-1-1-(?-1:'~'-methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 67: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was 1 o synthesized according to Method C 1 e. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.
Entry 69: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N
methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to 3o afford the urea.
Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the urea. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C l a to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.
Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea.
N-(5 (Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with 2o N,N dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. - 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1 a, 4-chloro 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(,'V-(?
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3 3o ((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloi=o-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(S-methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Dlc.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A
O
NHMe ~N
Step 3a. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in s MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF ( 1 L) at a rate which kept the internal temp. below S °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc ( 1 L) and filtered. The filtrate was washed with a saturated NaCI solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-N methyl-2-to pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; ~H-NMR (DMSO-db) 8 2.81 (s, 3H), 7.74 (dd, J 5.1, 2.2 Hz, 1 H), 8.00 (d, J 2.2, 1 H), 8.61 (d, J--5.1 Hz, 1 H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)+).
O
CI
~NHMe ~N
Step 3b. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from 4-15 chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered.
The filtrate 2o was washed with a saturated NaCI solution (2 x 100 mL), dried (NazS04) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.
O
O
NHMe Step 4. Synthesis of 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline 2s A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 mL) was treated with potassium tent-butoxide ( 10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at 2t room temp. for 2 h. The contents were treated with 4-chloro-N methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and KZC03 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (S00 mL) and a saturated NaCI solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI
solution (4 x 1000 mL), dried (NaZS04) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J--8.4 Hz, 4H), 7.06 (dd, J--5.5, 2.5 Hz, l0 1H), 7.33 (d, J--2.5 Hz, 1H), 8.44 (d, J--S.5 Hz, 1H), 8.73 (br d, 1H);
HPLC ES-MS m/z 244 ((M+H)+).
A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-Aminophenoxy)isoindoline-1,3-dione O
'N H
HO
O
Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated 2o at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%):
~H NMR
(DMSO-db) 8 7.00-7.03 (m, 2H), 7.56 (d, J--9.3Hz, 1 H).
02N ~ O
NH
O
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione To a stirnng slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C
was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise.
The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1 fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted slowly with water ( 150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30%
EtOAc/70%
hexane) Rf 0.28; 1H NMR (DMSO-db) 8 7.32 (d, J--12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, J--7.8 Hz, 1H), 8.29 (d, J--9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).
i ~ i H2N ~ O
NH
O
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give S-(4-2o aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC
(5O%
EtOAc/50% hexane) Rf0.27; iH NMR (DMSO-db) 8 5.14 (br s, 2H), 6.62 (d, J--8.7 Hz, 2H), 6.84 (d, J--8.7 Hz, 2H), 7.03 (d, J 2.1 Hz, 1 H), 7.23 (dd, 1 H), 7.75 (d, J
8.4 Hz, 1 H), 11.02 (s, 1 H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline N
Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (O.ImL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CHZC12 (10 mL) and sequentially washed with a 1 N HCl solution ( 15 mL), a 1 N NaOH solution ( 15 mL) and a saturated NaCI
solution (lSmL), dried ( MgS04) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g Si02;
gradient from 6%
to EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85%
hexane) Rf 0.67; ~H NMR (CDC13) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J--2.4 Hz, 1H); CI-MS mlz 273 ((M+H)+, 50%).
N
Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (SO mL) under an HZ atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite°. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf0.43; ~H NMR (CDC13) 8 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
A5. General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N
Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt O
NHMe HZN / . ~ N
HCI
Me A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with 1o water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (MgSO~) and concentrated under reduced pressure. The residual black oil was treated with Et~O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et20; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 °C
prior to use: ' H NMR
(DMSO-d6) b 2.41 (s, 3H), 2.78 (d, J--4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J--8.5, 2.6 Hz, 1H), 7.23 (dd, J--5.5, 2.6 Hz, 1H), 7.26 (d, J 2.6 Hz, 1H), 7.55 (d, J--2.6 Hz, 1H), 7.64 (d, J--8.8 Hz, 1,H), 8.55 (d, J--5.9 Hz, 1 H), 8.99 (q, J--4.8 Hz, 1 H).
2o A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N-Protection, Nucleophilic Aromatric Substitution and Deprotectioa.
Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline O ~ OH
F3C~H
CI
Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)pheno!
?5 Iron (3.24 ~, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added ?-chloro--t-nitrophenol ( 10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This ~~rav slum was stirred at room temp. for 6 d. The iron was filtered from solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCOz solution (SO mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCI solution (125 mL), dried (MgS04) and concentrated under reduced pressure. The 'H NMR (DMSO-db) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material 1o was taken on to the next step without further purification.
O
NHMe ~N
CI
Step 2: Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in t s dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into 20 cold water ( 100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40%
EtOAc/pet.
ether) to yield 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
O
O ~ NHMe i I ~N
Step 3. Synthesis of 4-(2-(N-h~tethylcarbamoyl)-4-pyridyloxy)-2-chloroaniline A solution of crude 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1N
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR
(DMSO-d6) 8 2.77 (d, J--4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J--8.5, 2.6 Hz, 1H), 6.76 (d, J--2.6 Hz, 1H), 7.03 (d, J--8.5 Hz, 1H), 7.07 (dd, J--5.5, 2.6, Hz, 1H), 7.27 (d, J--2.6 Hz, 1H), 8.46 (d, J--5.5 Hz, 1H), 8.75 (q, J--4.8, 1H).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline CI
OMe A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for 1 h. The resulting solution was allowed to cool to room temp. during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHC03 solution until the solution was basic. The organic layer was extracted with CHZC12 (3 x 50 mL). The combined organics were dried (MgSOa) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 'H
NMR (DMSO-db) b 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of w-Alkoxy-c~-carboxyphenyl Anilines.
Synthesis of 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline.
O
O OMe i OZN OMe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:
To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5- .
dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step l, 12 mmol) in acetone (50 mL) was added KzC03 (S g) and dimethyl sulfate (3.5 mL).
The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and s filtered through a pad of Celite~. The resulting solution was concentrated under reduced pressure, absorbed onto Si02, and purified by column chromatography (50% EtOAc i 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118 °C.
O
O OH
I
OZN OMe 1o Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp.
and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous 15 mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was ~ dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
O
O NHMe 02N OMe Step 3. 4-(3-(lV Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:
2o To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CHzCIZ ( 12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CHZCIz (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 ?, mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH~CI~ (25 mL).
The organic layer was dried (NazS04) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).
O
O
NHMe H2N OMe Step 4. 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline:
A slurry of 4-(3-(N methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of Hz (balloon) for 2.5 d, then was filtered through a pad of Celite~. The resulting solution was concentrated under reduced pressure to afford 4-(3-(N methylcarbamoly)-4-methoxyphenoxy)aniline as an off white solid (0.68 g, 96%): TLC (0.I% Et3N/99.9% EtOAc) Rf0.36.
A9. General Method for Preparation of w-Alkylphthalimide-containing Anilines. Synthesis of 5-(4-Aminopheuoxy)-2-methylisoindoline-1,3-dione O
O
N-Me O
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp.
overnight, then was cooled to °C and treated with water ( 10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
O
O
~ N-Me O
Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C
(0.10 g) in MeOH was stirred under 1 atm of HZ (balloon) overnight.' The resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure.
The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si02 (60%
EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
A10. General Method for Synthesis of w-Carbamoylaryl Anilines Through 1o Reaction of w-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline O
CI
~O
~ N N~N
Step 1. Synthesis of 4-Chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine ~s To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (SO
mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to 2o afford 4-chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf0.50.
O
O
~ N N~.N
Step 2. Synthesis of 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-s chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and KZC03 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C
overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCI solution (2s mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCI solution (3 x 25 mL) and concentrated under reduced pressure.
1o The resulting brown solids were purified by column chromatography (58 g;
gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf0.32.
A11. General Method for the Reduction of Nitroarenes to Arylamines.
15 Synthesis of 4-(3-Carboxyphenoxy)aniline.
O
O OH
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10%
Pd/C (0.50 g) in MeOH (120 mL) was stirred under an Hz atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite~, then concentrated under reduced pressure to 2o afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90%
CHzCIz) Rf 0.44 (streaking).
A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.
Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline.
HO
'NH
O
Step 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25%
MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf0.17;
HPLC ES-MS m/z 150 ((M+H)+).
I \ I NH
02N \\
O
1o Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp.
and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf0.35.
~ I NH
O
Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C
(0.20 g) in EtOH (50 mL) was stirred under an HZ atmosphere (balloon) for 4 h, then filtered through a pad of Celite~. The filtrate was concentrated under reduced pressure to afford 4-( 1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC ( 100% EtOAc} Rf 0.15.
A13. General Method for the Synthesis of c~-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-N Methylcarbamoylphenoxy)aniline.
O
O ~ OEt Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and KZC03 (41 g, 300 mmol) in DNiF (125 mL) was heated at the reflux temp.
overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NazS04) and concentrated under reduced pressure. The residue was purified by column chromatography 1o (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
O
O ~ OH
~ i Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH~HZO (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at SO °C
overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 2o solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
O
NHMe ~ i Step 3. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI~HC1 (3.63 g, 18.6 mmol), N methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CHZC12 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCI solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x SO mL). The combined organic phases were washed with a saturated NaCI
solution (50 mL), dried (NaZSOa), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
O
O ~ NHMe i Step 4. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)aniline A slurry of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an Hz atm (balloon) overnight. The a 5 resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95%
CHZCIZ).
The resulting oil solidified under vacuum overnight to give 4-(3-(N
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
2o A14. General Method for the Synthesis of w-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline O
O ~ I OMe 2, Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl S-hvdroxvnicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc ( 100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
O
O ~ OMe HZN N
Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an HZ atmosphere (balloon) for 72 h.
The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90%
hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H NMR (CDC13) 8 3.92 (s, 3H), 6.71 (d, ~ 5 2H), 6.89 (d, 2H), 7.73 (, 1 H), 8.51 (d, 1 H), 8.87 (d, 1 H).
A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
O~ ,O
S~NHMe Step 1. Synthesis of N methyl-3-bromobenzenesulfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL).
The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases 1o were sequentially washed with water (2 x 25 mL) and a saturated NaCI
solution (25 mL), dried (MgS04) and concentrated under reduced pressure to give N methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
O ,O
~ O , I S~NHMe Step 2. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)benzene To a slurry of phenol (1.9 g, 20 mmol), KZC03 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N methyl-3-bromobenzenesulfonamide (2.5 g, l Ommol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially 2o washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).
O~ ,O
O , I S~NHMe OzN
Step 3. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene To a solution of 4-(3-(N methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaN02 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCI solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carned on to the next step without further purification.
OSO
NHMe Step 4. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)aniline A slurry of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10%
Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an HZ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite~. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30%
EtOAc/70%
hexane) to give 4-(3-(N methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of w-ketones. Synthesis of 4-(4-(1-(N
methoxy)iininoethyl)phenoxyaniline HCI salt.
N.O~
HCI
O
To a slurry of 4-(4-acetylphenoxy)aniline HC1 salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine ( 1.0 mL) was added O-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and 3a concentrated under reduced pressure. The resulting solids were triturated with water ( 10 mL) and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCI salt as a yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf0.78; ~H NMR (DMSO-d6) 8 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)+).
A17. Synthesis of N (w-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
O
CI , N~O.Si \ N
Step 1. 4-Chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide To a solution of 4-chloro-N (2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added to triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water ( 10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgS04), and concentrated under reduced pressure to afford 4-chloro-2-(N (2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.
O
\ O ~ N~O'Si N
Step 2. 4-(4-(2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyriidyloxyaniline To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added 2o potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2 triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by KZC03 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. T'he mixture was cooled to 0 °C with an ice/water bath, then water (approx.
1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL).
The~combined organic layers were washed with a saturated NaCI solution (20 mL), dried (MgS04) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiOz; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).
A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-Methylpyridines. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.
~ o i Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
A mixture of S-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), KZC03 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCI solution ((100 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
O
I / ~ I oMe O
2o Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH ( 100 mL). The solution was treated with a conc HCI solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure.
The residue was separated between EtOAc (50 mL) and a 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).
W
OMe H2N N.
O
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.
A slurry of 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a HZ
atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite'~, to and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 70% EtOAc/30% hexane) to give 4-(S-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of w-Sulfonylphenyl Anilines. Synthesis of 4-(4-Methylsulfonylphenyoxy)aniline.
O
i ,Me 02N O S~O
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CHZCIz (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
z5 Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-nitrobenzene was reduced to the aniline in a manner analogous to that described Wlethod -~ 1 S, strp 3.
B. Synthesis of Urea Precursors B1. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.
Br NH2~HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution (1 M in Et20; 300 mL) dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g , l0 98%).
Br i NCO
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CHZCIZ (500 mL), then concentrated under reduced pressure. The CHZCIz treatment/concentration protocol was repeated and resulting 2o amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea CI ~ I 0 ~ I O I w NHMe ~N
N N
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CHZCIz (35 mL) was added dropwise to a suspension of 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CHzCl2 (35 mL) at 0 °C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CHZCIZ (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off white solid (28.5 g, 93%): mp 207-209 °C; ~H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J--2.5 Hz, t o 1 H), 7.62 (m, 4H), 8.11 (d, .l--2. S Hz, 1 H), 8.49 (d, J--S .S Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea Br / I O / I O I ~ NHMe W ~ ~ iN
N N
H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2;
8.0 g, 30.1 mmol) in CHzCIz (80 mL) was added dropwise to a solution of 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CHZC12 (40 mL) at 0 °C. The 2o resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CHZC12 (2 x 50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40 °C to afford N (4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid ( 13.2 g, 90%): mp 203-205 °C; 'H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J--2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J--8.8 Hz, 1H), 8.11 (d, J--2.5 Hz, 1 H), 8..19 (ci, ,l=>.s Hz; 1 H), 8.77 (br d, I H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/_ 509 ((:~~t~H )~ 1 Clc. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) Urea CI w O ~ O ~ NHMe N~N ~ I ~ , N
H H Me A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CHZCIz (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (S mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgS04) 1o and concentrated under reduced pressure to yield N (4-chloro-3-(trifluoromethyl)phenyl)-N' (2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 'H NMR (DMSO-db) 8 2.27 (s, 3H), 2.77 (d, J--4.8 Hz, 3H), 7.03 (dd, J--8.5, 2.6 Hz, 1H), 7.11 (d, J--2.9 Hz, 1H), 7.15 (dd, J--5.5, 2.6, Hz, 1H), 7.38 (d, J--2.6 Hz, 1H), 7.62 (app d, J--2.6 Hz, 2H), 7.84 (d, J--8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J--5.5 Hz, 1H), 8.78 (q, J--5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) Urea CI ~ O , NH2 I
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CHZCIz (308 rizL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CHZC12 ( 100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc ( 110 mL) and MeOH ( 1 SmL), and the clear solution was washed with a 0.05 ' HCl solution. The organic layer was concentrated under reduced pressure to afford impure N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (3.3 g): TLC ( 100°ro EtOAc) Rj 0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate s with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N' (4-ethoxycarbonylphenyl) Urea CI I ~ O ~ I OEt N~N
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CHZCIZ (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at to room temp. overnight. The resulting slurry was diluted with CHZC12 (50 mL) and filtered to afford N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea as a white solid (s.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 1s with an Aniline. Synthesis ofN (4-Chloro-3-(trifluoromethyl)phenyl)-N' (3-carboxyphenyl) Urea CI I ~ O , I O I ~ OH
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CHZCIZ
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the 2o resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.
The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea as an off white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with lV,:'V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N
methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O I ~ O I ~ NHMe W ~ ~ ~N
N N
OMe H H
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CHZCIz (15 mL) at 0 °C
was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N
methylcarbamoyl)-4 pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H20 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCI
solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67%
hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N (2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) Rf 0.62; 'H NMR (DMSO-db) 8 2.76 (d, J--4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11 H), 8.75 (d, J--4.8 Hz, 1 H), 9.55 (s, 1 H); FAB-MS
m/z 461 ((M+H)+)~
Zo C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,/V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O O
MeHN ~ ~ O ~ I O I ~ O I ~ NHMe N ~ ~ ~ ~ ~N
N N
H H
To a stirnng solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CHZCIz ( 15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp.
over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCI solution (100 ml), dried (MgS04) and concentrated under reduced pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N
methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf0.50;'H NMR (DMSO-db) b 2.76 (d, J--5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J--5.4 Hz, 1H), 8:75 (d, J--4.8 Hz, 2H),, 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)+).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea O
~N N ~O
OMe H H NH
O
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CHZC12 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CHZC12 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1 N HCl solution ( 15 mL) and a saturated NaCI solution ( 1 S
mL), dried (MgS04) and concentrated under reduced pressure to afford N (2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf0.50;'H NMR (DMSO-db) 8 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 1 I .27 (br s, 1 H); HPLC ES-MS 472.0 ((M+H)r, 100%).
-t6 C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O i I 0 I ~ NHMe / ~ ~ iN
~N N
N H H
To a stirring solution of CDI (0.21g, 1.30 mmol) in CHZCIz (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmo1) was then added in one portion. The resulting 1o mixture was heated at 36 °C overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N
solution ( lSmL), dried (MgSOa), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40%
EtOAc/60% hexane) Rf 0.24; 'H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J--4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J--5.4Hz, 1H), 8.57 (d, J--2.1 Hz, 1 H), 8.80 (br s, 1 H); HPLC ES-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of biphenyl Ureas Using 2o Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M).
This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial z5 was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.). followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.
C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O ~ O ~ NHMe i ~ w I ~ ~N
~N N
OMe H H
To a stirnng solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CHZC12 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2;
0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHC03 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCI
solution, combined, dried (MgS04), and concentrated under reduced pressure. The resulting prok-2o brown residue was dissolved in MeOH and absorbed onto Si02 (100 g). Column chromatography (300 g Si02; gradient from 1% Et3N/33% EtOAc/66% hexane to 1%
Et3N/99% EtOAc to 1 % Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with hexane ( 10 mL) to slowly form crystals of N (2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC ( 1 % Et3N/99%
EtOAc) Rf 0.40.
D. Interconversion of Ureas Dla. Conversion of w-Aminophenyl Ureas into w-(Aroylamino)phenyl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) Urea CI ~ O , N ~ I OMe I / ~ W I O O
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT~Hz0 (0.41 g, 3.03 mmol) and N methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI ~HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp.
overnight;
to diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80%
EtOAc/20% hexane) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC
(80%
EtOAc/20% hexane) Rf 0.75.
Dlb. Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) Urea CI ~ O , N w I NHMe N~N ~ I H O
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT~HZO (0.14 g, 1.07 mmol), and N-methylmorpholine (O.SmL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI~HC1 (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water ( l OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10%
MeOH/90% EtOAc) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%):
mp 225 229; TLC ( 100% EtOAc) Rf 0.23.
Dlc. Combinatorial Approach to the Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-1o pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea CI ~ O , N W I N ~N
~ ~ ~ I H o I ~
N N
H H
A mixture of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and N cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane ( 1 mL) was treated with a solution of 3-aminopyridine in CHZC12 ( 1 M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight.
Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was 2o stirred at 36 °C for 72 h, then cooled ~to room temp. and filtered.
The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%
EtOAc/30%
hexane) Rf 0.12.
D2. Conversion of w-Carboalkoxyaryl Ureas into w-Carbamoylaryl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) Urea CI ~ O ~ N w I NHMe i ~ ~ ( O O
N N
H H
To a sample of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC ( 100%
EtOAc) Rf0.35.
D3. Conversion of w-Carboalkoxyaryl Ureas into w-Carboxyaryl Ureas.
to Synthesis ofN=(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) Urea CI I ~ O / I OH
N~N
H H
To a slurry of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH
solution ~ 5 (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCI solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) urea as a white solid (5.0S g, 92%).
2o D4. General Method for the Conversion of cu-Alkoxy Esters into w-Alkyl Amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea CI \ I ~ I j O \ I OH
N N N
H H
Step 1. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) Urea N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting 1o precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).
CI \ I O I j O , I H~N~
N N N
H H
Step 2. Synthesis of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea A mixture of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N
dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N methylmorpholine (0.035 g, 0.28 mmol), 2o and EDCI~HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp.
overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL).
The organic phase was washed with water (35 mL), dried (MgS04) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2C12 (approximately 2 mL). The resulting solution was treated with Et20 dropwise to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%:'H NMR (DMSO-db) b 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1 H), 8.90 (s, 1 H), 9.14 (s, 1 H); HPLC ES-MS m/z 522 ((M+H)+).
D5. General Method for the Deprotection of N (w-Silyloxyalkyl)amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CI / O \ O / I N~O~gi \ N H
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method C 1 a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 to mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; gradient from 100%
hexane to 40% EtOAc/60% hexane) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above:
Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4-(3-N Methylcarbamoylphenoxy)aniline was prepared according to Method A13.
According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N Methylcarbamoylphenoxy)aniline to afford the urea.
Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI, followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-N Methylcarbamoylphenoxy)aniline, prepared according to Method A 13, was reacted with the isocyanate according to Method C 1 a to afford the urea.
1o Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to Method A3.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 5 (4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 7: 4-(1-Oxoisoindolin-S-yloxy)aniline was synthesized according to Method A12.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4 (1-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-N Methylcarbamoylphenoxy)aniline was synthesized according to Method AI3. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI
followed by 4-(3-N methylcarbamoylphenoxy)aniline to afford the urea.
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-S-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea.
Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford ~ 4-(4-acetylphenoxy)aniline: According to Method C3, S-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 11: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using to DMAC in place of DMF to give 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 13: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-o pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step :1 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to ~letho~l C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 1S: According to Method C2d, S-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 16: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method AS. 5-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method C 1 c to afford the urea.
Entry 17: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized ~ 5 according to Method A6. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
2o Entry 18: According to Method A2, Step 4, S-amino-2-methylphenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was 25 reacted with 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C 1 a to afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted 3o with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method 1 o C 1 a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline.
According to Method C 1 a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method C 1 a, S-(trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-carbamoylphenoxy)aniline to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method C 1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according 3o to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give .1-t ~-~.~'..~'-dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 25: 4-(I-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(I-(N methoxy)iminoethyl)phenoxyaniline HCI salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(1-(N methoxy)iminoethyl)phenoxyaniline HC1 salt to Method C 1 a to afford the urea.
Entry 27: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 2o A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to Method C 1 a to afford the urea.
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Vlethocl A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to :~lethocl A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-pyridinecarboxamide .was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline was to converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method t5 A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, 2o and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2.
Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-25 methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(S-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 3o to afford the amide.
Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N,N dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
1o Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. S
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N (5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 3 t 5 aminopyridine according to Method D 1 c.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-20 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (S-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N
(4-fluorophenyl)piperazine according to Method Dlc.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
25 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Dlc.
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
~-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl ~o isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according to Method Dlc.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-to (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method D 1 c.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method D 1 c.
2o Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N
(2-pyridyl)piperazine according to Method D 1 c.
Entry 41: 4-(3-(N Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A 13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4-(3-(N Methylcarbamoyl)phenoxy)aniline to afford the urea.
Entry 42: 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 45: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to 2o Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N methylcarbamoyl)-pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized ,o according to Method A5. According to Method Clc, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 48: 4-(3-N Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 49: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
to Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl 2o isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A 19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced 3o according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -1-j.l-methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N methyl-4-bromobenzenesulfonamide. N Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N methylsulfamoyl)phenoxy)benzene. 4-(4-(N
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N
methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N
Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford the urea.
to Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoXycarbonyl)pyridyloxy)-1-nitrobenzene.
The t5 nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C 1 a to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The rriethylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea.
The methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-5-pyridyloxy)phenyl) urea.
:o Entry ~7: lV-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford the urea.
Entry 58: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford N
(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.
According to Method D2, N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.
1o Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N
dimethylcarbamoyl)-4 ts pyridyloxy)aniline to afford the urea.
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was 2o converted to the 4-(4-(1-(N methoxy)iminoethyl) phenoxyaniline HCl salt according to Method A 16. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, 25 Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was . coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N (2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N (2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-o (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.
1o Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, 2o Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N ((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(( 1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 65: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 3o A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -l-1-1-(?-1:'~'-methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 67: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was 1 o synthesized according to Method C 1 e. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.
Entry 69: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N
methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to 3o afford the urea.
Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the urea. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C l a to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.
Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea.
N-(5 (Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step l, and the corresponding acid was coupled with 2o N,N dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. - 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1 a, 4-chloro 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(,'V-(?
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3 3o ((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloi=o-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(S-methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Dlc.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A
11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with N-(4-acetylphenyl)piperazine according to Method D 1 c.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 4-fluoroaniline according to Method D 1 c.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method D 1 c.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N
phenylethylenediamine according to Method Dlc.
Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 2-methoxyethylamine according to Method Dlc.
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with S-amino-2-methoxypyridine according to Method Dlc.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method D 1 c.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A l 1. 4-1o Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N (2-pyridyl)piperazine according to Method D 1 c.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-t5 hydroxyethylamine according to Method A2, Step 3b to form ' 4-chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1 a, 4-chloro-20 3-(trifluoromethyl)phenyl isocyanate was reacted. with 4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-25 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-30 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 86: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-to (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-2o bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 89: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
3o Entry 90: According to Method A2, Step 4, S-amino-2-methylphenol was reacted with -l-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. -1-Bromo-:-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(lV methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was 1o converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 92: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method t5 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline to afford the 20 urea.
Entry 93: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-25 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline to afford the urea.
3o Entry 94: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was convened into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, ~1-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
Entry 95: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1 a, 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
to Entry 96: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyariate according to Method B
1.
According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N=methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method 2o A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxv-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C l a, 4 chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 98: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxv-s-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-?-methoxv-s-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)ph~nvl isocyanate according to Method B 1. According to Method C 1 a, 4-chloro-2-methoxy-s-(trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B
1.
to According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl 2o isocyanate was reacted with 4-(2-(N,N dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 101: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method A1. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
3o Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-rert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI
followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:
Tables 2o The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.
Table 1. 3-tert-Butylphenyl Ureas O ~ w R.N~N /
H H
TLC Mass mp HPLC TLC SolventSpec. Synth.
En R C min. R S Source Method stem I O 0.2250% 418 A 13 NH EtOAc(M+H)+
Me / (HPLC
50% ES-MS) hexane 2 O 0.5850% 403 A13 ~ O ~ ~ EtOAc(M+H)+ C3 Me /50% (HPLC
hexaneES-MS
3 O 133- 0.68100% 448 A8 C2d NH 135 EtOAc(M+H)+
- Me (FAB) ~O ~ ~ OMe Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas O
R.N~N /
H H OMe TLC Mass mp HPLCTLC SolventSpec. Synth.
En R C min.R S Source Method stem 4 O 5.93 448 A 13 NH (M+H)+ B1 Me (HPLC Cla ES-MS) O 120- 0.67 100% 478 A8 NH 122 EtOAc(M+H)+ C2d / ~ - Me (FAB) ~O ~ ~ OMe 6 ~ ~ - ~ 0.40 50% 460 A 3 I
O ~ ~ EtOAc(MTH)+ C2d NH /50% (HPLC
hexaneES-MS) O
7 / \ -O - 0.7950% 446 A 12 O \ ~ EtOAc (M+H)+C2d NH / 50% (HPLC
hexaneES-MS
Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas F F F
O'' ~ W
R.N~N /
H H OMe TLC Mass mp HPLC TLC SolventSpec. Synth.
En R C min. R S stemSourceMethod NH (dec) (M+H)+C2a / \ - Me (FAB) ~O \
9 O 206- 0.5410% 446 A3 O 208 MeOH (M+H)+step 2, N \ / Me / 90% (HPLC A8 step CH2Cl ES-MS)4, 2 BI, Cla O 0.3350% 445 A13 \ O \ ~ EtOAc (M+H)+C3 Me / 50% (HPLC
pet ES-MS) ether 11 O 0.202% 461 A2 / \ Et3N/ (M+H)+C4 NH
~Me 98% (HPLC
O \ /N
EtOAc ES-MS) 12 O 0.271% 447 A2 / \ Et3N/ (M+H)+C4 _ 99% (HPLC
O \ /N
EtOAc ES-MS) 13 O 0.62100% 461 A2 C2a NH EtOAc (M+H)+
Me (FAB) \ O \ /N
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 4-fluoroaniline according to Method D 1 c.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method D 1 c.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N
phenylethylenediamine according to Method Dlc.
Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 2-methoxyethylamine according to Method Dlc.
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with S-amino-2-methoxypyridine according to Method Dlc.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method D 1 c.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A l 1. 4-1o Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N (2-pyridyl)piperazine according to Method D 1 c.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-t5 hydroxyethylamine according to Method A2, Step 3b to form ' 4-chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1 a, 4-chloro-20 3-(trifluoromethyl)phenyl isocyanate was reacted. with 4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-25 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-30 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 86: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-to (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-2o bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 89: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
3o Entry 90: According to Method A2, Step 4, S-amino-2-methylphenol was reacted with -l-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. -1-Bromo-:-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(lV methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was 1o converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 92: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method t5 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline to afford the 20 urea.
Entry 93: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-25 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline to afford the urea.
3o Entry 94: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was convened into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, ~1-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
Entry 95: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1 a, 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
to Entry 96: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyariate according to Method B
1.
According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N=methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to Method 2o A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxv-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C l a, 4 chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 98: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxv-s-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-?-methoxv-s-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)ph~nvl isocyanate according to Method B 1. According to Method C 1 a, 4-chloro-2-methoxy-s-(trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B
1.
to According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl 2o isocyanate was reacted with 4-(2-(N,N dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 101: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method A1. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
3o Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-rert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI
followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:
Tables 2o The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.
Table 1. 3-tert-Butylphenyl Ureas O ~ w R.N~N /
H H
TLC Mass mp HPLC TLC SolventSpec. Synth.
En R C min. R S Source Method stem I O 0.2250% 418 A 13 NH EtOAc(M+H)+
Me / (HPLC
50% ES-MS) hexane 2 O 0.5850% 403 A13 ~ O ~ ~ EtOAc(M+H)+ C3 Me /50% (HPLC
hexaneES-MS
3 O 133- 0.68100% 448 A8 C2d NH 135 EtOAc(M+H)+
- Me (FAB) ~O ~ ~ OMe Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas O
R.N~N /
H H OMe TLC Mass mp HPLCTLC SolventSpec. Synth.
En R C min.R S Source Method stem 4 O 5.93 448 A 13 NH (M+H)+ B1 Me (HPLC Cla ES-MS) O 120- 0.67 100% 478 A8 NH 122 EtOAc(M+H)+ C2d / ~ - Me (FAB) ~O ~ ~ OMe 6 ~ ~ - ~ 0.40 50% 460 A 3 I
O ~ ~ EtOAc(MTH)+ C2d NH /50% (HPLC
hexaneES-MS) O
7 / \ -O - 0.7950% 446 A 12 O \ ~ EtOAc (M+H)+C2d NH / 50% (HPLC
hexaneES-MS
Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas F F F
O'' ~ W
R.N~N /
H H OMe TLC Mass mp HPLC TLC SolventSpec. Synth.
En R C min. R S stemSourceMethod NH (dec) (M+H)+C2a / \ - Me (FAB) ~O \
9 O 206- 0.5410% 446 A3 O 208 MeOH (M+H)+step 2, N \ / Me / 90% (HPLC A8 step CH2Cl ES-MS)4, 2 BI, Cla O 0.3350% 445 A13 \ O \ ~ EtOAc (M+H)+C3 Me / 50% (HPLC
pet ES-MS) ether 11 O 0.202% 461 A2 / \ Et3N/ (M+H)+C4 NH
~Me 98% (HPLC
O \ /N
EtOAc ES-MS) 12 O 0.271% 447 A2 / \ Et3N/ (M+H)+C4 _ 99% (HPLC
O \ /N
EtOAc ES-MS) 13 O 0.62100% 461 A2 C2a NH EtOAc (M+H)+
Me (FAB) \ O \ /N
14 O . 114- 0.401% 447 A2 NH2 117 Et3N/ (M+H)+C4 _ 99% (FAB) ~ O N EtOAc 15 O 232- 0.54 100% 490 A8 C2d NH 235 EtOAc (M+H)+
- Me (FAB) ~O ~ ~ OMe 16 O 210- 0.29 5% 475 A5 Me NH 213 MeOH (M+H)+ B1 Clc _ j~e / 45% (HPLC
/ ~ O ~ / N 50 oc ES-MS) pet ether 17 O 187- 0.17 50% 495 A6 CI NH 188 EtOAc (M+H)+ B1 Cla _ j~e / 50% (HPLC
/ ~ O ~ / N pet ES-MS) ether 18 / ~ O 0.48 100% 475 A2 step Me NHy EtOAc (M+H)+ 4, _ (HPLC B1 Cla ES-MS) O ~ /N
- Me (FAB) ~O ~ ~ OMe 16 O 210- 0.29 5% 475 A5 Me NH 213 MeOH (M+H)+ B1 Clc _ j~e / 45% (HPLC
/ ~ O ~ / N 50 oc ES-MS) pet ether 17 O 187- 0.17 50% 495 A6 CI NH 188 EtOAc (M+H)+ B1 Cla _ j~e / 50% (HPLC
/ ~ O ~ / N pet ES-MS) ether 18 / ~ O 0.48 100% 475 A2 step Me NHy EtOAc (M+H)+ 4, _ (HPLC B1 Cla ES-MS) O ~ /N
19 O 194- 0.31 5% 475 A2 NH 196 MeOH (M+H)+ BI Cla ~Et / 45% (HPLC
/ ~ O ~ /N, E5~ ac ES-MS) °
pet ether 20 O 214- 0.25 5% 495 A2 C 1 a CI NH 216 MeOH (M+H)+
_ j~e /45% (HPLC
~ O \N EtOAc ES-MS) / 50%
pet ether 21 O 208- 0.30 50% 481 A 19 C2a / ~ O ~ ~ S~O 210 EtOAc (M+H)+
Me /50% (HPLC
hexane ES-MS
/ ~ O ~ /N, E5~ ac ES-MS) °
pet ether 20 O 214- 0.25 5% 495 A2 C 1 a CI NH 216 MeOH (M+H)+
_ j~e /45% (HPLC
~ O \N EtOAc ES-MS) / 50%
pet ether 21 O 208- 0.30 50% 481 A 19 C2a / ~ O ~ ~ S~O 210 EtOAc (M+H)+
Me /50% (HPLC
hexane ES-MS
22 O 188- 0.30 70% 447 A 15, NH2 190 EtOAc (M+H)+ step 4, _ / 50% (HPLC C 1 a / ~ O \ / hexane ES-MS) 23 / ~ - O 0.50 70% 472 A3 O ~ ~ EtOAc (M+H)+ B 1 C 1 a NH / 30% (FAB) hexane O
24 O Me 203- 0.13 100% 479 A2 E31 N 205 EtOAc (M+H)+ Cla ~Me (HPLC
/ ~. O N ES-;~1S) 78.
/ ~. O N ES-;~1S) 78.
25 ~ - O 0.09 75% 458 A12 ~ O ~ ~ EtOAc (M+H)+ C2d NH / 25% (HPLC
hexane ES-MS
hexane ES-MS
26 Me0 169- 0.67 50% 474 A 13 _ N 171 EtOAc (M+H)+ stepl, / 50% (HPLC A 13 step Me pet ES-MS) 4, ether A 16, Cla 27 O 218- 0.40 50% 477 A2 step NH 219 EtOAc (M+H)+ 3b, _ jyle / 50% (HPLC A2 step ~ S N pet ES-MS) 4, ether B 1, Cla 28 ~ ~ - O 212- 0.30 40% A9 O ~ ~ 214 EtOAc BI Cla NMe / 60%
hexane O
hexane O
29 / ~ O 0.33 50% 474 A2 step NH EtOAc (M+H)+ 3b, ~Me / 50% (HPLC A2 step w S ~ / N pet ES-MS) 4, ether B 1, Cla - ~Pr-i Cla ~O ~ /N
31 O 210- 0.43 10% A 14 NH 204 MeOH B1 O ~ / N CH2CI D4a O
32 O 247- 0.57 10% A14 NH 249 MeOH B1 / Me CH2C1 D4a 33 ~ O 217- 0.07 10% A14 NH 219 MeOH B 1 O ~ / ~N-M CH2CI D4a N Me 2 34 O 0.11 70% A 11 N H EtOAc B 1 / 30% Clf ~ O ~ ~ ~ ~ N hexane D 1 c 35 F 0.38 70% A11 EtOAc B 1 / 30% C l f hexane D 1 c N
'-N
O
O ~
'-N
O
O ~
36 ~ ~ 0.77 70% All F~NH EtOAc BI
O / 30% C l f - hexane D 1 c ~O ~
O / 30% C l f - hexane D 1 c ~O ~
37 Me~ 0.58 70% Al I
N ~ ~ N H EtOAc B 1 Me O / 30% Clf _ hexane D 1 c 38 N 0.58 70% All Me0 / ~ NH EtOAc B1 p / 30% Clf _ hexane D 1 c O ~
N ~ ~ N H EtOAc B 1 Me O / 30% Clf _ hexane D 1 c 38 N 0.58 70% All Me0 / ~ NH EtOAc B1 p / 30% Clf _ hexane D 1 c O ~
39 /~ ~ ~ 0.17 70% All ~N NH EtOAc B1 O / 30% Clf - hexane D 1 c O ~
40 N ~---1 0.21 70% A 11 N N . ~ ~ NH EtOAc B 1 U O / 30% Clf _ hexane D 1 c ~ O
Table 4. 3-(Trifluoromethyl)-4-cbloropbenyl Ureas F F F
O ~ CI
R.N~N
H H
TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 41 O. 163- 0.08 50% 464 A 13 NH 165 EtOAc/ (M+H)+ C3 - [yle 50% pet (HPLC
O ~ / ether ES-MS) 42 O 215 0.06 50% 465 A2 N H EtOAc/ (M+H)+ C 1 a _ j~e 50% pet (HPLC
~ / N ether ES-MS) 43 O 0.10 50% 451 A2 NHZ EtOAc/ (M+H)+ Cla _ 50% pet (HPLC
~ / N ether ES-MS) 44 / ~ O 0.25 30% 451 A2 NH2 EtOAc/ (M+H)+ Cla _ 70% pet (HPLC
O ~ / N ether ES-MS) 45 / \ O 0.31 30% 465 A2 N H EtOAc/ (M+H)+ C 1 a ~Me 70% pet (HPLC
O N ether ES-MS) 46 ~ ~ - O 176- 0.23 40% 476 A3 O ~ ~ 179 EtOAc/ (M+H)+ C 1 a NH 60% (FAB) hexane O
Table 4. 3-(Trifluoromethyl)-4-cbloropbenyl Ureas F F F
O ~ CI
R.N~N
H H
TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 41 O. 163- 0.08 50% 464 A 13 NH 165 EtOAc/ (M+H)+ C3 - [yle 50% pet (HPLC
O ~ / ether ES-MS) 42 O 215 0.06 50% 465 A2 N H EtOAc/ (M+H)+ C 1 a _ j~e 50% pet (HPLC
~ / N ether ES-MS) 43 O 0.10 50% 451 A2 NHZ EtOAc/ (M+H)+ Cla _ 50% pet (HPLC
~ / N ether ES-MS) 44 / ~ O 0.25 30% 451 A2 NH2 EtOAc/ (M+H)+ Cla _ 70% pet (HPLC
O ~ / N ether ES-MS) 45 / \ O 0.31 30% 465 A2 N H EtOAc/ (M+H)+ C 1 a ~Me 70% pet (HPLC
O N ether ES-MS) 46 ~ ~ - O 176- 0.23 40% 476 A3 O ~ ~ 179 EtOAc/ (M+H)+ C 1 a NH 60% (FAB) hexane O
47 O 0.29 5% 478 A5 Me NH MeOH/ (M+H)+ Clc ~ / N Me EtOAc/ ESPMS) 50 /o pet ether 48 O' ~O 206- A 15 ~S-NH 209 Cla ~ ~ - Me ~O
49 O 147- 0.22 50% 499 A6 CI NH 151 EtOAc/ (M+H)+ Cla _ j~e 50% pet (HPLC
~ O \N ether ES-MS) 50 / \ O 0.54 100% 479 A2 Me NH EtOAc (MtH)+ Cta Me (HPLC I
ES-VIS) O ~ /N
~ O \N ether ES-MS) 50 / \ O 0.54 100% 479 A2 Me NH EtOAc (MtH)+ Cta Me (HPLC I
ES-VIS) O ~ /N
51 O 187- 0.33 5% 479 A2 N H 189 MeOH/ (M+H)+ C 1 a / ~ - ~Et 45% (HPLC
~O N EtOAc/ ES-MS) / 50% pet ether 52 O 219 0.18 5% 499 A2 CI NH MeOH/ (M+H)+ Cla / \ Me 45% (HPLC
O N EtOAc/ ES-MS) 50% pet ether 53 O 246- 0.30 50% 485 A19, Cla / ~ O ~S~O 248 EtOAc/ (M+H)+
/ , Me 50% (HPLC
hexane ES-MS
~O N EtOAc/ ES-MS) / 50% pet ether 52 O 219 0.18 5% 499 A2 CI NH MeOH/ (M+H)+ Cla / \ Me 45% (HPLC
O N EtOAc/ ES-MS) 50% pet ether 53 O 246- 0.30 50% 485 A19, Cla / ~ O ~S~O 248 EtOAc/ (M+H)+
/ , Me 50% (HPLC
hexane ES-MS
54 O~ 196- 0.30 70% 502 A15 / ~ O ~ / S~O 200 EtOAc/ (M+H)+ Cia ~NH 30% (HPLC
Me hexane) ES-MS) 55 O 228- 0.30 30% 466 O 230 EtOAc/ (M+H)+
/ ~ Me 70% (HPLC
~O ~ ~N CH2C12 ES-MS) / ~ O ~ / 245 NH
Me 57 O 221- 0.75 80% 492 Cld O 222 EtOAc/ (M+H)+ D 1 a H O fv~e 20% (FAB) ~N ~ / hexane 58 O 247 0.35 100% Cld N H EtOAc D 1 a H O Me D2 ~N ~ /
Me hexane) ES-MS) 55 O 228- 0.30 30% 466 O 230 EtOAc/ (M+H)+
/ ~ Me 70% (HPLC
~O ~ ~N CH2C12 ES-MS) / ~ O ~ / 245 NH
Me 57 O 221- 0.75 80% 492 Cld O 222 EtOAc/ (M+H)+ D 1 a H O fv~e 20% (FAB) ~N ~ / hexane 58 O 247 0.35 100% Cld N H EtOAc D 1 a H O Me D2 ~N ~ /
59 O Me 198- 0.09 100% 479 A2 N 200 EtOAc (M+H)+ C 1 a / ~ - Me (HPLC
ES-MS) ~O ~ ~N
ES-MS) ~O ~ ~N
60 Me0 158- 0.64 50%
N 160 EtOAc/
/ ~ O ~ / / 50% pet Me ether 61 O 195- 0.39 10% A 13 NH 197 MeOH/ Cla O ~ / N~ 2 'O
N 160 EtOAc/
/ ~ O ~ / / 50% pet Me ether 61 O 195- 0.39 10% A 13 NH 197 MeOH/ Cla O ~ / N~ 2 'O
62 O 170- 0.52 10% A13 NH 172 MeOH/ C 1 a O ~ ~ ~N 2 63 O 168- 0.39 10% A 13 N~ 171 MeOH/ C I a O ~ ~ 2 64 O Et 176- 0.35 10% A13 NH N 177 MeOH/ Cla / ~ CH2C1 O. 2 (M+H)+ B 1 - Me (HPLC Cla S ~ / N ES-MS) NH Cla - ~Pr-i O ~ /N
67 O 225- 0.23 100% C 1 a NH 229 EtOAc D3 H O -~ Me Dlb ~N
68 ~ ~ - O 234- 0.29 40% A9 O ~ ~ 236 EtOAc/ C I a NMe 60%
hexane O
hexane O
69 / \ O 0.48 50% 481 NH EtOAc/ (M+H)+
Me 50% pet (HPLC
-v S N ether ES-MS) 70 O 0.46 5% 564 A 10 NH MeOH/ (M+H)+ C 1 a - ~ 95% (HPLC
O ~ / N N~ CH2C12 ES-MS) >O
Me 50% pet (HPLC
-v S N ether ES-MS) 70 O 0.46 5% 564 A 10 NH MeOH/ (M+H)+ C 1 a - ~ 95% (HPLC
O ~ / N N~ CH2C12 ES-MS) >O
71 O 199- 0.50 10% A 14 NH 201 MeOH/ Cla ~O ~ / N 2 N
O
O
72 O 235- 0.55 10% A14 NH 237 MeOH/ Cla / ~ Me CH2C1 D4 O ~ / 2 / N
73 O 200- 0.21 50% A 14 NH 201 MeOH/ Cla O ~ / N-Me 2 N Me O ~ ~ OSi(Pr-i)3 N
75 N \ 0.12 70%
~NH EtOAc/ (M+H)+ Clf O 30% (HPLC D 1 c _ hexane ES-MS) / ~ O ~ /
~NH EtOAc/ (M+H)+ Clf O 30% (HPLC D 1 c _ hexane ES-MS) / ~ O ~ /
76 O 0.18 70% A 11 Me EtOAc/ C 1 f 30% Dlc / hexane N
~N
O
/ ~ O ~ /
~N
O
/ ~ O ~ /
77 / \ - 0.74 70% A 11 F~ N H EtOAc/ C 1 f O 30% Dlc / ~ - hexane O ~ /
78 Me 0.58 70% A 11 'N / ~ NH EtOAc/ Clf Me O 30% Dlc hexane / ~ O
/
/
79 O 0.47 70% 569 A11 NH EtOAc/ (M+H)+ Cif _ 30% (HPLC Dlc / \ O \ / ~NH hexane ES-MS) \ /
80 O 0.18 70% 508 All NH EtOAc/ (M+H)+ Clf _ 30% (HPLC Dlc / \ O \ / OMe hexane ES-MS) 0.58 70% 557 A11 Me0 ~ \ NH EtOAc/ (M+H)+ Clf O 30% (HPLC Dlc _ hexane ES-MS) / \ O \ /
g2 ~--~ 0.37 70% 611 All ~N / \ NH EtOAc/ (M+H)+ Clf O 30% (HPLC Dlc hexane ES-MS) \ O \ /
g3 0.19 70% A11 ~N EtOAc/ C 1 f 30% Dlc N~ hexane 'N
O
\ O \
/ \ - Cla DS
~O \ /N OH
Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas F F F
~ Br O
R.N~N /
H H
TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 85 O 186- 0.13 50% 509 A2 NH 187 EtOAc/ (M+H)+ B1 _ jyle 50% pet (HPLC ES- C 1 a ether MS) O ~ /N
86 O 150- 0.31 50% 545 A6 CI NH 152 EtOAc/ (M+H)+ B1 _ jig 50% pet (HPLC ES- Cla ~ O ~ / N ether MS) 87 O 217- 0.16 50% 545 A2 CI NH 219 EtOAc/ (M+H)+ B1 _ j~e 50% pet (HPLC ES- Cla ether MS) O ~ /N
88 O 183- 0.31 50% 525 A2 NH 184 EtOAc/ (M+H)+ B1 ~Et 50% pet (HPLC ES- C 1 a ~ O ~ / N ether MS) 89 / \ O 0.21 50% 511 A2 NH EtOAc/ (M+H)+ B1 _ j~e . 50% pet (HPLC ES- C 1 a O \N ether MS) 90 / \ O 0.28 50% 525 A2 Me NH EtOAc/ (M+H)+ B1 ~Me 50% pet (HPLC ES- C 1 a O \N ether MS) 91 O Me 214- 0.28 50% 522 A2 N 216 EtOAc/ (M+H)+ B 1 ~Me 50% pet (HPLC ES- C 1 a / N ether MS) 92 O 0.47 50% 527 A2 step NH EtOAc/ (M+H)+ 3b, jig 50% pet (HPLC ES- A2 step ~S ~ /N ether MS) g1, Cla 93 / \ O 0.46 50% 527 A2 step NH EtOAc/ (M+H)+ 3b.
~Me 50% pet (HPLC ES- A2 step ether MS) 4.
S ~ /N B1, Cla 94 O 145- 0.415% A10 NH 150 MeOH/ B1 95% Cla ~O . \ /N N CH2C12 O
Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas F F F
O ~ CI
R.N~N I /
H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 95 O 140- 0.29 5% 495 A2 NH 144 MeOH/ (M+H)+ A7 \ O \ ~ N Me EtOAc/ ESPMS) C 1 a 50 /o pet ether 96 O 244- 0.39 5% 529 A6 CI NH 245 MeOH/
(M+H)+ A7 \ - Me 45% (HPLC B 1 O ~N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 97 O 220- 0.25 5% 529 A2 CI NH 221 MeOH/ (M+H)+ A7 \ - [~e 45% (HPLC B1 O N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 98 / \ O 0.27 5% 495 A2 NH MeOH/
(M+H)+ A7 Alle 45% (HPLC B 1 O N EtOAc/ ES-MS) C 1 a 50% pet ether '99 O 180- 0.52 5% 509 A2 NH 181 MeOH/ (M+H)+ A7 \ - ~Et 45% (HPLC B 1 ~O N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 100 O 162- . A2 \ - ~P r-i B 1 ~O \ /N Cla Table 7. Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 101 I ~ O 162- A 1 N~N ~ ~ ~ ~ Me C3 OMe H H
102 0.10 50% 442 A2 EtOAc/ (M+H)+ A4 NH 50% (HPLC C2d N N ~ ~ N Me hexane ES-MS) H H
Me \N/ Me 103 O 125- 0.24 40% 512 A2 (M+H)+ C2b HN ~ NH 130 EtOAc/
60% (FAB) \ hexane O O
/ \ ~ \
O O
NH-Me Me-NH
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
1 o From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
g2 ~--~ 0.37 70% 611 All ~N / \ NH EtOAc/ (M+H)+ Clf O 30% (HPLC Dlc hexane ES-MS) \ O \ /
g3 0.19 70% A11 ~N EtOAc/ C 1 f 30% Dlc N~ hexane 'N
O
\ O \
/ \ - Cla DS
~O \ /N OH
Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas F F F
~ Br O
R.N~N /
H H
TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 85 O 186- 0.13 50% 509 A2 NH 187 EtOAc/ (M+H)+ B1 _ jyle 50% pet (HPLC ES- C 1 a ether MS) O ~ /N
86 O 150- 0.31 50% 545 A6 CI NH 152 EtOAc/ (M+H)+ B1 _ jig 50% pet (HPLC ES- Cla ~ O ~ / N ether MS) 87 O 217- 0.16 50% 545 A2 CI NH 219 EtOAc/ (M+H)+ B1 _ j~e 50% pet (HPLC ES- Cla ether MS) O ~ /N
88 O 183- 0.31 50% 525 A2 NH 184 EtOAc/ (M+H)+ B1 ~Et 50% pet (HPLC ES- C 1 a ~ O ~ / N ether MS) 89 / \ O 0.21 50% 511 A2 NH EtOAc/ (M+H)+ B1 _ j~e . 50% pet (HPLC ES- C 1 a O \N ether MS) 90 / \ O 0.28 50% 525 A2 Me NH EtOAc/ (M+H)+ B1 ~Me 50% pet (HPLC ES- C 1 a O \N ether MS) 91 O Me 214- 0.28 50% 522 A2 N 216 EtOAc/ (M+H)+ B 1 ~Me 50% pet (HPLC ES- C 1 a / N ether MS) 92 O 0.47 50% 527 A2 step NH EtOAc/ (M+H)+ 3b, jig 50% pet (HPLC ES- A2 step ~S ~ /N ether MS) g1, Cla 93 / \ O 0.46 50% 527 A2 step NH EtOAc/ (M+H)+ 3b.
~Me 50% pet (HPLC ES- A2 step ether MS) 4.
S ~ /N B1, Cla 94 O 145- 0.415% A10 NH 150 MeOH/ B1 95% Cla ~O . \ /N N CH2C12 O
Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas F F F
O ~ CI
R.N~N I /
H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 95 O 140- 0.29 5% 495 A2 NH 144 MeOH/ (M+H)+ A7 \ O \ ~ N Me EtOAc/ ESPMS) C 1 a 50 /o pet ether 96 O 244- 0.39 5% 529 A6 CI NH 245 MeOH/
(M+H)+ A7 \ - Me 45% (HPLC B 1 O ~N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 97 O 220- 0.25 5% 529 A2 CI NH 221 MeOH/ (M+H)+ A7 \ - [~e 45% (HPLC B1 O N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 98 / \ O 0.27 5% 495 A2 NH MeOH/
(M+H)+ A7 Alle 45% (HPLC B 1 O N EtOAc/ ES-MS) C 1 a 50% pet ether '99 O 180- 0.52 5% 509 A2 NH 181 MeOH/ (M+H)+ A7 \ - ~Et 45% (HPLC B 1 ~O N EtOAc/ ES-MS) Cla \ ~ 50% pet ether 100 O 162- . A2 \ - ~P r-i B 1 ~O \ /N Cla Table 7. Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method 101 I ~ O 162- A 1 N~N ~ ~ ~ ~ Me C3 OMe H H
102 0.10 50% 442 A2 EtOAc/ (M+H)+ A4 NH 50% (HPLC C2d N N ~ ~ N Me hexane ES-MS) H H
Me \N/ Me 103 O 125- 0.24 40% 512 A2 (M+H)+ C2b HN ~ NH 130 EtOAc/
60% (FAB) \ hexane O O
/ \ ~ \
O O
NH-Me Me-NH
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
1 o From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (10)
1. A compound selected from the group consisting of:
N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (3- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (3- (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'-(4- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (4- (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N- (4-bromo-3- (trifluoromethyl)phenyl) -N'-(3- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N'- (3- (2- (N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (3- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (3- (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'-(4- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl)phenyl) -N'- (4- (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N- (4-bromo-3- (trifluoromethyl)phenyl) -N'-(3- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N'- (3- (2- (N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 selected from the group consisting of:
N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N- (4-bromo-3- (trifluoromethyl)phenyl) -N'-(4- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N- (4-bromo-3- (trifluoromethyl)phenyl) -N'-(4- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea.
4. The compound of claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl) -N'- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy)phenyl)urea.
5. The compound of any one of claims 1 to 4, which is a pharmaceutically acceptable salt thereof selected from the group consisting of:
a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid(tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing rations selected from the group consisting of alkaline rations, alkaline earth rations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid(tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing rations selected from the group consisting of alkaline rations, alkaline earth rations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
6. The compound of claim 1, which is a p-toluene sulphonic acid salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea.
7. The compound of claim 1, which is a p-toluene sulphonic acid salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.
8. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of i) carcinoma of the lungs, pancreas, thyroid, bladder, colon, ii) myeloid leukemia, or iii) villous colon adenoma.
10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of tumors.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2549558A CA2549558C (en) | 1999-01-13 | 2000-01-12 | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11587799P | 1999-01-13 | 1999-01-13 | |
US60/115,877 | 1999-01-13 | ||
US25726699A | 1999-02-25 | 1999-02-25 | |
US09/257,266 | 1999-02-25 | ||
US42522899A | 1999-10-22 | 1999-10-22 | |
US09/425,228 | 1999-10-22 | ||
PCT/US2000/000648 WO2000042012A1 (en) | 1999-01-13 | 2000-01-12 | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
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