NZ702851B - New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- NZ702851B NZ702851B NZ702851A NZ70285114A NZ702851B NZ 702851 B NZ702851 B NZ 702851B NZ 702851 A NZ702851 A NZ 702851A NZ 70285114 A NZ70285114 A NZ 70285114A NZ 702851 B NZ702851 B NZ 702851B
- Authority
- NZ
- New Zealand
- Prior art keywords
- phenyl
- pyrimidinyl
- thieno
- oxy
- methoxy
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 516
- 238000000034 method Methods 0.000 title claims abstract description 81
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 230000000861 pro-apoptotic Effects 0.000 claims abstract description 11
- -1 5-fluorofuranyl Chemical group 0.000 claims description 642
- 239000000203 mixture Substances 0.000 claims description 340
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 296
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 292
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 284
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 230
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 173
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 162
- 235000019260 propionic acid Nutrition 0.000 claims description 155
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 123
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 113
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 86
- 150000004672 propanoic acids Chemical compound 0.000 claims description 63
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 60
- 229910052757 nitrogen Chemical group 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 201000011510 cancer Diseases 0.000 claims description 44
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 27
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 25
- 125000003944 tolyl group Chemical compound 0.000 claims description 24
- 238000007792 addition Methods 0.000 claims description 23
- 239000001301 oxygen Substances 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 14
- 239000005864 Sulphur Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000005842 heteroatoms Chemical group 0.000 claims description 14
- 150000002829 nitrogen Chemical group 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 13
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 206010003816 Autoimmune disease Diseases 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 10
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- 206010021425 Immune system disease Diseases 0.000 claims description 10
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- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000001808 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
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- 125000005843 halogen group Chemical group 0.000 claims description 10
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- 210000004291 Uterus Anatomy 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000002148 esters Chemical group 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 239000000543 intermediate Substances 0.000 claims description 9
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- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 3
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims description 3
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000003207 proteasome inhibitor Substances 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- LAPGMTOHOQPDGI-UHFFFAOYSA-N 4-amino-2,5-difluorobenzonitrile Chemical group NC1=CC(F)=C(C#N)C=C1F LAPGMTOHOQPDGI-UHFFFAOYSA-N 0.000 claims description 2
- 229940100197 ANTIMETABOLITES Drugs 0.000 claims description 2
- 231100000614 Poison Toxicity 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims description 2
- 230000001738 genotoxic Effects 0.000 claims description 2
- 231100000024 genotoxic Toxicity 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 230000000394 mitotic Effects 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 239000002574 poison Substances 0.000 claims description 2
- 125000001325 propanoyl group Chemical compound O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 101710027366 ACVRL1 Proteins 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- FMPJPCHSXGNEMD-UHFFFAOYSA-N 1-butylpyrazole Chemical compound CCCCN1C=CC=N1 FMPJPCHSXGNEMD-UHFFFAOYSA-N 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
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- 230000002611 ovarian Effects 0.000 claims 1
- 125000003652 trifluoroethoxy group Chemical compound FC(CO*)(F)F 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 392
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 189
- 239000003480 eluent Substances 0.000 description 179
- 235000019439 ethyl acetate Nutrition 0.000 description 176
- 238000003818 flash chromatography Methods 0.000 description 158
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- 238000006243 chemical reaction Methods 0.000 description 119
- 239000000243 solution Substances 0.000 description 109
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 98
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 89
- 239000012044 organic layer Substances 0.000 description 82
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 64
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- 239000008346 aqueous phase Substances 0.000 description 36
- 239000008079 hexane Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- 150000002500 ions Chemical class 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
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- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
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- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl N-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 24
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- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 description 19
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
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- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
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- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- XCBFPVYUVHWYIT-LLVKDONJSA-N methyl (2R)-2-hydroxy-2-(3-methylphenyl)propanoate Chemical compound COC(=O)[C@](C)(O)C1=CC=CC(C)=C1 XCBFPVYUVHWYIT-LLVKDONJSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000020825 overweight Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108010025221 plasma protein Z Proteins 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- HVAHYVDBVDILBL-UHFFFAOYSA-M potassium;oxidooxy hydrogen sulfate Chemical compound [K+].OS(=O)(=O)OO[O-] HVAHYVDBVDILBL-UHFFFAOYSA-M 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- FWLKYEAOOIPJRL-UHFFFAOYSA-N prop-1-yn-1-ol Chemical compound CC#CO FWLKYEAOOIPJRL-UHFFFAOYSA-N 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitors Drugs 0.000 description 1
- LFCWHDGQCWJKCG-UHFFFAOYSA-N pyrazin-2-ylmethanol Chemical compound OCC1=CN=CC=N1 LFCWHDGQCWJKCG-UHFFFAOYSA-N 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000000754 repressing Effects 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 102000002933 thioredoxin family Human genes 0.000 description 1
- 108060008226 thioredoxin family Proteins 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
Compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R12, X, A and n are as defined in the description, processes for their preparation, pharmaceutical compositions containing them and their use as pro-apoptotic agents.
Description
NEW THIENOPYRIMIDINE DERIVATIVES,
A PROCESS FOR THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to new thienopyrimidine derivatives, to a process for their
preparation and to pharmaceutical compositions containing them.
The compounds of the present invention are new and have very valuable pharmacological
characteristics in the field of apoptosis and cancerology.
Apoptosis, or programmed cell death, is a physiological process that is crucial for
embryonic development and maintenance of tissue homeostasis.
Apoptotic-type cell death involves morphological changes such as condensation of the
nucleus, DNA fragmentation and also biochemical phenomena such as the activation of
caspases which cause damage to key structural components of the cell, so inducing its
disassembly and death. Regulation of the process of apoptosis is complex and involves the
activation or repression of several intracellular signalling pathways (Cory S. et al., Nature
Review Cancer 2002, 2, 647-656).
Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is
associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s
disease and ischaemia. Conversely, deficits in the implementation of apoptosis play a
significant role in the development of cancers and their chemoresistance, in auto-immune
diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is
one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).
The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies.
The involvement of proteins of the Bcl-2 family is described in numerous types of cancer,
such as colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer,
bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, lymphoma,
myeloma, acute myeloid leukemia, pancreatic cancer, etc. Overexpression of the anti-
apoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in resistance to
chemotherapy and in the clinical prognosis of patients affected by cancer. Notably,
Mcl-1, an anti-apoptotic Bcl-2 family member, is overexpressed in various types of cancer
(Beroukhim R. et al., Nature 2010, 899-905). There is, therefore, a therapeutic need for
compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.
In addition to being new, the compounds of the present invention have pro-apoptotic
properties making it possible to use them in pathologies involving a defect in apoptosis,
such as, for example, in the treatment of cancer and of immune and auto-immune diseases.
The present invention relates more especially to compounds of formula (I):
wherein:
A represents a linear or branched (C -C )alkyl group, a linear or branched
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or
2 6 2 6
branched (C -C )alkoxy group, -S-(C -C )alkyl group, a linear or branched
1 6 1 6
(C -C )polyhaloalkyl, a hydroxy group, a cyano, -NR R ’, -Cy or an halogen
1 6 10 10 6
atom,
R , R , R , R and R independently of one another represent a hydrogen atom, a
1 2 3 4 5
halogen atom, a linear or branched (C -C )alkyl group, a linear or branched
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or
2 6 2 6
branched (C -C )polyhaloalkyl, a hydroxy group, a linear or branched
(C1-C6)alkoxy group, -S-(C1-C6)alkyl group, a cyano, a nitro group,
-alkyl(C -C )-NR R ’, -O-Cy , -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy ,
0 6 8 8 1 0 6 1 2 6 1
-alkynyl(C -C )-Cy , -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’,
2 6 1 1 6 9 8 8 8 8
-NR -C(O)-R ’, -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’,
8 8 8 8 1 6 8 8 2 8 8
-SO -alkyl(C -C ),
2 1 6
or the substituents of one of the pairs (R , R ), (R , R ), (R , R ), (R , R ) when
1 2 2 3 1 3 4 5
grafted onto two adjacent carbon atoms, form together with the carbon atoms
carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring
members, which may contain from one to 3 heteroatoms selected from oxygen,
sulphur and nitrogen, it being understood that resulting ring may be substituted by a
group selected from a linear or branched (C -C )alkyl group, -NR R ’,
1 6 10 10
-alkyl(C0-C6)-Cy1 or an oxo,
X represents a carbon or a nitrogen atom,
R6 represents a hydrogen, a linear or branched (C1-C8)alkyl group, an aryl, an
heteroaryl group, an arylalkyl(C -C ) group, an heteroarylalkyl(C -C ) group,
1 6 1 6
R represents a linear or branched (C -C )alkyl group, a linear or branched
7 1 6
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy ,
2 6 2 6 3
-alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , -Cy -Cy ,
1 6 3 2 6 3 2 6 3 3 4
-alkynyl(C -C )-O-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , an halogen atom, a
2 6 3 3 0 6 0 6 4
cyano, -C(O)-R , -C(O)-NR R ’,
11 11 11
R and R ’ independently of one another represent a hydrogen atom, a linear or
branched (C -C )alkyl group, or -alkyl(C -C )-Cy ,
1 6 0 6 1
or (R , R ’) form together with the nitrogen atom carrying them an aromatic or non-
aromatic ring composed of from 5 to 7 ring members, which may contain in
addition to the nitrogen atom from one to 3 heteroatoms selected from oxygen,
sulphur and nitrogen, it being understood that the nitrogen in question may be
substituted by a group representing a hydrogen atom, or a linear or branched
(C -C )alkyl group and it being understood that one or more of the carbon atoms of
the possible substituents, may be deuterated,
R represents -Cy , -Cy -alkyl(C -C )-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy ,
9 1 1 0 6 2 1 0 6 0 6 2
-Cy -alkyl(C -C )-NR -alkyl(C -C )-Cy , -Cy -Cy -O-alkyl(C -C )-Cy ,
1 0 6 8 0 6 2 1 2 0 6 5
-C(O)-NR R ’, -NR R ’, -OR ,-NR -C(O)-R ’, -O-alkyl(C -C )-OR , -SO -R ,
8 8 8 8 8 8 8 1 6 8 2 8
-C(O)-OR , -NH-C(O)-NH-R ,
R , R ’, R and R ’ independently of one another represent a hydrogen atom or
10 11 11
an optionally substituted linear or branched (C -C )alkyl group,
R represents a hydrogen or a hydroxy group,
Cy , Cy , Cy , Cy , Cy and Cy independently of one another, represent a
1 2 3 4 5 6
cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group,
n is an integer equal to 0 or 1,
it being understood that:
- "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group,
- "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring
members, having at least one aromatic moiety and containing from 1 to 3
heteroatoms selected from oxygen, sulphur and nitrogen,
- "cycloalkyl" means any mono- or bi-cyclic non-aromatic carbocyclic group
containing from 3 to 10 ring members,
- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group
containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms
selected from oxygen, sulphur and nitrogen, which may include fused, bridged or
spiro ring systems,
it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined
and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected
from optionally substituted linear or branched (C -C )alkyl, optionally substituted linear or
branched (C -C )alkenyl group, optionally substituted linear or branched (C -C )alkynyl
2 6 2 6
group, optionally substituted linear or branched (C -C )alkoxy, optionally substituted
(C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-OR’,
-O-C(O)-R’, -C(O)-NR’R’’, -NR’R’’, -(C=NR’)-OR’’, linear or branched
(C1-C6)polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R’ and R’’
independently of one another represent a hydrogen atom or an optionally substituted linear
or branched (C -C )alkyl group, and it being understood that one or more of the carbon
atoms of the preceding possible substituents, may be deuterated,
their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base.
In another embodiment, the invention relates to compounds of formula (I-a):
(I-a)
wherein:
A represents a linear or branched (C -C )alkyl group or an halogen atom,
R , R , R , R and R independently of one another represent a hydrogen atom, a
1 2 3 4 5
halogen atom, a linear or branched (C -C )alkyl group, a linear or branched
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or
2 6 2 6
branched (C -C )polyhaloalkyl, a hydroxy group, a linear or branched
(C -C )alkoxy group, -S-(C -C )alkyl group, a cyano, a nitro group,
1 6 1 6
-alkyl(C -C )-NR R ’, -O-Cy , -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy ,
0 6 8 8 1 0 6 1 2 6 1
-alkynyl(C -C )-Cy , -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’,
2 6 1 1 6 9 8 8 8 8
-NR -C(O)-R ’, -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’,
8 8 8 8 1 6 8 8 2 8 8
-SO -alkyl(C -C ),
2 1 6
or the substituents of one of the pairs (R1, R2), (R2, R3), (R1, R3), (R4, R5) when
grafted onto two adjacent carbon atoms, form together with the carbon atoms
carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring
members, which may contain from one to 3 heteroatoms selected from oxygen,
sulphur and nitrogen, it being understood that resulting ring may be substituted by a
group selected from a linear or branched (C -C )alkyl group, -NR R ’,
1 6 10 10
-alkyl(C -C )-Cy or an oxo,
0 6 1
X represents a carbon or a nitrogen atom,
R represents a hydrogen, a linear or branched (C -C )alkyl group, an aryl, an
6 1 6
heteroaryl group, an arylalkyl(C -C ) group, an heteroarylalkyl(C -C ) group,
1 6 1 6
R represents a linear or branched (C -C )alkyl group, a linear or branched
7 1 6
(C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy ,
2 6 2 6 3
-alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , -Cy -Cy ,
1 6 3 2 6 3 2 6 3 3 4
-Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , an halogen atom, a cyano, -C(O)-R ,
3 0 6 0 6 4 11
-C(O)-NR R ’,
11 11
R and R ’ independently of one another represent a hydrogen atom, a linear or
branched (C -C )alkyl group, or -alkyl(C -C )-Cy ,
1 6 0 6 1
or (R , R ’) form together with the nitrogen atom carrying them an aromatic or non-
aromatic ring composed of from 5 to 7 ring members, which may contain in
addition to the nitrogen atom from one to 3 heteroatoms selected from oxygen,
sulphur and nitrogen, it being understood that the nitrogen in question may be
substituted by a group representing a hydrogen atom, a linear or branched
(C -C )alkyl group,
R represents -Cy , -Cy -alkyl(C -C )-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy ,
9 1 1 0 6 2 1 0 6 0 6 2
-Cy -alkyl(C -C )-NR -alkyl(C -C )-Cy , -C(O)-NR R ’, -NR R ’, -NR -C(O)R ’,
1 0 6 8 0 6 2 8 8 8 8 8 8
-OR , O-alkyl(C -C )-OR , -SO -R , -C(O)-OR , -NH-C(O)-NH-R ,
8 1 6 8 2 8 8 8
R , R ’, R and R ’ independently of one another represent a hydrogen atom or
10 11 11
an optionally substituted linear or branched (C -C )alkyl group,
R represents a hydrogen or a hydroxy group,
Cy , Cy , Cy and Cy , independently of one another, represent a cycloalkyl group,
1 2 3 4
a heterocycloalkyl group, an aryl or an heteroaryl group,
it being understood that:
- "aryl" means a phenyl, naphthyl, biphenyl or indenyl group,
- "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring
members, having at least one aromatic moiety and containing from 1 to 3
heteroatoms selected from oxygen, sulphur and nitrogen,
- "cycloalkyl" means any mono- or bi-cyclic non-aromatic carbocyclic group
containing from 3 to 10 ring members,
- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group
containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms
selected from oxygen, sulphur and nitrogen, which may include fused, bridged or
spiro ring systems,
it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined
and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected
from optionally substituted linear or branched (C -C )alkyl, optionally substituted linear or
branched (C -C )alkenyl group, optionally substituted linear or branched (C -C )alkynyl
2 6 2 6
group, optionally substituted linear or branched (C -C )alkoxy, optionally substituted
(C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-OR’,
-O-C(O)-R’, -C(O)-NR’R’’, -NR’R’’, -(C=NR’)-OR’’, linear or branched
(C -C )polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R’ and R’’
independently of one another represent a hydrogen atom or an optionally substituted linear
or branched (C -C )alkyl group,
their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying
any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid,
acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid,
glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid,
methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying
any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Advantageously, at least one of the groups selected from R , R and R does not represent a
1 2 3
hydrogen atom.
More especially, compounds of formula (I) to which preference is given are compounds
wherein n is an integer equal to 1.
In another embodiment of the invention, an advantageous possibility consists of
compounds of formula (I-b):
(I-b)
wherein A, R , R , R , R , R , R , R , R and X are as defined for formula (I).
1 2 3 4 5 6 7 12
In the preferred compounds of the invention, A represents a linear or branched
(C -C )alkyl group or a halogen atom. More preferably, A represents a methyl group, an
ethyl group, a bromine atom or a chlorine atom.
Atropisomers are stereoisomers arising because of hindered rotation about a single bond,
where energy differences due to steric strain or other contributors create a barrier to
rotation that is high enough to allow for isolation of individual conformers. For compounds
according to the invention, atropisomers are as follows:
Preferred atropisomer is (5S ) when X represents a carbon atom. Preferred atropisomer is
(5Ra) when X represents a nitrogen atom.
Preferably, X represents a carbon atom.
Advantageously, R represents a hydrogen atom.
In some preferred embodiment of the invention,
represents ,
wherein A, R and R ’ are as defined for formula (I).
In the preferred compounds of the invention,
represents ,
wherein R and R ’ are as defined for formula (I).
In another embodiment of the invention, R represents an optionally substituted linear or
branched (C -C )alkoxy group or a -O-alkyl(C -C )-R group. Advantageously, R
1 6 1 6 9 4
represents a 2,2,2-trifluoroethoxy group, a methoxy group, a 2-methoxyethoxy group or a -
O-alkyl(C -C )-R group.
1 6 9
R preferably represents a hydrogen atom.
In the preferred compounds of the invention,
represents ,
wherein R is as defined for formula (I).
In another embodiment of the invention, an advantageous possibility consists of
compounds of formula (I-c):
(I-c)
wherein R , R , R , R , R ’, R and A are as defined for formula (I).
4 6 7 8 8 12
Preferably, R represents a hydrogen, an optionally substituted linear or branched
(C -C )alkyl group, or an heteroarylalkyl(C -C ) group. Preferred R groups are as follows:
1 8 1 6 6
hydrogen; methyl; ethyl; 2-methoxyethyl; 2,2,2-trifluoroethyl; tert-
butylcarbonyloxymethyl; (5-methyloxo-1,3-dioxolyl)methyl; 2-(dimethylamino)
oxoethyl; 2-(2-methoxyethoxy)ethyl. Even more preferably, R represents hydrogen.
In the preferred compounds of the invention, R represents a linear or branched (C -
C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -
6 2 6 2
C )alkynyl group, an aryl or an heteroaryl group. Advantageously, R represents a linear or
branched (C -C )alkynyl group, an aryl or an heteroaryl group. More preferably, R
2 6 7
represents a propynyl group, a butynyl group, a phenyl group or a furanyl
group. In a more preferred embodiment, R represents a 4-(benzyloxy)phenyl group, a
4-(pyridinylmethoxy)phenyl group, a 4-phenylbutynyl group, a 4-fluorophenyl
group or a 5-fluorofuranyl group. Even more preferentially, R7 represents a 4-
fluorophenyl group.
In the preferred compounds of the invention, R and R ’ independently of one another
represent a linear or branched (C -C )alkyl group, or (R , R ’) form together with the
1 6 8 8
nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members,
which may contain in addition to the nitrogen atom from one to 3 heteroatoms selected
from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may
be substituted by a group representing a hydrogen atom, a linear or branched (C -C )alkyl
group. More preferably, R and R ’ represent a methyl group, or (R , R ’) form together a
8 8 8 8
4-methyl-piperazinyl group or a 4-ethyl-piperazinyl group. In a more preferred
embodiment, (R , R ’) form together a 4-methyl-piperazinyl group. In another preferred
embodiment, R and R ’ represent a methyl group.
Advantageously, R represents -Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy or
9 1 1 0 6 0 6 2
-Cy -alkyl(C -C )-Cy . More particularly, R represents -Cy , -Cy -O-CH -Cy , or
1 0 6 2 9 1 1 2 2
-Cy -Cy .
Cy preferably represents a heteroaryl group, particularly, a pyrimidinyl group, a pyrazolyl
group, a triazolyl group, a pyrazinyl group or a pyridinyl group. More preferably, Cy
represents a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl
group or a pyridinyl group. In the preferred compounds of the invention, Cy represents
a pyrimidinyl group.
In another embodiment of the invention, Cy represents a heteroaryl group which is
substituted by an optionally substituted linear or branched (C -C )alkyl group, an
optionally substituted linear or branched (C -C )alkoxy group, a -NR’R’’ group, or a linear
or branched (C -C )polyhaloalkyl group, it being understood that R’ and R’’ independently
of one another represent a hydrogen atom or an optionally substituted linear or branched
(C -C )alkyl group.
Cy preferably represents a phenyl group, a pyridinyl group, a pyrazolyl group, a
morpholinyl group, a furanyl group or a cyclopropyl group. More preferably, Cy
represents a phenyl group, a pyridinyl group, a pyridinyl group, a pyridinyl group,
a pyrazolyl group, a morpholinyl group, a furanyl group or a cyclopropyl group.
In the preferred compounds of the invention, Cy represents a phenyl group.
Other compounds of the invention to which preference is given are those wherein R
represents -Cy -Cy in which Cy represents a pyrimidinyl group and Cy represents a
1 2 1 2
phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group,
or a cyclopropyl group. Even more preferentially,
R represents
in which R and R independently of one another represent a hydrogen, an optionally
13 14
substituted linear or branched (C -C )alkyl, optionally substituted linear or branched
(C -C )alkoxy, hydroxy, linear or branched (C -C )polyhaloalkyl, or halogen atom.
1 6 1 6
Prefered R and R groups are as follows: hydrogen; methyl; ethyl; methoxy; ethoxy;
13 14
isopropoxy; methoxyethoxy; fluoro; hydroxy; trifluoromethyl. Advantageously, R
represents hydrogen and R is located at ortho position of the phenyl group.
Among the preferred compounds of the invention there may be mentioned:
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic
acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-methoxyethoxy)phenyl]
propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-trifluoro
ethoxy)phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazinylmethoxy)
phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propanyl)-1H-
pyrazolyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propanyl)-1H-
pyrazolyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(trifluoromethyl)
pyridinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-ethoxypyrimidin
yl)methoxy]phenyl}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(propanyloxy)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyethyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(cyclopropylmethoxy)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid,
- (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid,
- (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid,
- ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan-
2-yl)-1H-pyrazolyl]methoxy}phenyl)propanoate,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-cyclopropyl
pyrimidinyl)methoxy]phenyl}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(furanyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-propylpyrimidin
yl)methoxy]phenyl}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-
1H-pyrazolyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoro
ethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(thiophenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-ethoxypyrimidin-
4-yl)methoxy]phenyl}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyethoxy)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyethyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(1H-pyrazolyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-methoxypyridin-
4-yl)methoxy]phenyl}propanoic acid,
- (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){2-[(1-butyl-1H-1,2,3-triazolyl)methoxy]phenyl}{[(5S ){3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-trifluoro
ethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(2-methoxyethyl)
amino]pyrimidinyl}methoxy)phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methylphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-
1H-pyrazolyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(5-
fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-ethoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3,3,3-trifluoro
propoxy)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(methoxymethyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methylpyridin-
4-yl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-methylpyridinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-trifluoro
ethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid,
- ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoate,
- ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy
phenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- 2,2,2-trifluoroethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- propanyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)
ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- 2-methoxyethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)
ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoate,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridinyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(ethoxymethyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluorophenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-methoxy
pyrimidinyl)methoxy]phenyl}propanoic acid,
- (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propynyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-hydroxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(propanyloxy)
phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-methoxy
ethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-ethylphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4-methoxy
(trifluoromethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,5-dimethyl
pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(5-methoxy
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloroethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){2-bromochloro[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){2,3-dichloro[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)
pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5Sa){3-chloro-
4-[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]
pyrimidinyl]oxy}propanoic acid,
- (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R)[(6-[4-(benzyloxy)phenyl]-(5S ){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-[4-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}-
6-(4-phenylbutynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy
phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid,
- methyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy
phenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- ethyl (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]methyl
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluoro
phenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[5(5S )-{3-
chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoate,
- {[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy
phenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}methyl 2,2-
dimethylpropanoate,
- (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)
propanoate,
- 2-(dimethylamino)oxoethyl (2R){[(5Sa){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]
oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate,
- 2-(2-methoxyethoxy)ethyl (2R){[(5S ){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]
oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate.
The invention relates also to a process for the preparation of compounds of formula (I),
which process is characterised in that there is used as starting material the compound of
formula (II-a):
(II-a)
wherein R is as defined for formula (I),
which compound of formula (II-a) is subjected to coupling with a compound of
formula (III):
(III)
wherein R , R , R and n are as defined for formula (I), and Alk represents a linear or
4 5 12
branched (C -C )alkyl group,
to yield the compound of formula (IV):
(IV)
wherein R , R , R , R and n are as defined for formula (I) and Alk is as defined before,
4 5 7 12
compound of formula (IV) which is further subjected to coupling with compound of
formula (V):
wherein R , R , R , X and A are as defined for formula (I), and R and R represent a
1 2 3 B1 B2
hydrogen, a linear or branched (C -C ) alkyl group, or R and R form with the oxygen
1 6 B1 B2
carrying them an optionally methylated ring,
to yield the compound of formula (VI):
(VI)
wherein R , R , R , R , R , R , R , X, A and n are as defined for formula (I) and Alk is as
1 2 3 4 5 7 12
defined before,
the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield
the carboxylic acid, which may optionally be optionally be reacted with an alcohol of
formula R OH wherein R is as defined in formula (I),
to yield the compound of formula (I), which may be purified according to a conventional
separation technique, which is converted, if desired, into its addition salts with a
pharmaceutically acceptable acid or base and which is optionally separated into its isomers
according to a conventional separation technique,
it being understood that at any moment considered appropriate during the course of the
process described above, some groups (hydroxy, amino…) of the starting reagents or of
the synthesis intermediates can be protected, subsequently deprotected and functionalized,
as required by the synthesis.
In an other embodiment of the invention, compounds of formula (I) may be obtained using
an alternative process, which process is characterised in that there is used as starting
material the compound of formula (II-b):
(II-b)
which compound of formula (II-b) is converted into compound of formula (II-c):
(II-c)
which compound of formula (II-c) is subjected to coupling with a compound of
formula (V):
wherein R , R , R , X and A are as defined for formula (I), and R and R represent a
1 2 3 B1 B2
hydrogen, a linear or branched (C -C ) alkyl group, or R and R form with the oxygen
1 6 B1 B2
carrying them an optionally methylated ring,
to yield the compound of formula (VII):
(VII)
wherein R1, R2, R3, A and X are as defined in formula (I),
which compound of formula (VII) is further subjected to the action of I in the presence of
lithium diisopropylamide (strong base) to yield compound of formula (VIII):
(VIII)
wherein R , R , R , A and X are as defined in formula (I),
1 2 3
which compound of formula (VIII) is further subjected to coupling with a compound of
formula (IX):
(IX)
wherein R is as defined for formula (I), and R and R represent a hydrogen, a linear or
7 B3 B4
branched (C -C )alkyl group, or R and R form with the oxygen carrying them an
1 6 B3 B4
optionally methylated ring,
to yield compound of formula (X):
wherein R , R , R , A, X and R are as defined in formula (I),
1 2 3 7
which compound of formula (X) is further subjected to coupling with a compound of
formula (III):
(III)
wherein R , R , R and n are as defined for formula (I), and Alk represents a linear or
4 5 12
branched (C -C )alkyl group,
to yield the compound of formula (VI):
(VI)
wherein R , R , R , R , R , R , R , X, A and n are as defined for formula (I) and Alk is as
1 2 3 4 5 7 12
defined before,
the ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic
acid, which may optionally be optionally be reacted with an alcohol of formula R OH
wherein R is as defined in formula (I),
to yield the compound of formula (I), which may be purified according to a conventional
separation technique, which is converted, if desired, into its addition salts with a
pharmaceutically acceptable acid or base and which is optionally separated into its isomers
according to a conventional separation technique,
it being understood that at any moment considered appropriate during the course of the
process described above, some groups (hydroxy, amino…) of the starting reagents or of
the synthesis intermediates can be protected, subsequently deprotected and functionalized,
as required by the synthesis.
The compounds of formulae (II-a), (II-b), (III), (V), (IX) and the alcohol R OH are either
commercially available or can be obtained by the person skilled in the art using
conventional chemical reactions described in the literature.
Pharmacological study of the compounds of the invention has shown that they have pro-
apoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of
major therapeutic interest in the treatment of cancers and of immune and auto-immune
diseases.
More especially, the compounds according to the invention will be useful in the treatment
of chemo- or radio-resistant cancers.
Among the cancer treatments envisaged there may be mentioned, without implying any
limitation, treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid
leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute
myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian
cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung
cancer.
The present invention relates also to pharmaceutical compositions comprising at least one
compound of formula (I) in combination with one or more pharmaceutically acceptable
excipients. The present invention also relates to pharmaceutical compositions of the
invention for use as pro-apoptotic agents, for use in the treatment of cancers and of auto-
immune and immune system diseases, and for use in the treatment of cancers of the
bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon,
œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas,
melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung
cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
The present invention also relates to use of pharmaceutical compositions of the invention
in the manufacture of medicaments for use as pro-apoptotic agents, for use in the treatment
of cancers and of auto-immune and immune system diseases, and for use in the treatment
of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of
the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias,
lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-
cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
The present invention also relates to a compound of formula (I), or an addition salt thereof
with a pharmaceutically acceptable acid or base, for use as pro-apoptotic agents, for use in
the treatment of cancers and of auto-immune and immune system diseases, and for use in
the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid
leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute
myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian
cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung
cancer.
The present invention also relates to use of a compound of formula (I) or an addition salt
thereof with a pharmaceutically acceptable acid or base, in the manufacture of
medicaments for use as pro-apoptotic agents, for use in the treatment of cancers and of
auto-immune and immune system diseases, and for use in the treatment of cancers of the
bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon,
œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas,
melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung
cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
Among the pharmaceutical compositions according to the invention there may be
mentioned more especially those that are suitable for oral, parenteral, nasal, per- or
trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets
or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges,
suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the administration
route, the nature of the therapeutic indication, or of any associated treatments, and ranges
from 0.01 mg to 1 g per 24 hours in one or more administrations.
Furthermore, the present invention relates also to the combination of a compound of
formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, anti-
metabolites, proteasome inhibitors, kinase inhibitors and antibodies, and also to
pharmaceutical compositions comprising that type of combination and their use in the
manufacture of medicaments for use in the treatment of cancer. More specifically, the
present invention also relates to a pharmaceutical composition comprising the combination
in combination with one or more pharmaceutically acceptable excipients. The present
invention also relates to the combination for use in the treatment of cancers.
Advantageously, the present invention relates to the combination of a compound of
formula (I) with an EGFR inhibitor, and also to pharmaceutical compositions comprising
that type of combination.
In another embodiment, the present invention relates to the combination of a compound of
formula (I) with a mTOR/PI3K inhibitor, and also to pharmaceutical compositions
comprising that type of combination.
In a preferred embodiment, the present invention relates to the combination of a compound
of formula (I) with a MEK inhibitor, and also to pharmaceutical compositions comprising
that type of combination.
Preferably, the present invention relates to the combination of a compound of formula (I)
with a HER2 inhibitor, and also to pharmaceutical compositions comprising that type of
combination.
Advantageously, the present invention relates to the combination of a compound of
formula (I) with a RAF inhibitor, and also to pharmaceutical compositions comprising that
type of combination.
In another embodiment, the present invention relates to the combination of a compound of
formula (I) with a EGFR/HER2 inhibitor, and also to pharmaceutical compositions
comprising that type of combination.
In a preferred embodiment, the present invention relates to the combination of a compound
of formula (I) with a taxane, and also to pharmaceutical compositions comprising that type
of combination.
In another embodiment, the present invention relates to the combination of a compound of
formula (I) with a proteasome inhibitor, an immunomodulator or an alkylating agent, and
also to pharmaceutical compositions comprising that type of combination.
The combination of a compound of formula (I) with an anticancer agent may be
administered simultaneously or sequentially. The administration route is preferably the oral
route, and the corresponding pharmaceutical compositions may allow the instantaneous or
delayed release of the active ingredients. The compounds of the combination may
moreover be administered in the form of two separate pharmaceutical compositions, each
containing one of the active ingredients, or in the form of a single pharmaceutical
composition, in which the active ingredients are in admixture.
The compounds of the invention may also be used in combination with radiotherapy in the
treatment of cancer. Accordingly, in another embodiment, the present invention relates to
compound of formula (I) for use in the treatment of cancers requiring radiotherapy.
Finally, the compounds of the invention may be linked to monoclonal antibodies or
fragments thereof or linked to scaffold proteins that can be related or not to monoclonal
antibodies.
Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2, F(ab'),
scFv-Fc type or diabodies, which generally have the same specificity of binding as the
antibody from which they are descended. According to the present invention, antibody
fragments of the invention can be obtained starting from antibodies by methods such as
digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges
by chemical reduction. In another manner, the antibody fragments comprised in the present
invention can be obtained by techniques of genetic recombination likewise well known to
the person skilled in the art or else by peptide synthesis by means of, for example,
automatic peptide synthesizers such as those supplied by the company Applied
Biosystems, etc.
Scaffold proteins that can be related or not to monoclonal antibodies are understood to
mean a protein that contains or not an immunoglobulin fold and that yields a binding
capacity similar to a monoclonal antibody. The man skilled in the art knows how to select
the protein scaffold. More particularly, it is known that, to be selected, such a scaffold
should display several features as follow (Skerra A., J. Mol. Recogn. 2000, 13, 167-187):
phylogenetically good conservation, robust architecture with a well-known three-
dimensional molecular organization (such as, for example, crystallography or NMR), small
size, no or only a low degree of post-translational modifications, easy to produce, express
and purify. Such a protein scaffold can be, but without limitation, a structure selected from
the group consisting in fibronectin and preferentially the tenth fibronectin type III domain
(FNfn10), lipocalin, anticalin (Skerra A., J. Biotechnol. 2001, 74(4):257-75), the protein Z
derivative from the domain B of staphylococcal protein A, thioredoxin A or any protein
with a repeated domain such as an "ankyrin repeat" (Kohl et al., PNAS 2003, 100(4),
1700-1705), "armadillo repeat", "leucine-rich repeat" or "tetratricopeptide repeat". There
could also be mentioned a scaffold derivative from toxins (such as, for example, scorpion,
insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase
(PIN).
The following Preparations and Examples illustrate the invention but do not limit it in any
way.
General Procedures
All reagents obtained from commercial sources were used without further purification.
Anhydrous solvents were obtained from commercial sources and used without further
drying.
Flash chromatography was performed on ISCO CombiFlash Rf 200i with pre-packed
silica-gel cartridges (RediSep R Gold High Performance).
Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type
60 F254 silica-gel.
Microwave heating was performed in an Anton Parr MonoWave or CEM Discover®
instrument.
Preparative HPLC purifications were performed on an Armen Spot Liquid
Chromatography system with a Gemini-NX 10 µM C18, 250 mm × 50 mm i.d. column
running at a flow rate of 118 mL min with UV diode array detection (210 – 400 nm)
using 25 mM aqueous NH HCO solution and MeCN as eluents unless specified
otherwise.
Analytical LC-MS: The compounds of the present invention were characterized by high
performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent HP1200
with Agilent 6140 quadrupole LC/MS, operating in positive or negative ion electrospray
ionisation mode. Molecular weight scan range is 100 to 1350. Parallel UV detection was
done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in ACN, or in
THF/H O (1:1) with 5 µL loop injection. LCMS analyses were performed on two
instruments, one of which was operated with basic, and the other with acidic eluents.
Basic LCMS: Gemini-NX, 3 µm, C18, 50 mm × 3.00 mm i.d. column at 23 °C, at a flow
rate of 1 mL min using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile
(Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B
over various/certain duration of time.
Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 µm, 50 mm × 4.6 mm i.d. column at
40 °C, at a flow rate of 1 mL min using 0.02% v/v aqueous formic acid (Solvent A) and
0.02% v/v formic acid in acetonitrile (Solvent B) with a gradient starting from 100%
Solvent A and finishing at 100% Solvent B over various/certain duration of time.
H-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer and
Bruker Avance III 400 MHz spectrometer, using DMSO-d or CDCl as solvent. H NMR
data is in the form of delta values, given in part per million (ppm), using the residual peak
of the solvent (2.50 ppm for DMSO-d and 7.26 ppm for CDCl ) as internal standard.
Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of
doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets).
Combination gas chromatography and low resolution mass spectrometry were performed
on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m ×
0.25 mm column with 0.25 µm HP-5MS coating and helium as carrier gas. Ion source: EI ,
70 eV, 230°C, quadrupole: 150°C, interface: 300°C.
HRMS were determined on a Shimadzu IT-TOF, ion source temperature 200°C, ESI +/-,
ionization voltage: (+-)4.5 kV. Mass resolution min. 10000.
Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.
List of abbreviations
Abbreviation Name
2-Me-THF 2-methyl-tetrahydrofurane
Ac acetyl
Ad adamantyl
AIBN 2-[(1-cyanomethyl-ethyl)azo]methyl-propanenitrile
AtaPhos bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)
dichloropalladium(II)
CuTC copper(I) thiophenecarboxylate
DAST diethylaminosulfur trifluoride
dba dibenzylideneacetone
DCM methylene chloride
Dess-Martin periodinane 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol(1H)-
one
DIPA diisopropylamine
DIPEA diisopropylethylamine
DME 1,2-dimethoxyethane
DMF dimethylformamide
dppf 1,1'-bis(diphenylphosphino)ferrocene
eq. equivalent
Et ethyl
HMDS hexamethyldisilazane
Pr isopropyl
LDA lithium diisopropylamide
Me methyl
MeCN acetonitrile
NBS N-bromosuccinimide
Bu n-butyl
NCS N-chlorosuccinimide
Ph phenyl
PyBOP benzotriazolyloxy(tripyrrolidinyl)phosphonium
hexafluorophosphate
rt room temperature
Selectfluor 1-chloromethylfluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)
SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
TBAF tetrabutyl ammonium fluoride
TBAOH tetrabutyl ammonium hydroxyde
Bu tert-butyl
tBuXPhos 2-di(tert-butylphosphino)-2',4',6'-triisopropylbiphenyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofurane
TIPSCl triisopropylsilyl chloride
Preparation 1a: 5-Bromochloroiodo-thieno[2,3-d]pyrimidine
Step A: 6-Iodo-3H-thieno[2,3-d]pyrimidinone
A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and reflux
condenser was charged with the solution of 433 mL acetic acid, 13 mL sulfuric acid and
87 mL water. 69.3 g 3H-thieno[2,3-d]pyrimidinone (0.46 mol), 51.9 g periodic acid
(0.23 mol) and 104 g iodine (0.41 mol) were added to the stirred solution heated to 60 °C
for 1h. The resulting suspension was cooled to room temperature, filtered off, washed with
a mixture of acetic acid and water (5:1) and then with diethyl ether. The resulting beige
crystalline solid was air dried.
H NMR (500 MHz, DMSO-d ): 12.57 (brs, 1H), 8.09 (s, 1H), 7.65 (s, 1H).
Step B: 4-Chloroiodo-thieno[2,3-d]pyrimidine
A 1 L round bottomed flask equipped with mechanical stirrer, thermometer, reflux
condenser and a CaCl -tube was charged with 113 mL phosphorous oxychloride and
mL N,N-dimethylaniline (0.29 mol). 75.54g 6-iodo-3H-thieno[2,3-d]pyrimidinone
(0.27 mol) was added to the mixture in portions during 5 minutes. The reaction mixture
was stirred at 105 °C for 1 hour. The resulting suspension was cooled to 10 °C, filtered and
washed with hexane. The crude product was added to ice water and stirred for 10 minutes,
filtered off, washed with cold water, diethyl ether and air dried. Beige crystalline solid was
obtained.
H NMR (400 MHz, DMSO-d ): 8.89 (s, 1H), 7.98 (s, 1H).
Step C: 5-Bromochloroiodo-thieno[2,3-d]pyrimidine
A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and a bubbler
was charged with 600 mL acetonitrile. 84.9 g 4-chloroiodo-thieno[2,3-d]pyrimidine
(0.29 mol), 50.9 g NBS (0.29 mol) and 8.5 mL tetrafluoroboric acid diethyl ether complex
were added. The reaction mixture was stirred at room temperature for 16 hours. Further
22.9 g (0.12 mol) NBS was added to the mixture in three portions. After cooling the
suspension to 0 °C and stirring for further 1 hour the precipitate was filtered off, washed
with acetonitrile and air dried. The product was obtained as beige crystalline solid.
H NMR (500 MHz, DMSO-d ): 8.88 (s, 1H).
Preparation 1b: 4-Chloro-5,6-diiodo-thieno[2,3-d]pyrimidine
Step A: 5,6-Diiodo-3H-thieno[2,3-d]pyrimidinone
To a well stirred slurry of 61.3 g 3H-thieno[2,3-d]pyrimidinone (396 mmol), 92.4 g
periodic acid (405 mmol), 1 L acetic acid, 200 mL water and 6 mL cc. sulfuric acid was
added 203 g iodine (799 mmol). The reaction mixture was heated to 110 °C and stirred for
3 hours. The suspension was cooled to room temperature then 940 mL diethyl ether was
added and stirred further at 10 °C for 30 minutes. The precipitate was filtered off washed
with a 2:1 mixture of diethyl ether and ethanol (100 mL), finally with diethyl ether (3 x
250 mL) and air dried to give the product as a tan powder.
Step B: 4-Chloro-5,6-diiodo-thieno[2,3-d]pyrimidine
To a well stirred slurry of 180 g 5,6-diiodo-3H-thieno[2,3-d]pyrimidinone (445 mmol)
in 2.5 L phosphorous oxychloride was added 64 mL N,N-dimethylaniline. The reaction
mixture was heated to 105 °C and stirred for 1.5 hours. The resulting suspension was
cooled to room temperature and 1.5 L hexane was added and it was stirred further for 20
minutes. The precipitate was filtered off, washed with hexane (3 x 500 ml) and water (3 x
100 mL) then air dried to give the product as a grey crystalline solid.
H NMR (400 MHz, DMSO-d ): 8.88 (s, 1H).
Preparation 1c: 4-Chloroiodo-thieno[2,3-d]pyrimidine
52.8 g 4-chloro-5,6-diiodo-thieno[2,3-d]pyrimidine (Preparation 1b) (125 mmol) was
dissolved in 400 mL abs. THF and cooled to 0 °C. 100 ml BuMgCl (200 mmol, 2 M in
diethyl ether) was added over 15 minutes. 50 mL water was added then the solution was
decanted and concentrated under reduced pressure. The crude product was sonicated in a
mixture of acetonitrile and water (3:1) and then collected by filtration.
H NMR (400 MHz, DMSO-d ): 8.95 (s, 1H), 8.45 (s, 1H).
Preparation 1d: 4-Chloroethyliodo-thieno[2,3-d]pyrimidine
Step A: 6-Ethyl-3H-thieno[2,3-d]pyrimidinone
The mixture of 701 g 2-aminoethyl-thiophenecarboxylic acid ethyl ester (3.52 mol)
and 2200 mL formamide was heated to 200 °C and the lower boiling point solvents were
distilled off. After 2 hours further 250 mL formamide was added and the mixture was
stirred at the same temperature for another hour then at room temperature for 16 hours. The
resulting mixture was poured into 7.5 L water and the precipitate was filtered off, washed
with 1.5 L toluene and 3 L water then air dried to give the product as a brown crystalline
solid.
Step B: 6-Ethyliodo-3H-thieno[2,3-d]pyrimidinone
The mixture of 301 g 6-ethyl-3H-thieno[2,3-d]pyrimidinone, 847 g iodine, 1040 g silver
sulfate and 1.7 L ethanol was stirred at room temperature for 3 days. The resulting
precipitate was filtered off and washed with ethanol (3 x 400 ml). The product was eluted
from the filter cake with the following procedure: the filter cake was stirred with 800 mL
N,N-dimethylformamide at 50 °C for 1 hour then the suspension was filtered. This
sequence was repeated 6 times. The combined organic layer was evaporated to dryness to
give the product as a tan crystalline solid.
Step C: 4-Chloroethyliodo-thieno[2,3-d]pyrimidine
The mixture of stirred 880 ml phosphorous oxychloride and 102 mL N,N-dimethylaniline
was heated to 95 °C and 220 g 6-ethyliodo-3H-thieno[2,3-d]pyrimidinone (0.719
mol) was added quickly at the same temperature and then stirred for further 15 minutes.
The reaction mixture was cooled to 80 °C and poured on a stirred mixture of water (1 L),
crushed ice (2 kg) and DCM (700 ml). The resulting mixture was stirred for further 30
minutes while the temperature was kept below 20 °C. The phases were separated, the
inorganic layer was extracted with DCM (100 ml) and the organic layer was washed with
water (100 ml). The combined organic layer was dried with MgSO and concentrated
under reduced pressure to give the product as a tan crystalline solid.
H NMR (400 MHz, DMSO-d ): 8.79 (s, 1H), 3.02 (q, 2H), 1.39 (t, 3H).
Preparation 1e: 6-Bromochloroiodo-thieno[2,3-d]pyrimidine
Step A: 6-Bromo-3H-thieno[2,3-d]pyrimidinone
The mixture of 60.1 g 3H-thieno[2,3-d]pyrimidinone (0.395 mol), 605 mL acetic acid
and 24 mL bromine (0.468 mol) was stirred at room temperature for 16 hours. The reaction
mixture was monitored by LCMS. Further bromine was added in three portions (12 mL, 5
mL, 10 mL) until the conversion exceeded 95%. The precipitate was filtered off, washed
with acetic acid (3x50 mL), diethyl ether (3x100 mL) and then air dried to give the product
as a tan powder.
Step B: 6-Bromoiodo-3H-thieno[2,3-d]pyrimidinone
1 L cc. sulfuric acid was cooled with ice-water bath and 72.0 g potassium iodide (0.434
mol) was added in portions during 15 minutes and then 32.4 g sodium periodate (0.151
mol) during a 10 minutes period. The resulting mixture was stirred at room temperature for
minutes then 80.0 g 6-bromo-3H-thieno[2,3-d]pyrimidinone (0.346 mol) was added
to the mixture in portions in 30 minutes while the internal temperature was kept between -
21 °C and -19 °C. The reaction mixture was stirred at -20 °C for 1.5 hours. Ice (3 kg) was
added to the suspension then the precipitate was filtered off, washed with water (3x500
mL), finally with diethyl ether (3x200 mL) and air dried to give the product as a tan
crystalline solid.
Step C: 6-Bromochloroiodo-thieno[2,3-d]pyrimidine
To a well stirred slurry of 116 g 6-bromoiodo-3H-thieno[2,3-d]pyrimidinone (0.324
mol) in 910 mL phosphorous oxychloride 41 mL N,N-dimethylaniline was added. The
stirred reaction mixture was heated to 100 °C for 1.5 hours. The resulting suspension was
cooled to room temperature, hexane (1100 mL) was added and it was stirred for further 20
minutes. The precipitate was filtered off, washed with hexane (3x500 mL), water (3x100
mL) and diisopropyl ether (2x200 mL), finally air dried to give the Preparation 1e as a
green shaded powder.
H NMR (400 MHz, DMSO-d ): 8.95 (s, 1H)
Preparation 2a: 5-Bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine
75.08 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (200 mmol),
53.63 g 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mmol), 130 g
cesium carbonate (400 mmol), 2.245 g Pd(OAc) (10 mmol) and 8.50 g BuX-Phos (20
mmol) were placed in a 2 L flask. 600 mL THF and 200 mL water were added, and then
stirred overnight at 70°C under argon atmosphere. THF was evaporated, and then the
product was collected by filtration. Crude product was sonicated in 250 mL acetonitrile
and filtered again. Then Preparation 2a was crystalized from EtOH / THF (2:1).
H NMR (400 MHz, DMSO-d ): 9.02 (s, 1H), 7.80-7.77 (m, 2H), 7.47-7.43 (m, 2H).
Preparation 2b: 5-Bromochloro(5-fluorofuryl)thieno[2,3-d]pyrimidine
112.6 g (300 mmol) 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a),
254.4 g (1200 mmol) 2-(5-fluorofuryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 195.5 g
(600 mmol) cesium carbonate, 3.36 g (15 mmol) Pd(OAc) , 12.74 g (30 mmol) BuX-Phos
were placed in a 2 L flask. 1000 mL THF and 400 mL water were added, and then stirred
overnight at 70°C under argon atmosphere. THF was evaporated, and then the product was
collected by filtration. Crude product was dissolved in THF, and then celite was added and
the volatiles were evaporated under reduced pressure. The solid residue was purified by
flash chromatography on silica gel using heptane / EtOAc as eluents.
H NMR (400 MHz, DMSO-d ): 8.95 (s, 1H), 7.55 (t, 1H), 6.23 (dd, 1H).
Preparation 2c: 5-Bromochloro(2-furyl)thieno[2,3-d]pyrimidine
112.6 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (300 mmol),
93.14 g 2-(2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (480 mmol), 215.0 g cesium
carbonate (660 mmol), 3.367 g Pd(OAc)2 (15 mmol) and 12.74 g BuX-Phos (20 mmol)
were placed in a 2 L flask. 1000 mL THF and 300 mL water were added, and then stirred
for 7 hours at 70°C under argon atmosphere. THF was evaporated, and then the product
was collected by filtration. Crude product was sonicated in 250 mL acetonitrile and filtered
again. Then Preparation 2c was crystalized from EtOH / THF (2:1).
H NMR (400 MHz, DMSO-d ): 8.96 (s, 1H), 8.05 (dd, 1H), 7.59 (dd, 1H), 6.86 (dd, 1H).
Preparation 2d: 5-Bromochloro(5-chlorofuryl)thieno[2,3-d]pyrimidine
33.29 g 5-bromochloro(2-furyl)thieno[2,3-d]pyrimidine (Preparation 2c) (105.7
mmol) and 16.90 g NCS (126.6 mmol) were placed in a 1 L flask. 400 mL THF and 20 mL
TFA were added, and the stirred for 2 hours at room temperature. Reaction mixture was
washed with saturated NaHCO . The organic phas was dried over MgSO , filtered and
concentrated to give Preparation 2d.
H NMR (400 MHz, CDCl ): 8.84 (s, 1H), 7.52 (d, 1H), 6.45 (d, 1H).
Preparation 2e: 5-Bromochloro(4-fluoromethoxy-phenyl)thieno[2,3-d]
pyrimidine
.01 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (40 mmol),
12.10 g 2-(4-fluoromethoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44
mmol), 32.58 g cesium carbonate (100 mmol), 1.463 g Pd(dppf)Cl (2 mmol) were placed
in an 1 L flask. 150 mL THF and 150 mL water were added, and then stirred overnight at
70°C under argon atmosphere. To the reaction mixture brine was added and the pH was set
to 6 with 2 M HCl, and then extracted with DCM. The volatiles from the organic phase
were evaporated under reduced pressure and the crude product was purified by flash
chromatography on silica gel using heptane / DCM as eluents.
H NMR (400 MHz, DMSO-d ): 8.94 (s, 1H), 7.42 (dd, 1H), 7.36 (dd, 1H), 7.24-7.20 (m,
1H), 3.90 (s, 3H).
Preparation 2f: 4-Chloroiodo(propynyl)-thieno[2,3-d]pyrimidine
42.24 g 4-chloro-5,6-diiodo-thieno[2,3-d]pyrimidine (Preparation 1b) (100 mmol), 3.509
g Pd(PPh ) Cl (5 mmol) and 1.904 g CuI (10 mmol) were dissolved in 400 mL DIPA, then
propyne was bubbled through the reaction mixture, which was stirred for 6 hours at room
temperature. After full conversion the volatiles were evaporated under reduced pressure
and the crude product was purified by flash chromatography on silica gel using heptane /
EtOAc as eluents.
H NMR (400 MHz, DMSO-d ): 8.92 (s, 1H), 2.25 (s, 3H).
Preparation 2g: 5-Bromochloro(3,4-difluorophenyl)thieno[2,3-d]pyrimidine
9.39 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (25 mmol),
9.00 g 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.5 mmol), 16.29
g cesium carbonate (50 mmol), 912 mg Pd(dppf)Cl (1.25 mmol) were placed in a 250 mL
flask. 100 mL THF and 50 mL water were added, and then stirred for 2 hours at 70°C
under argon atmosphere. THF was evaporated, and then it was extracted with EtOAc. The
organic layer was dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via flash chromatography using DCM and MeOH as
eluents.
H NMR (400 MHz, DMSO-d ): 9.06 (s, 1H), 7.91 (m, 1H), 7.71 (m, 1H), 7.60 (m, 1H).
Preparation 2h: 5-Bromochloro(2,3-difluorophenyl)thieno[2,3-d]pyrimidine
9.39 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (25 mmol),
9.00 g 2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.5 mmol), 16.29
g cesium carbonate (50 mmol), 912 mg Pd(dppf)Cl (1.25 mmol) were placed in a 250 mL
flask. 100 mL THF and 50 mL water were added, and then stirred for 2 hours at 70°C
under argon atmosphere. THF was evaporated, and then it was extracted with EtOAc. The
organic layer was dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via flash chromatography using DCM and MeOH as
eluents to obtain Preparation 2h.
HRMS calculated for C H BrClF N S: 359.8935, found: 360.9013 (M+H).
12 4 2 2
Preparation 2i: 5-Bromochloro[4-(methoxymethoxy)phenyl]thieno[2,3-d]
pyrimidine
.904 g (42.4 mmol) 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation
1a), 16.784 g (63.5 mmol) 2-(4-methoxymethoxy-phenyl)-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane, 1.798 g (4.2 mmol) BuXPhos, 473 mg (2.1 mmol) Pd(OAc) and
41.365 g (127 mmol) Cs2CO3 were dissolved in 200 mL THF and 200 mL H2O. The
mixture was stirred at 70°C under N until no further conversion was observed. It was
diluted with brine, the pH was set to 7 with 2 M HCl, and then it was extracted with DCM.
The combined organic layers were dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to obtain Preparation 2i.
MS: (M+H) = 385.0, 387.0.
Unless otherwise specified, most of the compounds of Preparation 3aa to 3br were
obtained using General Procedures 3A, 3B or 3C described below.
General Procedure 3A:
Step A:
1.0 eq. ethyl (2R)acetoxy(2-hydroxyphenyl)propanoate (Preparation 3aa-(R)), 2.0
eq. of the appropriate alcohol and 2.0 eq. triphenylphosphine were dissolved in dry toluene
(0.2 M for the phenol), then 2.0 eq. di-tert-butyl azodicarboxylate was added. The mixture
was stirred at 50°C under nitrogen. After reaching an appropriate conversion the volatiles
were removed under reduced pressure, the crude intermediate was purified via flash
chromatography using heptane / EtOAc as eluents.
Step B:
The obtained intermediate was dissolved in ethanol (0.5 M for the Step A product) then
sodium ethoxide solution (1.0 M in ethanol) was added (2-5 mol%). The resulting mixture
was stirred at room temperature. Additional sodium ethoxide solution was added if
conversion was not complete. The mixture was concentrated to half of its volume, then
water and brine was added, and it was extracted with ethyl acetate. The combined organics
were dried over Na SO , filtered and evaporated under reduced pressure then it was
purified via flash chromatography using heptane / EtOAc as eluents or other solvents, if
indicated.
General Procedure 3B: (Tetrahedron Lett. 1994, 35, 5205-5208.)
Step A:
To a stirred mixture of 1.0 eq. of the appropriate carbaldehyde and 1.25 eq. ethyl
chloroacetate in THF (1.0 M for the carbaldehyde) at -78°C 1.25 eq. sodium
bis(trimethylsilyl-amide) solution (1.0 M in THF) was added dropwise. After addition
temperature was allowed to reach room temperature. When the reaction reached an
appropriate conversion to the oxirane the mixture was quenched with saturated NH Cl, the
layers were separated, the aqueous layer was extracted with Et2O, the combined organics
were dried over Na SO filtered and concentrated.
Step B:
The crude oxirane was dissolved in THF or EtOAc (1.0 M) and transferred to a
hydrogenating vessel, 5 mol% of Pd(OH) was added and the mixture was hydrogenated at
3-4.5 bars of hydrogen pressure. In case of a low conversion glacial acetic acid and
Pd(OH) were added to the mixture and hydrogenation was continued. When the
appropriate reduction occurred, the mixture was filtered through a pad of celite, the filtrate
was concentrated under reduced pressure and purified via flash chromatography using
heptane / EtOAc as eluents (or other solvents, if indicated).
General Procedure 3C:
Step A:
To a stirred mixture of water / tert-butanol (1:1, 0.2 M for the cinnamate derivative), 1.0
eq. methane sulfonamide, 1 g/mmol AD-mix-α and 1.0 eq. cinnamate derivative were
added at room temperature. The mixture was stirred at room temperature until no further
conversion was observed, and then the mixture was cooled to 0-5 °C and 2.5 eq. sodium
metabisulfite was added in small portions, then stirring was continued for 30 minutes at
room temperature. The mixture was diluted with water and extracted with ethyl acetate.
The combined organic layers were dried over Na SO , filtered and evaporated under
reduced pressure. The residue was purified via flash chromatography using DCM /
methanol as eluents to obtain the appropriate dihydroxy compound.
Step B:
The solution of the dihydroxy compound in dichloromethane / trifluoroacetic anhydride
(4:1, 0.25 M) was stirred at room temperature for 1 hour. The mixture was concentrated
under reduced pressure, and the residue was dissolved in methanol (~ 0.25 M), 5 mol%
Pd/C (10 m/m%) was added, and then it was stirred overnight at room temperature under
atmospheric hydrogen pressure. The reaction mixture was filtered through a pad of celite
and purified via flash chromatography using hexane / chloroform as eluents or other
solvents, if indicated.
Preparation 3aa-(rac): Ethyl 2-acetoxy(2-hydroxyphenyl)propanoate
Step A: [2-(Bromomethyl)phenyl]acetate
60.07 g 2-methylphenyl acetate (400 mmol) and 106.8 g NBS (600 mmol) were placed in a
1 L flask. 500 mL cyclohexane was added, and then with intensive stirring 3.284 g AIBN
(20 mmol) was added over 30 min. The mixture was stirred at 80°C until no further
conversion was observed, then cooled to room temperature. The precipitate was filtered off
and washed with cyclohexane. The mother liquor was concentrated under reduced
pressure, and the crude product was used in Step B without further purification.
Step B: Ethyl 2-acetoxy(2-hydroxyphenyl)propanoate
23.10 g anhydrous LiCl (545 mmol) and 65.36 g anhydrous ZnCl (479.6 mmol) were
placed in a 2 L flask, then dried at 160°C under 0.1 Hgmm for 1 hour. After cooling to
room temperature under argon atmosphere, 26.49 g magnesium turnings (1090 mmol) and
1 L dry pre-cooled (0°C) THF were added. The resulting mixture was immersed into an
ice-bath, and then stirred for 30 min.
100 g [2-(bromomethyl)phenyl] acetate -crude product from Step A- (~ 436 mmol) was
dissolved in 120 mL dry THF and was added to the precooled inorganics over 15 min.
After addition of the reagent the resulting mixture was stirred for 45 min while keeping the
temperature between 0-5°C. To the mixture 64.82 mL ethyl 2-oxoacetate (654 mmol, 50%
in toluene) was added over 5 mins and the resulting mixture was stirred for another 15
mins.
From the mixture the remaining inorganics were removed by filtration, and then 500 mL
MeOH was added to the filtrate. This mixture was stirred until the intramolecular acetyl
group migration from the phenolic oxygen to the alkyl oxygen was completed. To the
mixture 30 mL acetic acid was added then the volatiles were evaporated under reduced
pressure. To the residue 350 mL water was added and it was extracted with EtOAc. The
combined organic layers were washed with saturated NaHCO and with brine, and then
dried over MgSO , filtered and evaporated under reduced pressure. To the residue 100 mL
hexane was added and it was stirred for 30 mins at 0°C. The formed white crystals were
collected by filtration and washed with hexane yielding Preparation 3aa-(rac).
H NMR (500 MHz, DMSO-d ) δ 9.53 (s, 1H), 7.06 (t, 1H), 7.04 (d, 1H), 6.79 (d, 1H),
6.71 (t, 1H), 5.10 (dd, 1H), 4.05 (q, 2H), 3.06 (dd, 1H), 2.94 (dd, 1H), 2.00 (s, 3H), 1.09 (t,
3H).
Preparation 3aa-(S): Ethyl (2S)acetoxy(2-hydroxyphenyl)propanoate
and
Preparation 3aa-(R): Ethyl (2R)acetoxy(2-hydroxyphenyl)propanoate
Enantiomers of Preparation 3aa-(rac) were separated via chiral chromatography.
Column: OD; Eluents: heptane / EtOH; the enantiomer eluting earlier was collected as
Preparation 3aa-(S) with 99.8% ee and the enantiomer eluting later was collected as
Preparation 3aa-(R) with 99.9% ee.
Preparation 3ab-(R): Ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)
propanoate
Step A: Ethyl (2R)acetoxy(2-tetrahydropyranyloxyphenyl)propanoate
103.3 g ethyl (2R)acetoxy(2-hydroxyphenyl)propanoate (Preparation 3aa-(R)) (409
mmol) was dissolved in 280 mL 3,4-dihydro-2H-pyran. 300 mg para-toluenesulfonic acid
monohydrate was added and the mixture was stirred until no further conversion was
observed. Then it was diluted with 1 L ethyl acetate, washed with 200 mL saturated
NaHCO solution, then with 200 mL water. Combined organic layers were dried over
Na SO , filtered and concentrated. Then it was purified via flash chromatography using
heptane / EtOAc.
Step B: Ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
137.57 g ethyl (2R)acetoxy(2-tetrahydropyranyloxyphenyl)propanoate (409
mmol) was dissolved in 600 mL ethanol, then 20 mL sodium ethoxide solution (1.0 M in
ethanol) was added and it was stirred until no further conversion was observed. The
mixture was concentrated to half of its volume, then 300 mL water and 300 mL brine was
added, and it was extracted with ethyl acetate. The combined organics were dried over
sodium sulfate, filtered and concentrated. The enantiopurity of the starting material was
conserved.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers) δ 7.16 (t, 1H), 7.13 (d, 1H),
7.04 (d, 1H), 6.87 (t, 1H), 5.51/5.47 (m, 1H), 4.27 (m, 1H), 4.04/4.02 (q, 2H), 3.73/3.56
(m, 2H), 3.06/3.04/2.74/2.71 (dd, 2H), 1.95/1.64 (m, 2H), 1.79 (m, 2H), 1.65/1.50 (m, 2H),
1.12/1.10 (t, 3H).
Preparation 3ab-(S): Ethyl (2S)hydroxy(2-tetrahydropyranyloxyphenyl)
propanoate
Step A: Ethyl (2S)acetoxy(2-tetrahydropyranyloxyphenyl)propanoate
103.3 g ethyl (2S)acetoxy(2-hydroxyphenyl)propanoate (Preparation 3aa-(S)) (409
mmol) was dissolved in 280 mL 3,4-dihydro-2H-pyran. 300 mg para-toluenesulfonic acid
monohydrate was added and the mixture was stirred until no further conversion was
observed. Then it was diluted with 1 L ethyl acetate, washed with 200 mL saturated
NaHCO solution, then with 200 mL water. Combined organic layers were dried over
Na SO , filtered and concentrated. Then it was purified via flash chromatography using
heptane / EtOAc.
Step B: Ethyl (2S)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
137.57 g ethyl (2S)acetoxy(2-tetrahydropyranyloxyphenyl)propanoate (409 mmol)
was dissolved in 600 mL ethanol, then 20 mL sodium ethoxide solution (1.0 M in ethanol)
was added and it was stirred until no further conversion was observed. The mixture was
concentrated to half of its volume, then 300 mL water and 300 mL brine was added, and it
was extracted with ethyl acetate. The combined organics were dried over sodium sulfate,
filtered and concentrated. The enantiopurity of the starting material was conserved.
HRMS calculated for C H O : 294.1467, found: 317.1349 and 317.1343 (M+Na).
16 22 5
Preparation 3ac: Ethyl (2R)hydroxy[2-(pyrazinylmethoxy)phenyl]propanoate
Using General Procedure 3A and pyrazinylmethanol as the appropriate alcohol
Preparation 3ac was obtained. The product was purified by column chromatography
using DCM / methanol.
H NMR (400 MHz, DMSO-d6,) δ 8.88 (s, 1H), 8.64 (dd, 2H), 7.22-7.16 (m, 2H), 7.06 (d,
1H), 6.89 (t, 1H), 5.46 (d, 1H), 5.27 (dd, 2H), 4.29 (dq, 1H), 4.00 (q, 2H), 3.09 (dd, 1H),
2.79 (dd, 1H), 1.08 (t, 3H).
Preparation 3ad: Ethyl (2R)hydroxy(2-methoxyphenyl)propanoate
Preparation 3bi: Ethyl (2S)hydroxy(2-methoxyphenyl)propanoate
Using General Procedure 3B and 2-methoxy-benzaldehyde as the appropriate carbaldehyde
the lactic ester was obtained in racemic form.
H NMR (400 MHz, CDCl ) δ 7.23 (dt, 1H), 7.12 (dd, 1H), 6.89-6.84 (m, 2H), 5.26 (dd,
1H), 4.14 (dq, 2H), 3.24 (dd, 1H), 3.03 (dd, 1H), 2.04 (s, 3H), 1.19 (t, 3H).
Enantiomers were separated via chiral chromatography; Column: AD, Eluent: 2-PrOH; the
enantiomer eluting earlier was collected as Preparation 3ad with 99.8% ee and the
enantiomer eluting earlier was collected as Preparation 3bi with 97.8% ee.
Preparation 3ae: Ethyl (2R)hydroxy[2-[(4-methoxyphenyl)methoxy]phenyl]
propanoate
Using General Procedure 3A and (4-methoxyphenyl)methanol as the appropriate alcohol
Preparation 3ae was obtained.
H NMR (400 MHz, CDCl ) δ 7.38 (d, 2H), 7.21 (dt, 1H), 7.15 (dd, 1H), 6.92-6.88 (m,
4H), 5.29 (dd, 1H), 5.05 (d, 1H), 5.01 (d, 1H), 4.12 (dq, 2H), 3.31 (dd, 1H), 3.04 (dd, 1H),
2.02 (s, 3H), 1.16 (t, 3H).
Preparation 3af: Ethyl (2R)hydroxy[2-[[(2S)-tetrahydrofuranyl]methoxy]
phenyl]propanoate
Preparation 3bj: Ethyl (2R)hydroxy[2-[[(2R)-tetrahydrofuranyl]methoxy]
phenyl]propanoate
Using General Procedure 3A and tetrahydrofuranylmethanol as the appropriate alcohol
diastereoisomer mixture of the lactic esters were obtained. Diastereoisomers were
separated by chiral chromatography. Column: IC, Eluents: heptane / EtOH; the
diastereoisomer eluting earlier was collected as Preparation 3af with 99.6% de.
H NMR (400 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 6.92 (dt, 1H), 6.87 (d, 1H), 4.46-4.41
(m, 1H), 4.35-4.29 (m, 1H), 4.20 (dq, 2H), 4.04 (dd, 1H), 3.99-3.93 (m, 2H), 3.88-3.82 (m,
1H), 3.32 (d, 1H), 3.17 (dd, 1H), 3.00 (dd, 1H), 2.14-2.05 (m, 1H), 2.03-1.90 (m, 2H),
1.85-1.76 (m, 1H), 1.25 (t, 3H).
The diastereoisomer eluting later was collected as Preparation 3bj with 99.5% de.
H NMR (400 MHz, CDCl3) δ 7.23-7.15 (m, 2H), 6.91 (dt, 1H), 6.86 (d, 1H), 4.48-4.44
(m, 1H), 4.33-4.27 (m, 1H), 4.18 (dq, 2H), 4.06-3.97 (m, 3H), 3.87-3.82 (m, 1H), 3.35 (d,
1H), 3.18 (dd, 1H), 3.00 (dd, 1H), 2.14-2.05 (m, 1H), 2.04-1.92 (m, 2H), 1.90-1.82 (m,
1H), 1.24 (t, 3H).
Preparation 3ag: Methyl (2R)hydroxyphenyl-propanoate
1.66 g (2R)hydroxyphenyl-propanoic acid (10 mmol) was dissolved in 30 mL dry
methanol and stirred at in presence of catalytic amount of concentrated sulfuric acid until
no further conversion was observed. Reaction mixture was concentrated under reduced
pressure, to the residue 50 mL EtOAc was added and washed with saturated NaHCO and
with brine. Organic phase was dried over MgSO , filtered and evaporated under reduced
pressure to yield Preparation 3ag.
H NMR (400 MHz, CDCl ) δ 7.33-7.21 (m, 5H), 4.46 (q, 1H), 3.78 (s, 3H), 3.14 (dd, 1H),
2.98 (dd, 1H), 2.77 (d, 1H).
Preparation 3ah: Ethyl (2R)hydroxy[2-[(2-methoxypyrimidinyl)methoxy]
phenyl]propanoate
Using General Procedure 3A and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol Preparation 3ah was obtained.
H NMR (400 MHz, CDCl3) δ 8.64 (d, 1H), 7.29 (d, 1H), 7.21-7.17 (m, 2H), 6.98 (d, 1H),
6.89 (dt, 1H), 5.52 (d, 1H), 5.17 (d, 1H), 5.13 (d, 1H), 4.34-4.30 (m, 1H), 4.04 (dq, 2H),
3.92 (s, 3H), 3.11 (dd, 1H), 2.83 (dd, 1H), 1.10 (t, 3H).
Preparation 3ai: Methyl (2R)hydroxy[2-(trifluoromethoxy)phenyl]propanoate
Using General Procedure 3C and methyl (2E)[2-(trifluoromethoxy)phenyl]prop
enoate as the appropriate cinnamic acid derivative Preparation 3ai was obtained with
99.4% ee.
H NMR (400 MHz, CDCl ) δ 7.41-7.33 (m, 1H), 7.34-7.16 (m, 3H), 4.46 (ddd, 1H), 3.80
(s, 3H), 3.22 (dd, 1H), 3.03 (dd, 1H), 2.75 (d, 1H).
Preparation 3aj: Methyl (2R)[2-(difluoromethoxy)phenyl]hydroxy-propanoate
Using General Procedure 3C and methyl (2E)[2-(difluoromethoxy)phenyl]prop
enoate as the appropriate cinnamic acid derivative Preparation 3aj was obtained with
99.9% ee.
H NMR (500 MHz, CDCl ) δ 7.31 (dd, 1H), 7.29-7.24 (m, 1H), 7.21-7.15 (m, 1H), 7.11
(d, 1H), 6.53 (t, 1H), 4.46 (dd, 1H), 3.80 (s, 3H), 3.21 (dd, 1H), 3.03 (dd, 1H), 2.68 (br s,
1H).
Preparation 3ak: Methyl (2R)(3-fluorophenyl)hydroxy-propanoate
Using General Procedure 3C and methyl (2E)(3-fluorophenyl)propenoate as the
appropriate cinnamic acid derivative Preparation 3ak was obtained with 98.6% ee.
H NMR (500 MHz, CDCl ) δ 7.27-7.24 (m, 1H), 7.00 (d, 1H), 6.97-6.92 (m, 2H), 4.46
(dd, 1H), 3.79 (s, 3H), 3.13 (dd, 1H), 2.96 (dd, 1H), 2.64 (br s, 1H).
Preparation 3al: Methyl (2R)hydroxy(3-methoxyphenyl)propanoate
Using General Procedure 3C and methyl (2E)(3-methoxyphenyl)propenoate as the
appropriate cinnamic acid derivative Preparation 3al was obtained with 97.3% ee.
H NMR (500 MHz, CDCl ) δ 7.23 (t, 1H), 6.83-6.77 (m, 3H), 4.48 (dd, 1H), 3.81 (s, 3H),
3.80 (s, 3H), 3.12 (dd, 1H), 2.96 (dd, 1H), 2.33 (br s, 1H).
Preparation 3am: Methyl (2R)(2,3-difluorophenyl)hydroxy-propanoate
Using General Procedure 3C and methyl (2E)(2,3-difluorophenyl)propenoate as the
appropriate cinnamic acid derivative Preparation 3am was obtained with 96.9% ee.
H NMR (500 MHz, CDCl ) δ 7.19-6.93 (m, 3H), 4.48 (dd, 1H), 3.82 (s, 3H), 3.20 (dd,
1H), 3.06 (dd, 1H), 2.73 (br s, 1H).
Preparation 3an: Methyl (2R)hydroxy[2-(trifluoromethyl)phenyl]propanoate
Using General Procedure 3C and methyl (2E)[2-(trifluoromethyl)phenyl]propenoate
as the appropriate cinnamic acid derivative Preparation 3an was obtained with 99.6% ee.
H NMR (500 MHz, CDCl ) δ 7.67 (d, 1H), 7.53-7.47 (m, 2H), 7.37 (t, 1H), 4.43 (dd, 1H),
3.81 (s, 3H), 3.40 (dd, 1H), 3.01 (dd, 1H), 2.70 (br s, 1H).
Preparation 3ao: Methyl (2R)hydroxy(o-tolyl)propanoate
Using General Procedure 3C and methyl (2E)(o-tolyl)propenoate as the appropriate
cinnamic acid derivative Preparation 3ao was obtained with 99.3% ee.
H NMR (500 MHz, CDCl ) δ 7.20-7.14 (m, 4H), 4.44 (dd, 1H), 3.80 (s, 3H), 3.18 (dd,
1H), 2.95 (dd, 1H), 2.59 (br s, 1H), 2.37 (s, 3H).
Preparation 3ap: Methyl (2R)hydroxy(m-tolyl)propanoate
Using General Procedure 3C and methyl (2E)(m-tolyl)propenoate as the appropriate
cinnamic acid derivative Preparation 3ap was obtained with 96.7% ee.
H NMR (500 MHz, CDCl ) δ 7.20 (t, 1H), 7.07 (d, 1H), 7.05 (s, 1H), 7.02 (d, 1H), 4.46
(dd, 1H), 3.79 (s, 3H), 3.11 (dd, 1H), 2.94 (dd, 1H), 2.54 (br s, 1H), 2.35 (s, 3H).
Preparation 3aq: Ethyl (2R)(3-fluoromethoxy-phenyl)hydroxy-propanoate
Using General Procedure 3C and ethyl (2E)(3-fluoromethoxy-phenyl)propenoate
as the appropriate cinnamic acid derivative Preparation 3aq was obtained with 99.9% ee.
H NMR (400 MHz, CDCl ) δ 7.04-6.03 (m, 3H), 4.44 (q, 1H), 4.23 (dq, 2H), 3.96 (d, 3H),
3.17 (dd, 1H), 3.02 (dd, 1H), 1.27 (t, 3H).
Preparation 3ar: Ethyl (2R)(5-fluoromethoxy-phenyl)hydroxy-propanoate
Using General Procedure 3C and ethyl (2E)(5-fluoromethoxy-phenyl)propenoate
as the appropriate cinnamic acid derivative Preparation 3ar was obtained with 99.9% ee.
H NMR (400 MHz, CDCl ) δ 6.95-6.90 (m, 2H), 6.81-6.78 (m, 1H), 4.47 (q, 1H), 4.22
(dq, 2H), 3.83 (s, 3H), 3.14 (dd, 1H), 2.97 (dd, 1H), 1.28 (t, 3H).
Preparation 3as: Ethyl (2R)(4-fluoromethoxy-phenyl)hydroxy-propanoate
Using General Procedure 3C and ethyl (2E)(4-fluoromethoxy-phenyl)propenoate
as the appropriate cinnamic acid derivative Preparation 3as was obtained with 99.9% ee.
H NMR (500 MHz, CDCl3) δ 7.10 (t, 1H), 6.61-6.57 (m, 2H), 4.42 (q, 1H), 4.19 (dq, 2H),
3.82 (s, 3H), 3.07 (dd, 1H), 2.96 (dd, 1H), 2.80 (d, 1H), 1.25 (t, 3H).
Preparation 3at: Ethyl (2R)hydroxy(2-methoxymethyl-phenyl)propanoate
Using General Procedure 3C and ethyl (2E)(2-methoxymethyl-phenyl)propenoate
as the appropriate cinnamic acid derivative Preparation 3at was obtained with 99.9% ee.
H NMR (400 MHz, CDCl ) δ 7.04 (dd, 1H), 6.99 (d, 1H), 6.78 (d, 1H), 4.47 (dd, 1H),
4.21 (dq, 2H), 3.79 (s, 3H), 3.14 (dd, 1H), 2.98 (dd, 1H), 2.28 (s, 3H), 1.27 (t, 3H).
Preparation 3au: Ethyl (2R)hydroxy(2-methoxymethyl-phenyl)propanoate
Using General Procedure 3C and ethyl (2E)(2-methoxymethyl-phenyl)propenoate
as the appropriate cinnamic acid derivative Preparation 3au was obtained with 99.8% ee.
H NMR (500 MHz, CDCl ) δ 7.10-7.03 (m, 2H), 6.97 (t, 1H), 4.45 (q, 1H), 4.21 (dq, 2H),
3.26 (s, 3H), 3.16 (dd, 1H), 3.01 (d, 1H), 2.31 (s, 3H), 1.25 (t, 3H).
Preparation 3av: Ethyl (2R)[2-(tert-butoxycarbonylamino)phenyl]hydroxy-
propanoate
Using General Procedure 3C and ethyl (2E)[2-(tert-butoxycarbonylamino)phenyl]prop-
2-enoate as the appropriate cinnamic acid derivative Preparation 3av was obtained with
99.8% ee.
H NMR (500 MHz, CDCl ) δ 7.92 (br s, 1H), 7.75 (d, 1H), 7.24 (t, 1H), 7.10 (d, 1H), 7.01
(t, 1H), 4.51 (q, 1H), 4.27 (q, 2H), 3.34 (br s, 1H), 3.25 (dd, 1H), 3.01 (dd, 1H), 1.52 (s,
9H), 1.35 (t, 3H).
Preparation 3aw: Ethyl (2R)[2-[(tert-butoxycarbonylamino)methyl]phenyl]
hydroxy-propanoate
Using General Procedure 3C and ethyl (2E)[2-[(tert-butoxycarbonylamino)methyl]
phenyl]propenoate as the appropriate cinnamic acid derivative Preparation 3aw was
obtained with 98.8% ee.
H NMR (500 MHz, CDCl ) δ 7.34 (m, 1H), 5.63 (br s, 1H), 4.44-4.35 (m, 3H), 4.26 (q,
2H), 3.21 (dd, 1H), 3.10 (dd, 1H), 1.45 (s, 9H), 1.32 (t, 3H).
Preparation 3ax: Ethyl (2S)hydroxy[2-(2,2,2-trifluoroethylsulfanyl)phenyl]
propanoate
Preparation 3ay: Ethyl (2R)hydroxy[2-(2,2,2-trifluoroethylsulfanyl)phenyl]
propanoate
Step A: 1-Methyl(2,2,2-trifluoroethylsulfanyl)benzene
To a solution of 2.357 mL 2-methylbenzenethiol (20 mmol) in 30 mL dry DMF, 8.292 g
potassium carbonate (40 mmol) was added. After 5 min stirring 3.168 mL 2,2,2-
trifluoroethyl trifluoromethanesulfonate (28 mmol) was added over 5 mins. The resulting
mixture was stirred until no further conversion was observed. Brine was added and the
mixture was extracted with ethyl acetate. The combined organic layers were dried over
MgSO , filtered and evaporated under reduced pressure. The residue was purified via flash
chromatography using heptane / EtOAc as eluents.
H NMR (400 MHz, CDCl ) δ 7.48 (dd, 1H), 7.24-7.13 (m, 3H), 3.40 (q, 2H), 2.48 (s, 3H).
Step B: 1-(Bromomethyl)(2,2,2-trifluoroethylsulfanyl)benzene
3.100 g 1-methyl(2,2,2-trifluoroethylsulfanyl)benzene (15 mmol) and 4.005 g NBS
(22.50 mmol) were placed in a 25 mL flask. 10 mL CCl was added, and then 49.2 mg
AIBN was added over 5 mins. Mixture was stirred at 80°C overnight, then cooled to room
temperature; the precipitate was filtered off and washed with hexane. The mother liquor
was concentrated, and used in the next step without further purification.
Step C: Ethyl (2R)hydroxy[2-(2,2,2-trifluoroethylsulfanyl)phenyl]propanoate
632 mg anhydrous LiCl (14.90 mmol) and 1.787 g anhydrous ZnCl2 (13.11 mmol) were
placed in a 250 mL flask, then dried at 160°C under 0.1 Hgmm for 1 hour. After cooling to
room temperature under argon atmosphere 725 mg magnesium turnings (29.81 mmol) and
80 mL dry, pre-cooled (0°C) THF were added. The resulting mixture was immersed into an
ice-bath, and then 3.400 g 1-(bromomethyl)(2,2,2-trifluoroethylsulfanyl)benzene (~
11.92 mmol, from Step B) dissolved in 20 mL dry THF and was added to the pre-cooled
inorganics over 10 min. The reaction mixture was stirred for 45 min between 0-5°C. To the
prepared zinc organic compound 3.546 mL ethyl 2-oxoacetate (3.652 mmol, 50% in
toluene) was added over 5 min and further was stirred for 15 min. From the mixture the
remained inorganics were removed by filtration, and after addition of saturated NH Cl the
mixture was extracted with ethyl acetate. The combined organic phase was dried over
Mg SO , filtered and evaporated under reduced pressure. The residue was purified via
flash chromatography using heptane / ethyl acetate as eluents giving the appropriate lactic
ester in racemic form.
H NMR (400 MHz, CDCl ) δ 7.59 (dd, 1H), 7.33-7.23 (m, 3H), 4.48-4.43 (m, 1H), 4.29-
4.22 (m, 2H), 3.46-3.39 (m, 3H), 3.21 (dd, 1H), 2.78 (d, 1H), 1.29 (t, 1H).
Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane /
2-PrOH; the enantiomer eluting earlier was collected as Preparation 3ax with 99.6% ee
and the enantiomer eluting later was collected as Preparation 3ay with 99.5% ee.
Preparation 3az: Ethyl (2S)(2-fluorophenyl)hydroxy-propanoate
Preparation 3ba: Ethyl (2R)(2-fluorophenyl)hydroxy-propanoate
Using General Procedure 3B and 2-fluorobenzaldehyde as the appropriate carbaldehyde
lactic ester was obtained in racemic form.
H NMR (400 MHz, DMSO) δ 7.34-7.22 (m, 2H), 7.16-7.07 (m, 2H), 5.60 (d, 1H), 4.23
(dd, 1H), 4.05 (q, 2H), 2.99 (dd, 1H), 2.86 (dd, 1H), 1.12 (t, 3H).
Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane /
2-BuOH; the enantiomer eluting earlier was collected as Preparation 3az with 99.8% ee
and the enantiomer eluting later was collected as Preparation 3ba with 99.4% ee.
Preparation 3bb: Ethyl 3-(benzofuranyl)hydroxy-propanoate
Using General Procedure 3B and benzofurancarbaldehyde as the appropriate
carbaldehyde Preparation 3bb was obtained. Upon reduction the saturation of the furan
moiety was also observed, thus hydrogenolysis was stopped at the point, when the desired
product was present with the highest concentration in the mixture. The product was
purified via flash chromatography using DCM / EtOAc as eluents.
H NMR (500 MHz, DMSO) δ 7.98 (d, 1H), 7.51 (m, 1H), 7.16 (m, 2H), 6.94 (d, 1H), 5.63
(d, 1H), 4.40 (dd, 1H), 4.02 (q, 2H), 3.25 (dd, 1H), 3.09 (dd, 1H), 1.07 (t, 3H).
Preparation 3bc: Ethyl 3-(benzofuranyl)hydroxy-propanoate
Using General Procedure 3B and benzofurancarbaldehyde as the appropriate
carbaldehyde Preparation 3bc was obtained.
H NMR (400 MHz, CDCl ) δ 7.62 (d, 1H), 7.41 (d, 1H), 7.23 (t, 1H), 7.10 (d, 1H), 6.85
(dd, 1H), 4.53 (dd, 1H), 4.24-4.12 (m, 2H), 3.37 (dd, 1H), 3.21 (dd, 1H), 2.80 (bs, 1H),
1.24 (t, 3H).
Preparation 3bd: Ethyl (2R)(2,3-dihydrobenzofuranyl)hydroxy-propanoate
Preparation 3be: Ethyl (2S)(2,3-dihydrobenzofuranyl)hydroxy-propanoate
Using General Procedure 3B and benzofurancarbaldehyde as the appropriate
carbaldehyde and applying longer reaction time in Step B, the partially saturated lactic
ester was obtained as the main product in racemic form, which was purified via flash
chromatography using DCM / EtOAc as eluents.
H NMR (500 MHz, DMSO) δ 7.07 (m, 1H), 6.92 (m, 1H), 6.72 (t, 1H), 5.49 (d, 1H), 4.50
(m, 2H), 4.23 (m, 1H), 4.04 (q, 2H), 3.15 (t, 2H), 2.88 (dd, 1H), 2.71 (dd, 1H), 1.12 (t, 3H).
Enantiomers were separated via chiral chromatography. Column: OJ-H, Eluents: heptane /
1-PrOH; the enantiomer eluting earlier was collected as Preparation 3bd with 99.6% ee
and the enantiomer eluting later was collected as Preparation 3be with 92.4% ee.
Preparation 3bf: Ethyl (2R)[4-fluoro(methoxymethoxy)phenyl]hydroxy-
propanoate
Step A: 4-Fluoro(methoxymethoxy)benzaldehyde
To a solution of 1.242 g 4-fluorohydroxy-benzaldehyde (8.86 mmol) in 10 mL dry
acetone 2.444 g K CO (17.7 mmol) and 1.01 mL chloromethyl-methyl-ether (13.3 mmol)
were added and stirred at room temperature until no further conversion was observed. The
mixture was diluted with ethyl acetate and it was extracted with water and with brine. The
organic phase was dried over Na SO , filtered and concentrated under reduced pressure
giving 4-fluoro(methoxymethoxy)benzaldehyde.
H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 7.87 (dd, 1H), 6.96 (dd, 1H), 6.78 (dt, 1H),
.29 (s, 2H), 3.53 (s, 3H).
Step B: Ethyl (2R)[4-fluoro(methoxymethoxy)phenyl]hydroxy-propanoate
Using General Procedure 3B and 4-Fluoro(methoxymethoxy)benzaldehyde as the
appropriate carbaldehyde the desired lactic ester was obtained in racemic form.
Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane /
EtOH; the enantiomer eluting later was collected as Preparation 3bf with 96.6% ee.
H NMR (500 MHz, DMSO) δ 7.16 (dd, 1H), 6.90 (dd, 1H), 6.73 (m, 1H), 5.52 (brs, 1H),
.24 (s, 2H), 4.22 (brm, 1H), 4.03 (q, 2H), 3.40 (s, 3H), 2.94 (dd, 1H), 2.77 (dd, 1H), 1.10
(t, 3H).
Preparation 3bg: Ethyl (2R)(1,3-benzodioxolyl)hydroxy-propanoate
Preparation 3bh: Ethyl (2S)(1,3-benzodioxolyl)hydroxy-propanoate
(Tetrahedron Lett. 1994, 35, 5205-5208.)
1,3-Benzodioxolecarbaldehyde was reacted according to General method B with the
exception, that in Step A after the formation of the oxirane the aqueous workup was
completely omitted and the solution was directly carried further to in Step B resulting the
title compound in racemic form.
H NMR (500 MHz, DMSO) δ 6.78 (dd, 1H), 6.74 (t, 1H), 6.71 (dd, 1H), 5.96 (d, 2H),
.59 (d, 1H), 4.25 (m, 1H), 4.05 (q, 2H), 2.91 (dd, 1H), 2.76 (dd, 1H), 1.13 (t, 3H).
Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane /
1-BuOH; the enantiomer eluting earlier was collected as Preparation 3bg with 99.4% ee
and the enantiomer eluting later was collected as Preparation 3bh with 99.8% ee.
Preparation 3bk: Ethyl (2R)hydroxy[2-[2-(4-methylpiperazinyl)ethoxy]
phenyl]propanoate
and
Preparation 3bo: Ethyl (2S)hydroxy[2-[2-(4-methylpiperazinyl)ethoxy]
phenyl]propanoate
Using General Procedure 3A starting from ethyl 2-acetoxy(2-
hydroxyphenyl)propanoate (Preparation 3aa-(rac)) and 2-(4-methylpiperazin
yl)ethanol as the appropriate alcohol the lactic ester was obtained in racemic form.
H NMR (500 MHz, DMSO-d ) δ 7.17 (m, 1H), 7.10 (dm, 1H), 6.94 (dm, 1H), 6.83 (m,
1H), 5.4 (d, 1H), 4.28 (m, 1H), 4.06 (t, 2H), 4.02 (m, 2H), 2.97 (dd, 1H), 2.71 (dd, 1H),
2.69 (t, 2H), 2.49 (brs, 4H), 2.30 (brs, 4H), 2.13 (s, 3H), 1.11 (t, 3H).
Enantiomers were separated via chiral chromatography. Column: OD, Eluents: heptane /
1-PrOH; the enantiomer eluting earlier was collected as Preparation 3bk with 99.8% ee
and the enantiomer eluting later was collected as Preparation 3bo with 99.6% ee.
Preparation 3bl: Ethyl (2R)hydroxy[2-(2,2,2-trifluoroethoxy)phenyl]propanoate
Step A: Ethyl (2R)hydroxy(2-hydroxyphenyl)propanoate
To a solution of 13.633 g ethyl (2R)acetoxy(2-hydroxyphenyl)propanoate
(Preparation 3aa-(R)) (54 mmol) in 200 mL dry ethanol 30 mL sodium ethoxide (1.0 M)
solution was added and stirred at room temperature. If needed, the addition of the sodium
ethoxide solution was repeated until the cleavage of the acetyl group was complete. The
mixture was diluted with 600 mL water and it was extracted with ethyl acetate. The
combined organic layers were dried over Na SO filtered and evaporated under reduced
pressure. The obtained material was used in the next step without purification.
Step B: Ethyl (2R)hydroxy[2-(2,2,2-trifluoroethoxy)phenyl]propanoate
To a solution of 9.18 g ethyl (2R)hydroxy(2-hydroxyphenyl)propanoate (43.7 mmol)
in 130 mL dry DMF, 6.040 g potassium carbonate (43.7 mmol) was added. After 5 mins
stirring 7.7 mL 2,2,2-trifluoroethyl trifluoromethanesulfonate (48 mmol) was added over 5
mins. The resulting mixture was stirred until no further conversion was observed. The
reaction mixture was extracted with brine / EtOAc. The combined organic layers were
dried over Na SO , filtered and evaporated under reduced pressure. The product was
purified via flash chromatography using heptane / EtOAc as eluents.
H NMR (500 MHz, DMSO-d ) δ 7.23 (t, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95 (t, 1H),
.50 (d, 1H), 4.75 (q, 2H), 4.22 (m, 1H), 4.02 (q, 2H), 3.00 (dd, 1H), 2.76 (dd, 1H), 1.09 (t,
3H).
Preparation 3bm: Ethyl (2S)hydroxy[2-[[(2R)-tetrahydrofuranyl]methoxy]
phenyl]propanoate
Using General Procedure 3A starting from ethyl (2S)acetoxy(2-
hydroxyphenyl)propanoate (Preparation 3aa-(S)) and [(2R)-tetrahydrofuran
yl]methanol as the appropriate alcohol Preparation 3bm was obtained.
H NMR (400 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 6.92 (dt, 1H), 6.87 (d, 1H), 4.46-4.41
(m, 1H), 4.35-4.29 (m, 1H), 4.20 (dq, 2H), 4.04 (dd, 1H), 3.99-3.93 (m, 2H), 3.88-3.82 (m,
1H), 3.32 (d, 1H), 3.17 (dd, 1H), 3.00 (dd, 1H), 2.14-2.05 (m, 1H), 2.03-1.90 (m, 2H),
1.85-1.76 (m, 1H), 1.25 (t, 3H).
Preparation 3bn: Ethyl (2R)hydroxy[2-(2-pyridylmethoxy)phenyl]propanoate
Using General Procedure 3A and 2-pyridylmethanol as the appropriate alcohol
Preparation 3bn was obtained.
H NMR (500 MHz, DMSO-d ) δ 8.58 (dm, 1H), 7.85 (td, 1H), 7.59 (d, 1H), 7.35 (ddd,
1H), 7.19 (td, 1H), 7.17 (dd, 1H), 7.01 (d, 1H), 6.88 (td, 1H), 5.52 (d, 1H), 5.21 (d, 1H),
.17 (d, 1H), 4.32 (m, 1H), 4.02 (m, 2H), 3.09 (dd, 1H), 2.83 (dd, 1H), 1.09 (t, 3H).
Preparation 3bp: Ethyl (2R)hydroxy[2-[[2-(2,2,2-trifluoroethyl)pyrazolyl]
methoxy]phenyl]propanoate
.1 g (40 mmol) Preparation 3aa-(R), 10.8 g (60 mmol) Preparation 9du and 15.7 g
PPh (60 mmol) were dissolved in 120 mL dry toluene, then 13.8 g (60 mmol) ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under N until no further
conversion was observed. Volatiles were evaporated under reduced pressure. Residue was
purified via flash chromatography using EtOAc and MeOH as eluents. The obtained
intermediate was dissolved in 50 mL dioxane-water 1:1 and 4.0 g LiOH × H2O was added.
The mixture was stirred at room temperature until no further conversion was observed.
Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane.
The combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents. 688 mg from this intermediate was
dissolved in 10 mL EtOH and 0.3 mL cc. H SO was added. Mixture was stirred at 70 °C
until no further conversion was observed. Then it was diluted with brine, neutralized with
cc. NaHCO solution, extracted with dichloromethane. The combined organic phases were
dried over Na SO , filtered and concentrated under reduced pressure and purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 3bp.
MS: (M+H) = 373.2.
Preparation 3bq: Ethyl (2R)[2-[[2-(2-fluorophenyl)pyrimidinyl]methoxy]
phenyl]hydroxy-propanoate
3.98 g (15.8 mmol) ethyl (2R)hydroxy(2-hydroxyphenyl)propanoate, 4.84 g (23.7
mmol) Preparation 9eq and 6.22 g (23.7 mmol) PPh were dissolved in 17 mL abs.
toluene and 10.8 mL 40% (23.7 mmol) DEAD (in toluene) was added dropweise. The
mixture was stirred at 50°C under N until no further conversion was observed. Volatiles
were evaporated under reduced pressure. Residue was purified via flash chromatography
using EtOAc and MeOH as eluents. MS: (M+H) = 369.0. Then it was dissolved in 50 mL
EtOH, and 4 mL cc. H SO was added. The mixture was stirred at 50°C under N until no
2 4 2
further conversion was observed. Mixture was neutralized with cc. NaHCO solution and
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via flash chromatography using heptane
and EtOAc as eluents to obtain Preparation 3bq.
MS: (M+H) = 397.0.
Preparation 3br: (2R)Hydroxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]
methoxy]phenyl] propanoic acid
37.84 g (150 mmol) ethyl (2R)acetoxy(2-hydroxyphenyl)propanoate (Preparation
3aa-(R)), 48.65 g (225 mmol) [2-(2-methoxyphenyl)pyrimidinyl]methanol
(Preparation 9bp) and 59.01 g (225 mmol) triphenyl phosphine were dissolved in 160 mL
abs. toluene, then 102.47 mL (225 mmol) diethylazodicarboxylate was added. The mixture
was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles
were evaporated under reduced pressure. Then 400 mL Et O was added, the mixture was
sonicated and filtered (to remove PPh ). Et O was removed in vacuo. Residue was
dissolved in 130 mL THF, then 30 g NaOH in 130 mL H O was added. The mixture was
stirred at room temperature until no further conversion was observed. Then it was acidified
with 2 M HCl, THF was removed in vacou. 300 mL dichloromethane was added, and the
precipitate was filtered, washed with cold H O and DCM dried in vacuo to obtain
Preparation 3br.
H-NMR (400 MHz, DMSO-d ): 8.88 (d, 1H), 7.80 (d, 1H), 7.55 (dd, 1H), 7.4944 (m,
1H), 7.26 (dd, 1H), 7.17-7.11 (m, 2H), 7.06 (t, 1H), 6.98 (d, 1H), 6.88 (t, 1H), 5.22 (s, 2H),
3.81 (dd, 1H), 3.77 (s, 3H), 3.73 (dd, 1H), 2.44 (dd, 1H).
Preparation 3bs: Ethyl (2R)hydroxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]
methoxy]phenyl]propanoate
51.7 g (136 mmol) Preparation 3br was dissolved in 520 mL EtOH, then 20 mL cc.
H SO was added. The mixture was stirred at 60 C until no further conversion was
observed. Then it was diluted with water, neutralized with cc NaHCO solution and
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via flash chromatography
using EtOAc and MeOH as eluents to obtain Preparation 3bs.
HRMS calculated for C H N O : 408.1685, found: 409.1757 (M+H).
23 24 2 5
Preparation 4a: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetra-hydropyranyloxyphenyl)propanoate
48.45 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(141 mmol), 45.63 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)
propanoate (Preparation 3ab-(R)) (155 mmol) and 137.8 g Cs CO (423 mmol) were
placed in a 2 L flask. 1.4 L tert-butanol was added and the mixture was stirred at 70°C
under N until no further conversion was observed. Approximately 1 L solvent was
evaporated under reduced pressure, then it was diluted with water, the pH was set to 8 with
2 M HCl, and then it was extracted with DCM. The combined organic layers were dried
over Na SO , filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane and EtOAc as eluents to obtain
Preparation 4a as a mixture of diastereoisomers.
H NMR (500 MHz, DMSO-d ): 8.67/8.66 (s, 1H), 7.75 (m, 2H), 7.43 (dm, 1H), 7.41 (m,
2H), 7.19 (m, 1H), 7.08/7.06 (dm, 1H), 6.89 (m, 1H), 5.87/5.70 (dd, 1H), 5.60/5.55 (m,
1H), 4.23-4.08 (m, 2H), 3.80-3.48 (m, 2H), 3.52/3.49 (dd, 1H), 3.19/3.17 (dd, 1H), 2.09-
1.49 (m, 6H), 1.15/1.10 (t, 3H).
HRMS calculated for C H BrFN O S: 600.0730, found: 601.0809/601.0798 (M+H).
28 26 2 5
Preparation 4b: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-(pyrazinylmethoxy)phenyl]propanoate
1.718 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(5.00 mmol), 1.512 g ethyl (2R)hydroxy[2-(pyrazinylmethoxy)phenyl]propanoate
(Preparation 3ac) (5.00 mmol) and 5.700 g Cs CO (17.5 mmol) were placed in a 50 mL
flask. 15 mL tert-butanol was added and the mixture was stirred at 70°C under N until no
further conversion was observed. The reaction mixture was diluted with water, the pH was
set between 6-7 with 2 M HCl, and then it was extracted with DCM. The combined organic
layers were dried over Na SO , filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography using heptane and EtOAc as eluents
to obtain Preparation 4b.
MS: (M+H) = 609.0.
Preparation 4c: Ethyl (2R)[5-bromo(5-fluorofuryl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
50.03 g 5-bromochloro(5-fluorofuryl)thieno[2,3-d]pyrimidine (Preparation 2b)
(150 mmol), 44.15 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)
propanoate (Preparation 3ab-(R)) (150 mmol) and 146.6 g Cs CO (450 mmol) were
placed in a 2 L flask. 1.5 L tert-butanol was added and the mixture was stirred at 70°C
under N until no further conversion was observed. Approximately 1 L solvent was
evaporated, then it was diluted with DCM and water, the pH was set to 8 with 2 M HCl,
and then it was extracted with DCM. The combined organic layers were dried over
Na SO , filtered and concentrated under reduced pressure. The crude product was purified
via flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4c as
a mixture of diastereoisomers.
H NMR (500 MHz, DMSO-d ): 8.63/8.62 (s, 1H), 7.44 (dm, 1H), 7.42 (m, 1H), 7.19 (tm,
1H), 7.07 (d, 1H), 6.90 (t, 1H), 6.17 (m, 1H), 5.80/5.68 (dd, 1H), 5.61/5.55 (t, 1H), 4.14
(m, 2H), 3.78-3.40 (m, 2H), 3.51 (m, 1H), 3.18 (m, 1H), 2.00 (m, 1H), 1,82 (m, 2H), 1.68-
1.37 (m, 2H), 1.66 (m, 1H), 1.14/1.11 (t, 3H).
HRMS calculated for C H BrFN O S: 590.0522, found: 591.0599 (M+H).
26 24 2 6
Preparation 4d: Ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy
(2-tetrahydropyranyloxyphenyl)propanoate
36.87 g 5-bromochloro(2-furyl)thieno[2,3-d]pyrimidine (Preparation 2c) (117
mmol), 37.83 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 3ab-(R)) (129 mmol) and 98.00 g Cs CO (300 mmol) were placed in a 1 L
flask. 400 mL tert-butanol was added and the mixture was stirred at 50°C under N until no
further conversion was observed. The reaction mixture was diluted with DCM and brine,
and then it was extracted with DCM. The combined organic layers were dried over
Na SO , filtered and concentrated under reduced pressure. The crude product was purified
via flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4d as
a mixture of diastereoisomers.
MS: (M+H) = 609.0.
Preparation 4e: Ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy
(2-methoxyphenyl)propanoate
0.631 g 5-bromochloro(2-furyl)thieno[2,3-d]pyrimidine (Preparation 2c) (2.00
mmol), 0.673 g ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad)
(3.00 mmol) and 0.195 g Cs CO (6.00 mmol) were placed in a 25 mL flask. 10 mL tert-
butanol was added and the mixture was stirred at 60°C under N until no further
conversion was observed. The reaction mixture was diluted with DCM and brine, and then
it was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 4e.
H NMR (400 MHz, DMSO-d ): 8.60 (s, 1H), 7.94 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H),
7.22 (td, 1H), 6.96 (d, 1H), 6.86 (td, 1H), 6.77 (dd, 1H), 5.64 (dd, 1H), 4.10 (q, 2H), 3.79
(s, 3H), 3.87 (dd, 1H), 3.24 (dd, 1H), 1.10 (t, 3H).
Preparation 4f: Ethyl (2R)[5-bromo(5-chlorofuryl)thieno[2,3-d]pyrimidin
yl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl]propanoate
6.05 g 5-bromochloro(5-chlorofuryl)thieno[2,3-d]pyrimidine (Preparation 2d)
(17.3 mmol), 6.28 g ethyl (2R)hydroxy[2-[(4-methoxyphenyl)methoxy]phenyl]
propanoate (Preparation 3ae) (19.0 mmol) and 19.7 g Cs CO (60.5 mmol) were placed in
a 250 mL flask. 60 mL tert-butanol was added and the mixture was stirred at 80°C under
N until no further conversion was observed. Water was added, then it was extracted with
EtOAc. The combined organic layers were dried over Na SO , filtered and concentrated
under reduced pressure to obtain Preparation 4f.
MS: (M+H) = 643.0.
Preparation 4g: Ethyl (2R)[5-bromo(5-chlorofuryl)thieno[2,3-d]pyrimidin
yl]oxy[2-[[(2S)-tetrahydrofuranyl]methoxy]phenyl]propanoate
0.315 g 5-bromochloro(5-chlorofuryl)thieno[2,3-d]pyrimidine (Preparation 2d)
(0.90 mmol), 0.267 g ethyl (2R)hydroxy[2-[[(2S)-tetrahydrofuranyl]methoxy]
phenyl]propanoate (Preparation 3af) (0.90 mmol) and 0.977 g Cs CO (3.00 mmol) were
placed in a 25 mL flask. 5 mL tert-butanol was added and the mixture was stirred at 65°C
under N until no further conversion was observed. Water was added, the pH was set to 8
with 2 M HCl, then it was extracted with DCM. The combined organic layers were dried
over Na SO , filtered, concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane and EtOAc as eluents to obtain
Preparation 4g.
MS: (M+H) = 607.0.
Preparation 4h: Ethyl (2R)[5-bromo(4-fluoromethoxy-phenyl)thieno[2,3-
d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
24.00 g 5-bromochloro(4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidine
(Preparation 2e) (64.0 mmol), 22.69 g ethyl (2R)hydroxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 3ab-(R)) (77.0 mmol) and 62.8 g Cs CO (63.0
mmol) were placed in a 250 mL flask. 150 mL tert-butanol was added and the mixture was
stirred at 70°C under N until no further conversion was observed Water was added, then it
was extracted with DCM. The combined organic layers were dried over Na SO , filtered,
concentrated and purified via flash chromatography using heptane and EtOAc as eluents to
obtain Preparation 4h as a mixture of diastereoisomers.
MS: (M+H) = 631.0.
Preparation 4i: Methyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy
phenyl-propanoate
.00 g 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (15.4 mmol),
3.47 g methyl (2R)hydroxyphenyl-propanoate (Preparation 3ag) (19.3 mmol) and
6.28 g Cs CO (19.3 mmol) were placed in a 50 mL flask. 15 mL DMSO was added and
the mixture was stirred at 60°C under N until no further conversion was observed. The
reaction mixture was poured onto ice, the pH was adjusted to 4 with 2M HCl and the
mixture was extracted with DCM. The combined organic layers were dried over MgSO ,
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 4i.
H NMR (400 MHz, CDCl ): 8.48 (s, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.23 (m, 1H), 5.75
(dd, 1H), 3.73 (s, 3H), 3.44-3.40 (m, 2H), 2.93 (q, 2H), 1.33 (t, 3H).
Preparation 4j: Ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
tetrahydropyranyloxyphenyl)propanoate
3.25 g 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (10.0 mmol),
3.24 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 3ab-(R)) (11.0 mmol) and 9.77 g Cs CO (30.0 mmol) were placed in a 100
mL flask. 50 mL tert-butanol was added and the mixture was stirred at 70°C under N until
no further conversion was observed. Brine was added, then it was extracted with DCM.
The combined organic layers were dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to obtain Preparation 4j as a mixture of diastereoisomers.
MS: (M+H) = 583.0.
Preparation 4k: Ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy-
3-(2-methoxyphenyl)propanoate
0.669 g 4-chloroiodopropynyl-thieno[2,3-d]pyrimidine (Preparation 2f) (2.00
mmol), 0.673 g ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad)
(3.00 mmol) and 1.955 g Cs CO (6.00 mmol) were placed in a 25 mL flask. 10 mL tert-
butanol was added and the mixture was stirred at 60°C under N until no further
conversion was observed. The reaction mixture was diluted with brine, and then it was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 4k.
H NMR (400 MHz, CDCl ): 8.52 (s, 1H), 7.36 (dd, 1H), 7.23 (dd, 1H), 6.89-6.84 (m, 2H),
.78 (dd, 1H), 4.23-4.12 (m, 2H), 3.84 (s, 3H), 3.49 (dd, 1H), 3.39 (dd, 1H), 2.19 (s, 3H),
1.18 (t, 3H).
MS: (M+H) = 523.0.
Preparation 4l: Ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy
(2-tetrahydropyranyloxyphenyl)propanoate
8.92 g 4-chloroiodopropynyl-thieno[2,3-d]pyrimidine (Preparation 2f) (26.7
mmol), 8.83 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 3ab-(R)) (30.0 mmol) and 29.3 g Cs CO (90.0 mmol) were placed in a 500
mL flask. 300 mL tert-butanol was added and the mixture was stirred at 65°C under N
until no further conversion was observed. Brine was added, then it was extracted with
DCM. The combined organic layers were dried over Na SO , filtered, concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to obtain Preparation 4l as a mixture of diastereoisomers.
MS: (M+H) = 593.0
Preparation 4m: 2-(6-Ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoic acid
500 mg (2R)hydroxyphenyl-propanoic acid (2.77 mmol) was dissolved in 3 mL dry
DMF, then 133 mg sodium hydride (3.32 mmol, 60% in mineral oil) was added and it was
stirred for 15 minutes at room temperature. It was added dropwise to a DMF solution (5
mL) of 650 mg 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (2.00
mmol) and the mixture was stirred for 1 hour. Then 2.5 mL 10% NaOH solution was added
and the reaction mixture was stirred for 30 minutes. It was diluted with water and washed
with Et O. The aqueous phase was acidified and the yellow precipitate was filtered and
dried to obtain Preparation 4m.
H NMR (500 MHz, DMSO-d ): 13.29 (s, 1H), 8.57 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H),
7.21 (m, 1H), 5.62 (dd, 1H), 3.36 (dd, 1H), 3.29 (dd, 1H), 2.91 (q, 2H), 1.26 (t, 3H).
HRMS calculated for C H IN O S: 453.9848, found: 454.9918 (M+H).
17 15 2 3
Preparation 4n: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate
687 mg 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(2.00 mmol), 673 mg ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation
3ad) (3.00 mmol) and 1.955 g Cs CO (6.00 mmol) were placed in a 25 mL flask. 10 mL
tert-butanol was added and the mixture was stirred at 60°C under N until no further
conversion was observed. The reaction mixture was diluted with brine, and then it was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 4n.
MS: (M+H) = 531.0.
Preparation 4o: Ethyl (2R)[5-bromo(3,4-difluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
6.0 g 5-bromochloro(3,4-difluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2g)
(16.59 mmol), 5.97 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)
propanoate (Preparation 3ab-(R)) (18.25 mmol) and 18.93 g Cs CO (58.1 mmol) were
placed in a 250 mL flask. 100 mL tert-butanol was added and the mixture was stirred at
60°C under N2 until no further conversion was observed. Approximately 50 mL solvent
was evaporated under reduced pressure, then it was diluted with water, the pH was set to 8
with 2 M HCl, and then it was extracted with DCM. The combined organic layers were
dried over Na SO , filtered and concentrated under reduced pressure. The crude product
was purified via flash chromatography using heptane and EtOAc as eluents to obtain
Preparation 4o as a mixture of diastereoisomers.
H NMR (400 MHz, DMSO-d ): 8.69 (d, 1H), 7.87 (m, 1H), 7.67 (m, 1H), 7.57 (m, 1H),
7.44 (m, 1H), 7.20 (m, 1H), 7.07 (m, 1H), 6.90 (t, 1H), 5.82/5.70 (dd, 1H), 5.62/5.56 (t,
1H), 4.22-4.08 (m, 2H), 3.75/3.65 (td, 1H), 3.61-3.45 (m, 2H), 3.20/3.16 (d, 1H), 2.10-1.48
(m, 6H), 1.17/1.14 (t, 3H).
Preparation 4p: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-[[(2R)-tetrahydrofuranyl]methoxy]phenyl]propanoate
4.12 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(12.0 mmol) and 3.80 g ethyl (2R)hydroxy[2-[[(2R)-tetrahydrofuranyl]methoxy]
phenyl]propanoate (Preparation 3bj) (12.9 mmol) were dissolved in 30 mL tert-butanol,
then 13.03 g Cs CO (40.0 mmol) was added and the mixture was stirred at 65°C under N
2 3 2
until no further conversion was observed. Then it was poured onto icy water, the pH was
set to 6 with 2 M HCl, and it was filtered and washed with water to obtain Preparation 4p.
H NMR (400 MHz, DMSO-d ): 8.67 (s, 1H), 7.76 (m, 2H), 7.42 (m, 2H), 7.38 (dd, 1H),
7.21 (dt, 1H), 6.98 (d, 1H), 6.86 (t, 1H), 5.71 (dd, 1H), 4.20-4.09 (m, 3H), 4.04-3.96 (m,
2H), 3.79-3.73 (m, 1H), 3.69-3.64 (m, 1H), 3.40 (dd, 1H), 3.22 (dd, 1H), 2.04-1.78 (m,
4H), 1.12 (t, 3H).
Preparation 4q: Ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate
2.809 g 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (8.92 mmol),
1.00 g ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad) (4.46
mmol) and 1.598 g Cs CO (4.91 mmol) were dissolved in 5 mL dry DMSO and heated at
60°C until no further conversion was observed. Then it was diluted with water, the pH was
set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers
were dried over Na2SO4, filtered and concentrated under reduced pressure and purified via
flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4q.
MS: (M+H) = 513.0.
Preparation 4r: Ethyl (2S)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate
2.809 g 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (8.92 mmol),
1.00 g ethyl (2S)hydroxy(2-methoxyphenyl)propanoate (Preparation 3bi) (4.46
mmol) and 1.598 g Cs CO (4.91 mmol) were dissolved in 5 mL dry DMSO and heated at
60°C until no further conversion was observed. Then it was diluted with water, the pH was
set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4r.
MS: (M+H) = 513.0.
Preparation 4s: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-(2,2,2-trifluoroethoxy)phenyl]propanoate
.39 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(15.7 mmol) and 5.50 g ethyl (2R)hydroxy[2-(2,2,2-trifluoroethoxy)phenyl]
propanoate (Preparation 3bl) (18.8 mmol) were dissolved in 60 mL tert-butanol, then
.32 g Cs CO (47.0 mmol) was added and the mixture was stirred at 60°C under N until
2 3 2
no further conversion was observed. Then it was poured onto icy water, the pH was set to 6
with 2 M HCl, and it was filtered, washed with water to obtain Preparation 4s.
H NMR (400 MHz, CDCl ): 8.53 (s, 1H), 7.64 (m, 2H), 7.43 (d, 1H), 7.27-7.16 (m, 3H),
6.97 (t, 1H), 6.82 (d, 1H), 5.75 (dd, 1H), 4.45-4.38 (m, 2H), 4.22 (q, 2H), 3.55 (dd, 1H),
3.33 (dd, 1H), 1.24 (t, 3H).
Preparation 4t: Ethyl (2R)[5-bromo(2,3-difluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
6.00 g Preparation 2h (16.59 mmol), 5.97 g Preparation 3ab-(R) (18.25 mmol) and
18.93 g Cs2CO3 (58.1 mmol) were placed in a 250 mL flask. 100 mL tert-butanol was
added and the mixture was stirred at 60°C under N until no further conversion was
observed. Approximately 50 mL solvent was evaporated under reduced pressure, then it
was diluted with water, the pH was set to 8 with 2 M HCl, and then it was extracted with
DCM. The combined organic layers were dried over Na SO , filtered and concentrated
under reduced pressure. The crude product was purified via flash chromatography using
heptane and EtOAc as eluents to obtain Preparation 4t as a mixture of diastereoisomers.
HRMS calculated for C28H25BrF2N2O5S: 618.0636; found: 619.0695 (M+H).
Preparation 4u: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-[[2-(2-fluorophenyl)pyrimidinyl]methoxy]phenyl]propanoate
1.718 g (5 mmol) Preparation 2a and 2.18 g (6 mmol) Preparation 3bq were dissolved
in 50 mL dioxane then 4.887 g Cs CO (15 mmol) was added. The mixture was stirred at
70°C under N until no further conversion was observed. It was diluted with water, the pH
was set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic
layers were dried over Na SO , filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography using heptane and EtOAc as eluents
to obtain Preparation 4u.
+ 2+
MS: (M+H) = 702.6, (M+2H) = 351.0.
Preparation 4v: Ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate
.0 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(58.2 mmol), 23.77 g ethyl (2R)hydroxy[2-[[2-(2-methoxyphenyl)pyrimidin
yl]methoxy]phenyl]propanoate (Preparation 3bs) (58.2 mmol) and 56.89 g Cs CO (174.6
mmol) were placed in a flask, then 250 mL abs. THF was added and the mixture was
stirred at 70°C under N until no further conversion was observed. The reaction mixture
was diluted with water, then it was extracted with DCM. The combined organic layers
were dried over Na SO , filtered and concentrated under reduced pressure. The crude
product was purified via flash chromatography using dichloromethane and methanol as
eluents to obtain Preparation 4v.
MS: (M+H) = 715.0, 717.2.
Preparation 4w: Ethyl (2S)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetra-hydropyranyloxyphenyl)propanoate
48.45 g 5-bromochloro(4-fluorophenyl)thieno[2,3-d]pyrimidine (Preparation 2a)
(141 mmol), 45.63 g ethyl (2S)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 3ab-(S)) (155 mmol) and 137.8 g Cs CO (423 mmol) were placed in a 2 L
flask. 1.4 L tert-butanol was added and the mixture was stirred at 70°C under N until no
further conversion was observed. Approximately 1 L solvent was evaporated under
reduced pressure, then it was diluted with water, the pH was set to 8 with 2 M HCl, and
then it was extracted with DCM. The combined organic layers were dried over Na SO ,
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 4w as a
mixture of diastereoisomers.
MS: (M+H) = 601.2.
Preparation 5a: 2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenol
Step A: (4-Bromochloro-phenoxy)-trimethyl-silane
.8 g 4-bromochloro-phenol (100 mmol) was dissolved in 150 mL dry THF then 24.2
g HMDS (150 mmol) was added. The reaction mixture was stirred at 85°C under argon
atmosphere for 1.5 hours then concentrated under reduced pressure resulting in the product
used without further purification.
H NMR (200 MHz, CDCl ): 7.49 (d, 1H), 7.23 (dd, 1H), 6.75 (d, 1H), 0.26 (s, 9H).
Step B: 4-Bromochloromethyl-phenol
48 mL BuLi solution in hexanes (2.5 M, 120 mmol) was added dropwise to a solution of
12.1 g dry DIPA (120 mmol) in 250 mL dry THF at -78°C under argon atmosphere. The
mixture was stirred for 30 minutes at the same temperature then 28.0 g (4-bromochloro-
phenoxy)-trimethyl-silane (100 mmol) was added dropwise. After 2.5 hours 21.3 g MeI
(150 mmol) was added dropwise then the cooling bath was removed and the mixture was
stirred overnight. The reaction was quenched with 100 mL NH OH solution and 200 mL
NH4Cl solution and extracted with EtOAc, dried over Na2SO4, filtered and concentrated
under reduced pressure. The resulting dark mass was refluxed with pure hexane several
times (150-150 mL aliquots) and decanted leaving a black tar behind. Combined organic
phases were concentrated under reduced pressure affording 19.0 g crude product used
without further purification.
H NMR (200 MHz, CDCl ): 7.32 (d, 1H), 6.76 (d, 1H), 5.62 (s, 1H), 2.49 (s, 3H).
Step C: (4-Bromochloromethyl-phenoxy)-trimethyl-silane
20.8 g HMDS (129 mmol) was added to the solution of 19.0 g 4-bromochloromethyl-
phenol (86.0 mmol) in 150 mL dry THF. The mixture was stirred at 85°C under argon
balloon for 1.5 hours and then concentrated under reduced pressure. The obtained product
was used without further purification.
H NMR (200 MHz, CDCl ): 7.30 (d, 1H), 6.63 (d, 1H), 2.50 (s, 3H), 0.28 (s, 9H).
Step D: 2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
A solution of 25.2 g (4-bromochloromethyl-phenoxy)-trimethyl-silane (86.0 mmol)
in 250 mL dry THF was cooled to -78°C under argon and then 38 mL BuLi in hexanes
(2.5 M, 94.6 mmol) was added dropwise. After 5 minutes 19.2 g 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was
removed and the mixture was slowly allowed to warm up to room temperature. Then the
mixture was added to 200 mL NH Cl solution and extracted with EtOAc. Combined
organic layers were concentrated under reduced pressure and passed through a pad of silica
gel using hexane and EtOAc as eluents. The crude product was recrystallized from a
mixture of EtOAc and hexane to obtain Preparation 5a.
H NMR (500 MHz, DMSO-d ): 10.40 (s, 1H), 7.42 (d, 1H), 6.80 (d, 1H), 2.49 (s, 3H),
1.27 (s, 12H).
Preparation 5b: 1-[2-[2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]methyl-piperazine
10.0 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (37.2 mmol), 8.7 g 2-(4-methylpiperazinyl)ethanol (60.3 mmol) and
.8 g PPh3 (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl
azodicarboxylate (60.3 mmol, 40% solution in toluene) was added dropwise. The mixture
was stirred at 50°C under argon for 1.5 hours. The volatiles were evaporated under reduced
pressure and 100 mL Et O was added. The precipitated white crystals were filtered off and
washed with Et O. The filtrate was concentrated under reduced pressure and purified via
flash chromatography using CHCl and MeOH as eluents. The resulting light brown oil
was crystallized from hexane to give Preparation 5b as an off-white solid.
H NMR (500 MHz, DMSO-d6): 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51
(s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H).
Preparation 5c: [2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane
Step A: (4-Bromochloro-phenoxy)-triisopropyl-silane
200 g 4-bromochloro-phenol (0.97 mol) and 126 mL TIPSCl (1.18 mol) were dissolved
in 1.6 L DCM. 167 g imidazole (2.45 mol) was added and the mixture was stirred at room
temperature for 2 hours. The volatiles were evaporated under reduced pressure and the
residue was dissolved in 1.5 L EtOAc. The mixture was washed with brine, dried over
Na SO , filtered and concentrated under reduced pressure. The triisopropylsilyl hydroxide
impurity was removed by distillation (120°C at 0.01 mmHg). The residue was filtered
through a short pad of silica with hexane and concentrated under reduced pressure. The
product (colourless oil) was used in the next step without further purification.
H NMR (400 MHz, CDCl ): 7.49 (d, 1H), 7.21 (dd, 1H), 6.78 (d, 1H), 1.31 (septet, 3H),
1.14 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (30), 79 (24), 93 (41), 170 (17), 235
(19), 251 (16), 265 (24), 293 (23), 319 (77), 321 (100), 323 (28), 362 (1, [M ]).
Step B: (4-Bromochloromethyl-phenoxy)-triisopropyl-silane
76.0 mL dry DIPA (0.54 mol) was dissolved in 1.2 L dry THF under argon atmosphere and
51.2 mL BuLi solution (10 M in hexanes, 0.512 mol) was added dropwise at -78°C. The
mixture was stirred for 45 minutes at the same temperature. 178 g (4-bromochloro-
phenoxy)-triisopropyl-silane (0.488 mol) was added dropwise at -78°C and the white
suspension was stirred for 8 hours. 36.5 mL MeI (0.586 mmol) was added at this
temperature and the reaction mixture was stirred overnight without further cooling. The
volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L
EtOAc, washed with brine, dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was filtered through a short pad of silica using hexane as
eluent and concentrated under reduced pressure to obtain the product as pale yellow oil.
H NMR (400 MHz, CDCl3): 7.30 (d, 1H), 6.68 (d, 1H), 2.53 (s, 3H), 1.32 (septet, 3H),
1.14 (d, 18H).
Step C: [2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
178 g (4-bromochloromethyl-phenoxy)-triisopropyl-silane (0.472 mol) was dissolved
in 1.4 L dry THF under argon atmosphere and 52 mL BuLi solution (10 M in hexanes,
0.52 mol) was added dropwise at -78°C. The mixture was stirred for 5 minutes at this
temperature. Then 116 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.569
mol) was added and the mixture was allowed to warm up to room temperature. The
volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L
EtOAc, washed with brine, dried over Na SO , filtered and concentrated under reduced
pressure. The 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane impurity was removed
by distillation (80°C at 0.01 mmHg). The crude product was triturated in MeOH affording
Preparation 5c as a white solid.
H NMR (400 MHz, CDCl ): 7.53 (d, 1H), 6.74 (d, 1H), 2.60 (s, 3H), 1.34 (s, 12H), 1.32
(m, 3H), 1.12 (d, 18H).
Preparation 5d: 2-(3-Chloromethoxymethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane
.371 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (20.0 mmol) and 15.74 g PPh (60.0 mmol) were dissolved in 50 mL dry
MeOH under N , then 13.82 g ditertbutyl azodicarboxylate (60.0 mmol) was added and the
mixture was stirred at 50°C for 2 hours. Then it was concentrated under reduced pressure
and purified via flash chromatography using heptane and EtOAc as eluents to obtain
Preparation 5d.
H NMR (400 MHz, DMSO-d ): 7.59 (d, 1H), 6.98 (d, 1H), 3.85 (s, 3H), 2.52 (s, 3H), 1.29
(s, 12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 77 (21), 82 (100), 225 (29), 267 (18), 282
(32, [M] ), 284 (11, [M] ).
Preparation 5e: [2-Chloroethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane
Step A: (4-Bromochloroethyl-phenoxy)-triisopropyl-silane
7.07 g (4-bromochloro-phenoxy)-triisopropyl-silane (19.4 mmol, see Step A at
Preparation 5c) was dissolved in 60 mL dry THF under N and was cooled to -78°C with
dry ice-acetone. 11.7 mL LDA (23.3 mmol in 2 M THF, EtPh) was added and the mixture
was stirred for 1 hour. Then 4.23 g ethyl iodide (38.9 mmol) was added and the mixture
was allowed to warm up to room temperature. It was quenched with saturated NH Cl
solution, extracted with EtOAc, dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
as eluent to obtain a mixture of product and starting material. They were separated via
reversed phase chromatography using pure MeCN as eluent.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (15), 93 (65), 121 (26), 161 (15), 183
(13), 263 (10), 279 (14), 347 (71), 349 (100), 351 (28), 390 (1, [M ]), 392 (1, [M ]).
Step B: [2-Chloroethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
1.08 g (4-bromochloroethyl-phenoxy)-triisopropyl-silane (2.76 mmol) was dissolved
in 20 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 1.9 mL BuLi
(3.03 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then
1.02 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 mmol) was added
and the mixture was allowed to warm up to room temperature. It was quenched with
saturated NH Cl solution, extracted with EtOAc, dried over Na SO , filtered and
4 2 4
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5e.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 55 (25), 83 (100), 93 (50), 225 (14), 295
(9), 395 (67), 397 (26).
Preparation 5f: 1-[2-[2-Chlorofluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]methyl-piperazine
Step A: 1-[2-(4-Bromofluoro-phenoxy)ethyl]methyl-piperazine
1.91 g 4-bromofluoro-phenol (10.0 mmol), 1.73 g 2-(4-methylpiperazinyl)ethanol
(12.0 mmol) and 5.00 g immobilized PPh (15.0 mmol) were dissolved in 30 mL dry
toluene under N , then 2.99 g ditertbutyl azodicarboxylate (13.0 mmol) was added and the
mixture was stirred at 50°C for 6 hours. Then it was filtered, the filtrate was concentrated
under reduced pressure and purified via flash chromatography using EtOAc and MeOH as
eluents to obtain 1-[2-(4-bromofluoro-phenoxy)ethyl]methyl-piperazine.
MS (M+H): 317.2.
Step B: 1-[2-(4-Bromochlorofluoro-phenoxy)ethyl]methyl-piperazine
2.35 g 1-[2-(4-bromofluoro-phenoxy)ethyl]methyl-piperazine (7.41 mmol) was
dissolved in 40 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 7.2
mL LDA (14.4 mmol in 2 M THF, EtPh) was added and the mixture was stirred for 1 hour,
then 2.10 g 1,1,1,2,2,2-hexachloroethane (8.89 mmol) was added and the mixture was
allowed to warm up to room temperature. It was quenched with brine, extracted with
DCM, dried over Na SO , filtered and concentrated under reduced pressure. The crude
product was purified via flash chromatography using EtOAc and MeOH as eluents to
obtain 1-[2-(4-bromochlorofluoro-phenoxy)ethyl]methyl-piperazine.
MS (M+H): 351.0.
Step C: 1-[2-[2-Chlorofluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine
1.94 g 1-[2-(4-bromochlorofluoro-phenoxy)ethyl]methyl-piperazine (5.50 mmol)
was dissolved in 25 mL dry THF under N and was cooled to -78°C with dry ice-acetone.
4.2 mL BuLi (6.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5
minutes, then 2.04 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with brine, extracted with DCM, dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using EtOAc
and MeOH as eluents to obtain Preparation 5f.
MS (M+H): 399.2.
Preparation 5g: 2-Fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenol
Step A: (4-Bromofluoro-phenoxy)-triisopropyl-silane
3.82 g 4-bromofluoro-phenol (20.0 mmol) was dissolved in 50 mL DCM, then 5.14 mL
TIPSCl (24.0 mmol) and 2.72 g imidazole (40.0 mmol) was added and the mixture was
stirred at room temperature for 1 hour. Then it was concentrated under reduced pressure
and purified via flash chromatography using heptane as eluent to obtain (4-bromo
fluoro-phenoxy)-triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (35), 77 (100), 105 (44), 153 (43), 182
(25), 233 (75), 235 (75), 261 (9), 263 (9), 303 (17), 305 (17), 346 (3, [M ]), 348 (3, [M ]).
Step B: (4-Bromofluoromethyl-phenoxy)-triisopropyl-silane
6.50 g (4-bromofluoro-phenoxy)-triisopropyl-silane (18.7 mmol) was dissolved in 60
mL dry THF under N and was cooled to -78°C with dry ice-acetone. 11.2 mL LDA was
added (22.5 mmol in 2 M THF, EtPh) and the mixture was stirred for 1 hour, then 2.3 mL
MeI (37.4 mmol) was added and the mixture was allowed to warm up to room temperature.
It was quenched with saturated NH Cl solution, extracted with EtOAc, dried over Na SO ,
4 2 4
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane as eluent to obtain (4-bromofluoromethyl-phenoxy)-
triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (21), 77 (100), 61 (105), 167 (52), 196
(43), 247 (60), 249 (59), 275 (25), 277 (25), 317 (14), 319 (14), 360 (5, [M ]), 362 (5,
[M ]).
Step C: [2-Fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
6.61 g (4-bromofluoromethyl-phenoxy)-triisopropyl-silane (18.3 mmol) was
dissolved in 80 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 13.8
mL BuLi (22.0 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10
minutes, then 5.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.4 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with saturated NH4Cl solution, extracted with Et2O, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain [2-fluoromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 77 (39), 83 (100), 195 (26), 223 (20), 241
(10), 323 (4), 365 (4).
Step D: 2-Fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
6.00 g [2-fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane (14.7 mmol) was dissolved in 20 mL THF, then 16.2 mL TBAF (16.2
mmol in 1 M THF) was added and the mixture was stirred for 10 minutes. Then it was
diluted with EtOAc and Et O, washed with water and brine, dried over Na SO , filtered
2 2 4
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5g.
H NMR (400 MHz, DMSO-d ): 10.09 (s, 1H), 7.27 (dd, 1H), 6.75 (t, 1H), 2.36 (d, 3H),
1.27 (s, 12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 152 (100), 166 (18), 195 (21), 237 (18),
252 (19, [M ]).
Preparation 5h: 1-Methyl[2-[4-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]piperazine
Step A: 1-[2-(3-Bromomethyl-phenoxy)ethyl]methyl-piperazine
0.50 g 3-bromomethyl-phenol (2.67 mmol), 0.46 g 2-(4-methylpiperazinyl)ethanol
(3.21 mmol) and 0.84 g PPh (3.21 mmol) was dissolved in 10 mL dry THF under N , then
1.47 mL diethyl azodicarboxylate (3.21 mmol, 40% in toluene) was added and the mixture
was stirred at room temperature for 2 hours. Then it was concentrated under reduced
pressure and purified via reversed phase chromatography using aqueous 0.1% TFA
solution and MeCN as eluents to obtain 1-[2-(3-bromomethyl-phenoxy)ethyl]methyl-
piperazine.
MS (M+H): 313.1.
Step B: 1-Methyl[2-[4-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]piperazine
1.70 g 1-[2-(3-bromomethyl-phenoxy)ethyl]methyl-piperazine (5.43 mmol), 1.52 g
4,4,5,5-tetramethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3,2-dioxaborolane
(5.97 mmol), 395 mg PdCl × dppf (0.54 mmol) and 1.60 g KOAc (16.3 mmol) were
dissolved in 20 mL dry DMF under N . The mixture was stirred at 85°C for 5 hours, then it
was filtered through celite, diluted with Et O, washed with water, dried over Na SO ,
2 2 4
filtered and concentrated under reduced pressure. Then heptane was added, the solid
impurities were filtered and the filtrate was concentrated under reduced pressure. The
crude product was used as Preparation 5h without further purification.
MS (M+H): 361.2.
Preparation 5i: 2-(3-Chlorofluoromethoxymethyl-phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane
Step A: 1-Bromochlorofluoromethoxymethyl-benzene
13.01 g 3-chlorofluoromethoxymethyl-benzene (74.5 mmol) was dissolved in 200
mL AcOH, then 4.1 mL bromine (80.0 mmol) was added and the mixture was stirred at
room temperature. Additional 6 mL bromine needed to reach complete conversion. Then
the mixture was poured onto icy water, the pH was carefully set to 8 with solid KOH and
K CO , then saturated Na S O solution was added until the brown color of bromine
2 3 2 2 3
disappeared. Then it was extracted with Et O. The combined organics were washed with
water, then brine, then dried over Na SO , filtered and concentrated under reduced
pressure to give 1-bromochlorofluoromethoxymethyl-benzene.
H NMR (400 MHz, CDCl ): 7.29 (d, 1H), 3.95 (d, 3H), 2.47 (d, 3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 75 (26), 95 (42), 107 (25), 130 (96), 132
+ + +
(35), 237 (57), 239 (74), 252 (77, [M ]), 254 (100, [M ]), 256 (23, [M ]).
Step B: 2-(3-Chlorofluoromethoxymethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane
761 mg 1-bromochlorofluoromethoxymethyl-benzene (3.0 mmol) was
dissolved in 15 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 2.1
mL BuLi (3.3 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10
minutes, then 0.69 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.4 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with saturated NH Cl solution, extracted with DCM, dried over Na SO , filtered and
4 2 4
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5i.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 200 (100), 201 (57), 243 (52), 285 (26),
300 (35, [M ]), 302 (11, [M ]).
Preparation 5j: 1-[3-Chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl]methyl-piperazine
Step A: 1-(5-Bromochloromethoxymethyl-phenyl)methyl-piperazine
1.27 g 1-bromochlorofluoromethoxymethyl-benzene (5.00 mmol, see Step A at
Preparation 5i) was dissolved in 15 mL dry THF under N and was cooled to -78°C with
dry ice-acetone. Separately 0.58 mL 1-methylpiperazine (5.25 mmol) was dissolved also in
mL dry THF under N and was cooled to 0°C with icy water. Then 3.3 mL BuLi (5.25
mmol in 1.6 M hexanes) was added and the mixture was stirred for 10 minutes, then it was
cooled to -78°C with dry ice-acetone. This latter mixture was transferred to the THF
solution of 1-bromochlorofluoromethoxymethyl-benzene and the mixture was
allowed to warm up to room temperature. Water and brine were added and the mixture was
extracted with DCM, dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents.
MS (M+H): 333.0.
Step B: 1-[3-Chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl]methyl-piperazine
334 mg 1-(5-bromochloromethoxymethyl-phenyl)methyl-piperazine (1.00
mmol) was dissolved in 10 mL dry THF under N and was cooled to -78°C with dry ice-
acetone. 0.66 mL BuLi (1.05 mmol in 1.6 M hexanes) was added and the mixture was
stirred for 15 minutes, then 0.25 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.20 mmol) was added and the mixture was allowed to warm up to room temperature. It
was quenched with brine, extracted with DCM, dried over Na SO , filtered and
concentrated under reduced pressure and used as Preparation 5j without further
purification.
MS (M+H): 381.2.
Preparation 5k: 2-Chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol
Step A: 4-Bromomethoxymethyl-phenol
1.38 g 2-methoxymethyl-phenol (10.0 mmol) was dissolved in 20 mL THF, then 1.87 g
NBS (10.5 mmol) was added and the mixture was stirred at room temperature for 2 hours.
Then it was concentrated under reduced pressure and purified via flash chromatography
using heptane and EtOAc as eluents to obtain 4-bromomethoxymethyl-phenol.
H NMR (400 MHz, CDCl ): 7.00 (s, 1H), 6.82 (s, 1H), 5.46 (s, 1H), 3.87 (s, 3H), 2.30 (s,
3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 51 (44), 65 (40), 94 (88), 137 (22), 173
(29), 175 (30), 201 (83), 203 (78), 216 (100, [M ]), 218 (96, [M ]).
Step B: 4-Bromochloromethoxymethyl-phenol
1.09 g 4-bromomethoxymethyl-phenol (5.00 mmol) was dissolved in 20 mL THF,
then 701 mg NCS (5.25 mmol) was added and the mixture was stirred at room temperature
for 1 day. Then it was concentrated under reduced pressure and purified via reversed phase
chromatography using aqueous 0.1% TFA solution and MeCN as eluents to obtain 4-
bromochloromethoxymethyl-phenol.
H NMR (400 MHz, CDCl3): 6.98 (s, 1H), 5.81 (s, 1H), 3.88 (s, 3H), 2.43 (s, 3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (37), 128 (53), 171 (42), 209 (26), 237
+ + +
(67), 250 (77, [M ]), 252 (100, [M ]), 254 (24, [M ]).
Step C: (4-Bromochloromethoxymethyl-phenoxy)-triisopropyl-silane
772 mg 4-bromochloromethoxymethyl-phenol (3.07 mmol) and 788 L TIPSCl
(3.68 mmol) were dissolved in 10 mL DCM. 418 mg imidazole (6.14 mmol) was added
and the mixture was stirred at room temperature overnight. Then it was concentrated under
reduced pressure and purified via flash chromatography using heptane as eluent to obtain
(4-bromochloromethoxymethyl-phenoxy)-triisopropyl-silane.
H NMR (400 MHz, CDCl ): 6.95 (s, 1H), 3.77 (s, 3H), 2.44 (s, 3H), 1.30 (septet, 3H),
1.10 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 59 (19), 183 (15), 279 (27), 308 (13), 348
(76), 350 (100), 352 (28), 363 (66), 365 (89), 367 (24).
Step D: [2-Chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane
3.07 mmol (4-bromochloromethoxymethyl-phenoxy)-triisopropyl-silane was
dissolved in 20 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 2.1
mL BuLi (3.40 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5
minutes, then 820 L 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 mmol,
dissolved in 5 mL dry THF) was added and the mixture was allowed to warm up to room
temperature. It was quenched with saturated NH Cl solution, extracted with EtOAc, dried
over Na SO , filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-chloro-
6-methoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 225 (14), 254 (10), 296 (13), 396 (67),
398 (26), 411 (100), 413 (39).
Step E: 2-Chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenol
3.07 mmol [2-chloromethoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]-triisopropyl-silane was dissolved in 5 mL THF, then 3.5 mL TBAF (3.50
mmol in 1 M THF) was added and the mixture was stirred for 10 minutes. Then it was
diluted with EtOAc, washed with water and brine, dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5k.
H NMR (400 MHz, DMSO-d ): 9.71 (s, 1H), 7.09 (s, 1H), 3.79 (s, 3H), 2.44 (s, 3H), 1.28
(s, 12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 183 (23), 198 (100), 199 (52), 223 (13),
241 (9), 283 (6), 298 (51, [M ]), 300 (17, [M ]).
Preparation 5l: 2-Chloro-3,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenol
Step A: (4-Bromochloromethyl-phenoxy)-triisopropyl-silane
5.00 g 4-bromochloromethyl-phenol (22.6 mmol) and 5.80 mL TIPSCl (27.1 mmol)
were dissolved in 50 mL DCM. 3.07 g imidazole (45.1 mmol) was added and the mixture
was stirred at room temperature overnight. Then it was concentrated under reduced
pressure and purified via flash chromatography using heptane as eluent to obtain (4-bromo-
2-chloromethyl-phenoxy)-triisopropyl-silane.
H NMR (400 MHz, CDCl ): 7.31 (s, 1H), 7.15 (s, 1H), 2.62 (s, 3H), 1.39 (septet, 3H),
1.13 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 93 (33), 183 (30), 307 (14), 333 (87), 335
(100), 337 (30).
Step B: (4-Bromochloro-3,6-dimethyl-phenoxy)-triisopropyl-silane
6.70 g (4-bromochloromethyl-phenoxy)-triisopropyl-silane (17.7 mmol) was
dissolved in 80 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 10.6
mL LDA was added (21.2 mmol in 2 M THF, EtPh) and the mixture was stirred for 1 hour,
then 2.2 mL MeI (35.4 mmol) was added and the mixture was allowed to warm up to room
temperature. It was quenched with saturated NH Cl solution, extracted with Et O, dried
over Na SO , filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane as eluent. The unreacted starting material
was separated via reversed phase chromatography using MeCN as eluent to obtain (4-
bromochloro-3,6-dimethyl-phenoxy)-triisopropyl-silane.
H NMR (400 MHz, CDCl ): 7.23 (s, 1H), 2.47 (s, 3H), 2.24 (s, 3H), 1.40 (septet, 3H),
1.13 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 93 (23), 146 (17), 197 (26), 347 (76), 349
(100), 351 (27).
Step C: [2-Chloro-3,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
1.18 g (4-bromochloro-3,6-dimethyl-phenoxy)-triisopropyl-silane (3.00 mmol) was
dissolved in 15 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 2.25
mL BuLi (3.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15
minutes, then 1.02 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.00 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with saturated NH Cl solution, extracted with Et O, dried over Na SO , filtered and
4 2 2 4
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain [2-chloro-3,6-dimethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 83 (100), 101 (30), 225 (14), 395 (54),
397 (21).
Step D: 2-Chloro-3,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
968 mg [2-chloro-3,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane (2.20 mmol) was dissolved in 10 mL THF, then 2.4 mL TBAF (2.40
mmol in 1 M THF) was added and the mixture was stirred for 5 minutes. Then it was
diluted with Et O and EtOAc, washed with water and brine, dried over Na SO , filtered
2 2 4
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5l.
H NMR (400 MHz, CDCl ): 7.48 (s, 1H), 5.89 (s, 1H), 2.58 (s, 3H), 2.26 (s, 3H), 1.35 (s,
12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 91 (14), 147 (22), 182 (100), 183 (61),
225 (43), 267 (14), 282 (26, [M ]), 284 (9, [M ]).
Preparation 5m: 2-Chlorofluoromethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol
Step A: 4-Bromochlorofluoromethyl-phenol
3.21 g 2-chlorofluoromethyl-phenol (20.0 mmol) was dissolved in 60 mL THF, then
3.74 g NBS (21.0 mmol) was added and the mixture was stirred at room temperature for 10
minutes. Then it was concentrated under reduced pressure and purified via flash
chromatography using heptane and EtOAc as eluents to obtain 4-bromochlorofluoro-
3-methyl-phenol.
H NMR (400 MHz, CDCl ): 7.25 (d, 1H), 5.63 (s, 1H), 2.44 (d, 3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 75 (37), 95 (36), 159 (100), 161 (31), 238
+ + +
(47, [M ]), 240 (61, [M ]), 242 (15, [M ]).
Step B: (4-Bromochlorofluoromethyl-phenoxy)-triisopropyl-silane
4.06 g 4-bromochlorofluoromethyl-phenol (19.9 mmol) and 4.35 mL TIPSCl
(20.3 mmol) were dissolved in 50 mL DCM. 2.31 g imidazole (33.9 mmol) was added and
the mixture was stirred at room temperature for 1 hour. Then it was concentrated under
reduced pressure and purified via flash chromatography using heptane as eluent to obtain
(4-bromochlorofluoromethyl-phenoxy)-triisopropyl-silane.
H NMR (400 MHz, CDCl ): 7.21 (d, 1H), 2.45 (d, 3H), 1.32 (septet, 3H), 1.10 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 77 (100), 97 (37), 187 (22), 215 (58), 267
(42), 269 (54), 311 (13), 351 (32), 353 (43).
Step C: [2-Chlorofluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane
6.22 g (4-bromochlorofluoromethyl-phenoxy)-triisopropyl-silane (15.7 mmol)
was dissolved in 65 mL dry THF under N and was cooled to -78°C with dry ice-acetone.
11.8 mL BuLi (18.9 mmol in 1.6 M hexanes) was added and the mixture was stirred for
minutes, then 5.34 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.2
mmol) was added and the mixture was allowed to warm up to room temperature. It was
quenched with saturated NH4Cl solution, extracted with DCM, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain [2-chlorofluoro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane.
H NMR (400 MHz, CDCl ): 7.37 (d, 1H), 2.54 (d, 3H), 1.33 (m, 15H), 1.10 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 83 (100), 101 (18), 275 (8), 399 (7).
Step D: 2-Chlorofluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
5.18 g [2-chlorofluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane (11.7 mmol) was dissolved in 15 mL THF, then 12.9 mL
TBAF (12.9 mmol in 1 M THF) was added and the mixture was stirred for 5 minutes. Then
it was diluted with EtOAc, washed with pH 5 HCl solution, water and brine, dried over
Na SO , filtered and concentrated under reduced pressure. The crude product was purified
via flash chromatography using heptane and EtOAc as eluents to obtain Preparation 5m.
H NMR (400 MHz, CDCl ): 7.45 (d, 1H), 5.74 (s, 1H), 2.56 (d, 3H), 1.34 (s, 12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 59 (30), 85 (17), 151 (23), 186 (100), 187
(63), 229 (49), 272 (25), 286 (22, [M ]), 288 (7, [M ]).
Preparation 5n: 3-[2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenyl]-N,N-dimethyl-propanamine
Step A: 1-Bromochloroiodomethyl-benzene
7.93 g 4-bromochloroiodo-benzene (25.0 mmol) was dissolved in 300 mL dry THF
under N and was cooled to -78°C with dry ice-acetone. 13.8 mL LDA was added (27.5
mmol in 2 M THF, EtPh) and the mixture was stirred for 75 minutes, then 3.1 mL MeI
(50.0 mmol) was added and the mixture was allowed to warm up to room temperature. It
was quenched with saturated NH Cl solution and most of the volatiles were evaporated
under reduced pressure. Then it was extracted with DCM, dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane as eluent to obtain 1-bromochloroiodomethyl-
benzene.
H NMR (400 MHz, CDCl ): 7.55 (d, 1H), 7.17 (d, 1H), 2.62 (s, 3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (27), 89 (47), 124 (35), 251 (43), 330
+ + +
(81, [M ]), 332 (100, [M ]), 334 (25, [M ]).
Step B: 3-(4-Bromochloromethyl-phenyl)-N,N-dimethyl-propynamine
1.66 g 1-bromochloroiodomethyl-benzene (5.00 mmol), 626 L N,N-
dimethylpropynamine (7.00 mmol), 176 mg PdCl (PPh ) (0.25 mmol) and 95 mg
2 3 2
copper(I) iodide (0.50 mmol) were dissolved in 26 mL dry DIPA and the mixture was
stirred at 40°C under N for 30 minutes. Then it was concentrated under reduced pressure
and purified via flash chromatography using heptane and EtOAc as eluents. Then it was
further purified via reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain 3-(4-bromochloromethyl-phenyl)-N,N-
dimethyl-propynamine.
H NMR (400 MHz, CDCl ): 7.38 (d, 1H), 7.16 (d, 1H), 3.52 (s, 2H), 2.52 (s, 3H), 2.38 (s,
6H). MS (M+H): 286.0.
Step C: 3-(4-Bromochloromethyl-phenyl)-N,N-dimethyl-propanamine
641 mg 3-(4-bromochloromethyl-phenyl)-N,N-dimethyl-propynamine (2.13
mmol) was dissolved in 3 mL AcOH, then 300 mg red phosphorus and 5 mL HI (67%
aqueous solution) was added. The mixture was heated to 180°C for 20 minutes via
microwave irradiation. After cooling to room temperature it was neutralized with 2 M
NaOH, extracted with DCM, dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents to obtain 3-(4-bromochloro
methyl-phenyl)-N,N-dimethyl-propanamine.
H NMR (400 MHz, CDCl ): 7.35 (d, 1H), 6.92 (d, 1H), 2.70 (t, 2H), 2.51 (s, 3H), 2.29 (t,
2H), 2.21 (s, 6H), 1.74 (quint, 2H). MS (M+H): 290.0.
Step D: 3-[2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-
N,N-dimethyl-propanamine
378 mg 3-(4-bromochloromethyl-phenyl)-N,N-dimethyl-propanamine (1.30
mmol) was dissolved in 5 mL dry THF under N and was cooled to -78°C with dry ice-
acetone. 0.94 mL BuLi (1.50 mmol in 1.6 M hexanes) was added and the mixture was
stirred for 5 minutes, then 370 L 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.80 mmol) was added and the mixture was allowed to warm up to room temperature. It
was quenched with water and brine, extracted with EtOAc, dried over Na SO , filtered and
concentrated under reduced pressure and used as Preparation 5n without further
purification.
MS (M+H): 338.2.
Preparation 5o: [2-Bromomethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]-triisopropyl-silane
Step A: (2,4-Dibromophenoxy)-triisopropyl-silane
7.56 g 2,4-dibromophenol (30.0 mmol) and 7.7 mL TIPSCl (36.0 mmol) were dissolved in
100 mL DCM. 4.08 g imidazole (60.0 mmol) was added and the mixture was stirred at
room temperature overnight. Then it was concentrated under reduced pressure and purified
via flash chromatography using heptane as eluent to obtain (2,4-dibromophenoxy)-
triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 109 (39), 137 (43), 201 (22), 279 (24),
309 (27), 337 (20), 363 (48), 365 (100), 367 (52).
Step B: (2,4-Dibromomethyl-phenoxy)-triisopropyl-silane
11.15 g (2,4-dibromophenoxy)-triisopropyl-silane (27.3 mmol) was dissolved in 100 mL
dry THF under N and was cooled to -78°C with dry ice-acetone. 16.4 mL LDA (32.8
mmol in 2 M THF, EtPh) was added and the mixture was stirred for 1 hour, then 3.4 mL
MeI (54.6 mmol) was added and the mixture was allowed to warm up to room temperature.
It was quenched with saturated NH Cl solution, extracted with EtOAc, dried over Na SO ,
4 2 4
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane as eluent to obtain (2,4-dibromomethyl-phenoxy)-
triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 139 (19), 161 (14), 351 (13), 377 (54),
379 (100), 381 (53).
Step C: [2-Bromomethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
8.70 g (2,4-dibromomethyl-phenoxy)-triisopropyl-silane (20.6 mmol) was dissolved in
50 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 14.2 mL BuLi
(22.7 mmol in 1.6 M hexanes) was added and the mixture was stirred for 1 minute, then
6.1 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.0 mmol) was added and
the mixture was allowed to warm up to room temperature. It was quenched with saturated
NH4Cl solution, extracted with EtOAc, dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified via reversed phase chromatography
using MeCN as eluent to obtain Preparation 5o.
H NMR (400 MHz, CDCl ): 7.57 (d, 1H), 6.71 (d, 1H), 2.65 (s, 3H), 1.37-1.27 (m, 15H),
1.13 (d, 18H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 55 (54), 83 (100), 139 (27), 425 (53), 427
(54).
Preparation 5p: 1-[2-[2,3-Dichloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]ethyl]methyl-piperazine
Step A: 4-Bromo-2,3-dichloro-phenol
1.63 g 2,3-dichlorophenol (10.0 mmol) was dissolved in 30 mL DCM and was cooled to
0°C. Then 512 L bromine (10.0 mmol) was added and the mixture was allowed to warm
up to room temperature and the mixture was stirred at room temperature overnight. Then it
was washed with saturated Na S O solution, dried over Na SO , filtered and concentrated
2 2 3 2 4
under reduced pressure. The crude product was purified via flash chromatography using
heptane and EtOAc as eluents to obtain a mixture of 6-bromo-2,3-dichloro-phenol and 4-
bromo-2,3-dichloro-phenol.
MS (M-H): 239.0.
Step B: 1-[2-(4-Bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine
1.90 g mixture of 6-bromo-2,3-dichloro-phenol and 4-bromo-2,3-dichloro-phenol (7.85
mmol), 2.27 g 2-(4-methylpiperazinyl)ethanol (15.7 mmol) and 4.12 g PPh (15.7
mmol) were dissolved in 20 mL dry toluene under N2, then 3.62 g ditertbutyl
azodicarboxylate (15.7 mmol) was added and the mixture was stirred at room temperature
overnight. Then it was concentrated under reduced pressure and the regioisomers were
separated via flash chromatography using EtOAc and MeOH as eluents. The desired
isomer was further purified via reversed phase chromatography using water and MeCN as
eluents to obtain 1-[2-(4-bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine.
H NMR (400 MHz, DMSO-d ): 7.69 (d, 1H), 7.16 (d, 1H), 4.20 (t, 2H), 2.72 (t, 2H), 2.42-
2.18 (m, 8H), 2.13 (s, 3H). MS (M+H): 367.0.
Step C: 1-[2-[2,3-Dichloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine
2.10 g 1-[2-(4-bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine (5.70 mmol) was
dissolved in 25 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 3.9
mL BuLi (6.28 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5
minutes, then 2.0 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with brine, extracted with DCM, dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via reversed phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain Preparation 5p.
MS (M+H): 415.2.
Preparation 5q: 1-[2-[[3-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridyl]oxy]ethyl]methyl-piperazine
Step A: 5-Bromochloromethyl-pyridinol
4.86 g 5-bromomethyl-pyridinol (25.8 mmol) was dissolved in 250 mL THF, then
4.49 g NCS (33.6 mmol) was added and the mixture was stirred at 60°C in dark for 45
minutes. Then it was concentrated under reduced pressure and crystallized from Et O and
heptane to get an overweight product, which was crystallized from 100 mL MeCN to give
5-bromochloromethyl-pyridinol.
H NMR (400 MHz, DMSO-d ): 11.50 (br s, 1H), 7.74 (s, 1H), 2.36 (s, 3H). MS (M+H):
222.0, (M-H): 220.0.
Step B: 1-[2-[(5-Bromochloromethylpyridyl)oxy]ethyl]methyl-piperazine
2.326 g 5-bromochloromethyl-pyridinol (10.45 mmol), 2.163 g 2-(4-
methylpiperazinyl)ethanol (15.00 mmol) and 3.935 g PPh (15.00 mmol) were dissolved
in 30 mL dry toluene under N , then 3.454 g ditertbutyl azodicarboxylate (15.00 mmol)
was added and the mixture was stirred at room temperature under N for 20 minutes. Then
it was concentrated under reduced pressure and the structural isomers were separated via
flash chromatography using EtOAc and MeOH as eluents. The isomer eluting earlier was
collected as 1-[2-[(5-bromochloromethylpyridyl)oxy]ethyl]methyl-piperazine.
H NMR (400 MHz, DMSO-d ): 8.24 (s, 1H), 4.41 (t, 2H), 2.68 (t, 2H), 2.48-2.15 (m,
11H), 2.12 (s, 3H). MS (M+H): 348.0.
Step C: 1-[2-[[3-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
pyridyl]oxy]ethyl]methyl-piperazine
1.917 g 1-[2-[(5-bromochloromethylpyridyl)oxy]ethyl]methyl-piperazine (5.50
mmol) was dissolved in 30 mL dry THF under N and was cooled to -78°C with dry ice-
acetone. 4.1 mL BuLi (6.60 mmol in 1.6 M hexanes) was added and the mixture was
stirred for 5 minutes, then 1.46 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(7.15 mmol) was added and the mixture was allowed to warm up to room temperature. It
was quenched with brine, extracted with DCM, dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain Preparation 5q.
MS (M+H): 396.2.
Preparation 5r: 1-[3-[2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl]propyl]methyl-piperazine
Step A: 3-(4-Bromochloromethyl-phenyl)propynol
17.43 g 1-bromochloroiodomethyl-benzene (52.60 mmol, see Step A at
Preparation 5n), 3.37 mL propynol (57.86 mmol), 369 mg PdCl (PPh ) (0.53
2 3 2
mmol) and 501 mg copper(I) iodide (2.63 mmol) were dissolved in 100 mL dry DIPA and
the mixture was stirred at 40°C under N2 for 20 minutes. Then it was concentrated under
reduced pressure and purified via flash chromatography using heptane and EtOAc as
eluents to obtain 3-(4-bromochloromethyl-phenyl)propynol.
H NMR (400 MHz, CDCl ): 7.40 (d, 1H), 7.16 (d, 1H), 4.54 (d, 2H), 2.53 (s, 3H), 1.87 (t,
1H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (35), 115 (100), 223 (56), 258 (15,
+ + +
[M ]), 260 (18, [M ]), 262 (5, [M ]).
Step B: 3-(4-Bromochloromethyl-phenyl)propynyl methanesulfonate
5.427 g 3-(4-bromochloromethyl-phenyl)propynol (20.9 mmol) and 4.37 mL
DIPEA (25.1 mmol) was dissolved in 50 mL dry DCM under N , then 1.78 mL
methanesulfonyl chloride (23.0 mmol) was added carefully and the mixture was stirred for
minutes. Then it was concentrated under reduced pressure and purified via flash
chromatography using heptane and EtOAc as eluents to obtain 3-(4-bromochloro
methyl-phenyl)propynyl methanesulfonate.
H NMR (400 MHz, CDCl ): 7.45 (d, 1H), 7.19 (d, 1H), 5.12 (s, 2H), 3.18 (s, 3H), 2.53 (s,
3H).
Step C: 1-[3-(4-Bromochloromethyl-phenyl)propynyl]methyl-piperazine
4.31 g 3-(4-bromochloromethyl-phenyl)propynyl methanesulfonate (12.8 mmol)
was dissolved in 120 mL MeCN, and the mixture was added to the stirred mixture of 2.65
g K CO (19.2 mmol), 14.2 mL 1-methylpiperazine (127.7 mmol) and 120 mL MeCN. The
mixture was stirred for 30 minutes, then it was filtered and the filtrate was concentrated
under reduced pressure. Brine was added and the mixture was extracted with DCM, dried
over Na SO , filtered and concentrated under reduced pressure to obtain 1-[3-(4-bromo
chloromethyl-phenyl)propynyl]methyl-piperazine.
MS (M+H): 341.0.
Step D: 1-[3-(4-Bromochloromethyl-phenyl)propyl]methyl-piperazine
1.51 g 1-[3-(4-bromochloromethyl-phenyl)propynyl]methyl-piperazine (4.42
mmol) was dissolved in 15 mL AcOH, then 500 mg red phosphorus and 10 mL HI (67%
aqueous solution) was added. The mixture was heated to 180°C for 5 minutes via
microwave irradiation. After cooling to room temperature it was neutralized with 2 M
NaOH, extracted with DCM, dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents to obtain 1-[3-(4-bromochloro
methyl-phenyl)propyl]methyl-piperazine.
H NMR (400 MHz, DMSO-d ): 7.50 (d, 1H), 7.13 (d, 1H), 2.68 (t, 2H), 2.47 (s, 3H),
2.46-2.15 (m, 10H), 2.13 (s, 3H), 1.67 (quint, 2H). MS (M+H): 345.0.
Step E: 1-[3-[2-Chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]
propyl]methyl-piperazine
708 mg 1-[3-(4-bromochloromethyl-phenyl)propyl]methyl-piperazine (2.04
mmol) was dissolved in 10 mL dry THF under N and was cooled to -78°C with dry ice-
acetone. 1.7 mL BuLi (2.70 mmol in 1.6 M hexanes) was added and the mixture was
stirred for 5 minutes, then 0.61 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3.00 mmol) was added and the mixture was allowed to warm up to room temperature. It
was quenched with brine, extracted with DCM, dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Preparation 5r.
MS (M+H): 393.4.
Preparation 5s: 1-[2-[2,3-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
phenoxy]ethyl]methyl-piperazine
Step A: 4-Bromo-2,3-dimethyl-phenol
1.22 g 2,3-dimethylphenol (10.0 mmol) was dissolved in 50 mL MeCN, then 1.78 g NBS
(10.0 mmol) was added and the mixture was stirred at room temperature overnight. Then it
was concentrated under reduced pressure and purified via flash chromatography using
heptane and EtOAc as eluents to obtain 4-bromo-2,3-dimethyl-phenol.
H NMR (400 MHz, CDCl ): 7.24 (d, 1H), 6.52 (d, 1H), 4.68 (s, 1H), 2.37 (s, 3H), 2.22 (s,
3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 77 (45), 91 (62), 121 (100), 200 (76,
[M] ), 202 (74, [M] ).
Step B: 1-[2-(4-Bromo-2,3-dimethyl-phenoxy)ethyl]methyl-piperazine
1.54 g 4-bromo-2,3-dimethyl-phenol (7.66 mmol), 2.21 g 2-(4-methylpiperazin
yl)ethanol (15.3 mmol) and 6.03 g PPh (23.0 mmol) were dissolved in 20 mL dry toluene
under N , then 5.29 g ditertbutyl azodicarboxylate (23.0 mmol) was added and the mixture
was stirred at 45°C for 2 hours. Then it was concentrated under reduced pressure and
purified via flash chromatography using EtOAc and MeOH as eluents to obtain 1-[2-(4-
bromo-2,3-dimethyl-phenoxy)ethyl]methyl-piperazine.
H NMR (400 MHz, CDCl ): 7.31 (d, 1H), 6.58 (d, 1H), 4.06 (t, 2H), 2.83 (t, 2H), 2.70-
2.38 (m, 8H), 2.36 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).
Step C: 1-[2-[2,3-Dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine
2.10 g 1-[2-(4-bromo-2,3-dimethyl-phenoxy)ethyl]methyl-piperazine (6.42 mmol) was
dissolved in 25 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 4.2
mL BuLi (6.74 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15
minutes, then 1.44 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.06 mmol)
was added and the mixture was allowed to warm up to room temperature. It was quenched
with brine, extracted with DCM, dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to obtain Preparation 5s.
H NMR (400 MHz, DMSO-d ): 7.46 (d, 1H), 6.75 (d, 1H), 4.02 (t, 2H), 2.68 (t, 2H), 2.48
(br s, 4H), 2.38 (s, 3H), 2.30 (br s, 4H), 2.13 (s, 3H), 2.05 (s, 3H), 1.26 (s, 12H). MS
(M+H): 375.4.
Preparation 5t: 2-(4-Bromochloromethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane
2.92 g 1-bromochloroiodomethyl-benzene (8.81 mmol) was dissolved in 30 mL
dry THF under N2 and 4.8 mL EtMgCl (9.69 mmol in 2 M THF) was added dropwise at
room temperature. It was stirred for 10 minutes, then 5.4 mL 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (26.4 mmol) was added and the mixture was stirred for 10
minutes. Then it was concentrated under reduced pressure and purified via flash
chromatography using heptane and EtOAc as eluents to obtain Preparation 5t.
H NMR (400 MHz, DMSO-d ): 7.49 (d, 1H), 7.45 (d, 1H), 2.66 (s, 3H), 1.34 (s, 12H).
Preparation 5u: 1-[2-[2-Chloroethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]methyl-piperazine
Step A: 1-[2-(4-Bromochloro-phenoxy)ethyl]methyl-piperazine
.373 g (50 mmol) 4-bromochlorophenol, 14.442 g 2-(4-methylpiperazinyl)ethanol
(100 mmol) and 26.229 g PPh (100 mmol) were dissolved in 250 mL toluene, then 23.027
g ditertbutyl azodicarboxylate (100 mmol) was added. The mixture was stirred at 50°C
under N until no further conversion was observed. The toluene was evaporated under
reduced pressure and the residue was purified via flash chromatography using EtOAc and
MeOH as eluents
MS (M+H) = 333.0.
Step B: 1-[2-(4-Bromochloroethyl-phenoxy)ethyl]methyl-piperazine
2.0 g (6 mmol) 1-[2-(4-bromochloro-phenoxy)ethyl]methyl-piperazine was dissolved
in 50 mL dry THF under N and was cooled to -78°C with dry ice-acetone. 6 mL LDA (12
mmol in 2 M THF) was added and the mixture was stirred for 3 hour, then 982 mg (6.3
mmol) iodoethane was added and the mixture was allowed to warm up to room
temperature. It was quenched with saturated NH Cl solution, extracted with EtOAc, dried
over Na SO , filtered and concentrated under reduced pressure.
MS (M+H) = 360.8, 362.8.
Step C: 1-[2-[2-Chloroethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine
2099 mg (5.8 mmol) 1-[2-(4-bromochloroethyl-phenoxy)ethyl]methyl-piperazine
was dissolved in 30 mL dry THF under N2 and was cooled to -78°C with dry ice-acetone
and 4.645 mL BuLi (11.61 mmol in 2.5 M THF) was added dropwise. It was stirred for 5
h, then 2.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.77 mmol) was
added and the mixture was stirred for 30 minutes. Then it was concentrated under reduced
pressure and purified via flash chromatography using EtOAc and MeOH as eluents to
obtain Preparation 5u.
MS: (M+H) = 409.2
Preparation 5v: 1-[2-[3-Bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]methyl-piperazine
Step A: (2-Chloroiodo-phenoxy)-triisopropyl-silane
.178 g 2-chloroiodophenol (40.0 mmol), 11.06 g (80 mmol) K CO and 10.17 mL
TIPSCl (48.0 mmol) were dissolved in 100 mL ACN. The mixture was stirred at room
temperature for 1 h. Then it was concentrated under reduced pressure and purified via flash
chromatography using heptane as eluent to obtain (2-chloroiodo-phenoxy)-triisopropyl-
silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (6.5), 93 (8), 155 (9), 170 (10), 281
(7), 297 (7.5), 311 (10), 339 (17), 367 (100), 368 (20), 369 (40), 370 (6.5), 410 (1.5, [M ]).
Step B: (3-Bromochloroiodo-phenoxy)-triisopropyl-silane
820 mg (2-chloroiodo-phenoxy)-triisopropyl-silane (2 mmol) was dissolved in 10 mL
dry THF under N and was cooled to -78°C with dry ice-acetone. 1.15 mL LDA (2.3 mmol
in 2 M THF) was added and the mixture was stirred for 1 hour, then 814 mg (2.5 mmol)
1,2-dibromotetrachloroethane was added and the mixture was allowed to warm up to room
temperature. It was quenched with saturated NH Cl solution, extracted with EtOAc, dried
over Na SO , filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane as eluent to obtain (3-bromochloro
iodo-phenoxy)-triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (21), 79 (20), 93 (48), 195 (18), 248
(15), 250 (19), 445 (75), 447 (100), 448 (18), 449 (26), 488 (0.4, [M ]).
Step C: [3-Bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-
triisopropyl-silane
900 mg (3-bromochloroiodo-phenoxy)-triisopropyl-silane (1.84 mmol) was dissolved
in 10 mL dry THF under N and 1.01 mL EtMgCl (2.02 mmol in 2 M THF) was added
dropwise at room temperature. It was stirred for 10 minutes, then 0.47 mL 2-isopropoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 mmol) was added and the mixture was stirred
for 10 minutes. Then it was concentrated under reduced pressure and purified via flash
chromatography using heptane and EtOAc as eluents to obtain [3-bromochloro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane.
H-NMR (400 MHz, CDCl ): 7.39 (d, 1H), 6.84 (d, 1H), 1.38 (s, 12H), 1.32 (m, 3H), 1.12
(d, 18H).
Step D: 3-Bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
The resulting intermediate was dissolved in 10 mL THF and 0.5 mL 1M
tetrabutylammonium fluoride solution was added. The mixture was stirred at room
temperature until no further conversion was observed. Volatiles were evaporated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to obtain 3-bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenol.
H-NMR (400 MHz, DMSO-d ): 10.97 (s, 1H), 7.36 (d, 1H), 6.96 (d, 1H), 1.28 (s, 12H).
Step E: 1-[2-[3-Bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine
133 mg 3-bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (0.4
mmol) was dissolved in 5 mL toluene, 82 mg 2-(4-methylpiperazinyl)ethanol (0.57
mmol) and 149 mg PPh (0.57 mmol) were added, then 131 mg ditertbutyl
azodicarboxylate (0.57 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. The toluene was evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents
to obtain 1-[2-[3-bromochloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]
ethyl]methyl-piperazine (Preparation 5v).
MS: (M+H) = 459.2.
Preparation 5w: 1-[2-[2,3-Dichloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]ethyl]methyl-piperazine
Step A: 1-[2-(4-Bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine
2.0 g (6 mmol) 1-[2-(4-bromochloro-phenoxy)ethyl]methyl-piperazine (Preparation
, Step A) was dissolved in 50 mL dry THF under N and was cooled to -78°C with dry
ice-acetone. 6 mL LDA (12 mmol in 2 M THF) was added and the mixture was stirred for
3 hour, then 3125 mg (13.2 mmol) hexachloroethane was added and the mixture was
allowed to warm up to room temperature. It was quenched with saturated NH Cl solution,
extracted with EtOAc, dried over Na SO , filtered and concentrated under reduced
pressure to obtain 1-[2-(4-bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine.
Step B: 1-[2-[2,3-Dichloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]-
4-methyl-piperazine
1630 mg (4.43 mmol) 1-[2-(4-bromo-2,3-dichloro-phenoxy)ethyl]methyl-piperazine
was dissolved in 20 mL dry THF under N and was cooled to -78°C with dry ice-acetone
and 3.9 mL BuLi (2.5 M THF) was added dropwise. It was stirred for 5 h, then 2.1 mL 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.2 mmol) was added and the
mixture was stirred for 30 minutes. Then it was concentrated under reduced pressure and
purified via flash chromatography using EtOAc and MeOH as eluents to obtain
Preparation 5w.
MS: (M+H) = 415.0, 417.0.
Preparation 5x: (3-chlorocyanotriisopropylsilyloxy-phenyl)boronic acid
Step A: (4-bromochloroiodo-phenoxy)-triisopropyl-silane
.91 g (4-bromochloro-phenoxy)-triisopropyl-silane (Preparation 5c, Step A) (30
mmol) was dissolved in 100 mL dry THF, then cooled to -78°C. At this temperature 20 mL
(1.8 M in THF, 1.2 eq) LDA was added over 5 min. Resulting mixture further was stirred
for 90 min. Then 9.89 g (39 mmol, 1.3 eq) I was added at -78°C in one portion. After 20
min stirring it was quenched with saturated NH Cl solution, extracted with EtOAc, dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane as eluent to obtain (4-bromochloro
iodo-phenoxy)-triisopropyl-silane.
H NMR (400 MHz, DMSO-d ): 7.59 (d, 1H), 6.97 (d, 1H), 1.31 (m, 3H), 1.06 (d, 18H).
Step B: 6-bromochlorotriisopropylsilyloxy-benzonitrile
3.62 g (4-bromochloroiodo-phenoxy)-triisopropyl-silane (7.40 mmol) was dissolved
in 20 mL dry DMF and 0.795 g (8.88 mmol, 1.2 eq) CuCN was added, then stirred
overnight at 120°C. Reaction mixture was diluted with brine, and then extracted with
EtOAc. Organic phase was dried over MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by flash chromatography using heptane and
EtOAc as eluents to obtain 6-bromochlorotriisopropylsilyloxy-benzonitrile.
H NMR (400 MHz, CDCl ): 7.41 (d, 1H), 6.99 (d, 1H), 1.31 (m, 3H), 1.13 (d, 18H).
Step C: (3-chlorocyanotriisopropylsilyloxy-phenyl)boronic acid
1.50 g 6-bromochlorotriisopropylsilyloxy-benzonitrile (3.85 mmol) was dissolved in
mL dry THF under N and was cooled to -78°C with dry ice-acetone. 1.85 mL nBuLi
(4.63 mmol, 2.5 M in hexanes) was added and the mixture was stirred for 10 minutes, then
0.853 mL triethyl borate (5.01 mmol, 1.3 eq) was added and the mixture was allowed to
warm up to room temperature. It was quenched with saturated NH4Cl solution, extracted
with EtOAc, dried over Na SO , filtered and concentrated under reduced pressure to obtain
(3-chlorocyanotriisopropylsilyloxy-phenyl)boronic acid.
H NMR (400 MHz, DMSO-d ): 8.52 (bs, 2H), 7.59 (d, 1H), 7.27 (d, 1H), 1.34 (m, 3H),
1.07 (d, 18H).
Preparation 5y: [2-chloro(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenoxy]-triisopropyl-silane
Step A: 2-chlorotriisopropylsilyloxy-phenol
To a stirred solution of 10.0 g 2-chlorobenzene-1,3-diol (69.17mmol) in 100 mL dry
MeCN, 19.12 g potassium carbonate (138.35 mmol, 2 eq) and 16.15 mL TIPSCl (76.09
mmol. 1.1 eq) was added. Resulting mixture was stirred for 30 min. Potassium carbonate
was removed by filtration, then the filtrate was concentrated under reduced pressure. This
crude product was purified by flash chromatography using heptane and EtOAc as eluents
to obtain 2-chlorotriisopropylsilyloxy-phenol as colorless oil.
H NMR (400 MHz, CDCl ): 7.01 (t, 1H), 6.65 (dd, 1H), 6.52 (dd, 1H), 5.62 (bs, 1H), 1.33
(m, 3H), 1.14 (d, 18H).
Step B: [2-chloro(methoxymethoxy)phenoxy]-triisopropyl-silane
4.70 g 2-chlorotriisopropylsilyloxy-phenol (15.62 mmol) was dissolved in 50 mL dry
THF, and then it was cooled to 0°C under argon atmosphere. Then 0.687 g NaH (17.18
mmol, 1.1 eq, 60% in mineral oil) was added slowly and stirred for 15 min at this
temperature. After addition of 1.41 mL MOMCl (18.74 mmol, 1.2 eq) resulting mixture
was allowed to warm up to room temperature and stirred until no further conversion was
observed. From the reaction mixture the inorganics were removed by filtration. The filtrate
was evaporated under reduced pressure to obtain [2-chloro(methoxymethoxy)phenoxy]-
triisopropyl-silane as light-yellow oil, which was used in the next step without further
purification.
H NMR (400 MHz, CDCl ): 7.03 (t, 1H), 6.79 (dd, 1H), 6.63 (dd, 1H), 5.24 (s, 2H), 3.53
(s, 3H), 1.33 (m, 3H), 1.14 (d, 18H).
Step C: [2-chloro(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenoxy]-triisopropyl-silane
.39 g [2-chloro(methoxymethoxy)phenoxy]-triisopropyl-silane (15.62 mmol) was
dissolved in 50 mL dry THF, and then it was cooled to -78°C under argon atmosphere.
Then 7.50 mL butyl lithium (18.74 mmol, 1.2 eq, 2.5 M in hexan) was added. Resulting
mixture was stirred for 90 min. To the ortho-lithiated intermediate 4.78 mL 2-isopropoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.43 mmol, 1.5 eq) was added. After 30 min
stirring at -78°C we have observed full conversion. It was quenched with saturated NH Cl
solution, extracted with EtOAc, dried over Na SO , filtered and concentrated under
reduced pressure to obtain [2-chloro(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenoxy]-triisopropyl-silane as yellow oil.
H NMR (400 MHz, CDCl ): 7.52 (d, 1H), 6.71 (d, 1H), 5.15 (s, 2H), 3.67 (s, 3H), 1.35 (s,
12H), 1.33 (m, 3H), 1.14 (d, 18H).
Preparation 6a: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate
186.6 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetra-hydropyranyloxyphenyl)propanoate (Preparation 4a) (310.3 mmol) and 99.99 g
2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation
5a) (372.3 mmol) were dissolved in 1.2 L THF, then 202.2 g Cs2CO3 (620.6 mmol)
dissolved in 300 mL water was added. Then 11.0 g AtaPhos (15.51 mmol) was added, and
the mixture was stirred under nitrogen at reflux temperature until no further conversion
was observed. Most of the volatiles were evaporated under reduced pressure, then it was
diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set
to 8 with 2 M HCl. After phase separation the aqueous phase was extracted with
dichloromethane. The organic layers were combined and dried over Na SO , filtered and
concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair
eluting later was collected as Preparation 6a.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.27 (br s, 1H), 8.60 (s,
1H), 7.30 (m, 2H), 7.22 (m, 2H), 7.16/7.14 (d, 1H), 7.12 (m ,1H), 7.00 (d, 1H), 6.96 (d,
1H), 6.74/6.73 (t, 1H), 6.34/6.36 (d, 1H), 5.55/5.52 (m, 1H), 5.54/5.41 (dd, 1H), 4.06 (q,
2H), 3.68/3.54 (m, 2H), 3.10/3.07 (dd, 1H), 2.44 (dd, 1H), 1.98/1.90 (br s, 1H), 1.85/1.83
(s, 3H), 1.79 (br s, 2H), 1.64 (br s, 1H), 1.59 (br s, 1H), 1.54 (br s, 1H), 1.09/1.08 (t, 3H).
HRMS: (M+H) = 663.1728 and 663.1717.
Preparation 6b: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(pyrazinylmethoxy)phenyl]
propanoate
2.52 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-
(pyrazinylmethoxy)phenyl]propanoate (Preparation 4b) (4.1 mmol) and 2.2 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(8.2 mmol) were dissolved in 30 mL 1,4-dioxane, then 2.67 g Cs CO (8.2 mmol)
dissolved in 15 mL water was added. Then 284 mg AtaPhos (0.41 mmol) was added, and
the mixture was stirred under nitrogen at 100°C until no further conversion was observed.
Most of the volatiles were evaporated under reduced pressure, then it was diluted with
dichloromethane and brine. After shaking the pH of the aqueous phase was set to 7 with 2
M HCl. After phase separation the aqueous phase was extracted with dichloromethane. The
organic layers were combined and dried over Na SO , filtered and concentrated under
reduced pressure. The diastereoisomers were separated via flash chromatography using
heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as
Preparation 6b.
H NMR (500 MHz, DMSO-d ): 10.27 (s, 1H), 8.92 (d, 1H), 8.76-8.61 (m, 2H), 8.58 (s,
1H), 7.30 (m, 2H), 7.22 (m, 2H), 7.19 (m, 1H), 7.16 (d, 1H), 7.07 (dm, 1H), 6.97 (d, 1H),
6.76 (m, 1H), 6.30 (dm, 1H), 5.46 (dd, 1H), 5.30 (d, 1H), 5.25 (d, 1H), 4.07 (m, 1H), 4.04
(m, 1H), 3.16 (dd, 1H), 2.49 (dd, 1H), 1.80 (s, 3H), 1.08 (t, 3H).
HRMS: (M+H) = 671.1533.
Preparation 6c: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(5-
fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate
and
Preparation 6q: Ethyl (2R)[(5R )(3-chlorohydroxymethyl-phenyl)(5-
fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate
174.0 g ethyl (2R)[5-bromo(5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4c) (294.2 mmol) and 94.81 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(353.0 mmol) were dissolved in 1.18 L THF, then 191.7 g Cs CO (588.4 mmol) dissolved
in 300 mL water was added. Then 10.41 g AtaPhos (14.71 mmol) was added, and the
mixture was stirred under nitrogen at 60°C until no further conversion was observed. Most
of the volatiles were evaporated under reduced pressure, then it was diluted with
dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2
M HCl. After phase separation the aqueous phase was extracted with dichloromethane. The
organic layers were combined and dried over Na SO , filtered and concentrated under
reduced pressure. The diastereoisomers were separated via flash chromatography using
heptane and ethyl acetate as eluents.
The diastereoisomer pair eluting earlier was collected as Preparation 6q.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.44 (s, 1H), 8.58 (s, 1H),
7.11 (t, 1H), 7.02/7.00 (d, 1H), 6.98 (d, 1H), 6.95/6.94 (d, 1H), 6.73 (t, 1H), 6.21/6.19 (d,
1H), 5.87 (dd, 1H), 5.71 (t, 1H), 5.55/5.49 (t, 1H), 5.47/5.34 (dd, 1H), 4.10 (q, 1H), 4.08
(q, 1H), 3.66 (m, 1H), 3.52 (m, 1H), 3.23 (dd, 1H), 2.33 (dd, 1H), 2.22/2.21 (t, 3H), 2.03-
1.49 (m, 6H), 1.11/1.10 (t, 3H).
HRMS: (M+H) = 653.1518
The diastereoisomer pair eluting later was collected as Preparation 6c.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.40 (s, 1H), 8.58 (s, 1H),
7.15 (t, 1H), 7.10 (d, 1H), 7.04 (d, 1H), 7.01 (d, 1H), 6.81/6.80 (t, 1H), 6.38/6.36 (d, 1H),
5.89 (dd, 1H), 5.69 (t, 1H), 5.56/5.52 (t, 1H), 5.56/5.43 (dd, 1H), 4.05 (q, 2H), 3.68 (m,
1H), 3.54 (m, 1H), 3.13 (dd, 1H), 2.36 (dd, 1H), 1.95/1.94 (s, 3H), 1.82-1.51 (m, 6H), 1.09
(t, 3H).
HRMS: (M+H) = 653.1485 and 653.1492.
Preparation 6d: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate
36.3 g ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4d) (63.3 mmol) and 18.7 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(69.6 mmol) were dissolved in 400 mL THF, then 32.6 g Cs CO (100.0 mmol) dissolved
in 100 mL water was added. Then 1.8 g AtaPhos (2.5 mmol) was added, and the mixture
was stirred under nitrogen at reflux temperature until no further conversion was observed.
Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous
phase was set to 8 with 2 M HCl. After phase separation the aqueous phase was extracted
with dichloromethane. The organic layers were combined and dried over Na SO , filtered
and concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair
eluting later was collected as Preparation 6d.
H NMR (400 MHz, DMSO-d6, 1:1 mixture of diastereomers): 10.40 (s, 1H), 8.58/8.57 (s,
1H), 7.80/7.79 (d, 1H), 7.15 (tm, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 7.02 (d, 1H), 6.81 (m,
1H), 6.54 (dd, 1H), 6.39 (dm, 1H), 5.69 (dm, 1H), 5.57 (m, 1H), 5.55/5.43 (ddd, 1H), 4.06
(m, 2H), 3.68 (m, 1H), 3.54 (m, 1H), 3.33 (s, 3H), 3.13 (td 1H), 2.36 (m, 1H), 1.94/1.93 (s,
3H), 1.80 (m, 2H), 1.71-1.48 (m, 3H), 1.09 (td, 3H).
MS: (M+H) = 635.0.
Preparation 6e: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate
2.013 g ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4e) (4.0 mmol) and 1.396 g 2-chloromethyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (5.2 mmol) were
dissolved in 16 mL 1,4-dioxane, then 2.607 g Cs CO (8.0 mmol) dissolved in 4 mL water
was added. Then 57 mg AtaPhos (0.08 mmol) was added, rinsed with nitrogen, and heated
at 110°C via microwave irradiation until no further conversion was observed. Then it was
diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set
to 5 with 2 M HCl. After phase separation the aqueous phase was extracted with
dichloromethane. The organic layers were combined and dried over Na SO , filtered and
concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected as Preparation 6e.
H NMR (500 MHz, DMSO-d ): 10.40 (br s, 1H), 8.57 (s, 1H), 7.79 (d, 1H), 7.18 (td, 1H),
7.08 (d, 1H), 7.04 (d, 1H), 6.91 (d, 1H), 6.77 (t, 1H), 6.53 (dd, 1H), 6.36 (dd, 1H), 5.67 (d,
1H), 5.40 (dd, 1H), 4.04 (m, 2H), 3.77 (s, 3H), 3.00 (dd, 1H), 2.42 (dd, 1H), 1.92 (s, 3H),
1.07 (t, 3H).
HRMS: (M+H) = 565.1187.
Preparation 6f: Ethyl (2R)[6-(5-chlorofuryl)-(5S )(3-chlorohydroxy
methyl-phenyl)-thieno[2,3-d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]
phenyl]propanoate
11.11 g ethyl (2R)[5-bromo(5-chlorofuryl)thieno[2,3-d]pyrimidinyl]oxy[2-
[(4-methoxyphenyl)methoxy]phenyl]propanoate (Preparation 4f) (17.28 mmol) and 7.0 g
2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation
5a) (26.0 mmol) were dissolved in 100 mL 1,4-dioxane, then 11.4 g Cs CO (35.0 mmol)
dissolved in 50 mL water was added. Then 1.22 g AtaPhos (1.73 mmol) was added, and
the mixture was stirred under nitrogen at reflux temperature until no further conversion
was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of
the aqueous phase was set to 6 with 2 M HCl. After phase separation the aqueous phase
was extracted with dichloromethane. The organic layers were combined and dried over
Na2SO4, filtered and concentrated under reduced pressure. The diastereoisomers were
separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer eluting later was collected as Preparation 6f.
MS: (M+H) = 705.0.
Preparation 6g: Ethyl (2R)[6-(5-chlorofuryl)-(5S )(3-chlorohydroxy
methyl-phenyl)-thieno[2,3-d]pyrimidinyl]oxy[2-[[(2S)-tetrahydrofuranyl]
methoxy]phenyl]propanoate
547 mg ethyl (2R)[5-bromo(5-chlorofuryl)thieno[2,3-d]pyrimidinyl]oxy[2-
[[(2S)-tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 4g) (0.752 mmol)
and 403 mg 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (1.5 mmol) were dissolved in the mixture of 5 mL THF and 5 mL 1,4-
dioxane, then 652 mg Cs CO (2.0 mmol) dissolved in 5 mL water was added. Then 53 g
AtaPhos (0.075 mmol) was added, rinsed with nitrogen, heated at 100°C via microwave
irradiation until no further conversion was observed. Then it was diluted with
dichloromethane and brine. After shaking the pH of the aqueous phase was set to 6 with 2
M HCl. After phase separation the aqueous phase was extracted with dichloromethane. The
organic layers were combined and dried over Na SO , filtered and concentrated under
reduced pressure. The diastereoisomers were separated via flash chromatography using
heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as
Preparation 6g.
MS: (M+H) = 669.0.
Preparation 6h: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
22.0 g ethyl (2R)[5-bromo(4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 4h) (34.84 mmol)
and 11.23 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (41.80 mmol) were dissolved in 200 mL THF, then 34.05 g Cs CO
(104.5 mmol) dissolved in 200 mL water was added. Then 2.46 g AtaPhos (3.48 mmol)
was added, and the mixture was stirred under nitrogen at 60°C until no further conversion
was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of
the aqueous phase was set to 7 with 2 M HCl. After phase separation the aqueous phase
was extracted with dichloromethane. The organic layers were combined and dried over
Na SO , filtered and concentrated under reduced pressure. The diastereoisomers were
separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer pair eluting later was collected as Preparation 6h.
H NMR (400 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.30 (s, 1H), 8.61/8.60 (s,
1H), 7.26/7.23 (d, 1H), 7.19/7.17 (d, 1H), 7.13 (m, 1H), 7.01 (d, 1H), 6.99 (d, 1H), 6.94
(m, 1H), 6.87 (dd, 1H), 6.74 (m, 1H), 6.30 (m, 1H), 5.56/5.53 (m, 1H), 5.53/5.42 (m, 1H),
4.07 (m, 2H), 3.68/3.56 (m, 2H), 3.59/3.58 (s, 3H), 3.15 (m, 1H), 2.42 (dd, 1H), 2.03-1.89
(br s, 1H), 1.86/1.84 (s, 3H), 1.79 (br s, 2H), 1.71-1.48 (br s, 3H), 1.10 (td, 3H).
MS: (M+H) = 693.0.
Preparation 6i: Methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
Preparation 6n: Methyl (2R)[(5R )-(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
13.17 g methyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (Preparation 4i) (28.12 mmol) and 10.57 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (39.37 mmol) were
dissolved in 100 mL 2-Me-THF, then 40 mL TBAOH (1 M aqueous solution) was added.
Then 893 mg AtaPhos (1.406 mmol) was added, and the mixture was stirred under
nitrogen at reflux temperature until no further conversion was observed. It was diluted with
EtOAc and 1 mL HCl (2 M aqueous solution), then it was washed with water and brine.
The organic layer was dried over Na2SO4, filtered and concentrated under reduced
pressure. The diastereoisomers were separated via flash chromatography using heptane and
ethyl acetate as eluents. The diastereoisomer eluting earlier was collected as Preparation
H NMR (500 MHz, DMSO-d ):10.22 (br,s 1H), 8.53 (s, 1H), 7.16 (m, 3H), 7.07 (d, 1H),
7.00 (d, 1H), 6.66 (m, 2H), 5.45 (dd, 1H), 3.54 (s, 3H), 2.93 (dd, 1H), 2.66 (dd, 1H), 2.62
(m, 2H), 1.99 (s, 3H), 1.15 (t, 3H).
HRMS: (M+H) = 483.1137.
The diastereoisomer eluting later was collected as Preparation 6i.
H NMR (500 MHz, DMSO-d ): 10.26 (br s, 1H), 8.52 (s, 1H), 7.14 (m, 3H), 6.97 (d, 1H),
6.94 (d, 1H), 6.65 (m, 2H), 5.30 (dd, 1H), 3.64 (s, 3H), 2.99 (dd, 1H), 2.66 (m, 2H), 2.54
(dd, 1H), 2.17 (s, 3H), 1.15 (t, 3H).
HRMS: (M+H) = 483.1126.
Preparation 6j: Methyl (2R)[6-ethyl-(5S )(4-hydroxymethyl-phenyl)
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
Preparation 6o: Methyl (2R)[6-ethyl-(5R )(4-hydroxymethyl-phenyl)
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
2.25 g methyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (Preparation 4i) (2.67 mmol) and 1.76 g 3-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenol (8.0 mmol) were dissolved in 15 mL 2-Me-THF, then 2.75
g Ag CO (10.0 mmol) was added. Then 309 mg Pd(PPh ) (0.267 mmol) was added,
2 3 3 4
rinsed with nitrogen, heated at 100°C via microwave irradiation until no further conversion
was observed. It was diluted with ethyl acetate and brine. After shaking the pH of the
aqueous phase was set to 5 with 2 M HCl. After phase separation the organic layer was
dried over Na SO , filtered and concentrated under reduced pressure. The diastereoisomers
were separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer eluting earlier was collected as Preparation 6j.
H NMR (500 MHz, DMSO-d ): 9.44 (s, 1H), 8.52 (s, 1H), 7.16 (m, 3H), 7.05 (d, 1H),
6.78 (d, 1H), 6.76 (dd, 1H), 6.70 (m, 2H), 5.47 (dd, 1H), 3.54 (s, 3H), 2.95 (dd, 1H), 2.68
(dd, 1H), 2.62 (m, 2H), 1.84 (s, 3H), 1.15 (t, 3H).
HRMS: (M+H) = 449.1509.
The diastereoisomer eluting later was collected as Preparation 6o.
H NMR (500 MHz, DMSO-d ):9.64 (s, 1H), 8.50 (s, 1H), 7.14 (m, 3H), 6.94 (d, 1H), 6.82
(d, 1H), 6.77 (dd, 1H), 6.66 (m, 2H), 5.28 (dd, 1H), 3.64 (s, 3H), 2.97 (dd, 1H), 2.64 (m,
2H), 2.58 (dd, 1H), 2.08 (s, 3H), 1.14 (st, 3H).
HRMS: (M+H) = 449.1540.
Preparation 6k: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
.0 g ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-tetrahydropyran-
2-yloxyphenyl)propanoate (Preparation 4j) (9.33 mmol) and 3.22 g 2-chloromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (12.0 mmol) were
dissolved in 60 mL THF, then 6.52 g Cs CO (20.0 mmol) dissolved in 20 mL water was
added. Then 330 mg AtaPhos (0.466 mmol) was added, and the mixture was stirred under
nitrogen at 65 °C until no further conversion was observed. Then it was diluted with
dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2
M HCl. After phase separation the aqueous phase was extracted with dichloromethane. The
organic layers were combined and dried over Na SO , filtered and concentrated under
reduced pressure. The diastereoisomers were separated via flash chromatography using
heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as
Preparation 6k.
H NMR (400 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.24 (br s, 1H), 8.52/8.51
(s, 1H), 7.13 (m, 1H), 7.05 (d, 1H), 7.01 (dm, 1H), 6.98 (d, 1H), 6.79 (m, 1H), 6.35 (m,
1H), 5.55/5.51 (m, 1H), 5.50 (dd, 1H), 5.37 (dd, 1H), 4.03 (m, 2H), 3.67 (m, 1H), 3.53 (m,
1H), 3.06 (dd, 1H), 2.65 (dd, 1H), 2.58 (m, 1H), 2.41 (m, 1H), 1.98/1.97 (s, 3H), 1.79 (m,
2H), 1.68-1.47 (m, 3H), 1.15 (t, 3H), 1.06 (td, 3H).
MS: (M+H) = 597.2.
Preparation 6l: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)prop
ynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate
472 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (0.90 mmol) and 403 mg 2-chloromethyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (1.5 mmol) were
dissolved in 10 mL 1,4-dioxane, then 652 mg Cs CO (2.0 mmol) dissolved in 2 mL water
was added. Then 64 mg AtaPhos (0.09 mmol) was added, rinsed with nitrogen, heated at
110°C via microwave irradiation until no further conversion was observed. Then it was
diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set
to 5 with 2 M HCl. After phase separation the aqueous phase was extracted with
dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and
concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected as Preparation 6l.
H NMR (500 MHz, DMSO-d ):10.34 (br s, 1H), 8.61 (s, 1H), 7.16 (m, 1H), 7.09 (d, 1H),
6.98 (d, 1H), 6.89 (dm, 1H), 6.69 (m, 1H), 6.19 (dm, 1H), 5.34 (dd, 1H), 4.08 (m, 1H),
4.03 (m, 1H), 3.75 (s, 3H), 3.01 (dd, 1H), 2.49 (dd, 1H), 2.08 (s, 3H), 2.03 (s, 3H), 1.07 (t,
3H).
HRMS: (M+H) = 537.1247.
Preparation 6m: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)prop-
1-ynyl-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
.59 g ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4l) (17.87 mmol) and 5.76 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(21.45 mmol) were dissolved in 100 mL THF, then 11.64 g Cs CO (35.74 mmol)
dissolved in 30 mL water was added. Then 1.26 g AtaPhos (1.79 mmol) was added, and
the mixture was stirred under nitrogen at 60C until no further conversion was observed.
Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous
phase was set to 8 with 2 M HCl. After phase separation the aqueous phase was extracted
with dichloromethane. The organic layers were combined and dried over Na SO , filtered
and concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair
eluting later was collected as Preparation 6m.
MS: (M+H) = 607.0.
Preparation 6p: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(3,4-
difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
9.18 g ethyl (2R)[(5S )bromo(3,4-difluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 4o) (14.82 mmol)
and 5.17 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (19.26 mmol) were dissolved in 50 mL THF, then 6.52 g Cs CO (20
mmol) dissolved in 20 mL water was added. Then 525 mg AtaPhos (0.74 mmol) was
added, and the mixture was stirred under nitrogen at reflux temperature until no further
conversion was observed. Most of the volatiles were evaporated under reduced pressure,
then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous
phase was set to 8 with 2 M HCl. After phase separation the aqueous phase was extracted
with dichloromethane. The organic layers were combined and dried over Na SO , filtered
and concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair
eluting later was collected as Preparation 6p.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.33 (br s, 1H), 8.63/8.62
(s, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 7.19/7.17 (d, 1H), 7.13 (m ,2H), 7.00 (m, 2H),
6.76/6.76 (dd, 1H), 6.34/6.29 (d, 1H), 5.56/5.53 (m, 1H), 5.54/5.42 (dd, 1H), 4,07 (m, 2H),
3.68/3.54 (m, 2H), 3.11/3.08 (dd, 1H), 2.44 (dd, 1H), 2.05-1.89 (m, 1H), 1.86/1.84 (s, 3H),
1.80 (m, 2H), 1.72-1.45 (m, 3H), 1.09/1.08 (t, 3H).
MS: (M+H) = 681.0
Preparation 6r: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2R)-tetrahydrofuran
yl]methoxy]phenyl]propanoate
7.22 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-
[[(2R)-tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 4p) (12.00 mmol)
and 4.83 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (18.00 mmol) were dissolved in 60 mL dioxane, then 7.82 g Cs CO
(24.00 mmol) dissolved in 30 mL water was added. Then 708 mg AtaPhos (1.00 mmol)
was added, and the mixture was stirred under nitrogen at reflux temperature until no
further conversion was observed. Most of the volatiles were evaporated under reduced
pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the
aqueous phase was set to 6 with 2 M HCl. After phase separation the aqueous phase was
extracted with dichloromethane. The combined organic layers were dried over Na SO ,
filtered and concentrated under reduced pressure. The diastereoisomers were separated via
flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer
eluting later was collected as Preparation 6r.
H NMR (500 MHz, DMSO-d ): 10.25 (br s, 1H), 8.60 (s, 1H), 7.30 (m, 2H), 7.21 (m, 2H),
7.14 (t, 1H), 7.12 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.70 (t, 1H), 6.32 (d, 1H), 5.43 (dd,
1H), 4.15 (m, 1H), 4.03 (m, 2H), 3.97 (dd, 1H), 3.93 (dd, 1H), 3.74 (m, 1H), 3.66 (m, 1H),
2.97 (dd, 1H), 2.48 (dd, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.85 (s, 3H), 1.82 (m, 1H), 1.81
(m, 1H), 1.05 (t, 3H).
Preparation 6s: Ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(2,2,2-trifluoroethoxy)phenyl]
propanoate (mixture of diastereoisomers)
9.17 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-
(2,2,2-trifluoroethoxy)phenyl]propanoate (Preparation 4s) (15.35 mmol) and 4.95 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(18.42 mmol) were dissolved in 50 mL THF, then 15.00 g Cs CO (46.05 mmol) dissolved
in 50 mL water was added. Then 1.09 g AtaPhos (1.54 mmol) was added, and the mixture
was stirred under nitrogen at 60°C until no further conversion was observed. Then the most
of the volatiles were evaporated under reduced pressure and it was diluted with brine. The
pH was set to 6 with 2 M HCl, and the mixture was extracted with dichloromethane. The
combined organic layers were dried over Na SO , filtered and concentrated under reduced
pressure and purified via flash chromatography using heptane and ethyl acetate as eluents
to Preparation 6s as a mixture of diastereoisomers.
H NMR (400 MHz, DMSO-d ): 10.26 (br s, 1H), 8.60 (s, 1H), 7.32-7.26 (m, 2H), 7.24-
7.17 (m, 3H), 7.15-7.11 (m, 1H), 7.03-6.94 (m, 2H), 6.82-6.68 (m, 1H), 6.33/6.19 (dd, 1H),
.36/5.29 (dd, 1H), 4.83-4.64 (m, 2H), 4.09/4.04 (q, 2H), 3.15/3.01 (dd, 1H), 2.50/2.37 (dd,
1H), 2.32/1.85 (s, 3H), 1.11/1.07 (t, 3H).
Preparation 6t: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2,3-
difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate
9.18 g ethyl (2R)[(5S )bromo(2,3-difluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 4t) (14.82 mmol)
and 5.17 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
(Preparation 5a) (19.26 mmol) were dissolved in 50 mL THF, then 6.52 g Cs CO (20
mmol) dissolved in 20 mL water was added. Then 525 mg AtaPhos (0.74 mmol) was
added, and the mixture was stirred under nitrogen at reflux temperature until no further
conversion was observed. Most of the volatiles were evaporated under reduced pressure,
and then it was diluted with dichloromethane and brine. After shaking the pH of the
aqueous phase was set to 8 with 2 M HCl. After phase separation the aqueous phase was
extracted with dichloromethane. The organic layers were combined and dried over
Na SO , filtered and concentrated under reduced pressure. The diastereoisomers were
separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer pair eluting later was collected as Preparation 6t.
HRMS calculated for C H ClF N O S: 680.1559; found: 681.1618 and 681.1624 of the
31 2 2 6
two isomers.
Preparation 6u: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-fluorophenyl)pyrimidin
yl]methoxy]phenyl]propanoate
1.407 g (2 mmol) Preparation 4u and 699 mg 2-chloromethyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.6 mmol) were dissolved in 25 mL
THF, then 912 mg Cs CO (2.8 mmol) dissolved in 15 mL water was added. Then 71 mg
AtaPhos (0.1 mmol) was added, and the mixture was stirred under nitrogen at 90°C until
no further conversion was observed. Most of the volatiles were evaporated under reduced
pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the
aqueous phase was set to 6 with 2 M HCl. After phase separation the aqueous phase was
extracted with dichloromethane. The organic layers were combined and dried over
Na SO , filtered and concentrated under reduced pressure. The diastereoisomers were
separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer eluting later was collected as Preparation 6u.
MS: (M+H) = 764.6.
Preparation 6v: ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidin-
4-yl]methoxy]phenyl]propanoate
Using General Procedure (XXXIV) and Preparation 5a as the appropriate boronic acid
derivative Preparation 6v was obtained as the mixture of diastereomers.
MS (ESI+): 777.2
Preparation 6w: Ethyl (2R)[(5Ra)(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
186.6 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4a) (310.3 mmol) and 99.99 g 2-
chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a)
(372.3 mmol) were dissolved in 1.2 L THF, then 202.2 g Cs CO (620.6 mmol) dissolved
in 300 mL water was added. Then 11.0 g AtaPhos (15.51 mmol) was added, and the
mixture was stirred under nitrogen at reflux temperature until no further conversion was
observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted
with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8
with 2 M HCl. After phase separation the aqueous phase was extracted with
dichloromethane. The organic layers were combined and dried over Na SO , filtered and
concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair
eluting earlier was collected as Preparation 6w.
HRMS: (M+H) = 663.1717 and 663.1746
Preparation 6x: ethyl (2S)[5-(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
186.6 g ethyl (2S)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetra-hydropyranyloxyphenyl)propanoate (Preparation 4w) (310.3 mmol) and 99.99 g
2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation
5a) (372.3 mmol) were dissolved in 1.2 L THF, then 202.2 g Cs CO (620.6 mmol)
dissolved in 300 mL water was added. Then 11.0 g AtaPhos (15.51 mmol) was added, and
the mixture was stirred under nitrogen at reflux temperature until no further conversion
was observed. Most of the volatiles were evaporated under reduced pressure, then it was
diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set
to 8 with 2 M HCl. After phase separation the aqueous phase was extracted with
dichloromethane. The organic layers were combined and dried over Na SO , filtered and
concentrated under reduced pressure and the product was purified via flash
chromatography using heptane and ethyl acetate as eluents to give Preparation 6x as a
mixture of diastereoisomers.
MS: (M+H) = 663.2.
Preparation 7a: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
132.3 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6a) (199.5 mmol), 43.17 g 2-(4-methylpiperazinyl)ethanol (299.3 mmol)
and 94.20 g PPh (359.1 mmol) were dissolved in 1 L dry toluene, then 78.09 g ditertbutyl
azodicarboxylate (339.2 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. 980 mL toluene was evaporated, then 500 mL Et O
was added, and the mixture was stirred and sonicated. The precipitated white crystals were
filtered, washed with Et O to give 65.9 g pure triphenylphosphineoxide. The filtrate was
concentrated under reduced pressure and purified via flash chromatography using EtOAc
and MeOH as eluents to obtain Preparation 7a.
MS: (M+H) = 789.2.
Preparation 7b: Ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)
methyl-phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
4.94 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6a) (7.5 mmol), 1.34 g 2-(dimethylamino)ethanol (15 mmol) and 3.94 g
PPh (15 mmol) were dissolved in 30 mL dry toluene, then 3.45 g ditertbutyl
azodicarboxylate (15 mmol) was added. The mixture was stirred at 50°C under N2 until no
further conversion was observed. The toluene was evaporated under reduced pressure and
the residue was purified via flash chromatography using DCM and MeOH as eluents to
obtain Preparation 7b.
MS: (M+H) = 734.2.
Preparation 7c: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
11.55 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(5-fluoro
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6c) (7.5 mmol), 5.77 g 2-(4-methylpiperazinyl)ethanol (40 mmol), and
10.49 g PPh (40 mmol) were dissolved in 100 mL dry toluene, then 9.21 g ditertbutyl
azodicarboxylate (40 mmol) was added. The mixture was stirred at 50°C under N until no
further conversion was observed. The toluene was evaporated under reduced pressure and
the residue was purified via flash chromatography using DCM and MeOH as eluents to
obtain Preparation 7c.
MS: (M+H) = 695.2.
Preparation 7d: Ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)
methyl-phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
2.87 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(5-fluoro
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6c) (5.05 mmol), 1.35 g 2-(dimethylamino)ethanol (15.15 mmol) and 3.98 g
PPh3 (15.15 mmol) were dissolved in 100 mL dry toluene, then 3.49 g ditertbutyl
azodicarboxylate (15.15 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. The toluene was evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents
to obtain Preparation 7d.
MS: (M+H) = 724.2.
Preparation 7e: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
19.05 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-furyl)thieno[2,3-
d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 6d)
(30 mmol), 8.65 g 2-(4-methylpiperazinyl)ethanol (60 mmol) and 15.74 g PPh (60
mmol) were dissolved in 200 mL dry toluene, then 13.81 g ditertbutyl azodicarboxylate
(60 mmol) was added. The mixture was stirred at 50°C under N until no further
conversion was observed. The toluene was evaporated under reduced pressure and the
residue was purified via flash chromatography using EtOAc and MeOH as eluents to
obtain Preparation 7e.
MS: (M+H) = 761.2.
Preparation 7f: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy
(2-tetrahydropyranyloxyphenyl)propanoate
13.5 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-fluoro
methoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 6h) (13.5 mmol), 5.62 g 2-(4-methylpiperazin
yl)ethanol (39 mmol) and 10.22 g PPh (39 mmol) were dissolved in 250 mL dry toluene,
then 10.22 g ditertbutyl azodicarboxylate (39 mmol) was added. The mixture was stirred at
50°C under N until no further conversion was observed. The toluene was evaporated
under reduced pressure and the residue was purified via flash chromatography using
EtOAc and MeOH as eluents to obtain Preparation 7f.
MS: (M+H) = 819.0.
Preparation 7g: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
9.86 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 6k)
(6.46 mmol), 1.73 g 2-(4-methylpiperazinyl)ethanol (12.0 mmol) and 3.15 g PPh (12.0
mmol) were dissolved in 40 mL dry toluene, then 2.76 g ditertbutyl azodicarboxylate (12.0
mmol) was added. The mixture was stirred at 50°C under N until no further conversion
was observed. Toluene was evaporated under reduced pressure and the residue was
purified via flash chromatography using EtOAc and MeOH as eluents to obtain
Preparation 7g.
MS: (M+H) = 723.2.
Preparation 7h: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
6.60 g ethyl (2R)[(5S )-(3-chlorohydroxymethyl-phenyl)propynyl-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6m) (10.87 mmol), 2.88 g 2-(4-methylpiperazinyl)ethanol (20 mmol) and
.25 g PPh (20 mmol) were dissolved in 450 mL dry toluene, then 4.61 g ditertbutyl
azodicarboxylate (20 mmol) was added. The mixture was stirred at 50°C under N until no
further conversion was observed. The toluene was evaporated under reduced pressure and
the residue was purified via flash chromatography using EtOAc and MeOH as eluents to
obtain Preparation 7h.
MS: (M+H) = 733.2.
Preparation 7i: Ethyl (2R)[6-(5-chlorofuryl)(5S )-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]oxy[2-[(4-
methoxyphenyl)methoxy]phenyl]propanoate
5.30 g ethyl (2R)[6-(5-chlorofuryl)(5S )-(3-chlorohydroxymethyl-
phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl]
propanoate (Preparation 6f) (7.5 mmol), 2.16 g 2-(4-methylpiperazinyl)ethanol (15
mmol) and 3.93 g PPh (15 mmol) were dissolved in 30 mL dry toluene, then 3.45 g
ditertbutyl azodicarboxylate (15 mmol) was added. The mixture was stirred at 50°C under
N until no further conversion was observed. The toluene was evaporated under reduced
pressure and the residue was purified via flash chromatography using EtOAc and MeOH as
eluents to obtain Preparation 7i.
MS: (M+H) = 831.0.
Preparation 7j: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
6.85 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(3,4-difluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6p) (10.06 mmol), 2.90 g 2-(4-methylpiperazinyl)ethanol (20.12 mmol)
and 5.27 g PPh (20.12 mmol) were dissolved in 20 mL dry toluene, then 4.63 g ditertbutyl
azodicarboxylate (20.12 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. The toluene was evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents
to obtain Preparation 7j.
MS: (M+H) = 681.0.
Preparation 7k: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
Step A: 5-Bromochloro(2,3-difluorophenyl)thieno[2,3-d]pyrimidine
9.39 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (25 mmol),
9.00 g 2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.5 mmol), 16.29
g Cs CO (50 mmol), and 0.912 g Pd(dppf)Cl (1.25 mmol) were placed in a 250 mL flask.
2 3 2
100 mL THF and 50 mL water were added, and then stirred at 70°C under N until no
further conversion was observed. The reaction mixture was extracted with EtOAc. The
combined organic layers were dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via flash chromatography using DCM and MeOH
as eluents.
H NMR (500 MHz, DMSO-d ): 9.07 (s, 1H), 7.71 (m, 1H), 7.46 (m, 2H).
HRMS calculated for C H BrClF N S: 359.8935, found: 360.9013 (M+H).
12 4 2 2
Step B: Ethyl (2R)[5-bromo(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy
(2-tetrahydropyranyloxyphenyl)propanoate
8.3 g 5-bromochloro(2,3-difluorophenyl)thieno[2,3-d]pyrimidine (23 mmol), 7.48 g
ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation
3ab-(R)) (25.4 mmol) and 26.23 g Cs CO (80.5 mmol) were placed in a 250 mL flask.
100 mL tert-butanol was added and the mixture was stirred at 60°C under N until no
further conversion was observed. The reaction mixture was diluted with brine, the pH was
set between 6-7 with 2 M HCl, and then it was extracted with DCM. The combined organic
layers were dried over Na SO , filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography using heptane and EtOAc as eluents
to obtain the product of Step B as a mixture of diastereoisomers.
H NMR (500 MHz, DMSO-d ): 8.71 (d, 1H), 7.69 (m, 1H), 7.43 (m, 3H), 7.19 (m, 1H),
7.07 (m, 1H), 6.89 (t, 1H), 5.83/5.71 (dd, 1H), 5.60/5.56 (t, 1H), 4.15 (m, 2H), 3.75-3.18
(m, 4H), 1.99-1.56 (m, 4H), 1.82 (m, 2H), 1.15/1.16 (t, 3H).
HRMS calculated for C H BrF N O S: 618.0636, found: 619.0695 (M+H).
28 25 2 2 5
Step C: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2,3-difluoro
phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
8.75 g ethyl (2R)[(5S )bromo(2,3-difluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (14.1 mmol) and 4.92 g 2-chloro-
3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (18.3
mmol) were dissolved in 50 mL THF, then 6.11 g Cs CO (18.8 mmol) dissolved in 20 mL
water was added. Then 0.5 g AtaPhos (0.7 mmol) was added, and the mixture was stirred
under N at reflux temperature until no further conversion was observed. The reaction
mixture was diluted with brine and extracted with DCM. The organic combined layers
were dried over Na SO , filtered and concentrated under reduced pressure. The
diastereoisomers were separated via flash chromatography using heptane and EtOAc as
eluents. The diastereoisomer pair eluting later was collected as the product of Step C.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 10.24 (br s, 1H), 8.66/8.65
(s, 1H), 7.48 (m, 1H), 7.22 (m, 1H), 7.13 (m, 2H), 7.08 (d, 1H), 7.01 (d, 1H), 6.89 (d, 1H),
6.74 (t, 1H), 6.38/6.32 (d, 1H), 5.55 (m, 1H), 5.45 (dd, 1H), 4.04 (m, 2H), 3.68/3.54 (m,
2H), 3.32 (dd, 1H), 2.47 (dd, 1H), 2.06-1.48 (m, 6H), 1.90/1.88 (s, 3H), 1.07/1.06 (t, 3H).
HRMS calculated for C H ClF N O S: 680.1559, found: 681.1618/681.1624 (M+H).
31 2 2 6
Step D: Ethyl (2R)[(5Sa)[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
6.49 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2,3-difluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (9.5
mmol), 2.75 g 2-(4-methylpiperazinyl)ethanol (19 mmol) and 4.98 g PPh (19 mmol)
were dissolved in 20 mL dry toluene, then 4.38 g ditertbutyl azodicarboxylate (19 mmol)
was added. The mixture was stirred at 50°C under N until no further conversion was
observed. The toluene was evaporated under reduced pressure and the residue was purified
via flash chromatography using EtOAc and MeOH as eluents to obtain Preparation 7k.
H NMR (500 MHz, DMSO-d , 1:1 mixture of diastereomers): 8.67 (s, 1H), 7.48 (m, 1H),
7.22-7.17 (m, 3H), 7.13 (t, 1H), 7.10 (d, 1H), 7.01 (d, 1H), 6.72 (t, 1H), 6.33/6.28 (d, 1H),
.54/5.51 (m, 1H), 5.45 (dd, 1H), 4.18 (m, 2H), 4.03 (m, 2H), 3.68/3.54 (m, 2H), 3.02/2.99
(dd, 1H), 2.69 (t, 2H), 2.56 (m, 1H), 2.46 (br s, 4H), 2.22 (br s, 4H), 2.08 (s, 3H), 2.03-1.46
(m, 6H), 1.93/1.92 (s, 3H), 1.05 (t, 3H).
HRMS calculated for C H ClF N O S: 806.2716, found: 807.2763/807.2793 (M+H).
42 45 2 2 6
Preparation 7l: Ethyl (2R)[(5Sa)[3-chloromethyl[2-(dimethylamino)
ethoxy]phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
6.85 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2,3-difluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6t) (10.06 mmol), 1.793 g N,N-dimethylethanolamine (20.12 mmol) and
.27 g PPh (20.12 mmol) were dissolved in 20 mL dry toluene, then 4.63 g ditertbutyl
azodicarboxylate (20.12 mmol) was added. The mixture was stirred at 50°C under N2 until
no further conversion was observed. The toluene was evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents
to obtain Preparation 7l.
MS: (M+H) = 752.6.
Preparation 7m: Ethyl (2R)[(5Sa)[3-chloromethyl[2-(piperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
862 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6a) (1.3 mmol), 338 mg N-(2-hydroxyethyl)piperazine (2.6 mmol) and 682
mg PPh (2.6 mmol) were dissolved in 25 mL dry toluene, then 600 mg ditertbutyl
azodicarboxylate (2.6 mmol) was added. The mixture was stirred at 50°C under N until no
further conversion was observed. Toluene was evaporated, then 5 mL Et O was added, and
the mixture was stirred and sonicated. The precipitated white crystals were filtered, washed
with Et O. The filtrate was concentrated under reduced pressure and purified via flash
chromatography using DCM and MeOH as eluents to obtain Preparation 7m.
MS: (M+H) = 775.2.
Preparation 7n: Ethyl (2R)[(5Sa)[3-chloromethyl[2-(4-ethylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
862 mg ethyl (2R)[(5Sa)(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6a) (1.3 mmol), 411 mg 2-(4-ethylpiperazinyl)ethanol (2.6 mmol) and
682 mg PPh (2.6 mmol) were dissolved in 25 mL dry toluene, then 600 mg ditertbutyl
azodicarboxylate (2.6 mmol) was added. The mixture was stirred at 50°C under N until no
further conversion was observed. Toluene was evaporated, then 5 mL Et O was added, and
the mixture was stirred and sonicated. The precipitated white crystals were filtered, washed
with Et O (PPh O). The filtrate was concentrated under reduced pressure and purified via
flash chromatography using DCM and MeOH as eluents to obtain Preparation 7n.
MS: (M+H) = 802.4, 803.4.
Preparation 7o: Ethyl (2R)[(5R )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
132.3 g ethyl (2R)[(5R )(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6w) (199.5 mmol), 43.17 g 2-(4-methylpiperazinyl)ethanol (299.3 mmol)
and 94.20 g PPh (359.1 mmol) were dissolved in 1 L dry toluene, then 78.09 g ditertbutyl
azodicarboxylate (339.2 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. 980 mL toluene was evaporated, then 500 mL Et O
was added, and the mixture was stirred and sonicated. The precipitated white crystals were
filtered, washed with Et O to give 65.9 g pure triphenylphosphineoxide. The filtrate was
concentrated under reduced pressure and purified via flash chromatography using EtOAc
and MeOH as eluents to obtain Preparation 7o.
MS: (M+H) = 789.2.
Preparation 7p: Ethyl (2S)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate
132.3 g ethyl (2S)[5-(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)-
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6x) (199.5 mmol), 43.17 g 2-(4-methylpiperazinyl)ethanol (299.3 mmol)
and 94.20 g PPh (359.1 mmol) were dissolved in 1 L dry toluene, then 78.09 g ditertbutyl
azodicarboxylate (339.2 mmol) was added. The mixture was stirred at 50°C under N until
no further conversion was observed. 980 mL toluene was evaporated, then 500 mL Et O
was added, and the mixture was stirred and sonicated. The precipitated white crystals were
filtered, washed with Et O to give 65.9 g pure triphenylphosphineoxide. The filtrate was
concentrated under reduced pressure and purified via flash chromatography using EtOAc
and MeOH as eluents to obtain Preparation 7p.
MS: (M+H) = 789.2.
Preparation 8a: Ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
199.5 mmol ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyl-
oxyphenyl)-propanoate (Preparation 7a) was dissolved in 1 L EtOH, then 1 L 1.25 M HCl
in EtOH was added and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then Et2O was added and the
precipitated HCl salt (white solid) was filtered, washed with Et O. The HCl salt was
carefully treated with saturated NaHCO solution, extracted with DCM, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure
to give Preparation 8a.
H NMR (400 MHz, DMSO-d ): 9.53 (br s, 1H), 8.60 (s, 1H), 7.30 (m, 2H), 7.28 (d, 1H),
7.21 (m, 2H), 7.16 (d, 1H), 6.97 (t, 1H), 6.72 (d, 1H), 6.53 (t, 1H), 6.20 (d, 1H), 5.46 (dd,
1H), 4.22 (m, 2H), 4.04 (m, 2H), 2.92 (dd, 1H), 2.75 (m, 2H), 2.53 (br s, 4H), 2.44 (dd,
1H), 2.36 (br s, 4H), 2.17 (s, 3H), 1.88 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S: 704.2235, found: 705.2288 (M+H).
37 38 4 5
Preparation 8b: Ethyl (2R)[(5S )-[3-chloro(2-dimethylaminoethyloxy)methyl-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate
.60 mmol ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7b) was dissolved in 40 mL EtOH, then 20 mL 1.25
M HCl in EtOH was added and the mixture was stirred until no further conversion was
observed. Water and saturated NaHCO solution were added carefully and the mixture was
extracted with DCM, the combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and EtOAc as eluents to obtain Preparation 8b.
H NMR (500 MHz, DMSO-d ): 9.53 (br s, 1H), 8.61 (s, 1H), 7.30 (m, 2H), 7.29 (d, 1H),
7.31 (m, 2H), 7.16 (d, 1H), 6.97 (m, 1H), 6.71 (dm, 1H), 6.52 (m, 1H), 6.18 (dm, 1H), 5.46
(dd, 1H), 4.20 (t, 2H), 4.04 (m, 2H), 2.92 (dd, 1H), 2.69 (t, 2H), 2.43 (dd, 1H), 2.22 (s,
6H), 1.88 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S: 649.1813, found: 650.1887 (M+H).
34 33 3 5
Preparation 8c: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
184 mmol ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 7c) was dissolved in 1 L EtOH,
then 1 L 1.25 M HCl in EtOH was added and the mixture was stirred at room temperature
until no further conversion was observed. Most of the EtOH was evaporated, then Et O
was added and the precipitated HCl salt (white solid) was filtered, washed with Et O. The
HCl salt was carefully treated with saturated NaHCO solution, extracted with DCM, the
combined organic phases were dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via flash chromatography using DCM and MeOH
as eluents to obtain Preparation 8c.
H NMR (500 MHz, DMSO-d ): 9.55 (s, 1H), 8.58 (s, 1H), 7.25 (s, 2H), 6.99 (t, 1H), 6.72
(d, 1H), 6.59 (t, 1H), 6.23 (d, 1H), 5.88 (dd, 1H), 5.72 (t, 1H), 5.47 (dd, 1H), 4.27 (t, 2H),
4.04 (m, 2H), 2.95 (dd, 1H), 2.77 (t, 2H), 2.53 (br s, 4H), 2.35 (dd, 1H), 2.30 (br s, 4H),
2.13 (s, 3H), 1.97 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S: 694.2028, found: 695.2106 (M+H).
36 4 6
Preparation 8d: Ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)
methyl-phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
mL 1.25 M HCl in EtOH was added to 1.5 mmol ethyl (2R)[(5S )[3-chloro(2-
dimethylaminoethyloxy)methyl-phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidin
yl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 7d) and the mixture
was stirred until no further conversion was observed. The reaction mixture was carefully
diluted with saturated NaHCO solution and the mixture was extracted with DCM, the
combined organic phases were dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via flash chromatography using EtOAc and
MeOH as eluents to obtain Preparation 8d.
H NMR (500 MHz, DMSO-d ): 9.56 (br s, 1H), 8.58 (s, 1H), 7.25 (s, 2H), 6.99 (td, 1H),
6.72 (dd, 1H), 6.59 (td, 1H), 6.23 (dd, 1H), 5.88 (dd, 1H), 5.71 (t, 1H), 5.48 (dd, 1H), 4.25
(m, 2H), 4.04 (m, 2H), 2.96 (dd, 1H), 2.71 (t, 2H), 2.35 (dd, 1H), 2.23 (s, 6H), 1.98 (s, 3H),
1.06 (t, 3H).
HRMS calculated for C H ClFN O S: 639.1606, found: 640.1679 (M+H).
32 31 3 6
Preparation 8e: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate
mmol ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7e) was dissolved in 200 mL EtOH, then 200 mL
1.25 M HCl in EtOH was added and the mixture was stirred at room temperature until no
further conversion was observed. Saturated NaHCO solution was added, and the reaction
mixture was extracted with DCM. The combined organic layers were dried over Na SO ,
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain Preparation 8e.
H NMR (500 MHz, DMSO-d ): 9.55 (s, 1H), 8.58 (s, 1H), 7.80 (d, 1H), 7.26 (d, 1H), 7.24
(d, 1H), 6.99 (t, 1H), 6.72 (d, 1H), 6.60 (t, 1H), 6.53 (dd, 1H), 6.24 (d, 1H), 5.69 (d, 1H),
.48 (dd, 1H), 4.28 (t, 2H), 4.04 (m, 2H), 2.95 (dd, 1H), 2.78 (t, 2H), 2.51 (br s, 4H), 2.34
(dd, 1H), 2.31 (br s, 4H), 2.13 (br s, 3H), 1.96 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClN O S: 676.2122, found: 677.2194 (M+H).
37 4 6
Preparation 8f: Ethyl (2R)[(5S )(5-chlorofuryl)[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
200 mL 1.25 M HCl in EtOH was added to 7 mmol ethyl (2R)[6-(5-chlorofuryl)
(5S )-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]thieno[2,3-
d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl]propanoate (Preparation
7i) and the mixture was stirred at 80°C until no further conversion was observed. Saturated
NaHCO3 solution was added to the reaction mixture, and it was extracted with DCM. The
combined organic layers were dried over Na SO , filtered and concentrated under reduced
pressure and purified via flash chromatography using DCM and MeOH as eluents to obtain
Preparation 8f.
H NMR (500 MHz, DMSO-d ): 9.56 (br s, 1H), 8.59 (s, 1H), 7.25 (s, 2H), 6.99 (t, 1H),
6.72 (d, 1H), 6.59 (t, 1H), 6.55 (d, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.48 (dd, 1H), 4.28 (t,
2H), 4.04 (m, 2H), 2.95 (dd, 1H), 2.79 (t, 2H), 2.58 (br s, 4H), 2.44 (br s, 4H), 2.35 (dd,
1H), 2.23 (br s, 3H), 1.96 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H Cl N O S: 710.1733, found: 711.1797 (M+H).
36 2 4 6
Preparation 8g: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy
(2-hydroxyphenyl)propanoate
19 mmol ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 7f) was dissolved in 300 mL
EtOH, then 150 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room
temperature until no further conversion was observed. Saturated NaHCO solution was
added and the mixture was extracted with DCM. The combined organic layers were dried
over Na SO , filtered and concentrated under reduced pressure. The crude product was
purified via flash chromatography using DCM and MeOH as eluents to obtain
Preparation 8g.
H NMR (500 MHz, DMSO-d ): 9.57 (br s, 1H), 8.61 (s, 1H), 7.31 (d, 1H), 7.24 (dd, 1H),
7.19 (d, 1H), 6.97 (td, 1H), 6.93 (ddd, 1H), 6.86 (dd, 1H), 6.71 (d, 1H), 6.53 (t, 1H), 6.16
(d, 1H), 5.46 (dd, 1H), 4.23 (m, 2H), 4.05 (m, 2H), 3.57 (s, 3H), 2.95 (dd, 1H), 2.73 (m,
2H), 2.72 (br s, 4H), 2.68 (br s, 4H), 2.41 (dd, 1H), 2.10 (s, 3H), 1.88 (s, 3H), 1.07 (t, 3H).
HRMS calculated for C H ClFN O S: 734.2341, found: 735.2406 (M+H).
38 40 4 6
Preparation 8h: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
6 mmol ethyl (2R)[(5Sa)[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7g) was dissolved in 100 mL EtOH, then 40 mL
1.25 M HCl in EtOH was added and the mixture was stirred at room temperature until no
further conversion was observed. Saturated NaHCO solution was added and the reaction
was extracted with DCM. The combined organic layers were dried over Na SO , filtered
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain Preparation 8h.
H NMR (500 MHz, DMSO-d ): 9.53 (s, 1H), 8.53 (s, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 6.99
(t, 1H), 6.72 (d, 1H), 6.58 (t, 1H), 6.22 (d, 1H), 5.42 (dd, 1H), 4.25 (m, 2H), 4.02 (m, 2H),
2.90 (dd, 1H), 2.76 (m, 2H), 2.67 (m, 1H), 2.60 (m, 1H), 2.49 (br s, 4H), 2.41 (dd, 1H),
2.27 (br s, 4H), 2.11 (s, 3H), 2.01 (s, 3H), 1.17 (t, 3H), 1.05 (t, 3H).
HRMS calculated for C H ClFN O S: 638.2330, found: 639.2377 (M+H).
33 39 4 5
Preparation 8i: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
mmol ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7h) was dissolved in 100 mL EtOH, then 40 mL
1.25 M HCl in EtOH was added and the mixture was stirred at room temperature until no
further conversion was observed. The most of the EtOH was evaporated then saturated
NaHCO solution was added and the mixture was extracted with DCM. The combined
organic layers were dried over Na SO , filtered and concentrated under reduced pressure
and purified via flash chromatography using DCM and MeOH as eluents to obtain
Preparation 8i.
H NMR (500 MHz, DMSO-d ): 9.53 (s, 1H), 8.62 (s, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 6.97
(m, 1H), 6.70 (dm, 1H), 6.52 (m, 1H), 6.05 (dm, 1H), 5.41 (dd, 1H), 4.25 (t, 2H), 4.05 (m,
2H), 2.97 (dd, 1H), 2.76 (m, 1H), 2.74 (m, 1H), 2.51 (br s, 4H), 2.42 (dd, 1H), 2.26 (br s,
4H), 2.11 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.08 (t, 3H).
HRMS calculated for C H ClN O S: 648.2173, found: 649.2275 (M+H).
34 37 4 5
Preparation 8j: Ethyl (2R)[5-[5-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (mixture of diastereoisomers)
Step A: Ethyl (2R)[5-[5-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
1.504 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4a) (2.50 mmol) and 1.052 g 1-
[2-[[3-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
pyridyl]oxy]ethyl]methyl-piperazine (Preparation 5q) (2.66 mmol) were dissolved in
mL THF, then 1.63 g Cs CO (5.00 mmol) dissolved in 5 mL water was added. Then
177 mg AtaPhos (0.25 mmol) was added, and the mixture was stirred under nitrogen at
reflux temperature until no further conversion was observed. Then the mixture was diluted
with brine, extracted with DCM, the combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure, then purified via flash chromatography
using EtOAc and MeOH as eluents.
Step B: Ethyl (2R)[5-[5-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (mixture of diastereoisomers)
The obtained ethyl (2R)[5-[5-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate was dissolved in 50 mL EtOH, then 10 mL 1.25 M HCl in EtOH
was added and the mixture was stirred at room temperature until no further conversion was
observed. Saturated NaHCO solution was added carefully and the mixture was extracted
with DCM, the combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to give Preparation 8j as a mixture of
distereoisomers.
H NMR (400 MHz, DMSO-d ): 9.57 (br s, 1H), 8.65/8.64 (s, 1H), 8.07/7.68 (s, 1H), 7.37-
7.31 (m, 2H), 7.27-7.22 (m, 2H), 6.98/6.96 (td, 1H), 6.72/6.70 (dd, 1H), 6.54/6.48 (td, 1H),
6.29/6.05 (dd, 1H), 5.55/5.42 (dd, 1H), 4.60-4.41 (m, 2H), 4.07-4.01 (m, 2H), 3.05/2.92
(dd, 1H), 2.72/2.69 (t, 2H), 2.48-2.12 (m, 9H), 2.09 (s, 3H), 2.08/1.90 (s, 3H), 1.10/1.05 (t,
3H).
MS (M+H): 706.2.
Preparation 8k: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
7.85 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7j) (9.72 mmol) was dissolved in 70 mL EtOH,
then 50 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room
temperature until no further conversion was observed. The most of the EtOH was
evaporated then water and saturated NaHCO solution were added and the mixture was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain Preparation 8k.
H NMR (500 MHz, DMSO-d ): 9.54 (s, 1H), 8.63 (s, 1H), 7.46 (m, 1H), 7.32 (m, 1H),
7.30 (d, 1H), 7.18 (d, 1H), 7.11 (m, 1H), 6.97 (t, 1H), 6.71 (d, 1H), 6.53 (t, 1H), 6.19 (d,
1H), 5.46 (dd, 1H), 4.23 (m, 2H), 4.04 (m, 2H), 2.92 (dd, 1H), 2.73 (m, 2H), 2.50 (br s,
4H), 2.43 (dd, 1H), 2.25 (br s, 4H), 2.10 (s, 3H), 1.89 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClF N O S: 722.2141, found: 723.2211 (M+H).
37 37 2 4 5
Preparation 8l: Ethyl (2R)[(5S )(3-chloromethoxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
Step A: Ethyl (2R)[(5S )(3-chloromethoxymethyl-phenyl)(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
12.47 g ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetra-hydropyranyloxyphenyl)propanoate (Preparation 4a) (20.7 mmol) and 8.20 g 2-
(3-chloromethoxymethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Preparation 5d) (29.0 mmol) were dissolved in 145 mL THF, then 13.50 g Cs CO
(41.50 mmol) dissolved in 48 mL water was added. Then 1.17 g AtaPhos (1.66 mmol) was
added, and the mixture was stirred under nitrogen at reflux temperature until no further
conversion was observed. Then most of the volatiles were evaporated and the residue was
diluted with brine. The pH was set to 6 with 2 M HCl, and the mixture was extracted with
DCM. The combined organic layers were dried over Na SO , filtered and concentrated
under reduced pressure, then purified via flash chromatography using heptane and EtOAc
as eluents. The diastereoisomer pair eluting later was collected as ethyl (2R)[(5S )(3-
chloromethoxymethyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy
(2-tetrahydropyranyloxyphenyl)propanoate.
Step B: Ethyl (2R)[(5S )(3-chloromethoxymethyl-phenyl)(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
The product of Step A was dissolved in 300 mL EtOH, then 150 mL 1.25 M HCl in EtOH
was added and the mixture was stirred at room temperature until no further conversion was
observed. Most of the EtOH was evaporated, then saturated NaHCO solution was added
carefully, and the mixture was extracted with DCM, dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to give Preparation 8l.
H NMR (500 MHz, DMSO-d ): 9.52 (s, 1H), 8.61 (s, 1H), 7.30 (m, 3H), 7.22 (t, 2H), 7.14
(d, 1H), 6.97 (t, 1H), 6.71 (d, 1H), 6.53 (t, 1H), 6.18 (d, 1H), 5.45 (dd, 1H), 4.04 (m, 2H),
3.90 (s, 3H), 2.91 (dd, 1H), 2.44 (dd, 1H), 1.89 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S: 592.1235; found 593.1307 (M+H).
31 26 2 5
Preparation 8m: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
9.72 mmol ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7k) was dissolved in 70 mL EtOH, then 60 mL 1.25
M HCl in EtOH was added and the mixture was stirred at room temperature until no
further conversion was observed. Ice and saturated NaHCO3 solution were added and the
mixture was extracted with DCM. The combined organic layers were dried over Na SO ,
filtered and concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain Preparation 8m.
H NMR (500 MHz, DMSO-d ): 9.54 (br s, 1H), 8.66 (s, 1H), 7.48 (m, 1H), 7.22-7.18 (m,
3H), 7.09 (m, 1H), 6.97 (t, 1H), 6.72 (d, 1H), 6.52 (t, 1H), 6.21 (d, 1H), 5.47 (dd, 1H), 4.18
(m, 2H), 4.02 (m, 2H), 2.86 (dd, 1H), 2.72 (m, 2H), 2.53 (dd, 1H), 2.51 (br s, 4H), 2.39 (br
s, 4H), 2.19 (br s, 3H), 1.94 (s, 3H), 1.04 (t, 3H).
HRMS calculated for C H ClF N O S: 722.2141; found 723.2177 (M+H).
37 37 2 4 5
Preparation 8n: Ethyl (2R)[(5S )-[3-chloromethyl[2-(dimethylamino)ethoxy]
phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate
7.85 g ethyl (2R)[(5S )[3-chloromethyl[2-dimethylaminoethoxy]phenyl]
(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (Preparation 7l) (9.72 mmol) was dissolved in 70 mL EtOH,
then 50 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room
temperature until no further conversion was observed. The most of the EtOH was
evaporated then water and saturated NaHCO solution were added and the mixture was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain Preparation 8n.
MS: (M+H) = 667.8.
Preparation 8o: Ethyl (2R)[(5S )-[3-chloromethyl[2-(piperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate
900 mg ethyl (2R)[(5S )-[3-chloromethyl[2-(piperazinyl)ethoxy]-phenyl](4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyl-oxyphenyl)-
propanoate (Preparation 7m) was dissolved in 5 mL EtOH, then 5 mL 1.25 M HCl in
EtOH was added and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then Et2O was added and the
precipitated HCl salt (white solid) was filtered, washed with Et O. The HCl salt was
carefully treated with saturated NaHCO solution, extracted with DCM, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure
to give Preparation 8o.
MS: (M+H) = 691.0.
Preparation 8p: Ethyl (2R)[(5S )-[3-chloromethyl[2-(4-ethylpiperazinyl)
ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
952 mg ethyl (2R)[(5S )-[3-chloromethyl[2-(4-ethylpiperazinyl)ethoxy]-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyl-
oxyphenyl)-propanoate (Preparation 7n) was dissolved in 5 mL EtOH, then 5 mL 1.25 M
HCl in EtOH was added and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then Et O was added and the
precipitated HCl salt (white solid) was filtered, washed with Et O. The HCl salt was
carefully treated with saturated NaHCO solution, extracted with DCM, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure
to give Preparation 8p.
MS: (M+H) = 719.2.
Preparation 8q: Ethyl (2R)[(5R )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
199.5 mmol ethyl (2R)[(5R )-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyl-
oxyphenyl)-propanoate (Preparation 7o) was dissolved in 1 L EtOH, then 1 L 1.25 M HCl
in EtOH was added and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then Et O was added and the
precipitated HCl salt (white solid) was filtered, washed with Et O. The HCl salt was
carefully treated with saturated NaHCO solution, extracted with DCM, the combined
organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure
to give Preparation 8q.
MS: (M+H) = 705.2.
Preparation 8r: Ethyl (2S)[(5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate
199.5 mmol ethyl (2S)[(5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]-
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyl-
oxyphenyl)-propanoate (Preparation 7p) was dissolved in 1 L EtOH, then 1 L 1.25 M
HCl in EtOH was added and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then Et O was added and the
precipitated HCl salt (white solid) was filtered, washed with Et O. The HCl salt was
carefully treated with saturated NaHCO solution, extracted with DCM, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure
to give Preparation 8r.
MS: (M+H) = 705.2.
Unless otherwise specified, most of the compounds of Preparation 9aa to 9er were
obtained using General Procedures 9A to 9H described below.
General Procedure 9A:
The appropriate acetal (1.0 eq.) was stirred with 2N HCl solution (3 mL/mmol) at 60°C
until no further conversion was observed. Reaction mixture was cooled to 0°C, then NaOH
(5.7 eq.) was added portionwise. The pH was adjusted to 8 using 10% K CO solution,
then sodium borohydride (2.0 eq.) was added portionwise keeping the temperature under
°C and the mixture was stirred for 30 min at 0°C. Reaction mixture was extracted with
EtOAc, the combined organic phases were dried over Na SO , filtered and concentrated
under reduced pressure. The crude product was purified via flash chromatography using
heptane and EtOAc as eluents.
General Procedure 9B:
The appropriate acetal (1.0 eq.) was stirred with 1N HCl solution (3 mL/mmol) at 50°C for
45 min. Reaction mixture was cooled to 0°C, then NaOH (2.85 eq.) was added
portionwise. The pH was adjusted to 8 using 10% K CO solution, then sodium
borohydride (2.0 eq.) was added portionwise keeping the temperature under 5°C and
stirred for 30 min at 0°C. Reaction mixture was extracted with EtOAc, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via flash chromatography using heptane and EtOAc as
eluents.
General Procedure 9C:
To the mixture of the appropriate amidine hydrochloride (1.2 eq.) and (E)
(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1, 1.0 eq.) in dry
methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the
mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated
under reduced pressure. To the residue water was added and it was extracted with DCM.
The combined organic layers were dried over MgSO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents.
General Procedure 9D:
To the mixture of the appropriate hydrazine hydrochloride (1.2 eq.) and (E)
(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1, 1.0 eq.) in dry
methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the
mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated
under reduced pressure. To the residue water was added and it was extracted with DCM.
The combined organic phases were dried over MgSO , filtered and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents.
General Procedure 9E:
To the solution of the appropriate methylsulfonyl derivative (Preparation 9a3 1.0 eq.) in
dry acetonitrile (3ml/mmol) K CO (2.0 eq.) and the appropriate amine (1.5 eq.) were
added, and stirred at 70°C until no further conversion was observed. The reaction mixture
was cooled, filtered, the precipitate was washed with EtOAc, then the filtrate was
concentrated under reduced pressure. Crude product was purified via flash chromatography
using heptane and EtOAc as eluents.
General Procedure 9F:
To the solution of 1H-pyrazole (1.0 eq.) in DMF (0.5 mL/mmol) KOH (1.0 eq.) was added,
then it was cooled to 0°C, and the appropriate halide was added (1.0 eq.) dropwise. The
mixture was stirred at room temperature until no further conversion was observed. The
mixture was diluted with DCM and washed with water. The organic layer was dried over
MgSO , filtered and concentrated under reduced pressure. The crude product was purified
via flash chromatography using heptane and EtOAc as eluents.
General Procedure 9G:
To the suspension of sodium hydride (1.10 eq.) in tetrahydrofurane (0.20 mL/mmol) was
added the solution of pyrazole (1.0 eq.) in tetrahydrofurane (0.12 mL/mmol) dropwise,
while the temperature was kept under 20 °C. After the mixture was stirred at room
temperature for 30 minutes, the appropriate halide (1.20 eq.) was added and the mixture
was stirred further at same temperature for 16 hours. Next, the reaction mixture was
refluxed for 15 hours. After completion the resulting precipitate was filtered off, the filtrate
was concentrated then the residue was poured onto a mixture of water and ethyl acetate.
The phases were separated, and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via distillation.
General Procedure 9H:
To the solution of appropriate alkyl pyrazole (1.0 eq.) in dry tetrahydrofurane (1.5
mL/mmol) n-butyllithium (1.10 eq.) was added dropwise at -70 °C. The mixture was
stirred further at same temperature for 30 minutes; afterwards allowed to warm up to 0 °C
in approx. 30 minutes, and cooled in a dry ice bath. N,N-dimethylformamide (1.10 eq.) was
added dropwise at -70 °C, then the reaction mixture was stirred at room temperature
overnight. The mixture was cooled to 15 °C, and saturated ammonium chloride solution
was added dropwise to the mixture at 15 °C, then the mixture was poured into saturated
ammonium chloride solution. The phases were separated, the aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried over Na SO , and concentrated
under reduced pressure. The residue was used in the next step without further purification.
To the solution of the appropriate crude aldehyde (1.0 eq.) in ethanol (0.5 mL/mmol)
sodium borohydride (1.30 eq.) was added portionwise at -15 °C then the reaction mixture
was stirred at room temperature for 1 h. The mixture was poured onto crushed ice and
stirred for 16 hours. The precipitate was filtered off, and the filtrate was concentrated under
reduced pressure. The oily phase was separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried over Na SO , and concentrated to
dryness.
Preparation 9a1: (E)(Dimethylamino)-1,1-dimethoxy-butenone
502.1 g 1,1-dimethoxypropanone (4.25 mol) and 506.4 g 1,1-dimethoxy-N,N-dimethyl-
methanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105°C for 3 hours. The
formed MeOH was removed continuously via distillation. When MeOH formation stopped
(at 65°C head temperature) the reaction mixture was vacuum distilled (decreasing the
pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The
crude product was distilled at 0.1 mbar. Fractions were collected between 107-118°C head
temperature (bath temperature 160-165°C) to give a yellow oil.
H NMR (500 MHz, DMSO-d ): 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09
(s, 3H), 2.78 (s, 3H).
Preparation 9a2: 4-(Dimethoxymethyl)methylsulfanyl-pyrimidine
198 g sodium methoxide (3.67 mmol) was dissolved in 3 L MeOH and cooled to 0°C. 322
g thiocarbamide (4.23 mol) was added portionwise and the mixture was stirred for 1 hour.
Then 488 g (E)(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1)
(2.82 mol) was added dropwise at 0°C, then it was heated to 70°C for 4 hours. It was
cooled to room temperature, 237 mL methyl iodide (3.81 mol) was added dropwise,
keeping the temperature below 28°C, and the resulting mixture was stirred overnight at
room temperature. It was filtered, the filtrate was concentrated under reduced pressure,
diluted with EtOAc, washed with water and brine. The combined aqueous layers were
extracted with EtOAc. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The residue was dissolved in 500 mL Et O, filtered
through a pad of silica, using Et O as eluent. The filtrate was concentrated under reduced
pressure to give a light brown oil.
H NMR (400 MHz, DMSO-d ): 8.69 (d, 1H), 7.23 (d, 1H), 5.22 (s, 1H), 3.33 (s, 6H), 2.52
(s, 3H).
Preparation 9a3: 4-(Dimethoxymethyl)methylsulfonyl-pyrimidine
To solution of 180 g 4-(dimethoxymethyl)methylsulfanyl-pyrimidine (Preparation 9a2,
940 mmol) in 1.5 L methanol and 1.5 L H O 752 g Oxone (potassium peroxymonosulfate,
1220 mmol) was added portionwise at -5°C, then stirred at 0°C overnight. The reaction
mixture was concentrated under reduced pressure to half volume using a 30°C bath and
then the mixture was filtered, and the precipitates were was washed with DCM. The filtrate
was extracted with DCM. The combined organic layers were dried over MgSO , filtered
and concentrated under reduced pressure to give a light brown oil.
H NMR (400 MHz, CDCl ): 8.98 (d, 1H), 7.97 (d, 1H), 5.36 (s, 1H), 3.47 (s, 6H), 3.39 (s,
3H).
Preparation 9a4: 2-Methylsulfonyl(tetrahydropyranyloxymethyl)pyrimidine
Step A:
To solution of 7.24 g (2-methylsulfanylpyrimidinyl)methanol (Preparation 9aa, 47.5
mmol) and 30.0 g 3,4-dihydro-2H-pyran (357 mmol) in 150 mL DCM 452 mg of p-
toluenesulfonic acid monohydrate (2.30 mmol) was added and it was stirred at room
temperature for 2h. The reaction mixrture was diluted with DCM, then it was washed with
water and saturated aq. NaHCO . The organic layer was dried over Na SO and
3 2 4
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to give 2-methylsulfanyl(tetrahydropyran
yloxymethyl)pyrimidine.
MS: (M+H) = 241.2.
Step B:
To solution of 11.4 g 2-methylsulfanyl(tetrahydropyranyloxymethyl)pyrimidine
(47.5 mmol) in 500 mL DCM 24.6 g MCPBA (3-chloroperoxybenzoic acid, 143 mmol)
was added portionwise at 0°C and stirred at this temperature for 1 h. The precipitates were
filtered off, and the filtrate was washed water and saturated aq. NaHCO . The organic layer
was dried over Na SO and concentrated under reduced pressure. The residue was purified
via flash chromatography using heptane and EtOAc as eluents to give the title product.
H NMR (400 MHz, CDCl3): 9.05 (d, 1H), 7.86 (d, 1H), 4.83 (d, 1H), 4.80 (m, 1H), 4.74
(d, 1H), 3.77 (m, 1H), 3.48 (m, 1H), 3.41 (s, 3H), 1.88-1.40 (m, 6H).
Preparation 9a5: 5-(Dimethoxymethyl)-1H-pyrazole
To the mixture of the 4.11 g hydrazine hydrochloride (60.0 mmol) and 8.66 g (E)
(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1, 50.0 mmol) in dry
methanol 3.241 g sodium methoxide (60.0 mmol) was added portionwise and the mixture
was stirred at 50°C for 45 min. The reaction mixture was cooled and concentrated under
reduced pressure. To the residue water was added and it was extracted with DCM. The
combined organic layers were dried over MgSO and concentrated under reduced pressure.
The crude product was purified via flash chromatography using heptane and EtOAc as
eluents to give the title product.
H NMR (400 MHz, CDCl ): 12.78 (br s, 1H), 7.68 (s, 1H), 6.22 (d, 1H), 5.37 (s, 1H), 3.24
(s, 6H).
Preparation 9aa: (2-Methylsulfanylpyrimidinyl)methanol
Starting from 4-(dimethoxymethyl)methylsulfanyl-pyrimidine (Preparation 9a2) using
General Procedure 9A the title product was obtained as white crystals.
H NMR (400 MHz, DMSO-d ): 8.61 (d, 1H), 7.25 (d, 1H), 5.63 (t, 1H), 4.49 (d, 2H), 2.49
(s, 3H).
Preparation 9ab: [2-(2-Methoxyethylsulfanyl)pyrimidinyl]methanol
Step A:
1.51 g sodium methoxide (28.0 mmol) was dissolved in 15 mL MeOH and cooled to 0°C.
2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for 1
hour. Then 3.46 g (E)(dimethylamino)-1,1-dimethoxy-butenone (Preparation
9a1) (20.0 mol) was added dropwise at 0°C, then it was heated to 80°C and stirred there
for 2 hours. It was cooled to room temperature, 4.17 g 1-bromomethoxy-ethane (30
mmol) was added and the mixture was stirred for 1 hour at 50°C, then overnight at room
temperature. It was filtered, the filtrate was concentrated under reduced pressure, diluted
with EtOAc, washed with water and brine. The organic layer was dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and ethyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)-
2-(2-methoxyethylsulfanyl)pyrimidine).
H NMR (400 MHz, DMSO-d ): 8.68 (d, 1H), 7.24 (d, 1H), 5.23 (s, 1H), 3.59 (t, 2H), 3.33
(s, 6H), 3.32 (t, 2H), 3.28 (s, 3H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.60 (d, 1H), 7.25 (d, 1H), 5.63 (t, 1H), 4.48 (d, 2H), 3.57
(t, 2H), 3.29 (t, 2H), 3.27 (s, 3H).
Preparation 9ac: [2-(3-Methoxypropylsulfanyl)pyrimidinyl]methanol
Step A:
1.51 g sodium methoxide (28.0 mmol) was dissolved in 15 mL MeOH and cooled to 0°C.
2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for 1
hour. Then 3.46 g (E)(dimethylamino)-1,1-dimethoxy-butenone (Preparation
9a1) (20.0 mol) was added dropwise at 0°C, then it was heated at 80°C for 2 hours. It was
cooled to room temperature, 4.59 g 1-bromomethoxy-propane (30 mmol) was added
and was stirred 1 hour at 50°C, then overnight at room temperature. It was filtered, the
filtrate was concentrated under reduced pressure, diluted with EtOAc, washed with water
and brine. The organic layer was dried over Na SO , filtered and concentrated under
reduced pressure. The residue was purified using flash chromatography using heptane and
ethyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)(3-
methoxypropylsulfanyl)pyrimidine).
H NMR (400 MHz, DMSO-d6): 8.68 (d, 1H), 7.23 (d, 1H), 5.22 (s, 1H), 3.43 (t, 2H), 3.33
(s, 6H), 3.24 (s, 3H), 3.14 (m, 2H), 1.90 (m, 2H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.60 (d, 1H), 7.24 (d, 1H), 5.63 (t, 1H), 4.48 (d, 2H), 3.42
(t, 2H), 3.24 (s, 3H), 3.12 (t, 2H) 1.88 (m, 2H).
Preparation 9ad: (2-Ethoxypyrimidinyl)methanol
Step A:
To the solution of 1500 mg 4-(dimethoxymethyl)methylsulfonyl-pyrimidine
(Preparation 9a3, 6.46 mmol) in 60 mL ethanol 527 mg sodium ethoxide (7.75 mmol)
was added and stirred at room temperature for 1h. The volatiles were evaporated under
reduced pressure and the residue was purified via flash chromatography using heptane and
EtOAc as eluents to give 4-(dimethoxymethyl)ethoxy-pyrimidine.
MS: (M+H) = 199.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
MS: (M+H) = 155.2
Preparation 9ae: (2-Isopropoxypyrimidinyl)methanol
Step A:
To the solution of 1500 mg 4-(dimethoxymethyl)methylsulfonyl-pyrimidine
(Preparation 9a3, 6.46 mmol) in 50 mL propanol the solution of 310 mg sodium
hydride (60%, 7.75 mmol) in 10ml propanol was added and stirred at room temperature
for 1h. The volatiles were evaporated under reduced pressure and the residue was purified
via flash chromatography using heptane and EtOAc as eluents to give 4-
(dimethoxymethyl)isopropoxy-pyrimidine.
MS: (M+H) = 213.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
MS: (M+H) = 169.2
Preparation 9af: (2-Propoxypyrimidinyl)methanol
Step A:
To the solution of 1500 mg 4-(dimethoxymethyl)methylsulfonyl-pyrimidine
(Preparation 9a3, 6.46 mmol) in 50 mL propanol the solution of 310 mg sodium
hydride (60%, 7.75 mmol) in 10ml propanol was added and stirred at room temperature
for 1h. The volatiles were evaporated under reduced pressure and the residue was purified
via flash chromatography using heptane and EtOAc as eluents to give 4-
(dimethoxymethyl)propoxy-pyrimidine.
MS: (M+H) = 213.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
MS: (M+H) = 169.2
Preparation 9ag: [2-(2-Methoxyethoxy)pyrimidinyl]methanol
Step A:
2-Methoxyethanol (10 mL) was cooled to 0°C and 413 mg of sodium hydride (60%, 10.33
mmol) was added portionwise, then 2.00 g 4-(dimethoxymethyl)methylsulfonyl-
pyrimidine (Preparation 9a3) (8.61 mmol) was added and stirred at room temperature for
1h. The reaction mixture was concentrated under reduced pressure. To the residue water
was added and it was extracted with DCM. The combined organic layers were dried over
MgSO and concentrated under reduced pressure to give 4-(dimethoxymethyl)(2-
methoxyethoxy)pyrimidine.
MS: (M+H) = 229.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
MS: (M+H) = 185.2
Preparation 9ah: [2-(2-Ethoxyethoxy)pyrimidinyl]methanol
Step A:
mL 2-ethoxyethanol was cooled to 0°C, then 240 mg sodium hydride (6.00 mmol) was
added portionwise and the mixture was stirred at this temperature for 15 min. The solution
of 1.16 g 4-(dimethoxymethyl)methylsulfonyl-pyrimidine (Preparation 9a3, 5.00
mmol) in 3 mL 2-ethoxyethanol was added, then cooling was removed and reaction
mixture was stirred at room temperature for 2h. Brine was added then the mixture was
extracted with DCM. The combined organic layers were dried over MgSO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)(2-
ethoxyethoxy)pyrimidine.
H NMR (400 MHz, CDCl ): 8.54 (d, 1H), 7.17 (d, 1H), 5.18 (s, 1H), 4.53 (t, 2H), 3.82 (t,
2H), 3.59 (q, 2H), 3.42 (s, 6H), 1.22 (t, 3H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, CDCl ): 8.47 (d, 1H), 6.95 (d, 1H), 4.71 (br s, 2H), 4.56 (t, 2H), 3.84
(t, 2H), 3.62 (q, 2H), 1.25 (t, 3H).
Preparation 9ai: [2-(2,2,2-Trifluoroethoxy)pyrimidinyl]methanol
Step A:
To the solution of 5.00 g 4-(dimethoxymethyl)methylsulfonyl-pyrimidine (Preparation
9a3, 21.5 mmol) in 54 ml dry acetonitrile 5.95 g K CO (43.1 mmol) and 3.24 g 2,2,2-
trifluoroethanol (32.3 mmol) were added, and stirred at 60°C until no further conversion
was observed. The reaction mixture was cooled, filtered, the precipitate was washed with
EtOAc, then the filtrate was concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane and EtOAc as eluents to give 4-
(dimethoxymethyl)(2,2,2-trifluoroethoxy)pyrimidine.
H NMR (400 MHz, DMSO-d ): 8.74 (d, 1H), 7.32 (d, 1H), 5.25 (s, 1H), 5.05 (q, 2H), 3.34
(s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d6): 8.65 (d, 1H), 7.32 (d, 1H), 5.69 (t, 1H), 5.02 (q, 2H), 4.51
(d, 2H).
Preparation 9aj: [2-(3,3,3-Trifluoropropoxy)pyrimidinyl]methanol
Step A:
To the solution of 2.00 g Preparation 9a3 (8.61 mmol) in acetonitrile 2.38 g K CO (17.2
mmol), then 3,3,3-trifluoropropanol were added and the so obtained mixture was stirred
for 10h at 60°C. The reaction mixture was cooled, filtered and the filtrate concentrated
under reduced pressure. The residue was purified via flash chromatography using heptane
and ethyl-acetate as eluents to give 4-(dimethoxymethyl)(3,3,3-trifluoropropoxy)
pyrimidine.
H NMR (400 MHz, DMSO-d ): 8.68 (d, 1H), 7.22 (d, 1H), 5.22 (s, 1H), 4.53 (t, 2H), 3.33
(s, 6H), 2.83 (m, 2H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.59 (d, 1H), 7.22 (d, 1H), 5.63 (t, 1H), 4.49 (m, 4H),
2.81 (m, 2H).
Preparation 9ak: (2-Phenoxypyrimidinyl)methanol
Step A:
To the solution of 1.50 g Preparation 9a3 (6.46 mmol) in 50 mL THF 2.14 g K CO (15.5
mmol), then 729 mg of phenol (7.75 mmol) were added and the so obtained mixture was
stirred for 3 days at room temperature. The reaction mixture was concentrated under
reduced pressure. The residue was purified via flash chromatography using heptane and
ethyl-acetate as eluents to give 4-(dimethoxymethyl)phenoxy-pyrimidine.
MS: (M+H) = 247.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
MS: (M+H) = 203.2
Preparation 9al: (2-Aminopyrimidinyl)methanol
Step A:
To the stirred mixture of 2.29 g of guanidine hydrochloride (24.0 mmol) and 8 mL of
methanol 1.30 g sodium methoxide (24.0 mmol) and 3.46 g Preparation 9a1 (20.0 mmol)
were added, then stirred at 75 °C for 2 h. The reaction mixture was cooled, concentrated
under reduced pressure, then 30 mL water was added. The formed precipitate was filtered,
washed with water and dried to give 4-(dimethoxymethyl)pyrimidinamine.
H NMR (400 MHz, DMSO-d ): 8.26 (d, 1H), 6.71 (br s, 2H), 6.61 (d, 1H), 5.00 (s, 1H),
3.28 (s, 6H).
Step B:
The solution of 5.01 g 4-(dimethoxymethyl)pyrimidinamine (29.5 mmol) in 100 mL 2N
aq. HCl was stirred at 60°C for 5h. Reaction mixture was cooled to 0°C, then 7.60 g NaOH
(190 mmol) was added portionwise. The pH was adjusted to 8 using 10% K CO solution,
then 2.24 g sodium borohydride (59.0 mmol) was added portionwise keeping the
temperature under 5°C and stirred for 30 min at 0°C. The reaction mixture was extracted
with EtOAc, the combined organic phases were dried over Na SO and concentrated under
reduced pressure. The crude product was purified via flash chromatography (MeOH -
containing 1%NH - and DCM).
H NMR (400 MHz, DMSO-d ): 8.20 (d, 1H), 6.66 (d, 1H), 6.49 (br s, 2H), 5.35 (t, 1H),
4.30 (d, 2H).
Preparation 9am: [2-(Methylamino)pyrimidinyl]methanol
To the 2M solution of methylamine in THF (3 mL) 232 mg 4-(dimethoxymethyl)
methylsulfonyl-pyrimidine (Preparation 9a3, 1.00 mmol) was added and it was stirred at
room temperature for 1h. The reaction mixture was concentrated under reduced pressure,
the residue was diluted with EtOAc and washed with brine. The organic layer was dried
over MgSO and concentrated under reduced pressure. To the residue 3 mL 2N HCl was
added and it was stirred at 60°C for 2h. Than it was cooled to 0°C, the pH was adjusted to
9 using 2N NaOH solution, and then 76 mg sodium borohydride (2.0 mmol) was added
and the mixture was stirred for 1h. The reaction mixture was extracted with EtOAc, the
combined organic layers were dried over MgSO and concentrated under reduced pressure
to give the title product.
MS: (M+2H) = 141.4.
Preparation 9an: [2-(Dimethylamino)pyrimidinyl]methanol
To 3 mL dimethylamine solution (2M in THF, 6 mmol) 232 mg 4-(dimethoxymethyl)
methylsulfonyl-pyrimidine (Preparation 9a3, 1.00 mmol) was added and it was stirred at
room temperature for 1h. The reaction mixture was concentrated under reduced pressure,
the residue was diluted with EtOAc and washed with brine. The organic layer was dried
over MgSO and concentrated under reduced pressure. To the residue 3 mL 2N HCl was
added and it was stirred at 60°C for 2h. It was cooled to 0°C, the pH was adjusted to 9
using 2N NaOH solution, and then 76 mg sodium borohydride (2.0 mmol) was added and
stirred for 1h. The reaction mixture was extracted with EtOAc, and the combined organic
layers were dried over MgSO and concentrated under reduced pressure to give the title
product.
MS: (M+H) = 154.4.
Preparation 9ao: [2-(2-Methoxyethylamino)pyrimidinyl]methanol
Step A:
Starting from 4-(dimethoxymethyl)methylsulfonyl-pyrimidine (Preparation 9a3) and
2-methoxyethanamine using General Procedure 9E 4-(dimethoxymethyl)-N-(2-
methoxyethyl)pyrimidinamine was obtained.
H NMR (400 MHz, CDCl ): 8.32 (d, 1H), 6.73 (d, 1H), 5.61 (br s, 1H), 5.08 (s, 1H), 3.62
(m, 2H) 3.56 (m, 2H), 3.38 (s, 6H), 3.36 (s, 3H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, CDCl ): 8.22 (d, 1H), 6.48 (d, 1H), 5.64 (br s, 1H), 4.57 (s, 2H), 3.65
(m, 2H) 3.58 (m, 2H), 3.49 (s, 1H), 3.39 (s, 3H).
Preparation 9ap: [2-[2-Methoxyethyl(methyl)amino]pyrimidinyl]methanol
Step A:
Starting from 4-(dimethoxymethyl)methylsulfonyl-pyrimidine (Preparation 9a3) and
2-methoxy-N-methyl-ethanamine as amine reagent using General Procedure 9E 4-
(dimethoxymethyl)-N-(2-methoxyethyl)-N-methyl-pyrimidinamine was obtained.
H NMR (400 MHz, CDCl ): 8.32 (d, 1H), 6.66 (d, 1H), 5.04 (s, 1H), 3.82 (t, 2H) 3.58 (t,
2H), 3.40 (s, 6H), 3.34 (s, 3H), 3.21 (s, 3H).
Step B:
Starting from this product using General Procedure 9A the title product was obtained.
H NMR (400 MHz, CDCl ): 8.25 (d, 1H), 6.39 (d, 1H), 4.57 (d, 2H), 3.90 (br s, 1H), 3.85
(t, 2H) 3.61 (t, 2H), 3.37 (s, 3H), 3.24 (s, 3H).
Preparation 9aq: [2-(4-Methylpiperazinyl)pyrimidinyl]methanol
Step A:
Starting from 4-(dimethoxymethyl)methylsulfonyl-pyrimidine (Preparation 9a3) and
1-methylpiperazine using General Procedure 9E 4-(dimethoxymethyl)(4-
methylpiperazinyl)pyrimidine was obtained.
H NMR (400 MHz, CDCl ): 8.34 (d, 1H), 6.70 (d, 1H), 5.06 (s, 1H), 3.85 (m, 4H), 3.41
(s, 6H), 2.46 (m, 4H), 2.34 (s, 3H).
Step B:
Starting from 4-(dimethoxymethyl)(4-methylpiperazinyl)pyrimidine using General
Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.33 (d, 1H), 6.72 (d, 1H), 5.41 (t, 1H), 4.35 (d, 2H), 3.70
(m, 4H), 2.36 (m, 4H), 2.22 (s, 3H).
Preparation 9ar: (2-(Morpholinyl)pyrimidinyl)methanol
Step A:
3.50 g Preparation 9a3 (15.1 mmol) was stirred in 23 mL morpholine at room
temperature for 2h. The reaction mixture was concentrated under reduced pressure and the
residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to
give 4-[4-(dimethoxymethyl)pyrimidinyl]morpholine.
H NMR (400 MHz, DMSO-d ): 8.42 (d, 1H), 6.71 (d, 1H), 5.06 (s, 1H), 3.67 (m, 8H),
3.31 (s, 6H).
Step B:
Starting from 4-[4-(dimethoxymethyl)pyrimidinyl]morpholine using General
Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.36 (d, 1H), 6.76 (d, 1H), 5.43 (t, 1H), 4.36 (d, 2H), 3.65
(m, 8H).
Preparation 9as: [2-(1H-[1,2,3]Triazolyl)pyrimidinyl]methanol
Step A:
To the solution of 829 mg 1H-[1,2,3]triazole (12.0 mmol) in acetone 2.07 g K CO (15.0
mmol), then Preparation 9a3 were added and the mixture was stirred for 2h at room
temperature. The reaction mixture was filtered and concentrated under reduced pressure.
The residue was purified via flash chromatography using heptane and ethyl-acetate as
eluents to give 4-(dimethoxymethyl)(1H-[1,2,3]triazolyl)pyrimidine as white
crystals.
H NMR (400 MHz, DMSO-d ): 9.06 (d, 1H), 8.89 (d, 1H), 8.01 (d, 1H), 7.70 (d, 1H),
.44 (s, 1H), 3.40 (s, 6H).
Note: 4-(dimethoxymethyl)(1H-[1,2,3]triazolyl)pyrimidine was also obtained.
H NMR (400 MHz, DMSO-d ): 9.03 (d, 1H), 8.24 (s, 2H), 7.66 (d, 1H), 5.42 (s, 1H), 3.39
(s, 6H).
Step B:
Starting from 1.40 g 4-(dimethoxymethyl)(1H-[1,2,3]triazolyl)pyrimidine using
General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.97 (d, 1H), 8.88 (d, 1H), 7.99 (d, 1H), 7.70 (d, 1H),
.86 (t, 1H), 4.69 (d, 2H).
Preparation 9at: [2-(Benzylamino)pyrimidinyl]methanol
To the solution of 0.32 mL benzylamine in 4 mL DCM 460 mg 4-(dimethoxymethyl)
methylsulfonyl-pyrimidine (Preparation 9a3, 2.00 mmol) was added and it was stirred at
40°C for 16h. The reaction mixture was diluted with DCM and washed with brine. The
organic layer was dried over MgSO and concentrated under reduced pressure. To the
residue 6 mL 2N HCl was added and it was stirred at 60°C for 2h. It was cooled to 0°C, the
pH was adjusted to 9 using 2N NaOH solution, and then 152 mg sodium borohydride (2.0
mmol) was added and stirred for 1h. The reaction mixture was extracted with EtOAc, the
combined organic layers were dried over MgSO filtered and concentrated under reduced
pressure to give the title product.
MS: (M+H) = 216.2.
Preparation 9au: [2-(Cyclopropylmethoxy)pyrimidinyl]methanol
Step A:
mL cyclopropylmethanol was cooled to 0°C, then 1.10 g sodium hydride (27.5 mmol)
was added portionwise and the mixture was stirred at this temperature for 30 min. This
mixture was added to 953 mg of 2-methylsulfonyl(tetrahydropyran
yloxymethyl)pyrimidine (Preparation 9a4, 3.50 mmol) and it was stirred at room
temperature for 30 min. Water was added then the mixture was extracted with DCM. The
combined organic layers were dried over MgSO , filtered and concentrated under reduced
pressure. The residue was purified via flash chromatography using heptane and EtOAc as
eluents to give 2-(cyclopropylmethoxy)(tetrahydropyranyloxymethyl)pyrimidine.
MS: (M+H) = 265.2.
Step B:
To the solution of 732 mg of 2-(cyclopropylmethoxy)(tetrahydropyranyloxymethyl)
pyrimidine (2.77 mmol) in 50 mL EtOH 160 mg pyridinium p-toluenesulfonate (0.64
mmol) was added and the mixture was stirred at 50°C for 16h. The mixture was
concentrated under reduced pressure, the residue was purified via flash chromatography
using heptane and EtOAc as eluents to give the title product.
H NMR (400 MHz, DMSO-d ): 8.55 (d, 1H), 7.16 (d, 1H), 5.59 (t, 1H), 4.45 (m, 2H),
4.11 (d, 2H), 1.25 (m, 1H), 0.55 (m, 2H), 0.33 (m, 2H).
Preparation 9aw: [2-(4-Pyridylmethoxy)pyrimidinyl]methanol
To the solution of 164 mg of 4-pyridylmethanol (1.50 mmol) in 3 mL DMF 80 mg of
sodium hydride (60%, 2.0 mmol) was added at 0°C and stirred at room temperature for 30
min. This mixture was added to the solution of 272 mg of 2-methylsulfonyl
(tetrahydropyranyloxymethyl)pyrimidine (Preparation 9a4, 1.00 mmol) in 1 mL DMF.
The mixture was stirred at room temperature for 1h, then it was diluted with water, and
extracted with DCM. The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The residue was dissolved in 15 mL EtOH then 160
mg pyridinium p-toluenesulfonate (0.64 mmol) was added and stirred at 50°C for 16h. The
mixture was concentrated under reduced pressure, the residue diluted with water, and
extracted with DCM. The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to give the title product.
MS: (M+H) = 218.2.
Preparation 9ax: (2-Benzyloxypyrimidinyl)methanol
Step A:
To 4.25 mL phenylmethanol cooled to 0°C 545 mg sodium hydride (13.6 mmol) was
added portionwise and the mixture was stirred at room temperature for 30 min. This
mixture was added to 460 mg of 2-methylsulfonyl(tetrahydropyranyloxymethyl)
pyrimidine (Preparation 9a4, 1.69 mmol) and it was stirred at room temperature for 1h.
Water was added then the mixture was extracted with DCM. The combined organic layers
were dried over MgSO and concentrated under reduced pressure. The residue was purified
via flash chromatography using heptane and EtOAc as eluents to give 2-benzyloxy
(tetrahydropyranyloxymethyl)pyrimidine.
MS: (M+H) = 301.2.
Step B:
To the solution of 408 mg of 2-benzyloxy(tetrahydropyranyloxymethyl)pyrimidine
(1.36 mmol) in 50 mL EtOH 79 mg pyridinium p-toluenesulfonate (0.30 mmol) was added
and the mixture was stirred at 50°C for 16h. The mixture was concentrated under reduced
pressure, the residue was purified via flash chromatography using heptane and EtOAc as
eluents to give the title product.
H NMR (400 MHz, DMSO-d ): 8.59 (d, 1H), 7.47-7.30 (m, 5H), 7.21 (d, 1H), 5.62 (t,
1H), 5.37 (s, 2H), 4.49 (m, 2H).
Preparation 9ay: {2-[(1-methyl-1H-imidazolyl)methoxy]pyrimidinyl}methanol
To the solution of 224 mg of (1-methyl-1H-imidazolyl)methanol (2.00 mmol) in 5 mL
DMF 158 mg of sodium hydride (60%, 3.95 mmol) was added at 0°C and it was stirred at
room temperature for 30 min. This mixture was added to the solution of 500 mg of 2-
methylsulfonyl(tetrahydropyranyloxymethyl)pyrimidine (Preparation 9a4, 1.84
mmol) in 1 mL DMF. The reaction mixture was stirred at room temperature for 1h, then it
was diluted with water, and extracted with DCM. The combined organic layers were dried
over Na SO and concentrated under reduced pressure. The residue was dissolved in 5 mL
HCl in EtOH (1.25M) and stirred at room temperature for 1h. The mixture was
concentrated under reduced pressure, the residue diluted with water, and extracted with
DCM. The combined organic layers were dried over Na SO and concentrated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to give the title product.
MS: (M+H) = 221.2.
Preparation 9ba: (2-Ethylpyrimidinyl)methanol
Step A:
Starting from propanamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)ethyl-pyrimidine was obtained.
MS: (M+H) = 183.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.69 (d, 1H), 7.37 (d, 1H), 5.59 (t, 1H), 4.52 (d, 2H), 2.84
(q, 2H), 1.25 (t, 3H).
Preparation 9bb: (2-Propylpyrimidinyl)methanol
Step A:
Starting from butanamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)propyl-pyrimidine was obtained.
MS: (M+H) = 197.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.68 (d, 1H), 7.36 (d, 1H), 5.59 (t, 1H), 4.51 (d, 2H), 2.79
(t, 2H), 1.75 (h, 2H), 0.90 (t, 3H).
Preparation 9bc: (2-Butylpyrimidinyl)methanol
Step A:
Starting from n-pentanamidine hydrochloride using General Procedure 9C 2-butyl
(dimethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 7.36 (d, 1H), 5.25 (s, 1H), 3.32 (s, 6H), 2.87
(t, 2H), 1.73 (m, 2H), 1.32 (m, 2H), 0.90 (t, 3H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.70 (d, 1H), 7.36 (d, 1H), 5.59 (t, 1H), 4.51 (d, 2H), 2.81
(t, 2H), 1.70 (m, 2H), 1.31 (m, 2H), 0.89 (t, 3H).
Preparation 9bd: (2-Isopropylpyrimidinyl)methanol
Step A:
Starting from 2-methylpropanamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)isopropyl-pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.79 (d, 1H), 7.36 (d, 1H), 5.25 (s, 1H), 3.34 (s, 6H), 3.14
(h, 1H), 1.27 (d, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.70 (d, 1H), 7.37 (d, 1H), 5.59 (t, 1H), 4.52 (d, 2H), 3.08
(h, 1H), 1.25 (d, 6H).
Preparation 9be: (2-Cyclopropylpyrimidinyl)methanol
Step A:
Starting from cyclopropanecarboxamidine hydrochloride using General Procedure 9C 2-
cyclopropyl(dimethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.67 (d, 1H), 7.28 (d, 1H), 5.20 (s, 1H), 3.31 (s, 6H), 2.20
(m, 1H), 1.07-0.96 (m, 4H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.59 (d, 1H), 7.29 (d, 1H), 5.56 (t, 1H), 4.47 (d, 2H), 2.14
(m, 1H), 1.03-0.92 (m, 4H).
Preparation 9bf: (2-Isobutylpyrimidinyl)methanol
Step A:
Starting from 3-methylbutanamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)isobutyl-pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 7.36 (d, 1H), 5.25 (s, 1H), 3.32 (s, 6H), 2.75
(d, 2H), 2.22 (m, 1H), 0.89 (d, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.69 (d, 1H), 7.37 (d, 1H), 5.59 (t, 1H), 4.51 (d, 2H), 2.69
(d, 2H), 2.19 (m, 1H), 0.88 (d, 6H).
Preparation 9bg: [2-(Cyclopropylmethyl)pyrimidinyl]methanol
Step A:
Starting from 2-cyclopropylacetamidine hydrochloride using General Procedure 9C 2-
(cyclopropylmethyl)(dimethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.79 (d, 1H), 7.38 (d, 1H), 5.26 (s, 1H), 3.34 (s, 6H), 2.78
(d, 2H), 1.18 (m, 1H), 0.46 (m, 2H), 0.22 (m, 2H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.70 (d, 1H), 7.39 (d, 1H), 5.59 (t, 1H), 4.52 (d, 2H), 2.71
(d, 2H), 1.17 (m, 1H), 0.45 (m, 2H), 0.25 (m, 2H).
Preparation 9bh: (2-tert-Butylpyrimidinyl)methanol
Step A:
Starting from 2,2-dimethylpropanamidine hydrochloride using General Procedure 9C 2-
tert-butyl(dimethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.80 (d, 1H), 7.34 (d, 1H), 5.25 (s, 1H), 3.34 (s, 6H), 1.35
(s, 9H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.72 (d, 1H), 7.35 (d, 1H), 5.57 (t, 1H), 4.52 (d, 2H), 1.33
(s, 9H).
Preparation 9bi: (2-Cyclopentylpyrimidinyl)methanol
Step A:
Starting from cyclopentanecarboxamidine hydrochloride using General Procedure 9C 2-
cyclopentyl(dimethoxymethyl)pyrimidine was obtained.
MS: (M+H) = 223.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.68 (d, 1H), 7.34 (d, 1H), 5.57 (t, 1H), 4.51 (d, 2H), 3.25
(p, 1H), 1.98 (m, 2H), 1.87-1.57 (m, 6H).
Preparation 9bj: [2-(Trifluoromethyl)pyrimidinyl]methanol
Step A:
The mixture of 500 mg Preparation 9a1 (2.89 mmol) and 356 mg 2,2,2-
trifluoroacetamidine (3.18 mmol) was heated at 110°C for 40 min in a microwave reactor.
The crude product was purified via flash chromatography using heptane and EtOAc as
eluents to give 4-(dimethoxymethyl)(trifluoromethyl)pyrimidine.
H NMR (400 MHz, CDCl ): 8.97 (d, 1H), 7.77 (d, 1H), 5.36 (s, 1H), 3.48 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, CDCl ): 8.90 (d, 1H), 7.65 (d, 1H), 5.87 (br s, 1H), 4.91 (d, 2H).
Preparation 9bk: [2-(Methoxymethyl)pyrimidinyl]methanol
Step A:
Starting from 2-methoxyacetamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(methoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.86 (d, 1H), 7.47 (d, 1H), 5.30 (s, 1H), 4.58 (s, 2H), 3.37
(s, 3H), 3.34 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 7.47 (d, 1H), 5.66 (t, 1H), 4.55 (d, 2H), 4.53
(s, 2H), 3.36 (s, 3H).
Preparation 9bl: [2-(2-Methoxyethyl)pyrimidinyl]methanol
Step A:
Starting from 3-methoxypropanamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(2-methoxyethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.78 (d, 1H), 7.38 (d, 1H), 5.25 (s, 1H), 3.80 (t, 2H), 3.33
(s, 6H), 3.22 (s, 3H), 3.11 (t, 2H).
Note: 2-[4-(dimethoxymethyl)pyrimidinyl]-N,N-dimethyl-ethanamine was also
obtained.
MS: (M+H) = 226.2. (See also at Step A of Preparation 9bm)
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.70 (d, 1H), 7.39 (d, 1H), 5.60 (t, 1H), 4.52 (d, 2H), 3.78
(t, 2H), 3.22 (s, 3H), 3.06 (t, 2H).
Preparation 9bm: [2-(2-Dimethylaminoethyl)pyrimidinyl]methanol
Step A:
To the mixture of 1.63 g 3-(dimethylamino)propanamidine dihydrochloride (8.67 mmol)
and 1.25 g (E)(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1, 7.23
mmol) in 4 mL dry methanol sodium methoxide (17.3 mmol) was added portionwise and
the mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated
under reduced pressure. Water was added to the residue and it was extracted with EtOAc.
The combined organic layers were dried over MgSO and concentrated under reduced
pressure to give 2-[4-(dimethoxymethyl)pyrimidinyl]-N,N-dimethyl-ethanamine.
MS: (M+H) = 226.2.
Step B:
1.474 g crude 2-[4-(dimethoxymethyl)pyrimidinyl]-N,N-dimethyl-ethanamine obtained
in Step A was stirred with 20 mL 2N HCl solution at 60°C for 2h. The reaction mixture
was cooled to 0°C, then 1.52 NaOH (3.8 mmol) was added portionwise. The pH was
adjusted to 8 using 10% K CO solution, then 492 mg sodium borohydride (13.0 mmol)
was added portionwise keeping the temperature under 5°C and stirred for 30 min at 0°C.
Reaction mixture was salted (4g NaCl) then extracted with 2-Me-THF. The combined
organic layers were dried over Na SO and concentrated under reduced pressure to give the
title product.
H NMR (400 MHz, DMSO-d ): 8.69 (d, 1H), 7.39 (d, 1H), 5.64 (br s, 1H), 4.52 (s, 2H),
3.01 (m, 2H), 2.80 (m, 2H), 2.25 (s, 6H).
Preparation 9bn: [2-(Ethoxymethyl)pyrimidinyl]methanol
Step A:
Starting from 2-ethoxyacetamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(ethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.86 (d, 1H), 7.46 (d, 1H), 5.29 (s, 1H), 4.61 (s, 2H), 3.58
(q, 2H), 3.33 (s, 6H), 1.16 (t, 3H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 7.47 (d, 1H), 5.65 (t, 1H), 4.56 (m, 4H),
3.57 (q, 2H), 1.14 (t, 3H).
Preparation 9bo: [2-(4-Chlorophenyl)pyrimidinyl]methanol
Step A:
Starting from 4-chlorobenzamidine hydrochloride using General Procedure 9C 2-(4-
chlorophenyl)(dimethoxymethyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.97 (d, 1H), 8.40 (m, 2H), 7.61 (m, 2H), 7.50 (d, 1H),
5.38 (s, 1H), 3.39 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.89 (d, 1H), 8.39 (m, 2H), 7.59 (m, 2H), 7.52 (d, 1H),
.71 (t, 1H), 4.64 (d, 2H).
Preparation 9bp: [2-(2-Methoxyphenyl)pyrimidinyl]methanol
Step A:
Starting from 2-methoxybenzamidine acetic acid salt using General Procedure 9C 4-
(dimethoxymethyl)(2-methoxyphenyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.93 (d, 1H), 7.55-7.44 (m, 3H), 7.16 (d, 1H), 7.06 (m,
1H), 5.31 (s, 1H), 3.76 (s, 3H), 3.37 (s, 6H).
Step B:
261 mg 4-(dimethoxymethyl)(2-methoxyphenyl)pyrimidine (1.00 mmol) was dissolved
in 2 mL HCl in dioxane (4M solution), then 2 mL water was added and this mixture was
stirred at 50 °C for 16h. The reaction mixture was cooled to 0°C, then 320 mg NaOH (8.0
mmol) was added portionwise. The pH was adjusted to 8 using 10% K CO solution, then
76 mg sodium borohydride (2.0 mmol) was added and the mixture was stirred for 30 min
at 0°C. The reaction mixture was diluted with 5 mL water and extracted with EtOAc. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified via flash chromatography using heptane and
EtOAc as eluents to give the title product.
H NMR (400 MHz, DMSO-d ): 8.84 (d, 1H), 7.50-7.42 (m, 3H), 7.14 (d, 1H), 7.03 (m,
1H), 5.66 (t, 1H), 4.58 (d, 2H), 3.75 (s, 3H).
Preparation 9bq: [2-(2-Pyridyl)pyrimidinyl]methanol
Step A:
Starting from pyridinecarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(2-pyridyl)pyrimidine was obtained.
MS: (M+H) = 232.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.94 (d, 1H), 8.74 (d, 1H), 8.37 (d, 1H), 7.97 (m, 1H),
7.60 (d, 1H), 7.52 (m, 1H), 5.74 (t, 1H), 4.67 (d, 2H).
Preparation 9br: [2-(3-Pyridyl)pyrimidinyl]methanol
Step A:
Starting from pyridinecarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(3-pyridyl)pyrimidine was obtained.
MS: (M+H) = 232.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 9.51 (dd, 1H), 8.93 (d, 1H), 8.72 (dd, 1H), 8.66 (m, 1H),
7.56 (m, 2H), 5.73 (t, 1H), 4.67 (d, 2H).
Preparation 9bs: [2-(4-Pyridyl)pyrimidinyl]methanol
Step A:
Starting from pyridinecarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(4-pyridyl)pyrimidine was obtained.
MS: (M+H) = 232.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.98 (d, 1H), 8.77 (m, 2H), 8.25 (m, 2H), 7.63 (d, 1H),
.76 (t, 1H), 4.68 (d, 2H).
Preparation 9bt: [2-(3-Furyl)pyrimidinyl]methanol
Step A:
Starting from furancarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(3-furyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.85 (d, 1H), 8.43 (br s, 1H), 7.83 (dd, 1H), 7.39 (d, 1H),
7.04 (dd, 1H), 5.31 (s, 1H), 3.36 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 8.39 (br s, 1H), 7.80 (dd, 1H), 7.40 (d, 1H),
7.02 (dd, 1H), 5.65 (t, 1H), 4.58 (d, 2H).
Preparation 9bu: [2-(3-Thienyl)pyrimidinyl]methanol
Step A:
Starting from thiophenecarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(3-thienyl)pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.89 (d, 1H), 8.39 (dd, 1H), 7.81 (dd, 1H), 7.67 (dd, 1H),
7.40 (d, 1H), 5.33 (s, 1H), 3.38 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.81 (d, 1H), 8.36 (dd, 1H), 7.80 (dd, 1H), 7.65 (dd, 1H),
7.42 (d, 1H), 5.66 (t, 1H), 4.60 (d, 2H).
Preparation 9bv: [2-(2-Thienyl)pyrimidinyl]methanol
Step A:
Starting from thiophenecarboxamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(2-thienyl)pyrimidine was obtained.
MS: (M+H) = 237.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.77 (d, 1H), 7.93 (dd, 1H), 7.76 (dd, 1H), 7.40 (d, 1H),
7.20 (dd, 1H), 5.68 (t, 1H), 4.58 (d, 2H).
Preparation 9bw: (2-(1H-Pyrazolyl)pyrimidinyl)methanol
Step A:
To the stirred mixture of 4.18 g of pyrazolecarboxamidine hydrochloride (28.5 mmol)
and 120 mL of ethanol 4.05 g of Na HPO (28.5 mmol) and 4.12 g of Preparation 9a1
(23.78 mmol) were added, then it was stirred at 85 °C for 10 h. The reaction mixture was
cooled, concentrated under reduced pressure, and the crude product was purified via flash
chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)(1H-
pyrazolyl)-pyrimidine.
H NMR (400 MHz, DMSO-d ): 8.92 (d, 1H), 8.65 (d, 1H), 7.87 (br s, 1H), 7.50 (d, 1H),
6.62 (dd, 1H), 5.36 (s, 1H), 3.38 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d6): 8.84 (d, 1H), 8.65 (d, 1H), 7.84 (br s, 1H), 7.51 (d, 1H),
6.59 (dd, 1H), 5.77 (t, 1H), 4.63 (d, 2H).
Preparation 9bx: (2-Thiazolylpyrimidinyl)methanol
Step A:
To the stirred mixture of 1.00 g of thiazolecarboxamidine hydrochloride (6.11 mmol)
and 3 mL of methanol 330 mg sodium methoxide (6.11 mmol) and 1.05 g of Preparation
9a1 (6.11mmol) were added, then it was stirred at 75 °C for 7 h. The reaction mixture was
cooled, concentrated under reduced pressure, brine was added and it was extracted with
DCM. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to give 2-[4-(dimethoxymethyl)pyrimidinyl]thiazole.
MS: (M+H) = 238.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.91 (d, 1H), 8.03 (dd, 2H), 7.61 (d, 1H), 5.78 (t, 1H),
4.65 (d, 2H).
Preparation 9by: (2-Benzylpyrimidinyl)methanol
Step A:
Starting from 2-phenylacetamidine hydrochloride using General Procedure 9C 2-benzyl-
4-(dimethoxymethyl)pyrimidine was obtained.
MS: (M+H) = 245.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.71 (d, 1H), 7.39 (d, 1H), 7.28 (m, 4H), 7.20 (m, 1H),
5.61 (t, 1H), 4.52 (d, 2H), 4.16 (s, 2H).
Preparation 9bz: [2-(Phenoxymethyl)pyrimidinyl]methanol
Step A:
Starting from 2-phenoxyacetamidine hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)(phenoxymethyl)pyrimidine was obtained.
MS: (M+H) = 261.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.81 (d, 1H), 7.51 (d, 1H), 7.28 (m, 2H), 6.95 (m, 3H),
.68 (t, 1H), 5.21 (s, 2H), 4.57 (d, 2H).
Preparation 9ca: (5-Bromopyrimidinyl)methanol
Step A:
To the solution of 3.90 g of 4-(dimethoxymethyl)pyrimidine (25.3 mmol) in 100 mL
AcOH 4.15 g sodium acetate (50.6 mmol) and 8.08 g bromine (50.6 mmol) were added
and the mixture was stirred at 40°C for 7 h. Reaction mixture was concentrated under
reduced pressure, DCM was added to the residue, and it was washed with saturated aq.
NaHCO . The organic phase was dried over Na SO and concentrated under reduced
3 2 4
pressure. The crude product was purified via flash chromatography using heptane and
EtOAc as eluents to give 5-bromo(dimethoxymethyl)pyrimidine.
H NMR (400 MHz, DMSO-d ): 9.18 (s, 1H), 9.06 (s, 1H), 5.51 (s, 1H), 3.40 (s, 6H).
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 9.14 (s, 1H), 8.94 (s, 1H), 5.49 (t, 1H), 4.62 (d, 2H).
Preparation 9cb: (5-Bromomethoxy-pyrimidinyl)methanol
Step A:
Starting from methyl carbamimidate hydrochloride using General Procedure 9C 4-
(dimethoxymethyl)methoxy-pyrimidine was obtained.
H NMR (400 MHz, DMSO-d ): 8.66 (d, 1H), 7.18 (d, 1H), 5.20 (s, 1H), 3.92 (s, 3H) 3.33
(s, 6H).
Step B:
To the solution of 5.49 g of 4-(dimethoxymethyl)methoxy-pyrimidine (30.0 mmol) in
100 mL AcOH 4.92 g sodium acetate (60.0 mmol) and 9.59 g bromine (60.0 mmol) were
added and stirred at 40°C for 24 h. The reaction mixture was concentrated under reduced
pressure, to the residue DCM was added, and it was washed with saturated aq. NaHCO .
The organic phase was dried over Na SO and concentrated under reduced pressure. The
crude product was purified via flash chromatography using heptane and EtOAc as eluents
to give 5-bromo(dimethoxymethyl)methoxy-pyrimidine.
H NMR (400 MHz, DMSO-d ): 8.79 (s, 1H), 5.41 (s, 1H), 3.93 (s, 3H), 3.40 (s, 6H).
Step C:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.68 (s, 1H), 5.41 (t, 1H), 4.54 (d, 2H), 3.94 (s, 3H).
Preparation 9cc: [2-Methoxy(3-thienyl)pyrimidinyl]methanol
Step A:
To the solution of 766 mg of 5-bromo(dimethoxymethyl)methoxy-pyrimidine (the
product of Preparation 9cb, Step B, 2.91 mmol) in 15 mL THF-water (1:1) 934 mg
4,4,5,5-tetramethyl(3-thienyl)-1,3,2-dioxaborolane (4.45 mmol), 1.96 g Cs CO (6.00
mmol) and 522 mg tetrakis(triphenylphosphine)palladium(0) (0.450 mmol) were added
and the mixture was heated under N in a microwave reactor at 110°C for 30 h. The
reaction mixture was filtered; the filtrate was concentrated under reduced pressure. The
residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to
give 4-(dimethoxymethyl)methoxy(3-thienyl)pyrimidine.
MS: (M+H) = 267.2.
Step B:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 8.62 (s, 1H), 7.76 (m, 1H), 7.70 (m, 1H), 7.39 (dd, 1H),
.39 (t, 1H), 4.49 (d, 2H), 3.98 (s, 3H).
Preparation 9cd: (2,6-Dimethoxypyrimidinyl)methanol
Step A:
To the mixture of 12.16 g O-methylisourea hydrochloride (110 mmol) and 20.0 g ethyl
4,4-dimethoxyoxo-butanoate (91.6 mmol) in dry methanol 5.94 g sodium methoxide
(110 mmol) was added portionwise and the mixture was stirred at 75 °C for 2 h. The
reaction mixture was cooled, celite was added and the volatiles were removed under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to give 4-(dimethoxymethyl)methoxy-1H-pyrimidinone.
H NMR (400 MHz, DMSO-d ): 12.37 (br s, 1H), 6.03 (s, 1H), 5.08 (s, 1H), 3.87 (s, 3H),
3.57 (m, 4H), 1.15 (t, 6H).
Step B:
To the solution of 2.00 g 4-(dimethoxymethyl)methoxy-1H-pyrimidinone (8.76
mmol) in 8 mL DMF 1612 mg phosphoryl chloride (10.5 mmol) was added dropwise at
0°C and it was stirred at this temperature for 30 min. The mixture was diluted with 40 mL
DCM and it was poured onto ice. The organic layer was washed with water, then it was
dried over MgSO and concentrated under reduced pressure. The residue was dissolved in
mL methanol and 946 mg sodium methoxide (17.52 mmol) was added at 0°C, and it
was stirred at this temperature for 1h. Celite was added and the volatiles were removed
under under reduced pressure. The crude product was purified via flash chromatography
using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2,6-dimethoxy-
pyrimidine.
MS: (M+H) = 243.2.
Step C:
Starting from this material using General Procedure 9A the title product was obtained.
H NMR (400 MHz, DMSO-d ): 6.53 (br s, 1H), 5.53 (t, 1H), 4.40 (dd, 2H), 3.89 (s, 3H),
3.86 (s, 3H).
Preparation 9ce: (6-Chloropyrimidinyl)methanol
Step A:
To the solution of 3.00 g chloromethyl benzoate (17.59 mmol) in 21 mL MeCN 5.799 g
NaI (38.69 mmol) was added. The reaction mixture was stirred at room temperature for
14h. The precipitate was filtered and the organic phase was concentrated to give
iodomethyl benzoate as yellow oil.
Step B:
Preparation of activated zinc: Zinc was washed quickly with 10% HCl followed with
water then ethanol then diethyl ether. The activated zinc was stored under argon.
An excess of activated zinc was suspended in 3 mL THF, treated with 349 mg 1,2-
dibromoethane (160 µL, 1.857 mmol) and the resulting mixture was heated at 60 °C under
argon for 30 minutes. The reaction mixture was allowed to cool to room temperature,
treated with 154 mg trimethylchlorosilane (180 µL, 1.418 mmol) and the resulting mixture
was stirred at room temperature for 30 minutes. The reaction mixture was treated with 64.5
mg LiCl (1.521 mmol) and the resulting mixture was stirred at room temperature for 30
minutes.
A solution of iodomethyl benzoate (1.60 g, 6.11 mmol) in 3 mL THF was added and the
resulting mixture was stirred at room temperature for 1.5 h. This reaction mixture was
added to a solution of 537 mg 4,6-dichloropyrimidine (3.605 mmol) and 502 mg
tris[tris(3,5-bis(trifluoromethyl)-phenyl)phosphine]palladium(0) {Superstable Pd(0)
Catalyst} (0.180 mmol) in 6mL THF and the resulting mixture was stirred at room
temperature under argon for 18 h. The reaction mixture was filtered through celite, diluted
with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl
acetate layers were combined, dried on magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography.
Step C:
To the solution of 800 mg (6-chloropyrimidinyl)methyl benzoate (3.217 mmol) in 32
mL MeOH 17 mg NaOMe (0.315 mmol) was added. It was stirred at room temperature for
2.5h. The reaction mixture was concentrated under reduced pressure, and the residue was
purified by flash chromatography to give the title product.
H NMR (200 MHz, CDCl ): 8.94 (s, 1H), 7.47 (s, 1H), 4.76 (s, 2H).
Preparation 9cf: (2-Methoxymethyl-pyrimidinyl)methanol
To the solution of 1.00 g methyl 2-methoxymethyl-pyrimidinecarboxylate (5.49
mmol) in 15 mL abs THF 12 mL DIBAL-H (1M in THF) was added and it was stirred at
room temperature for 30 min, then further 12 mL DIBAL-H was added. After 1 h the
excess of DIBAL-H was quenched with propanol, then with water. Saturated aq. NaF
solution was added to the reaction mixture, then it was extracted with DCM. The combined
organic phases were dried over Na SO and concentrated under reduced pressure. The
crude product was purified via flash chromatography using heptane and EtOAc as eluents
to give the title product.
H NMR (400 MHz, DMSO-d ): 7.07 (s, 1H), 5.55 (t, 1H), 4.43 (m, 2H), 3.86 (s, 3H), 2.40
(s, 3H).
Preparation 9cg: (6-Phenylpyrimidinyl)methanol
To the solution of 1.00 g ethyl 6-phenylpyrimidinecarboxylate (4.38 mmol) in 15 mL
MeOH 175 mg NaBH (4.63 mmol) was added at room temperature and it was stirred at
70°C for 3h. The reaction mixture was concentrated, and the residue was diluted with
saturated aq. K CO and it was extracted with DCM. The combined organic phases were
dried over Na SO and concentrated under reduced pressure. The crude product was
purified via flash chromatography using heptane and EtOAc as eluents to give the title
product.
H NMR (400 MHz, CDCl ): 8.97 (s, 1H), 8.11 (d, 2H), 7.68-7.45 (m, 4H), 5.45 (d, 2H).
Preparation 9ch: (2-Chloropyrimidinyl)methanol
To the solution of 1860 mg methyl 2-chloropyrimidinecarboxylate (10.78 mmol) in 11
mL THF 21.6 mL DIBAL-H (1M in THF, 21.6 mmol) was added dropwise at -70°C and it
was stirred at this temperature for 16 h. 5 mL MeOH was added to it at -50°C, then 5 mL
water was added to it at 0°C. It was filtered through celite. The filtrate was concentrated
under reduced pressure, and then it was purified via flash chromatography using heptane
and EtOAc as eluents.
H NMR (200 MHz, CDCl ): 8.60 (d, 1H), 7.38 (d, 1H), 4.79 (s, 2H).
Preparation 9da: (1-Ethyl-1H-pyrazolyl)methanol
Step A:
Using bromoethane in General Procedure 9G 1-ethyl-1H-pyrazole was obtained.
Step B:
Starting from 1-ethyl-1H-pyrazole using General Procedure 9H the title product was
obtained.
H NMR (400 MHz, CDCl ): 7.36 (d, 1H), 6.15 (d, 1H), 4.66 (br s, 2H), 4.18 (q, 2H), 2.99
(br s, 1H), 1.42 (t, 3H).
Preparation 9db: (1-Propyl-1H-pyrazolyl)methanol
Step A:
Using 1-bromopropane in General Procedure 9G 1-propylpyrazole was obtained.
MS: (M+H) = 111.2.
Step B:
Starting from 1-propyl-1H-pyrazole using General Procedure 9H the title product was
obtained.
H NMR (400 MHz, CDCl ): 7.34 (d, 1H), 6.14 (d, 1H), 4.64 (s, 2H), 4.07 (dd, 2H), 1.85
(m, 2H), 0.89 (t, 3H).
MS: (M+H) = 141.2.
Preparation 9dc: [1-(Propanyl)-1H-pyrazolyl]methanol
Step A:
Using 2-bromopropane in General Procedure 9G 1-isopropylpyrazole was obtained.
Step B:
Starting from 1-isopropylpyrazole using General Procedure 9H the title product was
obtained.
H NMR (400 MHz, DMSO-d ): 7.32 (d, 1H), 6.10 (d, 1H), 5.21 (t, 1H), 4.60 (h, 1H), 4.50
(d, 2H), 1.36 (d, 6H).
MS: (M+H) = 141.2.
Preparation 9dd: (1-Butyl-1H-pyrazolyl)methanol
Starting from 1-butylpyrazole using General Procedure 9H the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.30 (d, 1H), 6.12 (d, 1H), 5.23 (t, 1H), 4.49 (d, 2H), 4.06
(t, 2H), 1.72 (m, 2H), 1.26 (m, 2H), 0.88 (t, 3H).
MS: (M+H) = 155.2.
Preparation 9de: [1-(3-Methylbutyl)-1H-pyrazolyl]methanol
Step A:
Using 1-bromomethyl-butane in General Procedure 9F 1-(3-methylbutyl)-1H-pyrazole
was obtained.
H NMR (400 MHz, DMSO-d ): 7.71 (d, 1H), 7.40 (d, 1H), 6.20 (t, 1H), 4.11 (t, 2H), 1.65
(q, 2H), 1.44 (h, 1H), 0.89 (d, 6H).
Step B:
Starting from 1-(3-methylbutyl)-1H-pyrazole using General Procedure 9H the title
product was obtained.
H NMR (400 MHz, DMSO-d ): 7.30 (d, 1H), 6.12 (d, 1H), 5.25 (t, 1H), 4.49 (d, 2H), 4.08
(m, 2H), 1.63 (m, 2H), 1.55 (h, 1H), 0.90 (d, 6H).
Preparation 9df: [1-(Cyclopropylmethyl)-1H-pyrazolyl]methanol
Starting from 1-(cyclopropylmethyl)-1H-pyrazole using General Procedure 9H the title
product was obtained.
H NMR (400 MHz, DMSO-d ): 7.31 (d, 1H), 6.14 (d, 1H), 5.26 (t, 1H), 4.51 (d, 2H), 3.96
(d, 2H), 1.24 (m, 1H), 0.51-0.24 (m, 4H).
MS: (M+H) = 153.2.
Preparation 9dg: (1-Cyclopentyl-1H-pyrazolyl)methanol
Step A:
Using bromocyclopentane in General Procedure 9G 1-cyclopentyl-1H-pyrazole was
obtained.
Step B:
Starting from 1-cyclopentyl-1H-pyrazole using General Procedure 9H the title product
was obtained.
H NMR (400 MHz, DMSO-d ): 7.31 (d, 1H), 6.11 (d, 1H), 5.20 (t, 1H), 4.77 (p, 1H), 4.51
(d, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.82 (m, 2H), 1.61 (m, 2H).
MS: (M+H) = 167.2.
Preparation 9dh: (1-Cyclohexyl-1H-pyrazolyl)methanol
Step A:
Using bromocyclohexane in General Procedure 9G 1-cyclohexyl-1H-pyrazole was
obtained.
MS: (M+H) = 151.2.
Step B:
Starting from 1-cyclohexyl-1H-pyrazole using General Procedure 9H the title product
was obtained.
H NMR (400 MHz, CDCl ): 7.44 (s, 1H), 6.17 (s, 1H), 4.70 (d, 2H), 4.20 (m, 1H), 2.05-
1.21 (m, 10H).
MS: (M+H) = 181.2.
Preparation 9di: (1-(Tetrahydro-2H-pyranyl)-1H-pyrazolyl)methanol
Step A:
The mixture of 596 mg pyrazole (8.75 mmol), 2.89 g 4-bromo-tetrahydropyran (17.5
mmol) and 1.47 g sodium hydrogen carbonate (17.5 mmol) was stirred at 120 °C for 10
days. After completion it was diluted with diethyl ether (30 mL), the precipitate was
filtered off and the volatiles were removed under reduced pressure at room temperature.
The crude oil was diluted with diethyl ether (20 mL) and washed with water. The aqueous
phase was extracted with ethyl acetate. The combined organic layers were dried over
Na SO and concentrated under reduced pressure. The residue was purified by column
chromatography (eluent: dichloromethane: ethanol=100:1) to give 1-(tetrahydro-2H-pyran-
4-yl)-1H-pyrazole.
MS: (M+H) = 153.2.
Step B:
Starting from 1-(tetrahydro-2H-pyranyl)-1H-pyrazole using General Procedure 9H the
title product was obtained.
H NMR (400 MHz, CDCl ): 7.46 (d, 1H), 6.19 (d, 1H), 4.71 (s, 2H), 4.46 (m, 1H), 4.12
(dd, 2H), 3.55 (m, 2H), 2.34 (m, 2H), 1.88 (m, 2H).
MS: (M+H) = 183.1.
Preparation 9dj: {1-[2-(Dimethylamino)ethyl]-1H-pyrazolyl}methanol
Step A:
The mixture of 5 g 1H-pyrazole (79.44 mmol), 11.64 g 2-chloro-N,N-dimethylethylamine
hydrochloride (80.79 mmol) and 30.0 g potassium carbonate (220.32 mmol) in 100 mL
DMF was stirred at 60 °C for 14 hours. After completion the volatiles were removed under
reduced pressure. The residue was diluted with chloroform (100 mL) and washed with
water. The organic layer was dried over Na SO and concentrated under reduced pressure.
The residue was diluted with ethanol (20 mL) and 34 mL HCl (5N in EtOH) was added.
The precipitate was filtered off, washed with diethyl ether and dried to give N,N-dimethyl-
2-(1H-pyrazolyl)-ethanamine.
MS: (M+H) = 140.2.
Step B:
Starting from N,N-dimethyl(1H-pyrazolyl)-ethanamine using General Procedure
9H the title product was obtained.
H NMR (400 MHz, CDCl ): 7.47 (br s, 1H), 6.25 (br s, 1H), 4.54 (s, 2H), 4.27 (m, 2H),
2.73 (m, 2H), 2.21 (s, 6H).
MS: (M+H) = 170.1.
Preparation 9dk: [1-(4-Methoxybenzyl)-1H-pyrazolyl]methanol
Step A:
Using 1-(bromomethyl)methoxy-benzene in General Procedure 9G 1-(4-
methoxybenzyl)-1H-pyrazole was obtained.
Step B:
Starting from 1-(4-methoxybenzyl)-1H-pyrazole using General Procedure 9H the title
product was obtained.
H NMR (400 MHz, CDCl ): 7.47 (d, 1H), 7.14 (m, 2H), 6.85 (m, 2H), 6.24 (d, 1H), 5.35
(s, 2H), 4.60 (s, 2H), 3.78 (s, 3H).
MS: (M+H) = 219.1.
Preparation 9dl: [1-(4,4,4-Trifluorobutyl)-1H-pyrazolyl]methanol
Step A:
Using 4-bromo-1,1,1-trifluoro-butane in General Procedure 9F 1-(4,4,4-trifluorobutyl)-
1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.75 (d, 1H), 7.46 (d, 1H), 6.24 (t, 1H), 4.19 (t, 2H), 2.26-
2.13 (m, 2H), 1.98 (m, 2H).
Step B:
Starting from 1-(4,4,4-trifluorobutyl)-1H-pyrazole using General Procedure 9H the title
product was obtained.
H NMR (400 MHz, DMSO-d ): 7.36 (d, 1H), 6.16 (d, 1H), 5.29 (br s, 1H), 4.50 (d, 2H),
4.16 (t, 2H), 2.31-2.18 (m, 2H), 1.99 (m, 2H).
Preparation 9dm: (1-Pentyl-1H-pyrazolyl)methanol
Step A:
Using 1-bromopentane in General Procedure 9F 1-pentyl-1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.70 (d, 1H), 7.41 (d, 1H), 6.20 (t, 1H), 4.08 (t, 2H), 1.75
(p, 2H), 1.28 (m, 2H), 1.17 (m, 2H), 0.84 (t, 3H).
Step B:
Starting from 1-pentyl-1H-pyrazole using General Procedure 9H the title product was
obtained.
H NMR (400 MHz, DMSO-d ): 7.31 (d, 1H), 6.12 (d, 1H), 5.25 (t, 1H), 4.49 (d, 2H), 4.05
(t, 2H), 1.74 (p, 2H), 1.34-1.17 (m, 4H), 0.86 (t, 3H).
Preparation 9dn and Preparation 9do: (1R or S)(1-pentyl-1H-pyrazolyl)ethanol
and (1S or R)(1-pentyl-1H-pyrazolyl)ethanol
To the solution of 2.00 g 1-pentyl-1H-pyrazole (Preparation 9dm, Step A, 14.47 mmol)
in 30 mL dry THF 10 mL n-BuLi (1.6 M, 16 mmol) was added dropwise at -78°C and the
mixture was stirred for 1 h at this temperature, then 848 mg acetaldehyde (20.0 mmol) was
added dropwise and stirred for 90 min at -78°C. The mixture was poured into cooled
saturated aq. NH Cl solution. Phases were separated; the aqueous phase was extracted with
EtOAc. The combined organic layers were dried over MgSO and concentrated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to give 1-(2-pentylpyrazolyl)ethanol.
H NMR (400 MHz, DMSO-d ): 7.30 (d, 1H), 6.11 (d, 1H), 5.24 (d, 1H), 4.80 (m, 1H),
4.08 (m, 2H), 1.75 (p, 2H), 1.41 (d, 3H), 1.35-1.15 (m, 4H), 0.86 (t, 3H).
The enantiomers were separated via chiral chromatography column: AD, eluents: heptane /
EtOH. The product eluting earlier was collected as Preparation 9dn, and the product
eluting later was collected as Preparation 9do.
Preparation 9dp: [1-(2-Methoxyethyl)-1H-pyrazolyl]methanol
Step A:
Starting from 5-(dimethoxymethyl)-1H-pyrazole (Preparation 9a5) and 1-bromo
methoxy-ethane using General Procedure 9F 5-(dimethoxymethyl)(2-methoxyethyl)-
1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.40 (d, 1H), 6.25 (d, 1H), 5.62 (s, 1H), 4.25 (t, 2H), 3.65
(t, 2H), 3.24 (s, 6H), 3.22 (s, 3H).
Note: 3-(dimethoxymethyl)(2-methoxyethyl)-1H-pyrazole was also obtained.
H NMR (400 MHz, DMSO-d ): 7.65 (d, 1H), 6.18 (d, 1H), 5.33 (s, 1H), 4.22 (t, 2H), 3.65
(t, 2H), 3.24 (s, 6H), 3.21 (s, 3H).
Step B:
Starting from 5-(dimethoxymethyl)(2-methoxyethyl)-1H-pyrazole using General
Procedure 9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.33 (d, 1H), 6.13 (d, 1H), 5.22 (t, 1H), 4.50 (d, 2H), 4.24
(t, 2H), 3.65 (t, 2H), 3.20 (s, 3H).
Preparation 9dq: [1-(3-Methoxypropyl)-1H-pyrazolyl]methanol
Step A:
Starting from 5-(dimethoxymethyl)-1H-pyrazole (Preparation 9a5) and 1-bromo
methoxy-propane using General Procedure 9F 5-(dimethoxymethyl)(3-
methoxypropyl)-1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.40 (d, 1H), 6.25 (d, 1H), 5.59 (s, 1H), 4.12 (t, 2H), 3.29
(t, 2H), 3.25 (s, 6H), 3.23 (s, 3H), 1.96 (m, 2H).
Note: 3-(dimethoxymethyl)(3-methoxypropyl)-1H-pyrazole was also obtained.
H NMR (400 MHz, DMSO-d ): 7.66 (d, 1H), 6.18 (d, 1H), 5.33 (s, 1H), 4.11 (t, 2H), 3.25
(t, 2H), 3.23 (s, 6H), 3.21 (s, 3H), 1.97 (m, 2H).
Step B:
Starting from 5-(dimethoxymethyl)(3-methoxypropyl)-1H-pyrazole using General
Procedure 9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.33 (d, 1H), 6.13 (d, 1H), 5.24 (t, 1H), 4.48 (d, 2H), 4.11
(t, 2H), 3.28 (t, 2H), 3.22 (s, 3H), 1.97 (m, 2H).
Preparation 9dr: [1-(2-Ethoxyethyl)-1H-pyrazolyl]methanol
Step A:
Starting from 5-(dimethoxymethyl)-1H-pyrazole (Preparation 9a5) and 1-bromo
ethoxy-ethane using General Procedure 9F 5-(dimethoxymethyl)(2-ethoxyethyl)-1H-
pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.40 (d, 1H), 6.25 (d, 1H), 5.65 (s, 1H), 4.24 (t, 2H), 3.68
(t, 2H), 3.38 (m, 2H), 3.24 (s, 6H), 1.06 (t, 3H).
Note: 3-(dimethoxymethyl)(2-ethoxyethyl)pyrazole was also obtained.
H NMR (400 MHz, DMSO-d ): 7.65 (d, 1H), 6.19 (d, 1H), 5.33 (s, 1H), 4.21 (t, 2H), 3.69
(t, 2H), 3.39 (q, 2H), 3.24 (s, 6H), 1.05 (t, 3H).
Step B:
Starting from 5-(dimethoxymethyl)(2-ethoxyethyl)-1H-pyrazole using General
Procedure 9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.33 (d, 1H), 6.13 (d, 1H), 5.20 (t, 1H), 4.51 (d, 2H), 4.23
(t, 2H), 3.68 (t, 2H), 3.38 (q, 2H), 1.05 (t, 3H).
Preparation 9ds: {1-[2-(2-Methoxyethoxy)ethyl]-1H-pyrazolyl}methanol
Step A:
Starting from 5-(dimethoxymethyl)-1H-pyrazole (Preparation 9a5) and 1-(2-
bromoethoxy)methoxy-ethane using General Procedure 9F 5-(dimethoxymethyl)[2-
(2-methoxyethoxy)ethyl]-1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d6): 7.40 (d, 1H), 6.25 (d, 1H), 5.67 (s, 1H), 4.25 (t, 2H), 3.72
(t, 2H), 3.47 (m, 2H), 3.39 (m, 2H), 3.25 (s, 6H), 3.21 (s, 3H).
Note: 3-(dimethoxymethyl)[2-(2-methoxyethoxy)ethyl]-1H-pyrazole was also obtained.
H NMR (400 MHz, DMSO-d ): 7.66 (d, 1H), 6.19 (d, 1H), 5.33 (s, 1H), 4.22 (t, 2H), 3.74
(t, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 3.24 (s, 6H), 3.21 (s, 3H).
Step B:
Starting from 5-(dimethoxymethyl)[2-(2-methoxyethoxy)ethyl]-1H-pyrazole using
General Procedure 9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.33 (d, 1H), 6.13 (d, 1H), 5.19 (t, 1H), 4.51 (d, 2H), 4.24
(t, 2H), 3.72 (t, 2H), 3.46 (m, 2H), 3.38 (m, 2H), 3.20 (s, 3H).
Preparation 9dt: (1-tert-Butyl-1H-pyrazolyl)methanol
Step A:
Starting from tert-butylhydrazine hydrochloride using General Procedure 9D 1-tert-
butyl(dimethoxymethyl)-1H-pyrazole was obtained.
H NMR (400 MHz, DMSO-d ): 7.34 (d, 1H), 6.34 (d, 1H), 5.74 (s, 1H), 3.24 (s, 6H), 1.57
(s, 9H).
Note: 1-tert-butyl(dimethoxymethyl)-1H-pyrazole was also obtained.
H NMR (400 MHz, DMSO-d ): 7.75 (d, 1H), 6.18 (d, 1H), 5.34 (s, 1H), 3.24 (s, 6H), 1.50
(s, 9H).
Step B:
Starting from 1-tert-butyl(dimethoxymethyl)-1H-pyrazole using General Procedure
9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.27 (d, 1H), 6.19 (d, 1H), 5.31 (t, 1H), 4.61 (d, 2H), 1.56
(s, 9H).
Preparation 9du: [1-(2,2,2-Trifluoroethyl)-1H-pyrazolyl]methanol
Step A:
Starting from 2,2,2-trifluoroethylhydrazine (70 w/w% in water) using General Procedure
9D in absence of sodium methoxide 5-(dimethoxymethyl)(2,2,2-trifluoroethyl)-4,5-
dihydro-1H-pyrazolol was obtained.
H NMR (400 MHz, DMSO-d ): 6.83 (t, 1H), 6.03 (s, 1H), 4.30 (s, 1H), 3.95 (m, 1H), 3.47
(m, 1H), 3.40 (d, 6H), 2.88 (m, 1H), 2.50 (m, 1H).
Step B:
Starting from 5-(dimethoxymethyl)(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazolol
using General Procedure 9B the title product was obtained.
H NMR (400 MHz, DMSO-d ): 7.48 (d, 1H), 6.27 (d, 1H), 5.46 (t, 1H), 5.08 (q, 2H), 4.56
(d, 2H).
Preparation 9dv: [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol
Preparation 9dw: [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol
Step A:
Starting from cyclohexylmethylhydrazine hydrochloride using General Procedure 9D 1-
(cyclohexylmethyl)(dimethoxymethyl)-1H-pyrazole was obtained. This product eluted
first.
H NMR (400 MHz, DMSO-d ): 7.38 (d, 1H), 6.25 (d, 1H), 5.59 (s, 1H), 3.91 (d, 2H), 3.24
(s, 6H), 1.89 (m, 1H), 1.66 (m, 2H), 1.61 (m, 2H), 1.48 (d, 2H), 1.16 (m, 2H), 0.95 (dd,
2H).
Note: The secondly eluted product was the 1-(cyclohexylmethyl)(dimethoxymethyl)-
1H-pyrazole.
H NMR (400 MHz, DMSO-d ): 7.64 (d, 1H), 7.17 (d, 1H), 5.33 (s, 1H), 3.91 (d, 2H), 3.23
(s, 6H), 1.77 (m, 1H), 1.66 (m, 2H), 1.60 (m, 2H), 1.47 (d, 2H), 1.16 (m, 2H), 0.92 (dd,
2H).
Step B1:
Starting from 1-(cyclohexylmethyl)(dimethoxymethyl)-1H-pyrazole using General
Procedure 9B [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol was obtained.
H NMR (400 MHz, DMSO-d ): 7.31 (d, 1H), 6.12 (d, 1H), 5.24 (t, 1H), 4.48 (d, 2H), 3.90
(d, 2H), 1.84 (m, 1H) 1.69-1.55 (m, 3H), 1.49 (m, 2H), 1.15 (m, 3H), 0.96 (m, 2H).
Step B2:
Starting from 1-(cyclohexylmethyl)(dimethoxymethyl)-1H-pyrazole using General
Procedure 9B [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol was obtained.
H NMR (400 MHz, DMSO-d ): 7.56 (d, 1H), 6.13 (d, 1H), 4.94 (t, 1H), 4.37 (d, 2H), 3.85
(d, 2H), 1.75 (m, 1H) 1.69-1.56 (m, 3H), 1.49 (m, 2H), 1.15 (m, 3H), 0.91 (m, 2H).
Preparation 9ea: [6-(2-Furyl)pyridyl]methanol
To the solution of 940 mg (6-bromopyridyl)methanol (5.00 mmol) in 20 mL dioxane
1.94 g 2-(2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 mmol), 4.89 g Cs CO
(15.0 mmol) and 577 mg tetrakis(triphenylphosphine)palladium(0) (0.50 mmol) were
added, and it was stirred under N at 70°C for 16 h. The reaction mixture was concentrated
under reduced pressure. The residue was purified via flash chromatography using heptane
and ethyl-acetate as eluents to give the title product.
MS: (M+H) = 176.2.
Preparation 9eb: [6-(2-Thienyl)pyridyl]methanol
To the solution of 624 mg (6-bromopyridyl)methanol (3.30 mmol) in 15 mL dioxane
850 mg 2-thienylboronic acid (6.60 mmol), 3.25 g Cs CO (10.0 mmol) and 385 mg
tetrakis(triphenylphosphine)palladium(0) (0.33 mmol) were added, and it was stirred under
N at 70°C for 16 h. The reaction mixture was concentrated under reduced pressure. The
residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to
give the title product.
MS: (M+H) = 192.2.
Preparation 9ec: (1-Butyl-1H-1,2,3-triazolyl)methanol
Step A:
To the solution of 690 mg 1H-[1,2,3]triazole (10.0 mmol) in 5 mL DMF 1.50 g K2CO3
(11.0 mmol) and 1.50 g bromobutane (11.0 mmol) were added and the mixture was stirred
at room temperature for 16 h. The reaction mixture was poured into 50 mL water and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The regioisomers were separated via flash
chromatography using heptane and EtOAc as eluents: 2-butyl-2H-[1,2,3]triazole eluted
first then 1-butyl-1H-[1,2,3]triazole.
H NMR (400 MHz, DMSO-d6) of 1-butyl-1H-[1,2,3]triazole: 7.62 (m, 1H), 7.53 (m, 1H),
4.32 (m, 2H), 1.82 (m, 2H), 1.27 (m, 2H), 0.87 (m, 3H).
Step B:
To the cooled solution of 428 mg 1-butyl-1H-[1,2,3]triazole (3.40 mmol) in 15 mL THF
under N 2.35 mL BuLi (1.6M, 3.74 mmol) was added at -78°C, and it was stirred for 15
min, then 0.300 mL DMF (3.74 mmol) was added. The reaction mixture was stirred at
room temperature for 24 h. It was poured onto 50 mL ice-water, and extracted with EtOAc.
The combined organic phases were dried over Na SO and concentrated under reduced
pressure. The residue was dissolved in 20 mL EtOH and 250 mg sodium borohydride (6.50
mmol) was added at 0°C and stirred for 1 h at this temperature, then it was stirred at room
temperature for 16 h. Then 1 mL water was added, and the volatiles were removed under
reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic
phase was dried over Na SO and concentrated under reduced pressure. The residue was
purified via flash chromatography using heptane and EtOAc as eluents to give the title
product.
H NMR (400 MHz, DMSO-d ): 7.59 (s, 1H), 5.46 (t, 1H), 4.58 (d, 2H), 4.32 (t, 2H), 1.79
(m, 2H), 1.29 (m, 2H), 0.90 (m, 3H).
Preparation 9ed: [1-(3-Methoxypropyl)-1H-1,2,3-triazolyl]methanol
Step A:
To the solution of 690 mg 1H-[1,2,3]triazole (10.0 mmol) in 5 mL acetonitrile 1.50 g
K CO (11.0 mmol) and 1.68 g 1-bromomethoxy-propane (11.0 mmol) were added and
the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and
concentrated under reduced pressure. The regioisomers were separated via flash
chromatography using heptane and EtOAc as eluents: 2-(3-methoxypropyl)-1H-
[1,2,3]triazole eluted first then 1-(3-methoxypropyl)-1H-[1,2,3]triazole.
H NMR (400 MHz, DMSO-d ) of 1-(3-methoxypropyl)-1H-[1,2,3]triazole: 8.12 (d, 1H),
7.72 (d, 1H), 4.42 (t, 2H), 3.29 (t, 2H), 3.23 (s, 3H), 2.04 (m, 2H).
Step B:
To the cooled solution of 378 mg 1-(3-methoxypropyl)-1H-[1,2,3]triazole (2.70 mmol) in
12 mL THF under N 1.90 mL BuLi (1.6M, 3.04 mmol) was added at -78°C, and it was
stirred for 30 min, then 0.220 mL DMF (3.00 mmol) was added. The reaction mixture was
stirred at room temperature for 4 h. It was poured onto 40 mL ice-water, and extracted with
EtOAc. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. The residue was dissolved in 16 mL EtOH and 200 mg sodium
borohydride (5.29 mmol) was added at 0°C and stirred for 1 h at this temperature, then it
was stirred at room temperature for 16 h. Then 1 mL water was added, and the volatiles
were removed under reduced pressure. The residue was diluted with EtOAc and washed
with brine. The organic phase was dried over Na SO and concentrated under reduced
pressure. The residue was purified via flash chromatography using heptane and EtOAc as
eluents to give the title product.
H NMR (400 MHz, DMSO-d ): 7.60 (s, 1H), 5.46 (t, 1H), 4.57 (d, 2H), 4.37 (t, 2H), 3.31
(t, 2H), 3.23 (s, 3H), 2.04 (m, 2H).
Preparation 9ee: (1-Phenyl-1H-1,2,3-triazolyl)methanol
Step A: (Tang, Bo-Xiao et al Synthesis 2008, 1707)
The mixture of 207 mg 1H-[1,2,3]triazole (3.00 mmol), 735 mg iodobenzene (3.60 mmol),
57 mg copper(I)oxide (0.60 mmol), 216 mg 1,10-phenantroline (1.20 mmol), and 2.35 g
TBAF hydrate (9.00 mmol) was heated at 115 °C for 22 h under argon. The reaction
mixture was diluted with EtOAc and washed with brine. The organic phase was dried over
Na SO and concentrated under reduced pressure. The residue was purified via flash
chromatography using heptane and EtOAc as eluents to give 1-phenyl-1H-[1,2,3]triazole.
H NMR (400 MHz, DMSO-d ): 8.84 (d, 1H), 7.99 (d, 1H), 7.92 (m, 2H), 7.61 (m, 2H),
7.49 (m, 1H).
Step B:
To the cooled solution of 216 mg 1-phenyl-1H-[1,2,3]triazole (1.50 mmol) in 7 mL THF
under N 1.00 mL BuLi (1.6M, 1.60 mmol) was added at -78°C, and it was stirred for 15
min, then 0.130 mL DMF (1.63 mmol) was added. The reaction mixture was stirred at
room temperature for 90min. It was poured onto 30 mL ice-water, and extracted with
EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under
reduced pressure. The residue was dissolved in 9 mL EtOH and 111 mg sodium
borohydride (2.94 mmol) was added at 0°C and stirred for 1 h at this temperature, then it
was stirred at room temperature for 16 h. Then 1 mL water was added and the reaction
mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and
washed with brine. The organic phase was dried over Na SO and concentrated under
reduced pressure to give the title product.
MS: (M+H) = 176.2.
Preparation 9ef: [1-(2-Methoxyethyl)-1H-1,2,3-triazolyl]methanol
Step A:
To the solution of 2.50 g ethyl 1H-[1,2,3]triazolecarboxylate (17.7 mmol) in 20 mL
acetonitrile and in 3 mL DMF 3.19 g K CO (23.1 mmol) and 3.20 g 1-bromomethoxy-
ethane (23.1 mmol) were added and the mixture was stirred at 35°C for 24 h. Then it was
filtered and concentrated under reduced pressure. The regioisomers were separated via
flash chromatography using heptane and EtOAc as eluents: ethyl 2-(2-methoxyethyl)-2H-
[1,2,3]triazolecarboxylate eluted first followed by ethyl 1-(2-methoxyethyl)-1H-1,2,3-
triazolecarboxylate.
H NMR (400 MHz, DMSO-d ) of ethyl 1-(2-methoxyethyl)-1H-1,2,3-triazole
carboxylate: 8.22 (s, 1H), 4.59 (t, 2H), 4.43 (q, 2H), 3.76 (t, 2H), 3.36 (s, 3H), 1.42 (t, 3H).
Step B:
To the solution of 223 mg ethyl 1-(2-methoxyethyl)-1H-1,2,3-triazolecarboxylate (1.12
mmol) in 5 mL EtOH 105 mg sodium borohydride (2.78 mmol) was added at 0°C and the
mixture was stirred for 1 h at this temperature, then it was stirred at room temperature for
16 h. Then 1 mL water was added, and the reaction mixture was concentrated under
reduced pressure. The residue was digerated with DCM, the solids were filtered off and the
filtrate was concentrated under reduced pressure to give the title product as yellow oil.
H NMR (400 MHz, DMSO-d ): 7.64 (s, 1H), 4.69 (s, 2H), 4.61 (t, 2H), 3.85 (t, 2H), 3.37
(s, 3H).
Preparation 9eg: 4-(2-Hydroxyethyl)methyl-piperazinone
To the mixture of 450 mg 1-methylpiperazinone (3.00 mmol) and 1.00 g K CO (7.24
mmol) in 5 mL THF 1 mL 2-bromoethanol (14.1mmol) was added and the mixture was
stirred at 65°C for 16h. The mixture was cooled to room temperature, filtered and
concentrated under reduced pressure. The residue was purified via flash chromatography
using DCM and MeOH to give 4-(2-hydroxyethyl)methyl-piperazinone.
MS: (M+H) = 159.4.
Preparation 9eh: 2-[4-(2,2,2-Trifluoroethyl)piperazinyl]ethanol
Step A:
To a solution of 5.208 g 2-piperazinylethanol (40 mmol) in 250 mL dry ethanol 8.063 g
4-dimethylaminopyridine (66 mmol) and 12.1 mL (2,2,2-trifluoroacetyl) 2,2,2-
trifluoroacetate (87 mmol) was added in portions and the mixture was stirred at room
temperature until no further conversion was observed. The mixture was concentrated under
reduced pressure and purified via flash chromatography using EtOAc and MeOH as
eluents to give 2,2,2-trifluoro[4-(2-hydroxyethyl)piperazinyl]ethanone.
Step B:
To a mixture of 3.300 g 2,2,2-trifluoro[4-(2-hydroxyethyl)piperazinyl]ethanone (14.6
mmol) and 1.988 g imidazole (29.2 mmol) in 50 mL THF 4.7 mL
chloro(triisopropyl)silane (21.9 mmol) was added dropwise and it was stirred at room
temperature until no further conversion was observed. Then the volatiles were evaporated
under reduced pressure and the residue was purified via flash chromatography using
heptane and EtOAc as eluents to give 2,2,2-trifluoro[4-(2-
triisopropylsilyloxyethyl)piperazinyl]ethanone.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 166 (5), 195 (100), 339 (11), 382 (1,
[M ]).
Step C:
To a solution of 1.55 g 2,2,2-trifluoro[4-(2-triisopropylsilyloxyethyl)piperazin
yl]ethanone (4.0 mmol) in 15 mL THF 12 mL BH3×THF (1.0 M in THF, 12 mmol) was
added with stirring and it was heated at 45°C until no further conversion was observed.
The mixture was cooled to room temperature, the excess of BH was decomposed by the
addition of MeOH. The volatiles were evaporated under reduced pressure and the residue
was co-evaporated with MeOH again. Then the crude product was purified via flash
chromatography using heptane and EtOAc as eluents to give triisopropyl-[2-[4-(2,2,2-
trifluoroethyl)piperazinyl]ethoxy]silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 138 (7), 165 (5), 181 (100) 325 (9), 368
(4, [M ]).
Step D:
To a solution of 0.536 g triisopropyl-[2-[4-(2,2,2-trifluoroethyl)piperazin
yl]ethoxy]silane (1.45 mmol) in 10 mL THF 1.52 mL TBAF (1.0 M in THF) was added
and it was stirred at room temperature until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the residue was purified via flash
chromatography using EtOAc and MeOH as eluents to give the title product.
H NMR (400 MHz, CDCl ): 3.64 (t, 2H), 3.06 (br s, 2H), 2.98 (q, 2H), 2.78-2.68 (m, 4H),
2.63-2.53 (m, 5H).
Preparation 9ei: 2-[4-(2,2-Difluoroethyl)piperazinyl]ethanol
Step A:
To a solution of 3.254 g 2-piperazinylethanol (25 mmol) in 60 mL dry ethanol 7.82 g 4-
dimethylaminopyridine (64 mmol) and 8 mL (2,2-difluoroacetyl) 2,2-difluoroacetate (64
mmol) was added and stirred at room temperature. Later a second portion of 7.82 g 4-
dimethylaminopyridine (64 mmol) and 8 mL (2,2-difluoroacetyl) 2,2-difluoroacetate (64
mmol) were added and the mixture was stirred at room temperature until no further
conversion was observed. The mixture was concentrated under reduced pressure and
purified via flash chromatography using EtOAc and MeOH as eluents to give 2,2-difluoro-
1-[4-(2-hydroxyethyl)piperazinyl]ethanone.
Step B:
1.800 g 2,2-difluoro[4-(2-hydroxyethyl)piperazinyl]ethanone (8.65 mmol) and 1.178
g imidazole (17.3 mmol) were dissolved in 25 mL THF and 2.8 mL
chloro(triisopropyl)silane (13.0 mmol) was added dropwise to the solution, which was
stirred at room temperature until no further conversion was observed. Then the volatiles
were evaporated under reduced pressure and the residue was purified via flash
chromatography using heptane and EtOAc as eluents to give 2,2-difluoro[4-(2-
triisopropylsilyloxyethyl)piperazinyl]ethanone.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 148 (4), 177 (100), 321 (5), 364 (1, [M ]).
Step C:
To a solution of 1.40 g 2,2-difluoro[4-(2-triisopropylsilyloxyethyl)piperazin
yl]ethanone (3.84 mmol) in 15 mL THF 7.7 mL BH ×THF (1.0 M in THF) was added with
stirring and the mixture was heated at 45°C until no further conversion was observed. After
cooling to room temperature the excess of BH was decomposed by the addition of MeOH.
The volatiles were evaporated under reduced pressure and the residue was co-evaporated
with MeOH again. Then the crude product was purified via flash chromatography using
heptane and EtOAc as eluents to give 2-[4-(2,2-difluoroethyl)piperazinyl]ethoxy-
triisopropyl-silane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 59 (5), 70 (7), 97 (5), 120 (9), 147 (3),
163 (100), 307 (3) 350 (1, [M ]).
Step D:
To a solution of 0.547 g 2-[4-(2,2-difluoroethyl)piperazinyl]ethoxy-triisopropyl-silane
(1.56 mmol) in 10 mL THF 1.64 mL TBAF (1.0 M in THF) was added and the mixture
was stirred at room temperature until no further conversion was observed. The volatiles
were evaporated under reduced pressure and the residue was purified via flash
chromatography using EtOAc and MeOH as eluents to give the title product.
H NMR (400 MHz, CDCl ): 5.87 (tt, 1H), 3.60 (t, 2H), 2.74 (td, 2H), 2.66-2.41 (m, 10H).
Preparation 9ej: [2-[4-Methoxy(trifluoromethyl)phenyl]pyrimidinyl]methanol
Step A: N'-Hydroxymethoxy(trifluoromethyl)benzamidine
1 eq. hydroxylamine hydrochloride was dissolved in MeOH (1ml / mmol) and 1 eq.
NaHCO was added. The mixture was stirred at room temperature for 20 min, then (4-
methoxy(trifluoromethyl)benzonitrile was added and the mixture was heated to reflux
until no further conversion was observed. MeOH was partially evaporated, residue was
filtered and dried under reduced pressure.
Step B: 4-(Dimethoxymethyl)[4-methoxy(trifluoromethyl)phenyl]pyrimidine
Using General Procedure 9C and this intermediate, 4-(dimethoxymethyl)[4-methoxy-
2-(trifluoromethyl)phenyl]pyrimidine was obtained.
HRMS calculated for C H N O F : 328.1035, found: 329.1099 (M+H).
15 2 3 3
H NMR (500MHz, DMSO-d ): 3.35 (s, 6H), 3.91 (s, 3H), 5.31 (s, 1H), 7.35 (m, 1H), 7.36
(m, 1H) 7.54 (d, 1H), 7.75 (d, 1H), 8.96 (d, 1H).
C NMR (125 MHz, DMSO-d ): 54.1, 56.3, 103.0, 107.7, 112.9, 116.8, 124.1, 129.1,
130.6, 134.1, 158.7, 160.3, 165.0, 165.5.
Step C: [2-[4-Methoxy(trifluoromethyl)phenyl]pyrimidinyl]methanol
Starting from 4-(dimethoxymethyl)[4-methoxy(trifluoromethyl)phenyl]pyrimidine
using General Procedure 9A Preparation 9ej was obtained.
MS: (M+H) = 285.2.
Preparation 9ek: [1-(4-Pyridylmethyl)pyrazolyl]methanol
Step A: 4-[[5-(Dimethoxymethyl)pyrazolyl]methyl]pyridine
Starting from (hydrazinomethyl)pyridine dihydrochloride using General Procedure 9D 4-
[[5-(dimethoxymethyl)pyrazolyl]methyl]pyridine was obtained.
H NMR: (500 MHz, DMSO-d6): 3.17 (s, 6H), 5.40 (s, 2H), 5.55 (s, 1H), 6.37 (d, 1h), 7.02
(d, 2H), 7.51 (d, 1H), 8.50 (d, 2H).
C NMR (125 MHz, DMSO-d ): 52.2, 53.3, 97.3, 106.7, 122.3, 139.0, 140.0, 147.1,
150.1.
Step B: [2-(4-Pyridylmethyl)pyrazolyl]methanol
Starting from 4-[5-(dimethoxymethyl)pyrazolyl]pyridine using General Procedure 9B
Preparation 9ek was obtained.
H NMR: (500 MHz, DMSO-d ) = 4.46 (d, 2H), 5.35 (br, 1H), 5.40 (s, 2H), 6.25 (d, 1H),
7.04 (dm, 2H), 7.43 (d, 1H), 8.49 (dm, 2H).
C NMR: (125 MHz, DMSO-d ) = 51.6, 54.3, 105.9, 122. 4, 138.9, 143.5, 147.2, 150.1.
Preparation 9el: [1-(2-Methoxyphenyl)pyrazolyl]methanol
Preparation 9em: [1-(2-Methoxyphenyl)pyrazolyl]methanol
Step A: 3-(Dimethoxymethyl)(2-methoxyphenyl)pyrazole and 5-(dimethoxymethyl)(2-
methoxyphenyl)pyrazole
Starting from 2-methoxyphenylhydrazine hydrochloride using General Procedure 9D 3-
(dimethoxymethyl)(2-methoxyphenyl)pyrazole was obtained as the product eluting first.
MS: (M+H) = 249.2.
The product eluting second was 3-(dimethoxymethyl)(2-methoxyphenyl)pyrazole.
MS: (M+H) = 249.2.
Step B1: [1-(2-Methoxyphenyl)pyrazolyl]methanol
Starting from 3-(dimethoxymethyl)(2-methoxyphenyl)pyrazole using General
Procedure 9B [1-(2-methoxyphenyl)pyrazolyl]methanol was obtained as Preparation
9el.
H NMR (400 MHz, CDCl ): 8.08 (d, 1H), 7.60 (dd, 1H), 7.34 (m, 1H), 7.23 (m, 1H), 7.06
(td, 1H), 6.42 (d, 1H), 5.13 (t, 1H), 4.49 (d, 2H), 3.86 (s, 3H).
Step B2: [1-(2-Methoxyphenyl)pyrazolyl]methanol
Starting from 5-(dimethoxymethyl)(2-methoxyphenyl)pyrazole using General
Procedure 9B [1-(2-methoxyphenyl)pyrazolyl]methanol was obtained as Preparation
9em.
H NMR (400 MHz, CDCl ): 7.55 (d, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 7.07
(td, 1H), 6.35 (m, 1H), 5.14 (t, 1H), 4.28 (d, 2H), 3.75 (s, 3H).
Preparation 9en: [1-[(2-Methoxyphenyl)methyl]pyrazolyl]methanol
Preparation 9eo: [1-[(2-Methoxyphenyl)methyl]pyrazolyl]methanol
Step A: 5-(Dimethoxymethyl)[(2-methoxyphenyl)methyl]pyrazole and 3-
(dimethoxymethyl)[(2-methoxyphenyl) methyl]pyrazole
Starting from (2-methoxyphenyl)methylhydrazine hydrochloride using General
Procedure 9D 5-(dimethoxymethyl)[(2-methoxyphenyl)methyl]pyrazole was obtained
as the product eluting first.
H NMR (500 MHz, DMSO-d ): 3.19 (s, 6H), 3.83 (s, 3H), 5.28 (s, 2H), 5.53 (s, 1H), 6.33
(d, 1H), 6.56 (dm 1H), 6.84 (m, 1H), 7.01 (dm, 1H), 7.25 (m, 1H), 7.46 (d, 1H).
C NMR (500 MHz, DMSO-d ): 48.2, 53.1, 55.2, 97.2, 106.2, 111.0, 120.7, 128.0, 129.1,
138.5.
The product eluting second was 3-(dimethoxymethyl)[(2-methoxyphenyl)
methyl]pyrazole.
H NMR (500 MHz, DMSO-d ): 3.23 (s, 6H), 3.82 (s, 3H), 5.25 (s, 2H), 5.33 (s, 1H), 6.22
(d, 1H), 6.82 (dm, 1H), 6.89 (m, 1H), 7.03 (dm, 1H), 7.29 (m, 1H), 7.69 (d, 1H).
C NMR (500 MHz, DMSO-d ): 50.5, 52.9, 55.9, 99.8, 104.0, 111.3, 120.8, 129.0, 129.6,
131.6.
Step B1: [2-[(2-Methoxyphenyl)methyl]pyrazolyl]methanol
Starting from 5-(dimethoxymethyl)[(2-methoxyphenyl)methyl]pyrazole using General
Procedure 9B [1-[(2-methoxyphenyl)methyl]pyrazolyl]methanol was obtained as
Preparation 9en.
H NMR (400 MHz, CDCl ): 7.39 (d, 1H), 7.25 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 6.53
(m, 1H), 6.22 (d, 1H), 5.29 (m, 2H), 5.28 (m, 1H), 4.46 (d, 2H), 3.83 (s, 3H).
Step B2: [1-[(2-Methoxyphenyl)methyl]pyrazolyl]methanol
Starting from 3-(dimethoxymethyl)[(2-methoxyphenyl)methyl]pyrazole using General
Procedure 9B [1-[(2-methoxyphenyl)methyl]pyrazolyl]methanol was obtained as
Preparation 9eo.
H NMR (400 MHz, CDCl ): 7.63 (d, 1H), 7.29 (m, 1H), 7.02 (m, 1H), 6.89 (m, 2H), 6.19
(d, 1H), 5.21 (s, 2H), 4.97 (t, 1H), 4.38 (d, 2H), 3.82 (s, 3H).
Preparation 9ep: [1-(2-Ethoxyethyl)pyrazolyl]methanol
Step A: 5-(Dimethoxymethyl)(2-ethoxyethyl)pyrazole
Starting from 5-(dimethoxymethyl)-1H-pyrazole (Preparation 9a5) and 2-bromoethyl
ethyl ether using General Procedure 9F 5-(dimethoxymethyl)(2-ethoxyethyl)pyrazole
was obtained.
MS: (M+H) = 215.2.
Step B: [1-(2-Ethoxyethyl)pyrazolyl]methanol
Starting from 5-(dimethoxymethyl)(2-ethoxyethyl)pyrazole, using General Procedure
9B [2-(2-ethoxyethyl)pyrazolyl]methanol (Preparation 9ep) was obtained.
HRMS calculated for C H N O : 170.1055, found: 171.1135 (M+H).
8 14 2 2
Preparation 9eq: [2-(2-Fluorophenyl)pyrimidinyl]methanol
Step A: 2-Fluoro-N'-hydroxy-benzamidine
11.48 g (165 mmol) hydroxylamine hydrochloride and 13.87 g ( 165 mmol) NaHCO were
dissolved in 120 mL MeOH and stirred at room temperature for 30 min. 10 g (82.6 mmol)
2-fluorobenzonitrile was added and the mixture was stirred at 75 C until no further
conversion was observed. Solvent was partially evaporated, residue was filtered, washed
with MeOH, filtrate was concentrated. It was diluted with water and extracted with EtOAc.
The combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure.
Step B: 2-Fluorobenzamidine
12.67 g 2-fluoro-N'-hydroxy-benzamidine (81.55 mmol) was dissolved in AcOH at 0 C
and 9.24 mL (97.86 mmol) Ac O was added. Mixture was stirred at room temperature until
no further conversion was observed. 630 mg 10% Pd/C was added and the mixture was
stirred under 4bar H until no further conversion was observed. Mixture was filtered on
celite and volatiles were removed in vacou to obtain 2-fluorobenzamidine.
MS: (M+H) = 139.4.
Step C: 4-(Dimethoxymethyl)(2-fluorophenyl)pyrimidine
Starting from 2-fluorobenzamidine using General Procedure 9C 4-(dimethoxymethyl)
(2-fluorophenyl)pyrimidine was obtained.
MS: (M+H) = 249.2.
Step D: [2-(2-Fluorophenyl)pyrimidinyl]methanol
Starting from 4-(dimethoxymethyl)(2-fluorophenyl)pyrimidine using General
Procedure 9A, [2-(2-fluorophenyl)pyrimidinyl]methanol (Preparation 9eq) was
obtained.
MS: (M+H) = 205.2.
Preparation 9er: [2-[2-(trideuteriomethoxy)phenyl]pyrimidinyl]methanol
Step A: N',2-dihydroxybenzamidine
17.5 g H N-OH×HCl (252 mmol) was dissolved in 250 mL methanol, then 21.1 g NaHCO
(252 mmol) was added and it was stirred at rt for 30 minutes. Then 15.0 g 2-
hydroxybenzonitrile (126 mmol) was added and refluxed for 5 h. The mixture was cooled
to 0°C, it was filtered, and the filtrate was concentrated to dryness. 75 mL water was added
and it was extracted with 3x75 mL ethylacetate. The combined organic layer was dried
over MgSO to give light yellow-brown crystals.
MS (ESI+): 153.2
Step B: 2-[4-(dimethoxymethyl)pyrimidinyl]phenol
18.0 g N'-hydroxymethoxy-benzamidine (118 mmol) was dissolved in 350 mL acetic
acid and 13.4 mL acetic anhydride (14.49 g, 141.9 mmol) was added dropwise at 40°C.
Then it was stirred at 50°C for 45 minutes to reach 100% conversion by HPLC. 1.26 g
Pd/C (7 m/m%, Pd on C, Strem Catalog No: 46-1900) was added and the mixture was
stirred under 4 bar H atmosphere for 4 hours to reach 100% conversion. Then it was
filtered through Celite, washed with acetic acid and the filtrate was concentrated to
dryness, then to the crude product 20mL of diethylether was added and the so obtained
mixture was sonicated for 10 minutes. It was filtered, precipitates were washed with 30 mL
diethylether, and then precipitates were dried to give light yellow crystals. The obtained
amidine acetic acid salt was used without further purification.
The crude amidine was dissolved in 350 mL methanol, then 16.0 g sodium methoxyde
(295 mmol) was added portionwise at room temperature, then 28.7 g (E)
(dimethylamino)-1,1-dimethoxy-butenone (Preparation 9a1) (166 mmol) was
added, and the reaction mixture was refluxed for 3 hours. The volatiles were evaporated,
then 150 ml brine was added and the pH was set to 6 using 2N HCl. The mixture was
extracted with 3 × 150 mL ethylacetate. The combined organic layers were dried over
magnesium sulphate, filtered and concentrated. The crude product was purified via flash
chromatography using heptane and ethylacetate as eluents to give the title compound as a
light yellow oil.
MS (ESI+): 247.2
Step C: 4-(dimethoxymethyl)[2-(trideuteriomethoxy)phenyl]pyrimidine
To the solution of 5.06 g 2-[4-(dimethoxymethyl)pyrimidinyl]phenol (20.5 mmol) in 60
ml DMF 7.70 g cesium carbonate (23.6 mmol) was added and the reaction mixture was
stirred at room temperature for 6 hours , then at 35°C for 1 hour. Reaction mixture was
concentrated under reduced pressure (55°C, 10 mbar), then 60 ml brine was added, and it
was extracted with 3x60 ml ethylacetate. Combined organic layer was dried over
magnesium sulphate, filtered and concentrated. The crude product was purified via flash
chromatography using heptane and ethylacetate as eluents.
MS (ESI+): 264.2
Step D: [2-[2-(trideuteriomethoxy)phenyl]pyrimidinyl]methanol
5N HCl (22 ml, 1.2 ml/mmol) was diluted with dioxan 22 ml (1.2 ml/mmol) then 4.81 g of
4-(dimethoxymethyl)[2-(trideuteriomethoxy)phenyl]pyrimidine (18.27 mmol) was
added and the reaction mixture was stirred under argon at 50°C for 16h to reach 98%
conversion by HPLC. Reaction mixture was cooled to 0°C. The pH was adjusted to 9 by
the portionwise addition of 5.6 g sodium hydroxyde (140 mmol) and K CO solution (aq,
%). At 0°C 795 mg sodium borohydride (1.15 eq, 21 mmol) was added portionwise to
the reaction mixture and it was stirred for 30 min. Then 20ml brine was added and it was
extracted with 2x60 ml of ethyl acetate. To the water phase 30 ml of saturated NH4Cl
solution was added, and it was extracted with 2x60 ml of ethyl acetate again. Organic
layers were combined, dried over magnesium sulphate, filtered and concentrated. The
crude product was purified on ISCO 80 g silica gold column using heptane and
ethylacetate as eluents to give Preparation 9er as white crystals.
MS (ESI+): 220.2
Preparation 10a: Ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
1.77 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8a) (2.5 mmol), 1.17 g (2-methylsulfanylpyrimidin
yl)methanol (Preparation 9aa) (7.5 mmol) and 1.97 g PPh (7.5 mmol) were dissolved in
50 mL dry toluene, then 1.74 g ditertbutyl azodicarboxylate (7.5 mmol) was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
toluene was evaporated under reduced pressure and the residue was purified via flash
chromatography using DCM and MeOH as eluents.
H NMR (500 MHz, DMSO-d ): 8.70 (d, 1H), 8.58 (s, 1H), 7.34 (d, 1H), 7.31 (d, 1H), 7.30
(m, 2H), 7.22 (m, 2H), 7.17 (t, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.74 (t, 1H), 6.31 (d, 1H),
.47 (dd, 1H), 5.17 (d, 1H), 5.11 (d, 1H), 4.20 (m, 1H), 4.16 (m, 1H), 4.06 (m, 2H), 3.12
(dd, 1H), 2.69 (m, 2H), 2.56 (dd, 1H), 2.50 (s, 3H), 2.46 (br s, 4H), 2.24 (br s, 4H), 2.10 (s,
3H), 1.86 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S : 842.2487, found: 843.2660 (M+H).
43 44 6 5 2
Preparation 10b: Ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)
methyl-phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
0.975 g ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8b) (1.5 mmol), 0.702 g (2-methylsulfanylpyrimidinyl)methanol
(Preparation 9aa) (4.5 mmol) and 1.180 g PPh (4.5 mmol) were dissolved in 50 mL dry
toluene, then 1.036 g ditertbutyl azodicarboxylate (4.5 mmol) was added. The mixture was
stirred at 50°C under nitrogen until no further conversion was observed. The toluene was
evaporated under reduced pressure, Et O was added, and the mixture was stirred and
sonicated. The precipitated white crystals were filtered, washed with Et O. The filtrate was
concentrated and purified via flash chromatography using DCM and MeOH as eluents.
H NMR (500 MHz, DMSO-d ): 8.69 (d, 1H), 8.60 (s, 1H), 7.34 (d, 1H), 7.30 (d, 1H), 7.30
(dd, 2H), 7.23 (t, 2H), 7.17 (d, 1H), 7.16 (t, 1H), 6.98 (d, 1H), 6.74 (t, 1H), 6.29 (dd, 1H),
.47 (dd, 1H), 5.17 (d, 1H), 5.11 (d, 1H), 4.19 (t, 1H), 4.15 (t, 1H), 4.08 (m, 1H), 4.05 (m,
1H), 3.13 (d, 1H), 2.64 (t, 2H), 2.56 (d, 1H), 2.50 (s, 3H), 2.19 (s, 6H), 1.85 (s, 3H), 1.06
(t, 3H).
HRMS calculated for C H ClFN O S : 787.2065, found: 788.2148 (M+H).
40 39 5 5 2
Preparation 10c: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
1.39 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8c) (2.00 mmol), 0.94 g (2-
methylsulfanylpyrimidinyl)methanol (Preparation 9aa) (6.00 mmol) and 1.57 g PPh
(6.00 mmol) were dissolved in 40 mL dry toluene, then 1.38 g ditertbutyl azodicarboxylate
(6.00 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further
conversion was observed. The toluene was evaporated under reduced pressure and the
residue was purified via flash chromatography using DCM and MeOH as eluents.
H NMR (500 MHz, DMSO-d ): 8.70 (d, 1H), 8.57 (s, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 7.25
(d, 1H), 7.19 (m, 1H), 7.00 (dm, 1H), 6.81 (m, 1H), 6.35 (dm, 1H), 5.89 (dd, 1H), 5.71 (t,
1H), 5.48 (dd, 1H), 5.18 (d, 1H), 5.12 (d, 1H), 4.26 (m, 1H), 4.22 (m, 1H), 4.08 (m, 1H),
4.05 (m, 1H), 3.15 (dd, 1H), 2.50 (s, 3H), 2.50 (br s, 4H), 2.49 (dd, 1H), 2.27 (br s, 4H),
2.11 (s, 3H), 1.95 (s, 3H), 1.06 (t, 3H).
HRMS calculated for C H ClFN O S : 832.2280, found: 833.2332 (M+H).
41 42 6 6 2
Preparation 10d: Ethyl (2R)[(5S )-[3-chloromethyl[2-(4-ethylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
1.80 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-ethylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8p) (2.5 mmol), 1.17 g (2-methylsulfanylpyrimidin
yl)methanol (Preparation 9aa) (7.5 mmol) and 1.97 g PPh (7.5 mmol) were dissolved in
50 mL dry toluene, then 1.74 g ditertbutyl azodicarboxylate (7.5 mmol) was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
toluene was evaporated under reduced pressure and the residue was purified via flash
chromatography using DCM and MeOH as eluents.
HRMS calculated for C H ClFN O S : 856.2644, found: 857.2743 (M+H).
44 46 6 5 2
Preparation 10e: Ethyl (2R)[(5R )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
1.77 g ethyl (2R)[(5R )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8q) (2.5 mmol), 1.17 g (2-
methylsulfanylpyrimidinyl)methanol (Preparation 9aa) (7.5 mmol) and 1.97 g PPh
(7.5 mmol) were dissolved in 50 mL dry toluene, then 1.74 g ditertbutyl azodicarboxylate
(7.5 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further
conversion was observed. The toluene was evaporated under reduced pressure and the
residue was purified via flash chromatography using DCM and MeOH as eluents.
MS: (M+H) = 843.2
Preparation 10f: Ethyl (2S)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate
1.77 g ethyl (2S)[(5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8r) (2.5 mmol), 1.17 g (2-methylsulfanylpyrimidinyl)methanol
(Preparation 9aa) (7.5 mmol) and 1.97 g PPh (7.5 mmol) were dissolved in 50 mL dry
toluene, then 1.74 g ditertbutyl azodicarboxylate (7.5 mmol) was added. The mixture was
stirred at 50°C under nitrogen until no further conversion was observed. The toluene was
evaporated under reduced pressure and the residue was purified via flash chromatography
using DCM and MeOH as eluents.
MS: (M+H) = 843.2
Preparation 11a: Ethyl (2R)[5-(3-chloroethylhydroxy-phenyl)(2-furyl)
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (mixture of
diastereoisomers)
403 mg ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4e) (0.80 mmol), 371 mg [2-chloroethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane (Preparation
5e) (0.85 mmol), 57 mg Ataphos (0.08 mmol) and 652 mg Cs CO (2.00 mmol) were
dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 110°C for 15
minutes via microwave irradiation. Then water was added and the pH was set to 6 with 2
M HCl. Then it was extracted with DCM, dried over Na SO , filtered and concentrated
under reduced pressure and purified via reversed phase chromatography, using MeCN as
eluent to obtain ethyl (2R)[5-(3-chloroethyltriisopropylsilyloxy-phenyl)(2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (MS (M+H):
735.2). Then it was dissolved in 2 mL toluene, 0.45 mL TBAF (0.45 mmol in 1 M THF)
was added and the mixture was stirred for 5 minutes. Then it was diluted with DCM,
washed with water and brine, dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via flash chromatography, using heptane and
EtOAc as eluents to obtain Preparation 11a as a mixture of diastereoisomers.
MS (M+H): 579.2 for both diastereomers.
Preparation 11b: Ethyl (2R)[5-(3-fluorohydroxymethyl-phenyl)(2-furyl)
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (mixture of
diastereoisomers)
503 mg ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4e) (1.00 mmol), 378 mg 2-fluoromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5g) (1.50 mmol), 21 mg
Ataphos (0.03 mmol) and 652 mg Cs CO (2.00 mmol) were dissolved in 8 mL dioxane
and 2 mL water. The mixture was heated to 110°C for 10 minutes via microwave
irradiation. Then water was added and the pH was set to 6 with 2 M HCl. Then it was
extracted with DCM, dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via flash chromatography, using heptane and EtOAc as
eluents to obtain Preparation 11b as a mixture of diastereoisomers.
MS (M+H): 549.0, (M-H): 547.0 for both diastereomers.
Preparation 12: 4-Chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]thieno[2,3-d]pyrimidine
.00 g 4-chloroiodo-thieno[2,3-d]pyrimidine (Preparation 1c) (84.31 mmol), 39.94 g
1-[2-[2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]
methyl-piperazine (Preparation 5b) (101.2 mmol) and 53.69 g K PO (252.9 mmol) were
dissolved in 300 mL DME and 200 mL water. 946 mg palladium acetate (4.221 mmol) and
3.021 g BuPAd (8.433 mmol) were added, and then the mixture was stirred at 60°C
under argon atmosphere until no further conversion was observed. Then the DME was
evaporated and the precipitated solid was filtered off and washed with water. To the
filtered solid 100 mL MeCN was added and it was sonicated, and then it was filtered to
give a pale yellow solid as Preparation 12.
H NMR (400 MHz, DMSO-d ): 8.98 (s, 1H), 7.97 (s, 1H), 7.22 (d, 1H), 7.09 (s, 1H),
4.25-4.16 (m, 2H), 2.76 (t, 2H), 2.54 (br s, 4H), 2.32 (br s, 4H), 2.14 (s, 3H), 2.06 (s, 3H).
Preparation 13: 4-Chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]iodo-thieno[2,3-d]pyrimidine
21.95 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno-[2,3-d]pyrimidine (Preparation 12) (50.20 mmol) was dissolved in 500 mL dry
THF under N2 and then it was cooled to -78°C. 50.20 mL lithium diisopropylamide (100.4
mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1
hour. Then 25.48 g iodine (100.4 mmol) was added and the mixture was allowed to warm
up to room temperature. The volatiles were evaporated; the residue was diluted with DCM,
washed with 10% sodium thiosulphate solution. The aqueous layer was extracted with
DCM. The combined organic phases were dried over Na SO , filtered and concentrated. 50
mL MeCN was added and it was sonicated for 10 minutes, filtered, washed with MeCN to
give a pale yellow solid as Preparation 13.
H NMR (500 MHz, DMSO-d ): 8.93 (s, 1H), 7.15 (d, 1H), 7.13 (d, 1H), 4.22 (t, 2H), 2.77
(t, 2H), 2.56 (br s, 4H), 2.34 (br s, 4H), 2.16 (s, 3H), 2.00 (s, 3H).
Preparation 14: 4-Chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](2-furyl)thieno[2,3-d]pyrimidine
3.00 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidine (Preparation 13) (5.32 mmol), 2.06 g 2-(2-furyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (9.05 mmol), 377 mg AtaPhos (0.53 mmol) and 5.205 g
cesium carbonate (15.97 mmol) were placed in an 250 mL flask. 80 mL dioxane and 20
mL water were added, and then stirred at 70°C under argon atmosphere until no further
conversion was observed. Brine was added to the reaction mixture and it was extracted
with EtOAc. The combined organic phases were dried over MgSO , filtered and
evaporated under reduced pressure, and then purified by flash chromatography using DCM
/ MeOH as eluents to give Preparation 14.
H NMR (500 MHz, DMSO-d ): 8.93 (s, 1H), 7.86 (d, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 6.55
(d, 1H), 5.65 (d, 1H), 4.23 (t, 2H), 2.78 (t, 2H), 2.15 (s, 3H), 2.04 (s, 3H).
Preparation 15a: Methyl (2R)[(5S )(3-chlorohydroxymethylnitro-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
483 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) (1.00 mmol) was dissolved in
10 mL MeCN, then 139 mg nitronium tetrafluoroborate (1.05 mmol) suspended in 10 mL
MeCN was added and the mixture was stirred at 0°C for 50 minutes. The volatiles were
evaporated under reduced pressure and the crude product was purified via flash
chromatography, using heptane and EtOAc as eluents to obtain Preparation 15a.
H NMR (400 MHz, DMSO-d ): 11.19 (br s, 1H), 8.59 (s, 1H), 7.87 (s, 1H), 7.14 (m, 3H),
6.72 (m, 2H), 5.59 (dd, 1H), 3.53 (s, 3H), 2.97 (dd, 1H), 2.74-2.61 (m, 3H), 2.07 (s, 3H),
1.18 (t, 3H).
HRMS calculated for C H ClN O S: 527.0918, found: 528.0986 (M+H).
22 3 6
Preparation 15b: Methyl (2R)[(5S )(5-aminochlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
1.339 g methyl (2R)[(5S )(3-chlorohydroxymethylnitro-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15a) (2.536 mmol)
was dissolved in 40 mL MeOH. 270 mg Selcat Q6 was added and the mixture was stirred
at 40°C under 4 atm. H pressure for 90 minutes. Then it was filtered through celite and the
volatiles were evaporated under reduced pressure. The crude product was purified via flash
chromatography, using heptane and EtOAc as eluents to obtain Preparation 15b.
H NMR (400 MHz, DMSO-d ): 8.78 (br s, 1H), 8.52 (s, 1H), 7.16 (m, 3H), 6.67 (m, 2H),
6.58 (s, 1H), 5.45 (dd, 1H), 4.88 (br s, 2H), 3.51 (s, 3H), 2.92 (dd, 1H), 2.78 (dd, 1H),
2.72-2.59 (m, 2H), 1.86 (s, 3H), 1.17 (t, 3H).
HRMS calculated for C H ClN O S: 497.1176, found: 498.1259 (M+H).
24 3 4
Preparation 15c: Methyl (2R)[(5S )[7-chloro(chloromethyl)methyl-1,3-
benzoxazolyl]ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
100 mg methyl (2R)[(5S )(5-aminochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15b) (0.20 mmol) was
dissolved in 0.5 mL dry toluene under N . 57 L triethyl-ortochloroacetate (0.30 mmol)
was added and the mixture was stirred at 100°C for 1 hour. The volatiles were evaporated
under reduced pressure. The crude product was purified via flash chromatography, using
heptane and EtOAc as eluents to obtain Preparation 15c.
MS (M+H): 556.0.
Preparation 15d: Methyl (2R)[(5S )(3-chlorohydroxyiodomethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
483 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) (1.0 mmol) was dissolved in
mL EtOH, then 305 mg iodine (1.2 mmol) and 405 mg Ag SO (1.3 mmol) were added
and the mixture was stirred at room temperature for 90 minutes. Then it was filtered, the
filtrate was concentrated under reduced pressure and the crude product was purified via
flash chromatography, using heptane and EtOAc as eluents to obtain Preparation 15d.
H NMR (400 MHz, DMSO-d ): 10.10 (br s, 1H), 8.55 (s, 1H), 7.64 (s, 1H), 7.15 (m, 3H),
6.63 (m, 2H), 5.49 (dd, 1H), 3.58 (s, 1H), 3.00 (dd, 1H), 2.69 (dd, 1H), 2.65 (m, 2H), 1.99
(s, 3H), 1.17 (t, 3H).
HRMS calculated for C H ClIN O S: 608.0034, found: 609.0130 (M+H).
22 2 4
Preparation 15e: Methyl (2R)[(5S )(3,5-dichlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
483 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) (1.0 mmol) was dissolved in
5 mL THF, then 147 mg NCS (1.1 mmol) was added and the mixture was stirred at 50°C
for 3 hours. The volatiles were evaporated under reduced pressure and the crude product
was purified via flash chromatography, using heptane and EtOAc as eluents to obtain
Preparation 15e.
H NMR (400 MHz, DMSO-d ): 10.21 (s, 1H), 8.56 (s, 1H), 7.33 (s, 1H), 7.16 (m, 3H),
6.66 (m, 2H), 5.52 (dd, 1H), 3.55 (s, 3H), 2.98 (dd, 1H), 2.70-2.60 (m, 3H), 1.99 (s, 3H),
1.17 (t, 3H).
HRMS calculated for C H Cl N O S: 516.0677, found: 517.0772 (M+H).
22 2 2 4
Preparation 15f: Methyl (2R)[(5S )(5-bromochlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
169 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) (0.35 mmol) was dissolved in
2 mL THF, then 64 mg NBS (0.36 mmol) was added and the mixture was stirred at 50°C
for 10 minutes. The volatiles were evaporated under reduced pressure and the crude
product was purified via flash chromatography, using heptane and EtOAc as eluents to
obtain Preparation 15f.
H NMR (400 MHz, DMSO-d ): 10.10 (br s, 1H), 8.54 (s, 1H), 7.44 (s, 1H), 7.15 (m, 3H),
6.65 (m, 2H), 5.50 (dd, 1H), 3.55 (s, 3H), 2.98 (dd, 1H), 2.70-2.59 (m, 3H), 1.97 (s, 1H),
1.16 (t, 3H).
MS (M+H): 561.0, (M-H): 559.0.
Unless otherwise specified, compounds of Preparation 16a to 16g were obtained using
General Procedure 16A described below.
General Procedure 16A:
2.5 eq. 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d), 1.0 eq. of the
appropriate alcohol and 1.5 eq. cesium carbonate were dissolved in dry DMSO (0.25 M for
Preparation 1d). The mixture was stirred at 100°C under nitrogen until no further
conversion was observed. The reaction mixture was cooled to room temperature, it was
diluted with water, the pH was set to 7 with 2 M HCl, and then it was extracted with ethyl
acetate. The combined organic phases were dried over Na SO , filtered, concentrated under
reduced pressure and purified via flash chromatography using heptane and ethyl acetate as
eluents.
Preparation 16a: Ethyl (2R)(1,3-benzodioxolyl)(6-ethyliodo-thieno[2,3-
d]pyrimidinyl)oxy-propanoate
Using General Procedure 16A and ethyl (2R)(1,3-benzodioxolyl)hydroxy-
propanoate (Preparation 3bg) as the appropriate alcohol we obtained Preparation 16a.
H NMR (400 MHz, CDCl ): 8.49 (s, 1H), 6.90 (dd, 1H), 6.75 (t, 1H), 6.73 (dt, 1H), 5.92
(dd, 2H), 5.82 (t, 1H), 4.20 (dq, 2H), 3.40 (d, 2H), 2.93 (q, 2H), 1.33 (t, 3H), 1.21 (t, 3H).
Preparation 16b: Ethyl (2R)(2,3-dihydrobenzofuranyl)(6-ethyliodo-
thieno[2,3-d]pyrimidinyl)oxy-propanoate
Using General Procedure 16A and ethyl (2R)(2,3-dihydrobenzofuranyl)hydroxy-
propanoate (Preparation 3bd) as the appropriate alcohol we obtained Preparation 16b.
H NMR (400 MHz, CDCl ): 8.48 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.76 (t, 1H), 5.81
(dd, 1H), 4.54 (dt, 2H), 4.19 (dq, 2H), 3.44-3.32 (m, 2H), 3.19 (t, 2H), 2.92 (q, 2H), 1.32 (t,
3H), 1.20 (t, 3H).
Preparation 16c: Ethyl (2S)(2,3-dihydrobenzofuranyl)(6-ethyliodo-
thieno[2,3-d]pyrimidinyl)oxy-propanoate
Using General Procedure 16A and ethyl (2S)(2,3-dihydrobenzofuranyl)hydroxy-
propanoate (Preparation 3be) as the appropriate alcohol we obtained Preparation 16c.
H NMR (400 MHz, CDCl ): 8.48 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.76 (t, 1H), 5.81
(dd, 1H), 4.54 (dt, 2H), 4.19 (dq, 2H), 3.44-3.32 (m, 2H), 3.19 (t, 2H), 2.92 (q, 2H), 1.32 (t,
3H), 1.20 (t, 3H).
Preparation 16d: Ethyl 3-(benzofuranyl)(6-ethyliodo-thieno[2,3-d]pyrimidin-
4-yl)oxy-propanoate
Using General Procedure 16A and ethyl 3-(benzofuranyl)hydroxy-propanoate
(Preparation 3bb) as the appropriate alcohol we obtained Preparation 16d.
H NMR (400 MHz, CDCl ): 8.47 (s, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.16 (t,
1H), 6.76 (d, 1H), 5.94 (dd, 1H), 4.18 (dq, 2H), 3.79-3.66 (m, 2H), 2.90 (q, 2H), 1.31 (t,
3H), 1.16 (t, 3H).
Preparation 16e: Ethyl (2S)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
fluorophenyl)propanoate
Using General Procedure 16A and ethyl (2S)(2-fluorophenyl)hydroxy-propanoate
(Preparation 3az) as the appropriate alcohol we obtained Preparation 16e.
H NMR (400 MHz, CDCl ): 8.48 (s, 1H), 7.45 (dt, 1H), 7.23 (m, 1H), 7.06 (t, 1H), 7.04
(t, 1H), 5.78 (dd, 1H), 4.19 (m, 2H), 3.53-3.41 (m, 2H), 2.92 (q, 2H), 1.33 (t, 3H), 1.20 (t,
3H).
Preparation 16f: Ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
fluorophenyl)propanoate
Using General Procedure 16A and ethyl (2R)(2-fluorophenyl)hydroxy-propanoate
(Preparation 3ba) as the appropriate alcohol we obtained Preparation 16f.
H NMR (400 MHz, CDCl ): 8.48 (s, 1H), 7.45 (dt, 1H), 7.23 (m, 1H), 7.06 (t, 1H), 7.04
(t, 1H), 5.78 (dd, 1H), 4.19 (m, 2H), 3.53-3.41 (m, 2H), 2.92 (q, 2H), 1.33 (t, 3H), 1.20 (t,
3H).
Preparation 16g: Ethyl (2S)(1,3-benzodioxolyl)(6-ethyliodo-thieno[2,3-
d]pyrimidinyl)oxy-propanoate
Using General Procedure 16A and ethyl (2S)(1,3-benzodioxolyl)hydroxy-
propanoate (Preparation 3bh) as the appropriate alcohol we obtained Preparation 16g.
H NMR (400 MHz, CDCl ): 8.49 (s, 1H), 6.90 (dd, 1H), 6.75 (t, 1H), 6.73 (dt, 1H), 5.92
(dd, 2H), 5.82 (t, 1H), 4.20 (dq, 2H), 3.40 (d, 2H), 2.93 (q, 2H), 1.33 (t, 3H), 1.21 (t, 3H).
Preparation 17a: Ethyl (2R)(1,3-benzodioxolyl)[(5R )(3-chlorohydroxy-
2-methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
Preparation 17b: Ethyl (2R)(1,3-benzodioxolyl)[(5S )(3-chlorohydroxy-
2-methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
0.482 g ethyl (2R)(1,3-benzodioxolyl)(6-ethyliodo-thieno[2,3-d]pyrimidin
yl)oxy-propanoate (Preparation 16a) (0.92 mmol), 0.737 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.74 mmol), 0.041g
Pd(OAc) (0.18 mmol) 0.130g BuPAd (0.36 mmol), 2.7 mL Bu NOH solution (2.7
2 2 4
mmol, 1.0 M in water) and 6.6 mL DME were heated under nitrogen at 100°C for 10 min
in microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and
then it was extracted with MTBE. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure. The diastereomers were separated via
flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer
eluting earlier as Preparation 17a, and the diastereomer eluting later as Preparation 17b.
Preparation 17a: H NMR (500 MHz, DMSO-d ): 10.28 (br s, 1H), 8.53 (s, 1H), 6.91 (d,
1H), 6.88 (d, 1H), 6.73 (d, 1H), 6.58 (t, 1H), 5.95 (s, 2H), 5.82 (d, 1H), 5.30 (dd, 1H), 4.09
(m, 2H), 2.97 (dd, 1H), 2.65 (m, 2H), 2.44 (dd, 1H), 2.15 (s, 3H), 1.15 (t, 3H), 1.09 (t, 3H).
Preparation 17b: H NMR (500 MHz, DMSO-d ): 10.23 (br s, 1H), 8.54 (s, 1H), 7.03 (d,
1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.62 (t, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.92 (d, 1H), 5.43
(dd, 1H), 4.02 (m, 2H), 2.86 (dd, 1H), 2.62 (m, 2H), 2.58 (dd, 1H), 1.95 (s, 3H), 1.15 (t,
3H), 1.04 (t, 3H).
Preparation 17c: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxy(2,3-dihydrobenzofuranyl)propanoate
0.525 g ethyl (2R)(2,3-dihydrobenzofuranyl)(6-ethyliodo-thieno[2,3-
d]pyrimidinyl)oxy-propanoate (Preparation 16b) (1.0 mmol), 0.670 g 2-chloro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.5
mmol), 0.063 g AtaPhos (0.09 mmol), 2.5 mL Bu NOH solution (2.5 mmol, 1.0 M in
water) and 4.5 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a
microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and
then it was extracted with MTBE. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure. The diastereomers were separated via
flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer
eluting later as Preparation 17c.
H NMR (500 MHz, DMSO-d ): 10.23 (br s, 1H), 8.52 (s, 1H), 7.04 (d, 1H), 7.02 (d, 1H),
6.96 (d, 1H), 6.62 (t, 1H), 6.12 (d, 1H), 5.38 (dd, 1H), 4.49 (m, 2H), 4.02 (m, 2H), 3.11 (t,
2H), 2.87 (dd, 1H), 2.61 (m, 2H), 2.45 (dd, 1H), 1.95 (s, 3H), 1.15 (t, 3H), 1.05 (t, 3H).
Preparation 17d: Ethyl (2S)[(5R )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxy(2,3-dihydrobenzofuranyl)propanoate
0.525 g ethyl (2S)(2,3-dihydrobenzofuranyl)(6-ethyliodo-thieno[2,3-
d]pyrimidinyl)oxy-propanoate (Preparation 16c) (1.0 mmol), 0.670 g 2-chloro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.5
mmol), 0.063 g AtaPhos (0.09 mmol), 2.5 mL Bu NOH solution (2.5 mmol, 1.0 M in
water) and 4.5 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a
microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and
then it was extracted with MTBE. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure. The diastereomers were separated via
flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer
eluting later as Preparation 17d.
H NMR (500 MHz, DMSO-d ): 10.23 (br s, 1H), 8.52 (s, 1H), 7.04 (d, 1H), 7.02 (d, 1H),
6.96 (d, 1H), 6.62 (t, 1H), 6.12 (d, 1H), 5.38 (dd, 1H), 4.49 (m, 2H), 4.02 (m, 2H), 3.11 (t,
2H), 2.87 (dd, 1H), 2.61 (m, 2H), 2.45 (dd, 1H), 1.95 (s, 3H), 1.15 (t, 3H), 1.05 (t, 3H).
Preparation 17e: Ethyl (2R)(benzofuranyl)[(5S )(3-chlorohydroxy
methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
and
Preparation 17f: Ethyl (2S)(benzofuranyl)[(5R )(3-chlorohydroxy
methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
0.647 g Ethyl 3-(benzofuranyl)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy-
propanoate (Preparation 16d) (1.24 mmol), 0.766 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.85 mmol), 0.087 g
AtaPhos (0.12 mmol), 2.5 mL Bu NOH solution (2.5 mmol, 1.0 M in water) and 5 mL 2-
MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor with
stirring. The pH of the mixture was set to 6 with 2 M HCl, it was filtered through a pad of
celite, and the pad was washed both with water and MTBE. The phases were then
separated, the aqueous layer was extracted with MTBE. The combined organic phases
were dried over Na SO , filtered and concentrated. The four stereoisomer containing
mixture was first separated via flash chromatography using heptane and EtOAc as eluents,
and collecting the racemic mixture eluting later. Then further separation of the mixture was
accomplished by chiral chromatography, Column: AD, Eluents: heptane / EtOH. The
enantiomer eluting earlier was collected as Preparation 17e with ee> 99.8% and the
enantiomer eluting later was collected as Preparation 17f with ee: 99.6%.
H NMR (500 MHz, DMSO-d ): 10.25 (br s, 1H), 8.52 (s, 1H), 7.97 (d, 1H), 7.49 (m, 1H),
7.06 (d, 1H), 7.04 (t, 1H), 7.01 (d, 1H), 6.91 (d, 1H), 6.36 (m, 1H), 5.57 (dd, 1H), 3.98 (m,
1H), 3.93 (m, 1H), 3.22 (dd, 1H), 2.90 (dd, 1H), 2.65 (m, 1H), 2.60 (m, 1H), 1.96 (s, 3H),
1.15 (t, 3H), 0.94 (t, 3H).
Preparation 17g: Ethyl (2S)[(5R )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxy(2-fluorophenyl)propanoate
0.425 g Ethyl (2S)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
fluorophenyl)propanoate (Preparation 16e) (0.85 mmol), 0.570 g 2-chloromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.12 mmol), 0.053
g AtaPhos (0.075 mmol), 2.13 mL Bu NOH solution (2.13 mmol, 1.0 M in water) and 4
mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor
with stirring. The pH of the mixture was set to 6 with 2 M HCl, it was filtered through a
pad of celite, the pad was washed both with water and MTBE. The phases were then
separated, the aqueous layer was extracted with MTBE. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure. The
diastereomers were separated via flash chromatography using heptane and EtOAc as
eluents, collecting the diastereomer eluting later as Preparation 17g.
H NMR (500 MHz, DMSO-d ): 10.23 (s, 1H), 8.54 (s, 1H), 7.24 (m, 1H), 7.09 (ddd, 1H),
7.05 (d, 1H), 6.98 (d, 1H), 6.97 (td, 1H), 6.45 (td, 1H), 5.42 (dd, 1H), 4.00 (m, 2H), 2.93
(dd, 1H), 2.72 (dd, 1H), 2.63 (m, 2H), 1.97 (s, 3H), 1.15 (t, 3H), 1.02 (t, 3H).
Preparation 17h: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxy(2-fluorophenyl)propanoate
0.425 g Ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-
fluorophenyl)propanoate (Preparation 16f) (0.85 mmol), 0.570 g 2-chloromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.12 mmol), 0.053
g AtaPhos (0.075 mmol), 2.13 mL Bu NOH solution (2.13 mmol, 1.0 M in water) and 4
mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor
with stirring. The pH of the mixture was set to 6 with 2 M HCl, it was filtered through a
pad of celite, the pad was washed both with water and MTBE. The phases were then
separated, the aqueous layer was extracted with MTBE. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure. The
diastereomers were separated via flash chromatography using heptane and EtOAc as
eluents, collecting the diastereomer eluting later as Preparation 17h.
H NMR (500 MHz, DMSO-d ): 10.23 (s, 1H), 8.54 (s, 1H), 7.24 (m, 1H), 7.09 (ddd, 1H),
7.05 (d, 1H), 6.98 (d, 1H), 6.97 (td, 1H), 6.45 (td, 1H), 5.42 (dd, 1H), 4.00 (m, 2H), 2.93
(dd, 1H), 2.72 (dd, 1H), 2.63 (m, 2H), 1.97 (s, 3H), 1.15 (t, 3H), 1.02 (t, 3H).
Preparation 17i: Ethyl (2S)(1,3-benzodioxolyl)[(5S )(3-chlorohydroxy
methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
Preparation 17j: Ethyl (2S)(1,3-benzodioxolyl)[(5R )(3-chlorohydroxy-
2-methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
0.482 g ethyl (2S)(1,3-benzodioxolyl)(6-ethyliodo-thieno[2,3-d]pyrimidin
yl)oxy-propanoate (Preparation 16g) (0.92 mmol), 0.737 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.74 mmol), 0.041g
Pd(OAc) (0.18 mmol), 0.130g BuPAd (0.36 mmol), 2.7 mL Bu NOH solution (2.7
2 2 4
mmol, 1.0 M in water) and 6.6 mL DME were heated under nitrogen at 100°C for 10 mins
in a microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and
then it was extracted with MTBE. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure. The diastereomers were separated via
flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer
eluting earlier as Preparation 17i, and the diastereomer eluting later as Preparation 17j.
Preparation 17i: H NMR (500 MHz, DMSO-d ): 10.28 (br s, 1H), 8.53 (s, 1H), 6.91 (d,
1H), 6.88 (d, 1H), 6.73 (d, 1H), 6.58 (t, 1H), 5.95 (s, 2H), 5.82 (d, 1H), 5.30 (dd, 1H), 4.09
(m, 2H), 2.97 (dd, 1H), 2.65 (m, 2H), 2.44 (dd, 1H), 2.15 (s, 3H), 1.15 (t, 3H), 1.09 (t, 3H).
Preparation 17j: H NMR (500 MHz, DMSO-d ): 10.23 (br s, 1H), 8.54 (s, 1H), 7.03 (d,
1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.62 (t, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.92 (d, 1H), 5.43
(dd, 1H), 4.02 (m, 2H), 2.86 (dd, 1H), 2.62 (m, 2H), 2.58 (dd, 1H), 1.95 (s, 3H), 1.15 (t,
3H), 1.04 (t, 3H).
Preparation 18a: Ethyl (2R)[(5S )(3-chlorohydroxymethoxymethyl-
phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate
444 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (0.85 mmol), 297 mg 2-chloromethoxy-
3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5k) (1.00
mmol), 62 mg PdCl × dppf (0.085 mmol) and 326 mg Cs CO (1.00 mmol) were
2 2 3
dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 110°C for 10
minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 M
HCl, extracted with DCM, dried over Na SO , filtered and concentrated under reduced
pressure. The crude product was purified via flash chromatography, using heptane and
EtOAc as eluents. The diastereoisomer eluting earlier was collected as Preparation 18a.
H NMR (400 MHz, DMSO-d6): 9.60 (br s, 1H), 8.62 (s, 1H), 7.15 (t, 1H), 6.89 (s, 1H),
6.87 (d, 1H), 6.66 (t, 1H), 6.05 (dd, 1H), 5.32 (dd, 1H), 4.11 (m, 2H), 3.86 (s, 3H), 3.75 (s,
3H), 3.10 (dd, 1H), 2.37 (dd, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 1.11 (t, 3H).
HRMS calculated for C H ClN O S: 566.1278, found: 567.1360 (M+H).
29 27 2 6
Preparation 18b: Ethyl (2R)[5-(3-chlorohydroxy-2,5-dimethyl-phenyl)prop
ynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (mixture of
diastereoisomers)
522 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (1.00 mmol), 351 mg 2-chloro-3,6-dimethyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5l) (1.24 mmol), 73
mg PdCl × dppf (0.10 mmol) and 489 mg Cs CO (1.50 mmol) were dissolved in 8 mL
2 2 3
dioxane and 2 mL water. The mixture was heated to 110°C for 12 minutes via microwave
irradiation. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM,
dried over Na SO , filtered and concentrated under reduced pressure. The crude product
was purified via flash chromatography, using heptane and EtOAc as eluents to obtain
Preparation 18b as a mixture of diastereoisomers.
H NMR (400 MHz, DMSO-d ): 9.25 (br s, 1H), 8.61 (s, 1H), 7.14 (t, 1H), 7.06/6.94 (s,
1H), 6.87 (d, 1H), 6.65/6.61 (t, 1H), 6.11/6.06 (dd, 1H), 5.33/5.25 (dd, 1H), 4.14-4.02 (m,
2H), 3.75 (s, 3H), 3.09/3.05 (dd, 1H), 2.44-2.34 (m, 1H), 2.27/2.26 (s, 3H), 2.18/2.09 (s,
3H), 2.04/2.02 (s, 3H), 1.09 (t, 3H).
HRMS calculated for C H ClN O S: 550.1329, found: 551.1412 (M+H).
29 27 2 5
Preparation 18c: Ethyl (2R)[(5S )(3-chlorofluorohydroxymethyl-
phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate
522 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (1.00 mmol), 403 mg 2-chlorofluoro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5m) (1.5
mmol), 71 mg AtaPhos (0.1 mmol) and 652 mg Cs CO (2.00 mmol) were dissolved in 8
mL dioxane and 2 mL water. The mixture was heated to 100°C for 15 minutes via
microwave irradiation. Then it was diluted with brine, neutralized with 2 M HCl, extracted
with DCM, dried over Na SO , filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography, using heptane and EtOAc as eluents.
The diastereoisomer eluting later was collected as Preparation 18c.
H NMR (400 MHz, DMSO-d ): 10.56 (br s, 1H), 8.64 (s, 1H), 7.17 (dt, 1H), 7.13 (d, 1H),
6.90 (d, 1H), 6.69 (t, 1H), 6.23 (dd, 1H), 5.41 (dd, 1H), 4.11-4.01 (m, 2H), 3.75 (s, 3H),
3.03 (dd, 1H), 2.52 (dd, 1H), 2.06 (m, 6H), 1.08 (t, 3H).
HRMS calculated for C H ClFN O S: 554.1078, found: 555.1166 (M+H).
28 24 2 5
Preparation 19a: Ethyl 3-(benzofuranyl)(5-iodopropynyl-thieno[2,3-
d]pyrimidinyl)oxy-propanoate
2.676 g 4-chloroiodopropynyl-thieno[2,3-d]pyrimidine (Preparation 2f) (8
mmol), 0.937 g ethyl 3-(benzofuranyl)hydroxy-propanoate (Preparation 3bc) (4
mmol) and 1.955 g Cs CO (6 mmol) were placed in a flask. 20 mL dry DMSO was added
and the mixture was stirred at room temperature until no further conversion was observed.
It was diluted with water, the pH was set to 8 with 2 M HCl, and then it was extracted with
DCM. The combined organic phases were dried over Na SO filtered and concentrated
under reduced pressure and purified via flash chromatography using heptane and ethyl
acetate as eluents to give Preparation 19a.
H NMR (400 MHz, CDCl ): 8.50 (s, 1H), 7.64 (d, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.22 (t,
1H), 6.94 (d, 1H), 5.82 (dd, 1H), 4.17 (m, 2H), 3.71-3.59 (m, 2H), 2.18 (s, 3H).
Preparation 20a: Ethyl (2R)(benzofuranyl)[(5S )(3-chlorohydroxy
methyl-phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
Preparation 20b: Ethyl (2S)(benzofuranyl)[(5R )(3-chlorohydroxy
methyl-phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
0.850 g ethyl 3-(benzofuranyl)(5-iodopropynyl-thieno[2,3-d]pyrimidin
yl)oxy-propanoate (Preparation 19a) (1.6 mmol), 0.859 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (3.2 mmol), 0.110 g
AtaPhos (0.16 mmol) and 1.043 g Cs CO (3.2 mmol) were placed in a microwave reactor
tube. 16 mL Dioxane and 4.8 mL H2O were added and the mixture was heated under
nitrogen at 80°C for 10 mins in microwave reactor. The mixture was filtered through a pad
of celite, the pad was washed both with water and MTBE. The pH of the filtrate was
adjusted to 7 with 2 M HCl, and then it was shaken. The aqueous phase was extracted with
MTBE, the combined organic layers were dried over Na SO , filtered and concentrated
under reduced pressure. The mixture containing four stereoisomers was first separated via
flash chromatography using heptane and EtOAc as eluents and the racemic mixture eluting
later was collected. Then this mixture was separated by chiral chromatography, Column:
AD, Eluents: heptane / ethanol. The product eluting earlier was collected as Preparation
20a with ee: 96.8%, the product eluting later was collected as Preparation 20b with
ee>99.8%.
H NMR (500 MHz, DMSO-d ): 10.31 (br s, 1H), 8.62 (s, 1H), 7.95 (dd, 1H), 7.41 (dd,
1H), 7.13 (dd, 1H), 7.05 (dd, 1H), 7.00 (dd, 1H), 6.82 (dd, 1H), 6.28 (dd, 1H), 5.49 (dd,
1H), 3.98 (m, 1H), 3.91 (m, 1H), 3.16 (dd, 1H), 2.98 (dd, 1H), 2.09 (s, 3H), 2.03 (s, 3H),
0.97 (t, 3H).
Preparation 21: Methyl (2R)(6-bromoiodo-thieno[2,3-d]pyrimidinyl)oxy
phenyl-propanoate
15.39 g 6-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1e) (41 mmol),
11.08 g methyl (2R)hydroxyphenyl-propanoate (61.5 mmol) and 26.71 g cesium
carbonate (82 mmol) were placed in a 100 mL flask. 40 mL dry DMSO was added and the
mixture was stirred at 70°C under argon atmosphere until no further conversion was
observed. The reaction mixture was poured onto 200 mL water, and then pH was set to ~5.
The precipitated product was collected by filtration.
MS (M+H) = 519.0.
Preparation 22: Methyl (2R)[6-bromo-(5S )(3-chlorohydroxymethyl-
phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
1.557 g methyl (2R)(6-bromoiodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (Preparation 21) (3.0 mmol), 1.289 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (4.8 mmol), 219 mg
Pd(ddpf)Cl (0.3 mmol) and 2.931 g cesium carbonate (9.0 mmol) were placed in a 30 mL
microwave tube. After addition of 12 mL dioxane and 6 mL water reaction was heated at
120°C under nitrogen with stirring for 25 min in a microwave reactor. Water was added to
the reaction mixture and the pH was set to 5 with 2 M HCl. The resulting mixture was
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure. Diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected as Preparation 22.
MS (M+H) = 532.0.
Preparation 23a: [2-Chloro(4-chlorothieno[2,3-d]pyrimidinyl)methyl-
phenoxy]-triisopropyl-silane
34.50 g 4-chloroiodo-thieno[2,3-d]pyrimidine (Preparation 1c) (116.3 mmol), 59.32 g
[2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-
silane (Preparation 5c) (139.6 mmol), 653 mg Pd(OAc) (2.908 mmol), 2.085 g BuPAd
(5.817 mmol) and 74.09 g K PO (349.0 mmol) were placed in a 1 L flask. After addition
of 450 mL DME and 150 mL water the reaction was stirred under nitrogen at 60°C until no
further conversion was observed. To the reaction mixture saturated aq. NH Cl was added
and then it was extracted with EtOAc. The combined organic layers were dried over
MgSO and concentrated under reduced pressure. The obtained solid was sonicated in
acetonitrile / water (3:1) and collected by filtration to give Preparation 23a.
H NMR (400 MHz, DMSO-d ): 8.95 (s, 1H), 7.98 (s, 1H), 7.13 (d, 1H), 6.91 (d, 1H), 2.05
(s, 3H), 1.40-1.29 (m, 3H), 1.10 (dd, 18H).
Preparation 23b: 4-Chloro(3-chloromethyl-phenyl)thieno[2,3-d]pyrimidine
Step A:
The mixture of 4.26 g (3-chloromethyl-phenyl)boronic acid (25.0 mmol) and 2.954 g
2,3-dimethylbutane-2,3-diol (25.0 mmol) was dissolved in 125 mL 2-Me-THF and 0.2 g
dry Amberlyst 15 H ion-exchange resin (previously co-evaporated with toluene) was
added and the mixture was stirred at room temperature until no further conversion was
observed. The solution was filtered through a pad of celite, it was washed with 2-MeTHF
and the filtrate was evaporated under reduced pressure to give 2-(3-chloromethyl-
phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The obtained material was used without
further purification.
Step B:
3.558 g 4-chloroiodo-thieno[2,3-d]pyrimidine (Preparation 1c) (12.0 mmol), 3.636 g
2-(3-chloromethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Step A, 14.4
mmol), 67.4 mg Pd(OAc) (0.3 mmol), 0.215 g BuPAd (0.6 mmol) and 7.645 g K PO
2 2 3 4
(36.0 mmol) were placed in a flask. After the addition of 45 mL DME and 15 mL water the
mixture was stirred under nitrogen at 60°C until no further conversion was observed. To
the reaction mixture saturated aq. NH Cl was added and it was extracted with EtOAc. The
combined organic layers were dried over MgSO and concentrated under reduced pressure.
The crude material was purified via flash chromatography using heptane and EtOAc as
eluents to obtain Preparation 23b.
H NMR (400 MHz, CDCl ): 8.89 (s, 1H), 7.47 (dd, 1H), 7.43 (s, 1H), 7.20 (t, 1H), 7.14
(dd, 1H), 2.14 (s, 3H).
Preparation 24a: [2-Chloro(4-chloroiodo-thieno[2,3-d]pyrimidinyl)methyl-
phenoxy]-triisopropyl-silane
38.00 g [2-chloro(4-chlorothieno[2,3-d]pyrimidinyl)methyl-phenoxy]-
triisopropyl-silane (Preparation 23a) (81.27 mmol) was dissolved in 1 L dry THF then
cooled to -78°C under argon atmosphere. 48.76 mL lithium diisopropylamide (97.53
mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1
hour. Then 24.75 g iodine (97.53 mmol) was added and the mixture was allowed to warm
up to room temperature. Saturated aq. NH Cl was added to the reaction mixture and it was
extracted with EtOAc. The combined organic layers were washed with Na S O solution,
2 2 3
then dried over Na SO and concentrated under reduced pressure. The obtained solid was
sonicated in acetonitrile / water (3:1) and collected by filtration.
H NMR (400 MHz, DMSO-d ): 8.91 (s, 1H), 7.05 (d, 1H), 6.97 (d, 1H), 1.99 (s, 3H),
1.39-1.30 (m, 3H), 1.10 (dd, 18H).
Preparation 24b: 4-Chloro(3-chloromethyl-phenyl)iodo-thieno[2,3-d]
pyrimidine
1.48 g 4-chloro(3-chloromethyl-phenyl)thieno[2,3-d]pyrimidine (Preparation 23b)
(5.0 mmol) was dissolved in 30 mL dry THF then cooled to -78°C under argon
atmosphere. 2.75 mL lithium diisopropylamide (5.5 mmol, 2 M in THF, EtPh, hexanes)
was added and the mixture was stirred at -78°C for 1 hour. Then 1.675 g iodine (6.5 mmol)
was added and the mixture was allowed to warm up to room temperature. Saturated aq.
NH Cl was added to the reaction mixture and it was extracted with EtOAc. The combined
organic layers were washed with Na S O solution, then dried over Na SO and
2 2 3 2 4
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to obtain Preparation 24b.
H NMR (400 MHz, CDCl ): 8.82 (s, 1H), 7.52 (dd, 1H), 7.25 (t, 1H), 7.05 (dd, 1H), 2.09
(s, 3H).
Preparation 25: Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate
37.85 g [2-chloro(4-chloroiodo-thieno[2,3-d]pyrimidinyl)methyl-phenoxy]-
triisopropyl-silane (Preparation 24a) (63.7 mmol), 15.71 g methyl (2R)hydroxy(2-
methoxyphenyl)propanoate (Preparation 3ad) (70 mmol) and 62.3 g Cs CO (191 mmol)
were placed in a 500 mL flask. 150 mL tert-butanol was added and the mixture was stirred
at 65°C until no further conversion was observed. It was diluted with icy water, the pH was
set to 6 with 2 M HCl, and then it was extracted with ethyl acetate. The combined organic
layers were dried over Na SO and concentrated under reduced pressure. The residue was
dissolved in 100 mL THF, 76.4 mL TBAF (1M in THF) was added and the mixture was
stirred at room temperature until no further conversion was observed. Approximately 50
mL solvent was evaporated under reduced pressure, then it was diluted with ethyl acetate,
washed with water and brine. The organic layer was dried over Na SO and concentrated
under reduced pressure and purified via flash chromatography using heptane and ethyl
acetate as eluents. The diastereoisomer eluting later was collected as Preparation 25.
H NMR (500 MHz, DMSO-d ): 10.33 (s, 1H), 8.55 (s, 1H), 7.18 (t, 1H), 7.00 (d, 1H),
6.98 (d, 1H), 6.90 (d, 1H), 6.75 (t, 1H), 6.29 (d, 1H), 5.36 (dd, 1H), 4.03 (m, 2H), 3.76 (s,
3H), 2.99 (dd, 1H), 2.42 (dd, 1H), 1.97 (s, 3H), 1.06 (t, 3H).
HRMS: (M+H) = 625.0055.
Preparation 26a: Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)
ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate
7.1 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-
thieno[2,3-d]pyrimidine (Preparation 13) (12.6 mmol), 4.45 g ethyl (2R)hydroxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 3ab-(R)) (15.12 mmol) and
12.32 g Cs CO (32.81 mmol) were placed in a 250 mL flask. 100 mL tert-butanol and 50
mL DMSO was added and the mixture was stirred at 90°C until no further conversion was
observed. It was diluted with ethyl acetate and then it was washed with brine. The organic
layer was dried over Na SO , filtered and concentrated under reduced pressure and purified
via flash chromatography using ethyl acetate and methanol as eluents to obtain
Preparation 26a as a mixture of diastereomers.
MS: (M+H) = 821.0.
Preparation 26b: Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate
6.7 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 26a) (8.15 mmol) was dissolved in 75 mL ethanol, then 75 mL HCl (1.25 M
in ethanol) was added and the mixture was stirred at room temperature until no further
conversion was observed. It was concentrated under reduced pressure and purified via
flash chromatography using ethyl acetate and methanol as eluents to obtain Preparation
26b as a mixture of diastereomers.
MS: (M+H) = 737.0.
Preparation 26c: Ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]
pyrimidinyl]oxy-propanoate
.5 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate (Preparation 26b)
(7.46 mmol), 2.3 g (1-butyl-1H-pyrazolyl)methanol (Preparation 9dd) (14.92 mmol)
and 3.91 g triphenyl phosphine (14.92 mmol) were dissolved in 100 mL abs. toluene, then
2.6 g ditertbutyl azodicarboxylate (14.92 mmol) was added. The mixture was stirred at
50°C under nitrogen until no further conversion was observed. It was concentrated under
reduced pressure and purified via flash chromatography using ethyl acetate and methanol
as eluents to obtain Preparation 26c as a mixture of diastereomers.
MS: (M+H) = 873.0.
Preparation 27: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy
[2-[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate
441 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8g) (0.6 mmol), 252 mg (2-methoxypyrimidin
yl)methanol (1.8 mmol) and 472 mg triphenyl phosphine (1.8 mmol) were dissolved in 10
mL abs. toluene, then 414 mg ditertbutyl azodicarboxylate (1.8 mmol) was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. It
was concentrated under reduced pressure and purified via flash chromatography using
dichloromethane and methanol as eluents to obtain Preparation 27.
MS: (M+H) = 856.6.
Preparation 28a: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorohydroxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-
[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate
857 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methoxy
pyrimidinyl)methoxy]phenyl]propanoate (Preparation 27) (1.0 mmol) was dissolved in
mL DCM, and 5.3 mL BBr (1M in DCM, 5.3 mmol) was added at 0°C. The mixture
was stirred at 0°C until no further conversion was observed. It was diluted with water, the
pH was set to 6 with NaHCO (saturated aqueous solution), and then it was extracted with
dichloromethane. The combined organic phases were dried over Na SO and concentrated
under reduced pressure and purified via flash chromatography using dichloromethane and
methanol as eluents to obtain Preparation 28a.
H NMR (400 MHz, DMSO-d6): 10.15 (br s, 1H), 8.66 (d, 1H), 8.59 (s, 1H), 7.29 (d, 1H),
7.28 (d, 1H), 7.17 (t, 1H), 7.16 (d, 1H), 7.13 (dd, 1H), 6.99 (d, 1H), 6.87 (dd, 1H), 6.75 (t,
1H), 6.65 (m, 1H), 6.32 (d, 1H), 5.48 (dd, 1H), 5.16 (d, 1H), 5.10 (d, 1H), 4.23 (m, 1H),
4.17 (m, 1H), 4.05 (m, 2H), 3.91 (s, 3H), 3.11 (dd, 1H), 2.89-2.47 (br s, 8H), 2.77 (br s,
2H), 2.57 (dd, 1H), 2.42 (br s, 3H), 1.89 (s, 3H), 1.05 (t, 3H).
MS: (M+H) = 843.2.
Preparation 28b: Ethyl (2R)[5-(3-chloromethoxymethyl-phenyl)(4-fluoro-
3-hydroxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methoxypyrimidin
yl)methoxy]phenyl]propanoate
Step A:
To the solution of 3.212 g 4-chloroiodo-thieno[2,3-d]pyrimidine (Preparation 1c,
.83 mmol), 6.897 g K PO (32.49 mmol), 388 mg bis(1-adamantyl)-butyl-phosphane
(1.083 mmol) in 50 ml dimethoxyethane and 15 ml water 4.609 g 2-(3-chloromethoxy-
2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 5d, 16.31 mmol)
and 729 mg palladium(II) acetate (1.083 mmol) was added, and it was stirred at 60°C for
2h under nitrogen atmosphere. The reaction mixture was diluted with water and the pH
was adjusted to 7 using 2N HCl. It was extracted with DCM, the combined organic phases
were dried over Na SO and concentrated under reduced pressure. The residue was
purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro
(3-chloromethoxymethyl-phenyl)thieno[2,3-d]pyrimidine.
H NMR (400 MHz, DMSO-d ): 8.98 (s, 1H), 7.98 (s, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 3.91
(s, 3H), 2.07 (s, 3H).
Step B :
2.706 g of the product of Step A (8.35 mmol) was dissolved in 50 ml THF, the mixture
was cooled to -78°C and 5 mL lithium diisopropylamide (2M in THF, 10 mmol) was
added dropwise and the mixture was stirred at this temperature for 30 minutes. Additional
4.5 mL lithium diisopropylamide (2M in THF, 9 mmol) was added dropwise, and the
stirring was continued at -78°C for 30 minutes and then 4.223 g of iodine (16.64 mmol)
was added to the reaction mixture. After 30 minutes it was left to warm to room
temperature. Water then saturated aq. NH4Cl solution was added to the mixture and then it
was extracted with diethylether. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to give 4-chloro(3-chloromethoxymethyl-
phenyl)iodo-thieno[2,3-d]pyrimidine.
MS: (M+H) = 452.0.
Step C:
2.055 g of the product of Step B (4.57 mmol), 1.540 g 2-[4-fluoro
(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation BA5,
.459 mmol) and 2.965 g cesium carbonate (9.10 mmol) were dissolved in 30 mL dioxane
and 10 mL water, and 322 mg bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)
dichloropalladium(II) (AtaPhos, 0.4548 mmol) was added. The reaction mixture was
stirred under nitrogen at 55°C until no further conversion was observed. The reaction
mixture was cooled to room temperature, it was diluted with water and the pH was
adjusted to 7 using 2 M HCl. It was extracted with DCM, the combined organic phases
were dried over Na SO and concentrated under reduced pressure. The residue was
purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro
(3-chloromethoxymethyl-phenyl)[4-fluoro(methoxymethoxy)phenyl]thieno
[2,3-d]pyrimidine.
MS: (M+H) = 479.0.
Step D:
To 1.824 g of the product of Step C (3.805 mmol) and 2.529 g ethyl (2R)hydroxy[2-
[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate (Preparation 3ah, 7.610 mmol)
in 40 mL tert-butanol 5.005 g cesium carbonate (15.36 mmol) was added and it was stirred
at 65°C until no further conversion was obtained. The reaction mixture was cooled to room
temperature, it was diluted with water and the pH was adjusted to 7 using 2 M HCl. It was
extracted with DCM, the combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to give ethyl (2R)[5-(3-chloromethoxy
methyl-phenyl)[4-fluoro(methoxymethoxy)phenyl]thieno[2,3-d]pyrimidinyl]oxy-
3-[2-[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate.
MS: (M+H) = 775.0.
Step E:
1.373 g of the product of Step D (1.771 mmol) was dissolved in 50 mL HCl (1.25 M in
EtOH) and the mixture was stirred at 50°C until no further conversion was observed. It
was cooled to room temperature then saturated aq. NaHCO solution was added to the
reaction mixture, and it was extracted with DCM. The combined organic phases were dried
over Na SO and concentrated under reduced pressure. The residue was purified via flash
chromatography using heptane and EtOAc as eluents to give Preparation 28b.
HRMS calculated for C H ClFN O S: 730.1664; found 731.1746 (M+H).
37 32 4 7
Preparation 29: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
chloropyrimidinyl)methoxy]phenyl]propanoate
Using Step A of General Procedure (Ia) and (2-chloropyrimidinyl)methanol as the
appropriate alcohol derivative Preparation 29 was obtained.
HRMS calculated for C H Cl FN O S: 830.2220; found 831.2275 (M+H).
42 41 2 6 5
Preparation 30: Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate
43.00 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidine ( (Preparation 13) ) (76.33 mmol), 34.3 g (2R)hydroxy
[2-[[2-(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl] propanoate (Preparation 3br)
(83.9 mmol) and 74.62 g Cs CO (229 mmol) were placed in a 1 L flask. 200 mL tert-
butanol and 200 mL DMSO were added and the mixture was stirred at 80°C under N until
no further conversion was observed. Reaction mixture was diluted with water then it was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. Residue was dissolved in 250 mL EtOH and 250
1.25 M HCl in EtOH and the mixture was stirred at room temperature until no further
conversion was observed. Most of the EtOH was evaporated, then the HCl salt was
carefully treated with saturated 10 % K2CO3 solution, extracted with DCM, the combined
organic phases were dried over Na SO , filtered and concentrated under reduced pressure.
The crude product was purified via flash chromatography using MeOH and EtOAc as
eluents to obtain Preparation 30.
HRMS calculated for C H ClIN O S: 934.1776, found: 468.0966 and 468.0966 for the
43 44 6 6
two diastereomers (M+2H)
Preparation 31: Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate
Using General Procedure (XXXIIIa) and 4-hydroxyphenylboronic acid as the appropriate
boronic acid derivative Preparation 31 was obtained as a mixture of diastereomers.
HRMS calculated C H ClN O S: 900.3072; found 451.1630 (M+2H).
49 49 6 7
Preparation 32: Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[1-
(2,2,2-trifluoroethyl)pyrazolyl]methoxy]phenyl]propanoate
386 mg (1 mmol) 5-bromochloro[4-(methoxymethoxy)phenyl]thieno[2,3-d]
pyrimidine (Preparation 2i), and 403 mg (1.05 mmol) ethyl 2-hydroxy[2-[[2-(2,2,2-
trifluoroethyl)pyrazolyl]methoxy]phenyl]propanoate (Preparation 3bp) were dissolved
in 6 mL dioxane, then 977 mg (3 mmol) Cs CO was added. The mixture was stirred at
70°C under N until no further conversion was observed. Then 0.473 g (1.16 mmol)
Preparation 5b, 71 mg AtaPhos (0.1 mmol) and 5 mL H O were added, and the mixture
was stirred under nitrogen at 70°C until no further conversion was observed. Most of the
volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane
and brine. After shaking the pH of the aqueous phase was set to 5 with 2 M HCl. After
phase separation the aqueous phase was extracted with dichloromethane. The organic
layers were combined and dried over Na SO , filtered and concentrated under reduced
pressure. The product was separated via flash chromatography using DCM and MeOH as
eluents. This intermediate was dissolved in 3 mL 1.25 M HCl/EtOH and stirred at 50°C
until no further conversion was observed. Mixture was poured into ice-water, pH was
adjusted to 6 with saturated NaHCO solution and extracted with dichloromethane. The
organic layers were combined and dried over Na2SO4, filtered and concentrated under
reduced pressure. The product was separated via flash chromatography using DCM and
MeOH as eluents to obtain Preparation 32.
MS: (M+H) = 865.2; (M-H) = 863.0.
Preparation 33: Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-
(2,2,2-trifluoroethoxy]phenyl]propanoate
Step A:
386 mg (1 mmol) 5-bromochloro[4-(methoxymethoxy)phenyl]thieno[2,3-
d]pyrimidine (Preparation 2i), 351 mg (1.2 mmol) ethyl (2R)hydroxy[2-(2,2,2-
trifluoroethoxy)phenyl]propanoate (Preparation 3bl) and 977 mg (3 mmol) Cs CO were
dissolved in 6ml dioxane and stirred at 70°C under N until no further conversion was
observed. Then 473 mg (1.2 mmol) Preparation 5b, 71 mg (0.1 mmol) Ataphos, and 5 mL
H O were added to the mixture and stirred at 70°C under N until no further conversion
was observed. It was diluted with brine, the pH was set to 6 with 2 M HCl, and then it was
extracted with DCM. The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents. The diastereoisomer eluting later was
collected.
MS: (M+H)+ = 829.2.
Step B:
This intermediate was dissolved in 3 mL 1.25 M HCl/EtOH and 4 mL EtOH and stirred at
50 C until no further conversion was observed. Mixture was poured into ice-water, the pH
was set to 6 with 2 M HCl, and then it was extracted with DCM. The combined organic
layers were dried over Na SO , filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography using DCM and MeOH as eluents to
obtain Preparation 33.
MS: (M+H) = 785.2. (M-H) = 783.0.
Preparation 34: 2-(2-methyl-2,6-diazaspiro[3.3]heptanyl)ethanol
Step A: 2-(2-tert-butoxycarbonyl-2,6-diazaspiro[3.3]heptanyl)ethanol
1.441 g (5 mmol) 2,6-diazaspiro[3.3]heptanecarboxylic acid tert-butyl ester
hemioxylate was dissolved in 10 ml ACN, then 1.25 g (10 mmol) 2-bromoethanol and
2.073 g (15 mmol) K CO were added and the mixture was heated to reflux for 16 hours.
Mixture was then filtered and concentrated in vacuo and purified via flash chromatography
using DCM and MeOH as eluents.
MS (EI, 70 eV) m/z (% relative intensity, [ion]):55 (35), 56 (37), 57 (70), 82 (33), 155
(100), 169 (17), 211 (56), 242 (2, [M ]).
Step B: 2-(2-methyl-2,6-diazaspiro[3.3]heptanyl)ethanol
0.464 g (1.9 mmol) of the intermediate obtained from the above Step A was dissolved in
ml dry THF and cooled to 0 C. 5.7 ml 1M (in THF) LiAlH solution was added under
N and the mixture was heated to reflux until no further conversion was observed. Then
215 µl water, 215 µl 15% NaOH solution were added and the mixture was stirred at 0 C
overnight. Mixture was filtered, filtrate was concentrated in vacuo to obtain Preparation
H-NMR (500 MHz, dmso-d6) δ ppm 4.34 (br, 1 H), 3.28 (t, 2 H), 3.13 (s, 4 H), 3.1 (s, 4
H), 2.34 (t, 2 H), 2.12 (s, 3 H).
C-NMR: (500 MHz, dmso-d6) δ ppm 66.2, 64.8, 61.8, 59.7, 46.1.
Preparation 35a: 1-iodoethyl acetate
Using General Procedure (XXXVII) and acetyl chloride as the appropriate alkanoyl-
chloride derivative Preparation 35a was obtained.
H NMR (400 MHz, CDCl ) δ 6.84 (q, 1H), 2.20 (d, 3H), 2.09 (s, 3H)
Preparation 35b: 1-iodoethyl 2,2-dimethylpropanoate
Using General Procedure (XXXVII) and 2,2-dimethylpropanoyl chloride as the appropriate
alkanoyl-chloride derivative Preparation 35b was obtained.
H NMR (400 MHz, CDCl3) δ 6.87 (q, 1H), 2.22 (d, 3H), 1.21 (s, 9H)
Preparation 35c: 1-iodoethyl propanoate
Using General Procedure (XXXVII) and propanoyl chloride as the appropriate alkanoyl-
chloride derivative Preparation 35c was obtained.
H NMR (400 MHz, CDCl ) δ 6.88 (q, 1H), 2.37 (q, 2H), 2.22 (d, 3H), 1.17 (t, 3H)
Preparation 35d: 1-iodoethyl 2-methylpropanoate
Using General Procedure (XXXVII) and 2-methylpropanoyl chloride as the appropriate
alkanoyl-chloride derivative Preparation 35d was obtained.
H NMR (400 MHz, CDCl ) δ 6.88 (q, 1H), 2.56 (sept, 1H), 2.22 (d, 3H), 1.19 (d, 6H)
Preparation 35e: 1-iodoethyl 2-methoxyacetate
Using General Procedure (XXXVII) and methoxyacetyl chloride as the appropriate
alkanoyl-chloride derivative Preparation 35e was obtained.
H NMR (400 MHz, CDCl ) δ 6.94 (q, 1H), 4.06 (s, 2H), 3.49 (s, 3H), 2.24 (d, 3H)
Preparation 36: Ethyl (2R)[5-(3-chlorocyanohydroxy-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidin-
4-yl]methoxy]phenyl]propanoate
Using General Procedure (XXXIV, Step A) and (3-chlorocyanotriisopropylsilyloxy-
phenyl)boronic acid (Preparation 5x) as the appropriate boronic acid we observed
complete desililation during the Suzuki-coupling. After purification of the crude product
by flash chromatography using heptane and EtOAc as eluents the ethyl (2R)[5-(3-
chlorocyanohydroxy-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy
[2-[[2-(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate was obtained as a
mixture of the diastereoisomers.
MS: (M+H) = 788.0
Preparation 37: Ethyl (2R)[5-[3-chloro(methoxymethoxy)[2-(4-
methylpiperazinyl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate
Using General Procedure (XXXIV, Step A) and [2-chloro(methoxymethoxy)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane (Preparation 5y) as the
appropriate boronic ester. The crude product was purified by flash chromatography using
heptane and EtOAc as eluents the ethyl (2R)[5-[3-chloro(methoxymethoxy)
triisopropylsilyloxy-phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-
(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate intermediate was obtained
as a mixture of the diastereoisomers.
MS (M+H): 979.2.
The resulting intermediate was dissolved in dry THF and 1.2 eq (1 M in THF)
tetrabutylammonium fluoride solution was added. The mixture was stirred at room
temperature until no further conversion was observed. Volatiles were evaporated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to obtain ethyl (2R)[5-[3-chlorohydroxy
(methoxymethoxy)phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate as a diastereoisomer mixture.
MS (M-H): 821.0.
Using General Procedure (XXXVIII) and this intermediate as the appropriate phenol
derivative and and 2-(4-methylpiperazinyl)ethanol as the appropriate alcohol
Preparation 37 was obtained as a mixture of the diastereoisomers.
MS (M+H): 948.8.
Preparation 38: Ethyl (2R)[5-[3-chlorohydroxy[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate
2.00 g ethyl (2R)[5-[3-chloro(methoxymethoxy)[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate (Preparation 37) (2.10
mmol) was dissolved in 20 ml 1.25 M HCl in EtOH and stirred at room temperature until
no further conversion was observed. The pH was adjusted to ~ 6 and with NH CO , and
then it was extracted with EtOAc. Organic phase was dried over Na SO , filtered and
evaporated under reduced pressure to obtain Preparation 38 as a mixture of the
diastereoisomers.
MS (M+H): 904.8.
Preparation BA1: 4,4,5,5-tetramethylthieno[3,2-b]thiophenyl-1,3,2-
dioxaborolane
0.782 g 3-bromothieno[3,2-b]thiophene (3.6 mmol), 3.626 g 4,4,5,5-tetramethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1,3,2-dioxaborolane (14 mmol), 0.783 g PdCl ×dppf
(1.07 mmol) and 2.102 g KOAc (21.4 mmol) were dissolved in 4 mL dioxane under N2. It
was heated to 60°C for 5 hours. The reaction mixture was cooled down and filtered
through celite. The filtrate was concentrated and purified via flash chromatography using
heptane and EtOAc as eluents to give Preparation BA1.
H NMR (500 MHz, DMSO-d ): 8.11 (d, 1H), 7.67 (dd, 1H), 7.45 (d, 1H), 1.32 (s, 12H).
HRMS calculated for C H BO S : 266.0607, found: 267.0682 (M+H).
12 15 2 2
Preparation BA2: 4,4,5,5-tetramethylthieno[3,2-b]thiophenyl-1,3,2-
dioxaborolane
0.982 g thieno[3,2-b]thiophene (7.0 mmol) was dissolved in 40 mL THF under N and
cooled to -78°C. 7 ml BuLi (1.6 M in hexanes, 7.0 mmol) was added and the mixture was
stirred at -78°C for 1 hour. Then 1.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (7.7 mmol) was added and after 10 minutes stirring the mixture was allowed
to warm up to room temperature. It was quenched with saturated aq. NH Cl solution, then
extracted with THF, dried over Na SO , filtered and concentrated and purified via flash
chromatography using heptane and EtOAc as eluents to give Preparation BA2.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 120 (19), 165 (25), 166 (100), 167 (44),
180 (17), 206 (22), 223 (60), 266 (68, [M ]).
Preparation BA3: 2-[4-fluoro(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane
0.801 g LiCl (19 mmol) was heated at 250°C for 10 minutes under N . Then it was cooled
to room temperature and the flask was charged with 0.911 g Mg (38 mmol) and 30 mL dry
THF. The Mg was activated with 0.15 mL iBu AlH (1 M in THF, 0.15 mmol) for 10
minutes, then it was cooled to 0°C and 3.313 g 4-bromofluoro
(methoxymethyl)benzene (15 mmol) was added. After formation of the Grignard reagent
(appr. 30 minutes) at 0°C 4 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20
mmol) was added and the reaction mixture was stirred for 30 minutes, then filtered through
celite, diluted with EtOAc and washed with saturated aq. NH Cl. The aqueous phase was
back-extracted with EtOAc. The combined organic phases were dried over Na SO ,
filtered, concentrated and purified via flash chromatography using heptane and EtOAc as
eluents to give Preparation BA3.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 59 (21), 85 (20), 134 (24), 135 (100), 136
(28), 150 (30), 165 (24), 166 (43), 167 (95), 192 (20), 251 (44, [M ]).
Preparation BA4: 2-(5-fluorofuryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
In a 2 L flask 57.7 g 5-bromofuroic acid (300 mmol) and 108.1 g Selectfluor (300
mmol) were added to 900 mL pentane, than 270 mL saturated NaHCO solution (300
mmol) was added in portions. The reaction mixture was stirred at room temperature for 1
hour. The layers were separated, and the aqueous layer was extracted with pentane. The
combined organic layers were dried over MgSO , than filtered into a dried 3-necked 4 L
flask. The resulting solution was diluted with 450 mL dry THF under N , than cooled to -
78°C. 18 mL BuLi (10 M in hexanes, 180 mmol) was added dropwise (T < -65°C) than
the reaction mixture was stirred for 5 minutes. 36 mL 2-isopropoxy-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (180 mmol) was added slowly (T < -70°C) and the reaction mixture
was stirred for 10 minutes. Cooling was removed, and the reaction mixture was warmed up
to -15°C than quenched with 600 mL saturated aq. NH Cl solution and stirred for 15
minutes. The layers were separated and the aqueous layer was extracted with Et O. The
combined organic layers were dried over MgSO , filtered and concentrated to give
Preparation BA4.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 85.1 (21), 112.2 (20), 126.1 (26), 127.1
(100), 169.1 (21), 197.0 (14), 212.0 (21, [M ]).
H NMR (400 MHz, DMSO-d ): 7.08 (t, 1H), 5.86 (dd, 1H), 1.26 (s, 12H).
Preparation BA5: 2-[4-fluoro(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane
Step A:
1.91 g 5-bromofluoro-phenol (10 mmol) was dissolved in acetone (5 mL). 1.20 g
chloro(methoxy)methane (15 mmol) and 2.76 g K CO (20 mmol) was added and the
reaction mixture was stirred at room temperature until no further conversion was observed.
The volatiles were evaporated under reduced pressure, and the residue was diluted with
water and extracted with DCM. The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using heptane and EtOAc as eluents to obtain 4-bromofluoro
(methoxymethoxy)benzene.
H NMR (400 MHz, CDCl ):7.37 (dd, 1H), 7.13-7.09 (m, 1H), 6.99 (dd, 1H), 5.22 (s, 2H),
3.54 (s, 3H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (40), 81 (71), 82 (45), 94 (100), 96
(35), 161 (91), 163 (87), 175 (34), 177 (35), 204 (28), 206 (27), 234 (91, [M ]), 236 (89,
[M ]).
Step B:
0.319 g LiCl (7.5 mmol) was heated at 250°C for 10 minutes under N . Then it was cooled
to room temperature and the flask was charged with 0.366 g Mg (15 mmol) and 15 mL dry
THF. The Mg was activated with 0.06 mL iBu AlH (1 M in THF, 0.06 mmol) for 10
minutes, then it was cooled to 0°C and 1.416 g 4-bromofluoro
(methoxymethoxy)benzene (6 mmol) was added. After formation of the Grignard reagent
(appr. 30 minutes) at 0°C 1.5 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(7.5 mmol) was added and the reaction mixture was stirred for 30 minutes, then filtered
through celite, diluted with EtOAc and washed with saturated aq. NH Cl. The aqueous
phase was extracted with EtOAc. The combined organic phases were dried over Na SO
and concentrated under reduced pressure and purified via flash chromatography using
heptane and EtOAc as eluents to obtain Preparation BA5.
H NMR (400 MHz, CDCl ): 7.60 (dd, 1H), 7.48-7.44 (m, 1H), 7.10 (dd, 1H), 5.27 (s, 2H),
3.56 (s, 3H), 1.35 (s, 12H).
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 57 (42), 59 (54), 83 (31), 85 (30), 138
(40), 151 (51), 152 (54), 153 (42), 166 (100), 237 (31), 252 (69), 282 (49, [M ]).
Compounds of the invention display axial chirality. They can be isolated as a mixture of
atropoisomers or as individual atropoisomers (S or R ).
General Procedure (Ia)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8a), 2 eq. of the appropriate alcohol and 2 eq. triphenyl
phosphine were dissolved in abs. toluene (0.2 M for the phenol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (Ib)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methylsulfanyl
pyrimidinyl)methoxy]phenyl]propanoate (Preparation 10a), 3.0 eq. of the appropriate
boronic acid derivative and 3.0 eq. copper(I) thiophenecarboxylate were dissolved in dry
THF (0.1 M for Preparation 10a), then 0.15 eq. Pd(PPh ) was added. The mixture was
stirred at 70°C under nitrogen until no further conversion was observed. Then it was
concentrated under reduced pressure and the crude intermediate was purified via flash
chromatography using dichloromethane and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents.
Example 1 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (Ia) and methanol as the appropriate alcohol, Example 1 was
obtained. HRMS calculated for C H ClFN O S: 690.2079; found 691.2147 (M+H).
36 36 4 5
Example 2 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-tetrahydrofuran-
2-ylmethoxy]phenyl}propanoic acid
Using General Procedure (Ia) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 2 was obtained. HRMS calculated for C H ClFN O S: 760.2498;
40 42 4 6
found 761.2550 (M+H).
Example 3 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
211 mg ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8a) (0.3 mmol) and 138 mg K CO (1.0 mmol)
were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate
(1.0 mmol) was added. The mixture was stirred at room temperature under nitrogen until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, extracted with dichloromethane, dried over Na SO , filtered and concentrated under
reduced pressure.
Step B:
The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH ×
H O (3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane, dried over Na SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 5 mM
aqueous NH HCO solution and MeCN as eluents to obtain Example 3. HRMS calculated
for C H ClF N O S: 758.1953; found 759.1999 (M+H).
37 35 4 4 5
Example 4 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2-
difluoroethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and 2,2-difluoroethanol as the appropriate alcohol, Example
4 was obtained. HRMS calculated for C H ClF N O S: 740.2047; found 741.2119
37 36 3 4 5
(M+H).
Example 5 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1R or S)
(1-pentyl-1H-pyrazolyl)ethoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1R or S)(1-pentyl-1H-pyrazolyl)ethanol
(Preparation 9dn) as the appropriate alcohol, Example 5 was obtained. HRMS calculated
for C H ClFN O S: 840.3236; found 421.1674 (M+2H).
45 50 6 5
Example 6 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1S or R)
(1-pentyl-1H-pyrazolyl)ethoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1S or R)(1-pentyl-1H-pyrazolyl)ethanol
(Preparation 9do) as the appropriate alcohol, Example 6 was obtained. HRMS calculated
for C45H50ClFN6O5S: 840.3236; found 421.1679 (M+2H).
Example 7 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-methoxy-
2-phenylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (6-methoxyphenyl-pyrimidinyl)methanol
(prepared according to Tabei K. et al., J. Heterocyclic Chem. 1985 22, 569-574,) as the
appropriate alcohol, Example 7 was obtained. HRMS calculated for C H ClFN O S:
47 44 6 6
874.2716; found 438.1444 (M+2H).
Example 8 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2,6-
dimethoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2,6-dimethoxypyrimidinyl)methanol (Preparation
9cd) as the appropriate alcohol, Example 8 was obtained. HRMS calculated for
C H ClFN O S: 828.2508; found 415.1340 (M+2H).
42 42 6 7
Example 9 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-methyl-
1,2-oxazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (5-methyl-1,2-isoxazolyl)methanol as the appropriate
alcohol, Example 9 was obtained. HRMS calculated for C H ClFN O S: 771.2294;
40 39 5 6
found 386.6226 (M+2H).
Example 10 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
fluoropyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (5-fluoropyridyl)methanol as the appropriate alcohol,
Example 10 was obtained. HRMS calculated for C41H38ClF2N5O5S: 785.2250; found
393.6212 (M+2H).
Example 11 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[6-(furan
yl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [6-(2-furyl)pyridyl]methanol (Preparation 9ea) as
the appropriate alcohol, Example 11 was obtained. HRMS calculated for
C H ClFN O S: 833.2450; found 417.6304 (M+2H).
45 41 5 6
Example 12 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[6-
(morpholinyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (6-(morpholinyl)-pyridinyl)methanol (prepared
according to WO 02/42305 A1) as the appropriate alcohol, Example 12 was obtained.
HRMS calculated for C H ClFN O S: 852.2872; found 427.1494 (M+2H).
45 46 6 6
Example 13 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
ethoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (6-ethoxypyridyl)methanol as the appropriate alcohol,
Example 13 was obtained. HRMS calculated for C H ClFN O S: 811.2607; found
43 43 5 6
406.6361 (M+2H).
Example 14 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and 2-pyridylmethanol as the appropriate alcohol, Example
14 was obtained. HRMS calculated for C41H39ClFN5O5S: 767.2344; found 384.6257
(M+2H).
Example 15 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(cyclohexylmethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol
(Preparation 9dw) as the appropriate alcohol, Example 15 was obtained. HRMS
calculated for C H ClFN O S: 852.3236; found 427.1688 (M+2H).
46 50 6 5
Example 16 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methylpyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-methylpyridyl)methanol as the appropriate alcohol,
Example 16 was obtained. HRMS calculated for C H ClFN O S: 781.2501; found
42 41 5 5
391.6327 (M+2H).
Example 17 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(trifluoromethyl)pyridyl]methanol as the
appropriate alcohol, Example 17 was obtained. HRMS calculated for C H ClF N O S:
42 38 4 5 5
835.2218; found 836.2334 (M+H).
Example 18 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(thiophenyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-thienyl)pyridyl]methanol (Preparation 9eb) as
the appropriate alcohol, Example 18 was obtained. HRMS calculated for
C H ClFN O S : 849.2222; found 425.6192 (M+2H).
45 41 5 5 2
Example 19 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
chloropyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-chloropyridyl)methanol as the appropriate alcohol,
Example 19 was obtained. HRMS calculated for C H Cl FN O S: 801.1955; found
41 38 2 5 5
802.2017 (M+H).
Example 20 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(morpholinyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(morpholinyl)pyridinyl]methanol as the
appropriate alcohol, Example 20 was obtained. HRMS calculated for C H ClFN O S:
45 46 6 6
852.2872; found 427.1490 (M+2H).
Example 21 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-methoxypyridyl)methanol as the appropriate
alcohol, Example 21 was obtained. HRMS calculated for C H ClFN O S: 797.2450;
42 41 5 6
found 399.6302 (M+2H).
Example 22 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyethoxy)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyethoxy)pyridinyl]methanol as the
appropriate alcohol, Example 22 was obtained. HRMS calculated for C44H45ClFN5O7S:
841.2712; found 421.6410 (M+2H).
Example 23 (2R){2-[(2-tert-butylpyrimidinyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno
[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (2-tert-butylpyrimidinyl)methanol (Preparation 9bh)
as the appropriate alcohol, Example 23 was obtained. HRMS calculated for
C H ClFN O S: 824.2923; found 413.1528 (M+2H).
44 46 6 5
Example 24 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(propan-
2-yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-isopropylpyrimidinyl)methanol (Preparation 9bd)
as the appropriate alcohol, Example 24 was obtained. HRMS calculated for
C H ClFN O S: 810.2766; found 406.1465 (M+2H).
43 44 6 5
Example 25 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-trifluoromethylpyrimidinyl)methanol
(Preparation 9bj) as the appropriate alcohol, Example 25 was obtained. HRMS
calculated for C41H37ClF4N6O5S: 836.2171; found 837.2295 (M+H).
Example 26 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
cyclopropylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-cyclopropylpyrimidinyl)methanol (Preparation
9be) as the appropriate alcohol, Example 26 was obtained. HRMS calculated for
C H ClFN O S: 808.2610; found 405.1363 (M+2H).
43 42 6 5
Example 27 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-
chlorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(4-chlorophenyl)pyrimidinyl]methanol
(Preparation 9bo) as the appropriate alcohol, Example 27 was obtained. HRMS
calculated for C H Cl FN O S: 878.2220; found 879.2355 (M+H).
46 41 2 6 5
Example 28 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
cyclopentylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-cyclopentylpyrimidinyl)methanol (Preparation
9bi) as the appropriate alcohol, Example 28 was obtained. HRMS calculated for
C H ClFN O S: 836.2923; found 419.1537 (M+2H).
45 46 6 5
Example 29 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
phenylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-phenylpyrimidinyl)methanol as the appropriate
alcohol, Example 29 was obtained. HRMS calculated for C H ClFN O S: 844.2610;
46 42 6 5
found 423.1363 (M+2H).
Example 30 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyphenyl)pyrimidinyl]methanol
(Preparation 9bp) as the appropriate alcohol, Example 30 was obtained. HRMS
calculated for C H ClFN O S: 874.2716; found 438.1415 (M+2H).
47 44 6 6
Example 31 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin-
2-yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-pyridyl)pyrimidinyl]methanol (Preparation
9bq) as the appropriate alcohol, Example 31 was obtained. HRMS calculated for
C H ClFN O S: 845.2562; found 423.6373 (M+2H).
45 41 7 5
Example 32 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin-
3-yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(3-pyridyl)pyrimidinyl]methanol (Preparation
9br) as the appropriate alcohol, Example 32 was obtained. HRMS calculated for
C H ClFN O S: 845.2562; found 423.6337 (M+2H).
45 41 7 5
Example 33 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(thiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-thienyl)pyrimidinyl]methanol (Preparation
9bv) as the appropriate alcohol, Example 33 was obtained. HRMS calculated for
C44H40ClFN6O5S2: 850.2174; found 851.2245 (M+H).
Example 34 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin-
4-yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(4-pyridyl)pyrimidinyl]methanol (Preparation
9bs) as the appropriate alcohol, Example 34 was obtained. HRMS calculated for
C H ClFN O S: 845.2562; found 423.6358 (M+2H).
45 41 7 5
Example 35 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(furan
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(3-furyl)pyrimidinyl]methanol (Preparation 9bt)
as the appropriate alcohol, Example 35 was obtained. HRMS calculated for
C H ClFN O S: 834.2403; found 835.2443 (M+H).
44 40 6 6
Example 36 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(1,3-
thiazolyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-thiazolyl)pyrimidinyl]methanol (Preparation
9bx) as the appropriate alcohol, Example 36 was obtained. HRMS calculated for
C H ClFN O S : 851.2127; found 426.6120 (M+2H).
43 39 7 5 2
Example 37 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
ethylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-ethylpyrimidinyl)methanol (Preparation 9ba) as
the appropriate alcohol, Example 37 was obtained. HRMS calculated for
C42H42ClFN6O5S: 796.2610; found 399.1381 (M+2H).
Example 38 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methylpropyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-methylpropyl)pyrimidinyl]methanol
(Preparation 9bf) as the appropriate alcohol, Example 38 was obtained. HRMS
calculated for C H ClFN O S: 824.2923; found 825.2998 (M+H).
44 46 6 5
Example 39 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(cyclopropylmethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(cyclopropylmethyl)pyrimidinyl]methanol
(Preparation 9bg) as the appropriate alcohol, Example 39 was obtained. HRMS
calculated for C H ClFN O S: 822.2766; found 412.1458 (M+2H).
44 44 6 5
Example 40 (2R){2-[(2-benzylpyrimidinyl)methoxy]phenyl}{[(5S ){3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (2-benzylpyrimidinyl)methanol (Preparation 9by) as
the appropriate alcohol, Example 40 was obtained. HRMS calculated for
C H ClFN O S: 858.2766; found 430.1471 (M+2H).
47 44 6 5
Example 41 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
propylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-propylpyrimidinyl)methanol (Preparation 9bb) as
the appropriate alcohol, Example 41 was obtained. HRMS calculated for
C43H44ClFN6O5S: 810.2766; found 406.1459 (M+2H).
Example 42 (2R){2-[(2-butylpyrimidinyl)methoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (2-butylpyrimidinyl)methanol (Preparation 9bc) as
the appropriate alcohol, Example 42 was obtained. HRMS calculated for
C H ClFN O S: 824.2923; found 413.1500 (M+2H).
44 46 6 5
Example 43 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(dimethylamino)ethyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-[2-(dimethylamino)ethyl]pyrimidinyl]methanol
(Preparation 9bm) as the appropriate alcohol, Example 43 was obtained. HRMS
calculated for C H ClFN O S: 839.3032; found 420.6614 (M+2H).
44 47 7 5
Example 44 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyethyl)pyrimidinyl]methanol
(Preparation 9bl) as the appropriate alcohol, Example 44 was obtained. HRMS
calculated for C H ClFN O S: 826.2716; found 414.1439 (M+2H).
43 44 6 6
Example 45 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(methoxymethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(methoxymethyl)pyrimidinyl]methanol
(Preparation 9bk) as the appropriate alcohol, Example 45 was obtained. HRMS
calculated for C42H42ClFN6O6S: 812.2559; found 813.2622 (M+H).
Example 46 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(phenoxymethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(phenoxymethyl)pyrimidinyl]methanol
(Preparation 9bz) as the appropriate alcohol, Example 46 was obtained. HRMS
calculated for C H ClFN O S: 874.2716; found 875.2790 (M+H).
47 44 6 6
Example 47 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(ethoxymethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(ethoxymethyl)pyrimidinyl]methanol
(Preparation 9bn) as the appropriate alcohol, Example 47 was obtained. HRMS
calculated for C H ClFN O S: 826.2716; found 827.2783 (M+H).
43 44 6 6
Example 48 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(2-
methoxyethyl)(methyl)amino]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-[2-methoxyethyl(methyl)amino]pyrimidin
yl]methanol (Preparation 9ap) as the appropriate alcohol, Example 48 was obtained.
HRMS calculated for C H ClFN O S: 855.2981; found 428.6583 (M+2H).
44 47 7 6
Example 49 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(1H-
pyrazolyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-(1H-pyrazolyl)pyrimidinyl)methanol
(Preparation 9bw) as the appropriate alcohol, Example 49 was obtained. HRMS
calculated for C43H40ClFN8O5S: 834.2515; found 418.1327 (M+2H).
Example 50 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-
methylpiperazinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(4-methylpiperazinyl)pyrimidinyl]methanol
(Preparation 9aq) as the appropriate alcohol, Example 50 was obtained. HRMS
calculated for C H ClFN O S: 866.3141; found 434.1640 (M+2H).
45 48 8 5
Example 51 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(1H-
1,2,3-triazolyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(1H-1,2,3-triazolyl)pyrimidinyl]methanol
(Preparation 9as) as the appropriate alcohol, Example 51 was obtained. HRMS
calculated for C H ClFN O S: 835.2467; found 418.6292 (M+2H).
42 39 9 5
Example 52 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(morpholinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 52 was obtained. HRMS
calculated for C H ClFN O S: 853.2825; found 427.6484 (M+2H).
44 45 7 6
Example 53 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(2-
methoxyethyl)amino]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyethylamino)pyrimidinyl]methanol
(Preparation 9ao) as the appropriate alcohol, Example 53 was obtained. HRMS
calculated for C43H45ClFN7O6S: 841.2825; found 421.6505 (M+2H).
Example 54 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol, Example 54 was obtained. HRMS calculated for C41H40ClFN6O6S: 798.2403;
found 400.1284 (M+2H).
Example 55 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(propan-
2-yloxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-isopropoxypyrimidinyl)methanol (Preparation
9ae) as the appropriate alcohol, Example 55 was obtained. HRMS calculated for
C H ClFN O S: 826.2716; found 414.1442 (M+2H).
43 44 6 6
Example 56 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
phenoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-phenoxypyrimidinyl)methanol (Preparation 9ak)
as the appropriate alcohol, Example 56 was obtained. HRMS calculated for
C H ClFN O S: 860.2559; found 431.1333 (M+2H).
46 42 6 6
Example 57 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
ethoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-ethoxypyrimidinyl)methanol (Preparation 9ad) as
the appropriate alcohol, Example 57 was obtained. HRMS calculated for
C42H42ClFN6O6S: 812.2559; found 407.1342 (M+2H).
Example 58 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2,2,2-trifluoroethoxy)pyrimidinyl]methanol
(Preparation 9ai) as the appropriate alcohol, Example 58 was obtained. HRMS calculated
for C H ClF N O S: 866.2276; found 434.1195 (M+2H).
42 39 4 6 6
Example 59 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin-
4-ylmethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(4-pyridylmethoxy)pyrimidinyl]methanol
(Preparation 9aw) as the appropriate alcohol, Example 59 was obtained. HRMS
calculated for C H ClFN O S: 875.2668; found 438.6442 (M+2H).
46 43 7 6
Example 60 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(1-
methyl-1H-imidazolyl)methoxy]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and {2-[(1-methyl-1H-imidazolyl)methoxy]pyrimidin
yl}methanol (Preparation 9ay) as the appropriate alcohol, Example 60 was obtained.
HRMS calculated for C H ClFN O S: 878.2777; found 440.1451 (M+2H).
45 44 8 6
Example 61 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
propoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (2-propoxypyrimidinyl)methanol (Preparation 9af)
as the appropriate alcohol, Example 61 was obtained. HRMS calculated for
C43H44ClFN6O6S: 826.2716; found 414.1423 (M+2H).
Example 62 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3,3,3-
trifluoropropoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(3,3,3-trifluoropropoxy)pyrimidinyl]methanol
(Preparation 9aj) as the appropriate alcohol, Example 62 was obtained. HRMS
calculated for C H ClF N O S: 880.2433; found 441.1294 (M+2H).
43 41 4 6 6
Example 63 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyethoxy)pyrimidinyl]methanol
(Preparation 9ag) as the appropriate alcohol, Example 63 was obtained. HRMS
calculated for C H ClFN O S: 842.2665; found 422.1385 (M+2H).
43 44 6 7
Example 64 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
ethoxyethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-(2-ethoxyethoxy)pyrimidinyl]methanol
(Preparation 9ah) as the appropriate alcohol, Example 64 was obtained. HRMS
calculated for C H ClFN O S: 856.2821; found 429.1497 (M+2H).
44 46 6 7
Example 65 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(methylsulfanyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (2-methylsulfanylpyrimidinyl)methanol (Preparation
9aa) as the appropriate alcohol, Example 65 was obtained. HRMS calculated for
C41H40ClFN6O5S2: 814.2174; found 815.2260 (M+H).
Example 66 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(3-
methoxypropyl)sulfanyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-(3-methoxypropylsulfanyl)pyrimidinyl]methanol
(Preparation 9ac) as the appropriate alcohol, Example 66 was obtained. HRMS
calculated for C H ClFN O S : 872.2593; found 437.1384 (M+2H).
44 46 6 6 2
Example 67 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(2-
methoxyethyl)sulfanyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-(2-methoxyethylsulfanyl)pyrimidinyl]methanol
(Preparation 9ab) as the appropriate alcohol, Example 67 was obtained. HRMS
calculated for C H ClFN O S : 858.2436; found 430.1286 (M+2H).
43 44 6 6 2
Example 68 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and pyrimidinylmethanol as the appropriate alcohol,
Example 68 was obtained. HRMS calculated for C H ClFN O S: 768.2297; found
40 38 6 5
769.2358 (M+H).
Example 69 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-methyl-1H-imidazolyl)methanol as the appropriate
alcohol, Example 69 was obtained. HRMS calculated for C H ClFN O S: 770.2453;
40 40 6 5
found 771.2527 (M+H).
Example 70 (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (1-tert-butyl-1H-pyrazolyl)methanol (Preparation
9dt) as the appropriate alcohol, Example 70 was obtained. HRMS calculated for
C H ClFN O S: 812.2923; found 813.3030 (M+H).
43 46 6 5
Example 71 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan-
2-yl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(propanyl)-1H-pyrazolyl]methanol
(Preparation 9dc) as the appropriate alcohol, Example 71 was obtained. HRMS
calculated for C H ClFN O S: 798.2766; found 400.1469 (M+2H).
42 44 6 5
Example 72 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
cyclopentyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-cyclopentyl-1H-pyrazolyl)methanol (Preparation
9dg) as the appropriate alcohol, Example 72 was obtained. HRMS calculated for
C H ClFN O S: 824.2923; found 413.1559 (M+2H).
44 46 6 5
Example 73 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
cyclohexyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-cyclohexyl-1H-pyrazolyl)methanol (Preparation
9dh) as the appropriate alcohol, Example 73 was obtained. HRMS calculated for
C45H48ClFN6O5S: 838.3079; found 839.3165 (M+H).
Example 74 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-phenyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-phenyl-1H-pyrazolyl)methanol as the appropriate
alcohol, Example 74 was obtained. HRMS calculated for C45H42ClFN6O5S: 832.2610;
found 833.2656 (M+H).
Example 75 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(tetrahydro-2H-pyranyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and (1-(tetrahydro-2H-pyranyl)-1H-pyrazol
yl)methanol (Preparation 9di) as the appropriate alcohol, Example 75 was obtained.
HRMS calculated for C H ClFN O S: 840.2872; found 841.2913 (M+H).
44 46 6 6
Example 76 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol, Example 76 was obtained. HRMS calculated for
C H ClFN O S: 784.2610; found 785.2679 (M+H).
41 42 6 5
Example 77 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-
trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 77 was obtained. HRMS
calculated for C41H39ClF4N6O5S: 838.2327; found 839.2389 (M+H).
Example 78 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(cyclopropylmethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(cyclopropylmethyl)-1H-pyrazolyl]methanol
(Preparation 9df) as the appropriate alcohol, Example 78 was obtained. HRMS
calculated for C H ClFN O S: 810.2766; found 406.1464 (M+2H).
43 44 6 5
Example 79 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(4-
methoxybenzyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(4-methoxybenzyl)-1H-pyrazolyl]methanol
(Preparation 9dk) as the appropriate alcohol, Example 79 was obtained. HRMS
calculated for C H ClFN O S: 876.2872; found 439.1531 (M+2H).
47 46 6 6
Example 80 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(cyclohexylmethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(cyclohexylmethyl)-1H-pyrazolyl]methanol
(Preparation 9dv) as the appropriate alcohol, Example 80 was obtained. HRMS
calculated for C H ClFN O S: 852.3236; found 427.1679 (M+2H).
46 50 6 5
Example 81 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-propyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-propyl-1H-pyrazolyl)methanol (Preparation 9db)
as the appropriate alcohol, Example 81 was obtained. HRMS calculated for
C42H44ClFN6O5S: 798.2766; found 400.1433 (M+2H).
Example 82 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(3-
methylbutyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(3-methylbutyl)-1H-pyrazolyl]methanol
(Preparation 9de) as the appropriate alcohol, Example 82 was obtained. HRMS
calculated for C H ClFN O S: 826.3079; found 827.3123 (M+H).
44 48 6 5
Example 83 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (1-butyl-1H-pyrazolyl)methanol (Preparation 9dd)
as the appropriate alcohol, Example 83 was obtained. HRMS calculated for
C H ClFN O S: 812.2923; found 407.1551 (M+2H).
43 46 6 5
Example 84 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(4,4,4-
trifluorobutyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(4,4,4-trifluorobutyl)-1H-pyrazolyl]methanol
(Preparation 9dl) as the appropriate alcohol, Example 84 was obtained. HRMS
calculated for C H ClF N O S: 866.2640; found 434.1385 (M+2H).
43 43 4 6 5
Example 85 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-pentyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-pentyl-1H-pyrazolyl)methanol (Preparation 9dm)
as the appropriate alcohol, Example 85 was obtained. HRMS calculated for
C44H48ClFN6O5S: 826.3079; found 827.3206 (M+H).
Example 86 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(3-
methoxypropyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(3-methoxypropyl)-1H-pyrazolyl]methanol
(Preparation 9dq) as the appropriate alcohol, Example 86 was obtained. HRMS
calculated for C H ClFN O S: 828.2872; found 415.1505 (M+2H).
43 46 6 6
Example 87 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({1-[2-
(dimethylamino)ethyl]-1H-pyrazolyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and {1-[2-(dimethylamino)ethyl]-1H-pyrazolyl}methanol
(Preparation 9dj) as the appropriate alcohol, Example 87 was obtained. HRMS
calculated for C H ClFN O S: 827.3032; found 414.6592 (M+2H).
43 47 7 5
Example 88 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxyethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2-methoxyethyl)-1H-pyrazolyl]methanol
(Preparation 9dp) as the appropriate alcohol, Example 88 was obtained. HRMS
calculated for C H ClFN O S: 814.2716; found 408.1423 (M+2H).
42 44 6 6
Example 89 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
ethoxyethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2-ethoxyethyl)-1H-pyrazolyl]methanol
(Preparation 9dr) as the appropriate alcohol, Example 89 was obtained. HRMS
calculated for C43H46ClFN6O6S: 828.2872; found 415.1510 (M+2H).
Example 90 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({1-[2-(2-
methoxyethoxy)ethyl]-1H-pyrazolyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and {1-[2-(2-methoxyethoxy)ethyl]-1H-pyrazol
yl}methanol (Preparation 9ds) as the appropriate alcohol, Example 90 was obtained.
HRMS calculated for C H ClFN O S: 858.2978; found 430.1571 (M+2H).
44 48 6 7
Example 91 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and pyrazinylmethanol as the appropriate alcohol,
Example 91 was obtained. HRMS calculated for C H ClFN O S: 768.2297; found
40 38 6 5
769.2422 (M+H).
Example 92 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-
1H-imidazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-methyl-1H-imidazolyl)methanol as the appropriate
alcohol, Example 92 was obtained. HRMS calculated for C H ClFN O S: 770.2453;
40 40 6 5
found 771.2523 (M+H).
Example 93 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and pyrimidinylmethanol as the appropriate alcohol,
Example 93 was obtained. HRMS calculated for C H ClFN O S: 768.2297; found
40 38 6 5
769.2379 (M+H).
Example 94 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-phenyl-
1H-1,2,3-triazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (1-phenyl-1H-1,2,3-triazolyl)methanol (Preparation
9ee) as the appropriate alcohol, Example 94 was obtained. HRMS calculated for
C H ClFN O S: 833.2562; found 834.2620 (M+H).
44 41 7 5
Example 95 (2R){2-[(1-butyl-1H-1,2,3-triazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (1-butyl-1H-1,2,3-triazolyl)methanol (Preparation
9ec) as the appropriate alcohol, Example 95 was obtained. HRMS calculated for
C H ClFN O S: 813.2875; found 814.2964 (M+H).
42 45 7 5
Example 96 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(3-
methoxypropyl)-1H-1,2,3-triazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(3-methoxypropyl)-1H-1,2,3-triazolyl]methanol
(Preparation 9ed) as the appropriate alcohol, Example 96 was obtained. HRMS
calculated for C H ClFN O S: 829.2825; found 830.2876 (M+H).
42 45 7 6
Example 97 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxyethyl)-1H-1,2,3-triazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2-methoxyethyl)-1H-1,2,3-triazolyl]methanol
(Preparation 9ef) as the appropriate alcohol, Example 97 was obtained. HRMS calculated
for C41H43ClFN7O6S: 815.2668; found 408.6427 (M+2H).
Example 98 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-oxazol-
4-ylmethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and oxazolylmethanol as the appropriate alcohol,
Example 98 was obtained. HRMS calculated for C39H37ClFN5O6S: 757.2137; found
758.2245 (M+H).
Example 99 (2R){2-[(5-bromomethoxypyrimidinyl)methoxy]phenyl}{[(5S )-
-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (5-bromomethoxy-pyrimidinyl)methanol
(Preparation 9cb) as the appropriate alcohol, Example 99 was obtained. HRMS
calculated for C H BrClFN O S: 876.1508; found 439.0864 (M+2H).
41 39 6 6
Example 100 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-methoxy-
-(thiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [2-methoxy(3-thienyl)pyrimidinyl]methanol
(Preparation 9cc) as the appropriate alcohol, Example 100 was obtained. HRMS
calculated for C H ClFN O S : 880.2280; found 441.1229 (M+2H).
45 42 6 6 2
Example 101 (2R){2-[(5-bromopyrimidinyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ia) and (5-bromopyrimidinyl)methanol (Preparation 9ca) as
the appropriate alcohol, Example 101 was obtained. HRMS calculated for
C40H37BrClFN6O5S: 846.1402; found 424.0775 (M+2H).
Example 102 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(4-methyl-
4H-1,2,4-triazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Ia) and (4-methyl-4H-1,2,4-triazolyl)methanol as the
appropriate alcohol, Example 102 was obtained. HRMS calculated for C39H39ClFN7O5S:
771.2406; found 772.2411 (M+H).
Example 103 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
fluoroethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and 2-fluoroethanol as the appropriate alcohol, Example 103
was obtained. HRMS calculated for C H ClF N O S: 722.2141; found 723.2244 (M+H).
37 37 2 4 5
Example 104 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (Ia) and 2-methoxyethanol as the appropriate alcohol, Example
104 was obtained. HRMS calculated for C H ClFN O S: 734.2341; found 735.2455
38 40 4 6
(M+H).
Example 105 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-(2-
methoxyethoxy)ethoxy]phenyl}propanoic acid
Using General Procedure (Ia) and 2-(2-methoxyethoxy)ethanol as the appropriate alcohol,
Example 105 was obtained. HRMS calculated for C H ClFN O S: 778.2603; found
40 44 4 7
390.1362 (M+2H).
Example 106 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{2-[2-(2-
methoxyethoxy)ethoxy]ethoxy}phenyl)propanoic acid
Using General Procedure (Ia) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol as the
appropriate alcohol, Example 106 was obtained. HRMS calculated for C H ClFN O S:
42 48 4 8
822.2865; found 412.1520 (M+2H).
Example 107 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (4-methoxyphenyl)boronic acid as the appropriate
boronic acid derivative, Example 107 was obtained. HRMS calculated for
C H ClFN O S: 874.2716; found 438.1407 (M+2H).
47 44 6 6
Example 108 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(6-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (6-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 108 was obtained. HRMS calculated for
C H ClFN O S: 859.2719; found 430.6436 (M+2H).
46 43 7 5
Example 109 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[6-
(trifluoromethyl)pyridinyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ib) and [6-(trifluoromethyl)pyridyl]boronic acid as the
appropriate boronic acid derivative, Example 109 was obtained. HRMS calculated for
C H ClF N O S: 913.2436; found 914.2521 (M+H).
46 40 4 7 5
Example 110 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(6-
chloropyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (6-chloropyridyl)boronic acid as the appropriate
boronic acid derivative, Example 110 was obtained. HRMS calculated for
C45H40Cl2FN7O5S: 879.2173; found 440.6161 (M+2H).
Example 111 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(6-
methoxypyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (6-methoxypyridyl)boronic acid as the appropriate
boronic acid derivative, Example 111 was obtained. HRMS calculated for
C H ClFN O S: 875.2668; found 438.6403 (M+2H).
46 43 7 6
Example 112 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (3-methoxyphenyl)boronic acid as the appropriate
boronic acid derivative, Example 112 was obtained. HRMS calculated for
C H ClFN O S: 874.2716; found 875.2836 (M+H).
47 44 6 6
Example 113 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methylphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and o-tolylboronic acid as the appropriate boronic acid
derivative, Example 113 was obtained. HRMS calculated for C H ClFN O S: 858.2766;
47 44 6 5
found 430.1464 (M+2H).
Example 114 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-fluorophenyl)boronic acid as the appropriate boronic
acid derivative, Example 114 was obtained. HRMS calculated for C H ClF N O S:
46 41 2 6 5
862.2516; found 432.1342 (M+2H).
Example 115 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
ethoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-ethoxyphenyl)boronic acid as the appropriate boronic
acid derivative, Example 115 was obtained. HRMS calculated for C H ClFN O S:
39 38 6 7
788.2195; found 395.1179 (M+2H).
Example 116 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 116 was obtained. HRMS calculated for
C H ClFN O S: 859.2719; found 430.6429 (M+2H).
46 43 7 5
Example 117 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(furan
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and 2-furylboronic acid as the appropriate boronic acid
derivative, Example 117 was obtained. HRMS calculated for C H ClFN O S: 834.2403;
44 40 6 6
found 418.1278 (M+2H).
Example 118 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 118 was obtained. HRMS calculated for
C46H43ClFN7O5S: 859.2719; found 430.6409 (M+2H).
Example 119 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
chloropyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-chloropyridyl)boronic acid as the appropriate
boronic acid derivative, Example 119 was obtained. HRMS calculated for
C H Cl FN O S: 879.2173; found 440.6186 (M+2H).
45 40 2 7 5
Example 120 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (3-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 120 was obtained. HRMS calculated for
C H ClFN O S: 859.2719; found 860.2808 (M+H).
46 43 7 5
Example 121 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methylthiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (2-methylthienyl)boronic acid as the appropriate
boronic acid derivative, Example 121 was obtained. HRMS calculated for
C H ClFN O S : 864.2331; found 433.1239 (M+2H).
45 42 6 5 2
Example 122 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(5-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (5-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 122 was obtained. HRMS calculated for
C46H43ClFN7O5S: 859.2719; found 430.6450 (M+2H).
Example 123 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (4-methylpyridyl)boronic acid as the appropriate
boronic acid derivative, Example 123 was obtained. HRMS calculated for
C H ClFN O S: 859.2719; found 430.6434 (M+2H).
46 43 7 5
Example 124 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-
methylthiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and (4-methylthienyl)boronic acid as the appropriate
boronic acid derivative, Example 124 was obtained. HRMS calculated for
C H ClFN O S : 864.2331; found 433.1256 (M+2H).
45 42 6 5 2
Example 125 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1H-pyrazol-
-ylmethoxy)phenyl]propanoic acid
Step A:
1.058 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8a) (1.5 mmol), 982 mg [1-(4-methoxybenzyl)-
1H-pyrazolyl]methanol (Preparation 9dk) (4.5 mmol) and 1.18 g PPh (4.5 mmol)
were dissolved in 30 mL dry toluene, then 1.036 g ditertbutyl azodicarboxylate (4.5 mmol)
was added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure, and the crude
intermediate was purified via flash chromatography using dichloromethane and methanol
as eluents.
Step B:
226 mg (0.25 mmol) from the obtained intermediate was dissolved in 13 mL TFA and it
was stirred at 100°C for 1 hour. The volatiles were evaporated under reduced pressure,
then the residue was diluted with DCM, washed with saturated aqueous NaHCO solution.
The organic layer was dried over Na SO , filtered and concentrated under reduced
pressure.
Step C:
The obtained crude intermediate was dissolved in 6 mL dioxane-water 1:1 and 105 mg
LiOH × H O (2.5 mmol) was added. The mixture was stirred at room temperature until no
further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, dried over Na SO , filtered and concentrated under reduced pressure
and purified via preparative reversed phase chromatography using 5 mM aqueous
NH HCO solution and MeCN as eluents to give Example 125. HRMS calculated for
C H ClFN O S: 756.2297; found 757.2303 (M+H).
39 38 6 5
General Procedure (IIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl](4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8b), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were
dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using ethyl acetate and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was purified via preparative
reversed phase chromatography using 5 mM aqueous NH HCO solution and MeCN as
eluents.
General Procedure (IIb)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl](4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methylsulfanylpyrimidin
yl)methoxy]phenyl]propanoate (Preparation 10b), 3.0 eq. of the appropriate boronic acid
derivative and 3.0 eq. copper(I) thiophenecarboxylate were dissolved in dry THF (0.1 M
for Preparation 10b), then 0.15 eq. Pd(PPh ) was added. The mixture was stirred at 70°C
under nitrogen until no further conversion was observed. Then it was concentrated under
reduced pressure and the crude intermediate was purified via flash chromatography using
dichloromethane and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM.
The combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 5 mM
aqueous NH HCO solution and MeCN as eluents.
Example 126 (2R){[(5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-tetrahydrofuran
ylmethoxy]phenyl}propanoic acid
Using General Procedure (IIa) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 126 was obtained. HRMS calculated for C H ClFN O S: 705.2076;
37 37 3 6
found 706.2163 (M+H).
Example 127 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
195 mg ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8b) (0.3 mmol) and 138 mg K CO (1.0 mmol) were dissolved in 2 mL
DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added.
The mixture was stirred at room temperature under nitrogen until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , filtered and concentrated
under reduced pressure.
Step B:
The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH ×
H O (3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 127. HRMS calculated for C H ClF N O S: 703.1531; found 704.1634 (M+H).
34 30 4 3 5
Example 128 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridinyl)pyrimidin
yl]methoxy}phenyl)propanoic acid
Using General Procedure (IIa) and [2-(4-pyridyl)pyrimidinyl]methanol (Preparation
9bs) as the appropriate alcohol, Example 128 was obtained. HRMS calculated for
C H ClFN O S: 790.2140; found 396.1147 (M+2H).
42 36 6 5
Example 129 (2R){[(5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl)pyrimidin-
4-yl]methoxy}phenyl)propanoic acid
Using General Procedure (IIa) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 129 was obtained. HRMS
calculated for C H ClFN O S: 798.2403; found 799.2458 (M+H).
41 40 6 6
Example 130 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-ethoxypyrimidin
yl)methoxy]phenyl}propanoic acid
Using General Procedure (IIa) and (2-ethoxypyrimidinyl)methanol (Preparation 9ad)
as the appropriate alcohol, Example 130 was obtained. HRMS calculated for
C H ClFN O S: 757.2137; found 758.2212 (M+H).
39 37 5 6
Example 131 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIa) and [2-(2,2,2-trifluoroethoxy)pyrimidinyl]methanol
(Preparation 9ai) as the appropriate alcohol, Example 131 was obtained. HRMS
calculated for C H ClF N O S: 811.1854; found 812.1956 (M+H).
39 34 4 5 6
Example 132 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-1H-
pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIa) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 132 was obtained. HRMS
calculated for C38H34ClF4N5O5S: 783.1905; found 784.1969 (M+H).
Example 133 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IIa) and (1-butyl-1H-pyrazolyl)methanol (Preparation 9dd)
as the appropriate alcohol, Example 133 was obtained. HRMS calculated for
C H ClFN O S: 757.2501; found 758.2596 (M+H).
40 41 5 5
Example 134 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IIa) and pyrazinylmethanol as the appropriate alcohol,
Example 134 was obtained. HRMS calculated for C H ClFN O S: 713.1875; found
37 33 5 5
714.1931 (M+H).
Example 135 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and (2-methoxyphenyl)boronic acid as the appropriate
boronic acid, Example 135 was obtained. HRMS calculated for C H ClFN O S:
44 39 5 6
819.2294; found 410.6206 (M+2H).
Example 136 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and (2-methylpyridyl)boronic acid as the appropriate
boronic acid, Example 136 was obtained. HRMS calculated for C H ClFN O S:
43 38 6 5
804.2297; found 403.1234 (M+2H).
Example 137 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and (3-methylpyridyl)boronic acid as the appropriate
boronic acid, Example 137 was obtained. HRMS calculated for C H ClFN O S:
43 38 6 5
804.2297; found 403.1237 (M+2H).
Example 138 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-methylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and (4-methylpyridyl)boronic acid as the appropriate
boronic acid, Example 138 was obtained. HRMS calculated for C H ClFN O S:
43 38 6 5
804.2297; found 403.1220 (M+2H).
General Procedure (IIIa)
1.0 eq. of ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(pyrazin
ylmethoxy)phenyl]propanoate (Preparation 6b), 2.0 eq. of the appropriate alcohol and 2.0
eq. triphenylphosphine were dissolved in dry toluene (0.2 M for the phenol), then 2 eq.
ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using EtOAc
and MeOH as eluents. The obtained intermediate was dissolved in dioxane-water 1:1 (10
mL/mmol) and 10 eq LiOH × H O was added. The mixture was stirred at room
temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried
over Na SO , filtered and concentrated under reduced pressure and purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents.
Example 139 (2R){[(5S )(3-chloromethyl{[(3R)methylpyrrolidin
yl]methoxy}phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IIIa) and [(3R)methylpyrrolidinyl]methanol as the
appropriate alcohol, Example 139 was obtained. HRMS calculated for C H ClFN O S:
39 35 5 5
739.2031; found 740.2136 (M+H).
Example 140 (2R){[(5S )(3-chloromethyl{[(3S)methylpyrrolidin
yl]methoxy}phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IIIa) and [(3S)methylpyrrolidinyl]methanol as the
appropriate alcohol, Example 140 was obtained. HRMS calculated for C H ClFN O S:
39 35 5 5
739.2031; found 740.2095 (M+H).
Example 141 (2R){[(5S ){3-chloromethyl[((3S or R)methylpiperidin
yl)oxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Example 142 (2R){[(5S ){3-chloromethyl[((3R or S)methylpiperidin
yl)oxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Example 143 (2R){[(5S ){3-chloromethyl[(1-methylpyrrolidin
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)
0.470 g ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(pyrazin
ylmethoxy)phenyl]propanoate (Preparation 6b) (0.7 mmol), 0.330 g 1-methylpiperidin
ol (2.0 mmol), and 0.524 g triphenyl phosphine (2.0 mmol) were dissolved in 15 mL dry
toluene, then 0.461 g ditertbutyl azodicarboxylate (2.0 mmol) was added. The mixture was
stirred at 50°C under nitrogen. During the reaction rearrangement of the methylpiperidine
moiety was also observed. When no further conversion was observed, the volatiles were
evaporated under reduced pressure, and the constitutional isomers were separated via flash
chromatography using DCM and MeOH as eluents. The mixture of compounds eluting
earlier were the precursors of Example 141 and 142, while the mixture of compounds
eluting later were the precursors of Example 143. The obtained precursor derivatives were
separately dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH × H O was
added. The mixtures were stirred at room temperature until no further conversion was
observed. Then they were individually diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified separately via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 141 [HRMS calculated for C H ClFN O S: 739.2031; found 740.2119
39 35 5 5
(M+H)], Example 142 [HRMS calculated for C H ClFN O S: 739.2031; found
39 35 5 5
740.2088 (M+H)], and Example 143 [HRMS calculated for C H ClFN O S: 739.2031;
39 35 5 5
found 740.2101 and 740.2078 (M+H)].
Example 144 (2R){[(5S ){3-chloromethyl[(1-methylazepan
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)
Using General Procedure (IIIa) and 2-(1-methylpiperidyl)ethanol as the appropriate
alcohol in the course of the reaction the ring-expansion of the piperidyl moiety was
observed, thus Example 144 was obtained. HRMS calculated for C H ClFN O S:
41 39 5 5
767.2344; found 768.2399 and 768.2398 (M+H).
Example 145 (2R){[(5S ){3-chloromethyl[(1-methylpyrrolidin
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)
Using General Procedure (IIIa) and (1-methylpyrrolidinyl)methanol as the appropriate
alcohol, Example 145 was obtained. HRMS calculated for C H ClFN O S: 739.2031;
39 35 5 5
found 740.2081 (M+H).
Example 146 (2R){[(5S ){3-chloromethyl[3-(1-methylpyrrolidin
yl)propoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)
Using General Procedure (IIIa) and 2-(1-methylpiperidyl)ethanol as the appropriate
alcohol in the course of the reaction the ring-contraction of the piperidyl moiety was
observed, thus Example 146 was obtained. HRMS calculated for C H ClFN O S:
41 39 5 5
767.2344; found 768.2454 (M+H).
Example 147 (2R){[(5S ){3-chloro[3-(dimethylamino)propoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IIIa) and 3-(dimethylamino)propanol as the appropriate
alcohol, Example 147 was obtained. HRMS calculated for C H ClFN O S: 727.2031;
38 35 5 5
found 728.2085 (M+H).
Example 148 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IIIa) and 2-(morpholinyl)ethanol as the appropriate alcohol,
Example 148 was obtained. HRMS calculated for C H ClFN O S: 755.1981; found
39 35 5 6
756.2052 (M+H).
General Procedure (IVa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8c), 2 eq. of the appropriate alcohol and 2 eq.
triphenyl phosphine were dissolved in dry toluene (0.2 M for the phenol), then 2 eq.
ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using ethyl
acetate and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 149 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (IVa) and methanol as the appropriate alcohol, Example 149 was
obtained. HRMS calculated for C H ClFN O S: 680.1872; found 681.1947 (M+H).
34 34 4 6
Example 150 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 150 was obtained. HRMS calculated for C H ClFN O S: 750.2290;
38 40 4 7
found 751.2375 (M+H).
Example 151 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(methylamino)oxoethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and 2-hydroxy-N-methyl-acetamide as the appropriate
alcohol, Example 151 was obtained. HRMS calculated for C H ClFN O S: 737.2086;
36 37 5 7
found 738.2195 (M+H).
Example 152 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(cyclopentylamino)oxoethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and N-cyclopentylhydroxy-acetamide as the appropriate
alcohol, Example 152 was obtained. HRMS calculated for C H ClFN O S: 791.2556;
40 43 5 7
found 792.2658 (M+H).
Example 153 (2R){2-[2-(benzylamino)oxoethoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IVa) and N-benzylhydroxy-acetamide as the appropriate
alcohol, Example 153 was obtained. HRMS calculated for C H ClFN O S: 813.2399;
42 41 5 7
found 814.2492 (M+H).
Example 154 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-oxo
(propylamino)ethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and 2-hydroxy-N-propyl-acetamide as the appropriate
alcohol, Example 154 was obtained. HRMS calculated for C H ClFN O S: 765.2399;
38 41 5 7
found 766.2459 (M+H).
Example 155 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{2-oxo
[(2-phenylethyl)amino]ethoxy}phenyl)propanoic acid
Using General Procedure (IVa) and 2-hydroxy-Nphenylethyl-acetamide as the
appropriate alcohol, Example 155 was obtained. HRMS calculated for C H ClFN O S:
43 43 5 7
827.2556; found 828.2580 (M+H).
Example 156 (2R){2-[2-(butylamino)oxoethoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IVa) and N-butylhydroxy-acetamide as the appropriate
alcohol, Example 156 was obtained. HRMS calculated for C H ClFN O S: 779.2556;
39 43 5 7
found 780.2614 (M+H).
Example 157 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{2-[(2-
methoxyethyl)amino]oxoethoxy}phenyl)propanoic acid
Using General Procedure (IVa) and 2-hydroxy-N-(2-methoxyethyl)acetamide as the
appropriate alcohol, Example 157 was obtained. HRMS calculated for C H ClFN O S:
38 41 5 8
781.2348; found 782.2478 (M+H).
Example 158 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
209 mg ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8c) (0.3 mmol) and 138 mg K CO (1.0 mmol)
were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate
(1.0 mmol) was added. The mixture was stirred at room temperature under nitrogen until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, extracted with DCM. The combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure.
Step B:
The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH ×
H O (3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 158. HRMS calculated for C H ClF N O S: 748.1745; found 749.1819 (M+H).
33 4 4 6
Example 159 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[4-
(trifluoromethyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [4-(trifluoromethyl)pyridyl]methanol as the
appropriate alcohol, Example 159 was obtained. HRMS calculated for C H ClF N O S:
40 36 4 5 6
825.2011; found 413.6085 (M+2H).
Example 160 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxymethylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (2-methoxymethyl-pyrimidinyl)methanol
(Preparation 9cf) as the appropriate alcohol, Example 160 was obtained. HRMS
calculated for C40H40ClFN6O7S: 802.2352; found 402.1241 (M+2H).
Example 161 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
methylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (6-methylpyrimidinyl)methanol as the appropriate
alcohol, Example 161 was obtained. HRMS calculated for C H ClFN O S: 772.2246;
39 38 6 6
found 387.1188 (M+2H).
Example 162 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (6-methoxypyrimidinyl)methanol (Preparation
9ce) as the appropriate alcohol, Example 162 was obtained. HRMS calculated for
C H ClFN O S: 788.2195; found 395.1165 (M+2H).
39 38 6 7
Example 163 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
fluoropyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (5-fluoropyridyl)methanol as the appropriate
alcohol, Example 163 was obtained. HRMS calculated for C H ClF N O S: 775.2043;
39 36 2 5 6
found 776.2161 (M+H).
Example 164 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[6-
(trifluoromethyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [6-(trifluoromethyl)pyridyl]methanol as the
appropriate alcohol, Example 164 was obtained. HRMS calculated for C H ClF N O S:
40 36 4 5 6
825.2011; found 826.2100 (M+H).
Example 165 (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin-
2-ylmethoxy)phenyl]propanoic acid
Example 166 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin-
2-ylmethoxy)phenyl]propanoic acid
Step A:
591 mg 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidine (Preparation 13) (1.05 mmol), 915 mg ethyl (2R)
hydroxy[2-(2-pyridylmethoxy)phenyl]propanoate (Preparation 3bn) (1.045 mmol) and
977 mg Cs CO (3.0 mmol) were placed in a flask. 10 mL tert-butanol was added and the
mixture was stirred at 60°C until no further conversion was observed. Then it was diluted
with brine and extracted with dichloromethane. The combined organic phases were dried
over Na SO , filtered and concentrated under reduced pressure and purified via preparative
reversed phase chromatography using 5 mM aqueous NH HCO solution and MeCN as
eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy[2-(2-
pyridylmethoxy)phenyl]propanoate as a mixture of diastereoisomers. MS: (M+H) = 828.0.
Step B:
518 mg ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-iodo-thieno[2,3-d]pyrimidinyl]oxy[2-(2-pyridylmethoxy)phenyl]propanoate (0.625
mmol) and 565 mg 2-(5-fluorofuryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.66
mmol) were dissolved in 5 ml 1,4-dioxane, then 407 mg Cs CO (1.25 mmol) dissolved in
1 mL water was added. Then 46 mg PdCl × dppf (0.0625 mmol)was added. The mixture
was heated at 100°C via microwave irradiation until no further conversion was observed.
Then it was diluted with brine, extracted with DCM. The combined organic phases were
dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and
MeCN as eluents.
Step C:
The obtained intermediate was dissolved in 10 mL dioxane-water 1:1 (10 mL/mmol) and
200 mg LiOH × H O (4.77 mmol) was added. The mixture was stirred at room temperature
until no further conversion was observed. Then it was diluted with brine, neutralized with 2
M HCl, extracted with DCM, dried over Na SO , filtered and concentrated under reduced
pressure and purified via preparative reversed phase chromatography using 5 mM aqueous
NH HCO solution and MeCN as eluents. The diastereoisomer eluting earlier was
collected as Example 165. HRMS calculated for C H ClFN O S: 757.2137; found
39 37 5 6
379.6156 (M+2H). The diastereoisomer eluting later was collected as Example 166.
HRMS calculated for C H ClFN O S: 757.2137; found 379.6159 (M+2H).
39 37 5 6
Example 167 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(trifluoromethyl)pyridyl]methanol as the
appropriate alcohol, Example 167 was obtained. HRMS calculated for C H ClF N O S:
40 36 4 5 6
825.2011; found 826.2124 (M+H).
Example 168 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (2-methoxypyridyl)methanol as the appropriate
alcohol, Example 168 was obtained. HRMS calculated for C H ClFN O S: 787.2243;
40 39 5 7
found 394.6210 (M+2H).
Example 169 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 169 was obtained. HRMS
calculated for C H ClF N O S: 826.1963; found 827.2059 (M+H).
39 35 4 6 6
Example 170 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
cyclopropylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (2-cyclopropylpyrimidinyl)methanol (Preparation
9be) as the appropriate alcohol, Example 170 was obtained. HRMS calculated for
C H ClFN O S: 798.2403; found 400.1265 (M+2H).
41 40 6 6
Example 171 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(thiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(2-thienyl)pyrimidinyl]methanol (Preparation
9bv) as the appropriate alcohol, Example 171 was obtained. HRMS calculated for
C H ClFN O S : 840.1967; found 421.1070 (M+2H).
42 38 6 6 2
Example 172 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(4-pyridyl)pyrimidinyl]methanol (Preparation
9bs) as the appropriate alcohol, Example 172 was obtained. HRMS calculated for
C H ClFN O S: 835.2355; found 418.6246 (M+2H).
43 39 7 6
Example 173 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(thiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(3-thienyl)pyrimidinyl]methanol (Preparation
9bu) as the appropriate alcohol, Example 173 was obtained. HRMS calculated for
C H ClFN O S : 840.1967; found 841.2059 (M+H).
42 38 6 6 2
Example 174 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(2-methoxyethyl)pyrimidinyl]methanol
(Preparation 9bl) as the appropriate alcohol, Example 174 was obtained. HRMS
calculated for C H ClFN O S: 816.2508; found 409.1335 (M+2H).
41 42 6 7
Example 175 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(morpholinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 175 was obtained. HRMS
calculated for C H ClFN O S: 843.2617; found 422.6360 (M+2H).
42 43 7 7
Example 176 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol, Example 176 was obtained. HRMS calculated for C H N O FSCl: 788.2195;
39 38 6 7
found 789.2289 (M+H).
Example 177 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
ethoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (2-ethoxypyrimidinyl)methanol (Preparation 9ad)
as the appropriate alcohol, Example 177 was obtained. HRMS calculated for
C H ClFN O S: 802.2352; found 402.1255 (M+2H).
40 40 6 7
Example 178 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(2,2,2-trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [2-(2,2,2-trifluoroethoxy)pyrimidinyl]methanol
(Preparation 9ai) as the appropriate alcohol, Example 178 was obtained. HRMS
calculated for C H ClF N O S: 856.2069; found 857.2110 (M+H).
40 37 4 6 7
Example 179 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(pyrimidinylmethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and pyrimidinylmethanol as the appropriate alcohol,
Example 179 was obtained. HRMS calculated for C H ClFN O S: 758.2090; found
38 36 6 6
759.2166 (M+H).
Example 180 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
methyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 180 was obtained. HRMS calculated for C H ClFN O S:
38 38 6 6
760.2246; found 761.2343 (M+H).
Example 181 (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuran
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IVa) and (1-tert-butyl-1H-pyrazolyl)methanol (Preparation
9dt) as the appropriate alcohol, Example 181 was obtained. HRMS calculated for
C H ClFN O S: 802.2716; found 402.1422 (M+2H).
41 44 6 6
Example 182 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(propanyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [1-(propanyl)-1H-pyrazolyl]methanol
(Preparation 9dc) as the appropriate alcohol, Example 182 was obtained. HRMS
calculated for C H ClFN O S: 788.2559; found 789.2663 (M+H).
40 42 6 6
Example 183 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
cyclopentyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (1-cyclopentyl-1H-pyrazolyl)methanol
(Preparation 9dg) as the appropriate alcohol, Example 183 was obtained. HRMS
calculated for C H ClFN O S: 814.2716; found 815.2796 (M+H).
42 44 6 6
Example 184 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol, Example 184 was obtained. HRMS calculated for
C H ClFN O S: 774.2403; found 388.1265 (M+2H).
39 40 6 6
Example 185 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 185 was obtained. HRMS
calculated for C H ClF N O S: 828.2120; found 415.1131 (M+2H).
39 37 4 6 6
Example 186 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(cyclopropylmethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (IVa) and [1-(cyclopropylmethyl)-1H-pyrazolyl]methanol
(Preparation 9df) as the appropriate alcohol, Example 186 was obtained. HRMS
calculated for C H ClFN O S: 800.2559; found 401.1355 (M+2H).
41 42 6 6
Example 187 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
propyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IVa) and (1-propyl-1H-pyrazolyl)methanol (Preparation
9db) as the appropriate alcohol, Example 187 was obtained. HRMS calculated for
C H ClFN O S: 788.2559; found 395.1357 (M+2H).
40 42 6 6
Example 188 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuran
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IVa) and (1-butyl-1H-pyrazolyl)methanol (Preparation 9dd)
as the appropriate alcohol, Example 188 was obtained. HRMS calculated for
C H ClFN O S: 802.2716; found 402.1447 (M+2H).
41 44 6 6
Example 189 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin-
2-ylmethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and pyrazinylmethanol as the appropriate alcohol,
Example 189 was obtained. HRMS calculated for C H ClFN O S: 758.2090; found
38 36 6 6
759.2159 (M+H).
Example 190 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(pyrimidinylmethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and pyrimidinylmethanol as the appropriate alcohol,
Example 190 was obtained. HRMS calculated for C H ClFN O S: 758.2090; found
38 36 6 6
759.2198 (M+H).
Example 191 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-
oxazolylmethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and 1,3-oxazolylmethanol as the appropriate alcohol,
Example 191 was obtained. HRMS calculated for C H ClFN O S: 747.1930; found
37 35 5 7
748.1970 (M+H).
Example 192 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(dimethylamino)ethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and 2-(dimethylamino)ethanol as the appropriate alcohol
Example 192 was obtained. HRMS calculated for C H ClFN O S: 737.2450; found
37 41 5 6
369.6277 (M+2H).
Example 193 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
hydroxyethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and ethylene glycol as the appropriate alcohol, Example
193 was obtained. HRMS calculated for C H ClFN O S: 710.1977; found 711.2037
36 4 7
(M+H).
Example 194 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (IVa) and 2-methoxyethanol as the appropriate alcohol, Example
194 was obtained. HRMS calculated for C H ClFN O S: 724.2134; found 725.2224
36 38 4 7
(M+H).
Example 195 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-(2-
hydroxyethoxy)ethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and 2-(2-hydroxyethoxy)ethanol as the appropriate alcohol,
Example 195 was obtained. HRMS calculated for C H ClFN O S: 754.2239; found
37 40 4 8
755.2279 (M+H).
Example 196 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-(2-
methoxyethoxy)ethoxy]phenyl}propanoic acid
Using General Procedure (IVa) and 2-(2-methoxyethoxy)ethanol as the appropriate
alcohol, Example 196 was obtained. HRMS calculated for C H ClFN O S: 768.2396;
38 42 4 8
found 769.2481 (M+H).
Example 197 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{2-[2-(2-
methoxyethoxy)ethoxy]ethoxy}phenyl)propanoic acid
Using General Procedure (IVa) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol as the
appropriate alcohol, Example 197 was obtained. HRMS calculated for C H ClFN O S:
40 46 4 9
812.2658; found 407.1384 (M+2H).
Example 198 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Step A:
417 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate (Preparation 10c) (0.5 mmol),
205 mg (3-methylpyridyl)boronic acid (1.5 mmol) and 286 mg copper(I)
thiophenecarboxylate (1.5 mmol) were dissolved in 5 mL dry THF, then 58 mg Pd(PPh )
(0.05 mmol) was added. The mixture was stirred at 70°C under nitrogen until no further
conversion was observed. Then it was concentrated under reduced pressure and the crude
intermediate was purified via flash chromatography using DCM and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in 3 mL methanol and 150 mg NaOH (3.75
mmol) was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated
under reduced pressure and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 198. HRMS
calculated for C H ClFN O S: 849.2512; found 425.6338 (M+2H).
44 41 7 6
General Procedure (Va)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl](5-
fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8d), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were
dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using ethyl acetate and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 199 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic
acid
Using General Procedure (Va) and methanol as the appropriate alcohol, Example 199 was
obtained. HRMS calculated for C H ClFN O S: 625.1450; found 626.1509 (M+H).
31 29 3 6
Example 200 (2R){[(5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
192 mg (2R)[(5S )[3-chloro(2-dimethylaminoethyloxy)methyl-phenyl](5-
fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8d) (0.3 mmol) and 138 mg K2CO3 (1.0 mmol) were dissolved in 2 mL
DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added.
The mixture was stirred at room temperature under nitrogen until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
DCM, dried over Na SO , filtered and concentrated under reduced pressure.
Step B:
The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH ×
H O (3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 200. HRMS calculated for C H ClF N O S: 693.1323; found 694.1382 (M+H).
32 28 4 3 6
Example 201 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Va) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol Example 201 was obtained. HRMS
calculated for C H ClF N O S: 771.1541; found 772.1604 (M+H).
36 30 4 5 6
Example 202 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Va) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol Example 202 was obtained. HRMS
calculated for C H ClFN O S: 788.2195; found 395.1179 (M+2H).
39 38 6 7
Example 203 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Va) and [2-(2,2,2-trifluoroethoxy)pyrimidinyl]methanol
(Preparation 9ai) as the appropriate alcohol Example 203 was obtained. HRMS
calculated for C H ClF N O S: 801.1647; found 802.1706 (M+H).
37 32 4 5 7
Example 204 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-1H-pyrazol
yl)methoxy]phenyl}propanoic acid
Using General Procedure (Va) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol Example 204 was obtained. HRMS calculated for
C H ClFN O S: 719.1981; found 720.2064 (M+H).
36 35 5 6
Example 205 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-1H-
pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Va) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol Example 205 was obtained. HRMS
calculated for C H ClF N O S: 773.1698; found 774.1771 (M+H).
36 32 4 5 6
Example 206 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Va) and pyrazinylmethanol as the appropriate alcohol
Example 206 was obtained. HRMS calculated for C H ClFN O S: 703.1668; found
31 5 6
704.1726 (M+H).
General Procedure (VIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8e), 2 eq. of the appropriate alcohol and 2 eq. triphenylphosphine were
dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. Then it was concentrated under reduced pressure and the crude intermediate was
purified via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 207 (2R){[-[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
hydroxyphenyl)propanoic acid
Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate (Preparation
8e) was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH × H O was added.
The mixture was stirred at room temperature until no further conversion was observed.
Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane.
The combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 207. HRMS
calculated for C H ClN O S: 648.1809; found 649.1862 (M+H).
33 33 4 6
Example 208 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1R)(pyridin-
4-yl)ethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1R)(4-pyridyl)ethanol as the appropriate alcohol,
Example 208 was obtained. HRMS calculated for C H ClN O S: 753.2388; found
40 40 5 6
377.6276 (M+2H).
Example 209 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIa) and methanol as the appropriate alcohol, Example 209 was
obtained. HRMS calculated for C H ClN O S: 662.1966; found 663.2028 (M+H).
34 35 4 6
Example 210 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(propan
yloxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-propanol as the appropriate alcohol, Example 210
was obtained. HRMS calculated for C H ClN O S: 690.2279; found 691.2344 (M+H).
36 39 4 6
Example 211 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 211 was obtained. HRMS calculated for C H ClN O S: 732.2384;
38 41 4 7
found 733.2453 (M+H).
Example 212 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(cyclopentyloxy)phenyl]propanoic acid
Using General Procedure (VIa) and cyclopentanol as the appropriate alcohol, Example
212 was obtained. HRMS calculated for C H ClN O S: 716.2435; found 717.2481
38 41 4 6
(M+H).
Example 213 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(5,6,7,8-
tetrahydroquinolinyloxy)phenyl]propanoic acid
Using General Procedure (VIa) and 5,6,7,8-tetrahydroquinolinol as the appropriate
alcohol, Example 213 was obtained as mixture of the diastereoisomers. HRMS calculated
for C H ClN O S: 779.2544; found 390.6369 (M+2H) and 390.6355 (M+2H).
42 42 5 6
Example 214 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
methylpyrrolidinyl)oxy]phenyl}propanoic acid
Using General Procedure (VIa) and 1-methylpyrrolidinol as the appropriate alcohol,
Example 214 was obtained as mixture of the diastereoisomers. HRMS calculated for
C H ClN O S: 731.2544; found 366.6362 (M+2H) and 366.6354 (M+2H).
38 42 5 6
Example 215 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
ethoxyphenyl)propanoic acid
Using General Procedure (VIa) and ethanol as the appropriate alcohol, Example 215 was
obtained. HRMS calculated for C H ClN O S: 676.2122; found 677.2216 (M+H).
37 4 6
Example 216 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(propyn
yloxy)phenyl]propanoic acid
Using General Procedure (VIa) and propynol as the appropriate alcohol, Example
216 was obtained. HRMS calculated for C H ClN O S: 686.1966; found 687.2056
36 35 4 6
(M+H).
Example 217 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(dimethylamino)oxoethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and 2-hydroxy-N,N-dimethyl-acetamide as the appropriate
alcohol, Example 217 was obtained. HRMS calculated for C H ClN O S: 733.2337;
37 40 5 7
found 734.2407 (M+H).
Example 218 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(methylamino)oxoethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and 2-hydroxy-N-methyl-acetamide as the appropriate
alcohol, Example 218 was obtained. HRMS calculated for C H ClN O S: 719.2180;
36 38 5 7
found 720.2263 (M+H).
Example 219 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-oxo
(phenylamino)ethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and 2-hydroxy-N-phenyl-acetamide as the appropriate
alcohol, Example 219 was obtained. HRMS calculated for C H ClN O S: 781.2337;
41 40 5 7
found 391.6225 (M+2H).
Example 220 (2R){2-[2-(butylamino)oxoethoxy]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (VIa) and N-butylhydroxy-acetamide as the appropriate
alcohol, Example 220 was obtained. HRMS calculated for C H ClN O S: 761.2650;
39 44 5 7
found 762.2703 (M+H).
Example 221 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
677 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8e) (1 mmol) and 276 mg K CO (2.0 mmol)
were dissolved in 5 mL DMF, then 141 µL 2,2,2-trifluoroethyl trifluoromethanesulfonate
(1.2 mmol) was added. The mixture was stirred at room temperature under nitrogen until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, extracted with dichloromethane, and the combined organic phases were dried over
Na SO , filtered and concentrated under reduced pressure.
Step B:
The obtained intermediate was dissolved in 10 mL dioxane-water 1:1 and 420 mg LiOH ×
H O (10.0 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane, the combined organic phases were dried over Na2SO4,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to
obtain Example 207. HRMS calculated for C H ClF N O S: 730.1840; found 731.1875
34 3 4 6
(M+H).
Example 222 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(4-chloropyridin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (4-chloropyridyl)methanol as the appropriate
alcohol, Example 222 was obtained. HRMS calculated for C H Cl N O S: 773.1842;
39 37 2 5 6
found 387.6008 (M+2H).
Example 223 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(4-
methoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (4-methoxypyridyl)methanol as the appropriate
alcohol, Example 223 was obtained. HRMS calculated for C H ClN O S: 769.2337;
40 40 5 7
found 385.6252 (M+2H).
Example 224 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
phenylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (6-phenylpyrimidinyl)methanol (Preparation 9cg)
as the appropriate alcohol, Example 224 was obtained. HRMS calculated for
C H ClN O S: 816.2497; found 409.1321 (M+2H).
44 41 6 6
Example 225 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1,3-dimethyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1,3-dimethyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 225 was obtained. HRMS calculated for C H ClN O S:
39 41 6 6
756.2497; found 379.1313 (M+2H).
Example 226 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(3-cyclopropyl-
1-methyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (3-cyclopropylmethyl-1H-pyrazolyl)methanol as
the appropriate alcohol, Example 226 was obtained. HRMS calculated for
C H ClN O S: 782.2653; found 392.1398 (M+2H).
41 43 6 6
Example 227 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl
phenyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methylphenyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 227 was obtained. HRMS calculated for C H ClN O S:
44 43 6 6
818.2653; found 819.2735 (M+H).
Example 228 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[3-(furanyl)
methyl-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [3-(furanyl)methyl-1H-pyrazolyl]methanol as
the appropriate alcohol, Example 228 was obtained. HRMS calculated for
C H ClN O S: 808.2446; found 809.2524 (M+H).
42 41 6 7
Example 229 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(cyclopropylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and cyclopropylmethanol as the appropriate alcohol,
Example 229 was obtained. HRMS calculated for C H N O SCl: 702.2279; found
37 39 4 6
703.2374 (M+H).
Example 230 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(isoquinolin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and isoquinolinylmethanol as the appropriate alcohol
Example 230 was obtained. HRMS calculated for C H ClN O S: 789.2388; found
43 40 5 6
395.6256 (M+2H).
Example 231 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-chloropyridin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-chloropyridyl)methanol as the appropriate
alcohol, Example 231 was obtained. HRMS calculated for C H Cl N O S: 773.1842;
39 37 2 5 6
found 774.1921 (M+H).
Example 232 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-fluoropyridin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-fluoropyridyl)methanol as the appropriate
alcohol, Example 232 was obtained. HRMS calculated for C H ClFN O S: 757.2137;
39 37 5 6
found 758.2199 (M+H).
Example 233 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
methoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-methoxypyridyl)methanol as the appropriate
alcohol, Example 233 was obtained. HRMS calculated for C H ClN O S: 769.2337;
40 40 5 7
found 385.6241 (M+2H).
Example 234 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(quinolin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and quinolinylmethanol as the appropriate alcohol,
Example 234 was obtained. HRMS calculated for C H ClN O S: 789.2388; found
43 40 5 6
395.6253 (M+2H).
Example 235 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
methylpyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (6-methylpyridyl)methanol as the appropriate
alcohol, Example 235 was obtained. HRMS calculated for C H ClN O S: 753.2388;
40 40 5 6
found 377.6262 (M+2H).
Example 236 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-chloropyridin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (6-chloropyridyl)methanol as the appropriate
alcohol, Example 236 was obtained. HRMS calculated for C H Cl N O S: 773.1842;
39 37 2 5 6
found 774.1906 (M+H).
Example 237 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[6-(pyrrolidin
yl)pyridinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and (6-pyrrolidinylpyridyl)methanol as the
appropriate alcohol, Example 237 was obtained. HRMS calculated for C H ClN O S:
43 45 6 6
808.2810; found 405.1472 (M+2H).
Example 238 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(6-
methoxypyridinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (6-methoxypyridyl)methanol as the appropriate
alcohol, Example 238 was obtained. HRMS calculated for C H ClN O S: 769.2337;
40 40 5 7
found 770.2432 (M+H).
Example 239 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(cyclopentylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and cyclopentylmethanol as the appropriate alcohol,
Example 239 was obtained. HRMS calculated for C H ClN O S: 730.2592; found
39 43 4 6
731.2639 (M+H).
Example 240 (2R)[2-(benzyloxy)phenyl]{[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Using General Procedure (VIa) and phenylmethanol as the appropriate alcohol, Example
240 was obtained. HRMS calculated for C H ClN O S: 738.2279; found 739.2319
40 39 4 6
(M+H).
Example 241 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-pyridylmethanol as the appropriate alcohol,
Example 241 was obtained. HRMS calculated for C H ClN O S: 739.2231; found
39 38 5 6
370.6197 (M+2H).
Example 242 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 3-pyridylmethanol as the appropriate alcohol,
Example 242 was obtained. HRMS calculated for C H ClN O S: 739.2231; found
39 38 5 6
370.6178 (M+2H).
Example 243 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and pyridazinylmethanol as the appropriate alcohol,
Example 243 was obtained. HRMS calculated for C H ClN O S: 740.2184; found
38 37 6 6
741.2227 (M+H).
Example 244 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(furan
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-furylmethanol as the appropriate alcohol, Example
244 was obtained. HRMS calculated for C H ClN O S: 728.2071; found 729.2112
38 37 4 7
(M+H).
Example 245 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(thiophen
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-thienylmethanol as the appropriate alcohol,
Example 245 was obtained. HRMS calculated for C H ClN O S : 744.1843; found
38 37 4 6 2
745.1895 (M+H).
Example 246 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 246 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 372.1234 (M+2H).
Example 247 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-methylpyrimidinyl)methanol as the appropriate
alcohol, Example 247 was obtained. HRMS calculated for C H ClN O S: 754.2340;
39 39 6 6
found 755.2446 (M+H).
Example 248 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 248 was obtained. HRMS
calculated for C H ClF N O S: 808.2058; found 809.2126 (M+H).
39 36 3 6 6
Example 249 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
chloropyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-chloropyrimidinyl)methanol (Preparation 9ch)
as the appropriate alcohol, Example 249 was obtained. HRMS calculated for
C H Cl N O S: 774.1794; found 775.1863 (M+H).
38 36 2 6 6
Example 250 (2R){2-[(2-aminopyrimidinyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (VIa) and (2-aminopyrimidinyl)methanol (Preparation 9al)
as the appropriate alcohol, Example 250 was obtained. HRMS calculated for
C H ClN O S: 755.2293; found 378.6217 (M+2H).
38 38 7 6
Example 251 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(dimethylamino)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [2-(dimethylamino)pyrimidinyl]methanol
(Preparation 9an) as the appropriate alcohol, Example 251 was obtained. HRMS
calculated for C H ClN O S: 783.2606; found 392.6366 (M+2H).
40 42 7 6
Example 252 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 252 was obtained. HRMS
calculated for C H ClN O S: 825.2711; found 413.6424 (M+2H).
42 44 7 7
Example 253 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(methylamino)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [2-(methylamino)pyrimidinyl]methanol
(Preparation 9am) as the appropriate alcohol, Example 253 was obtained. HRMS
calculated for C H ClN O S: 769.2449; found 385.6305 (M+2H).
39 40 7 6
Example 254 (2R)(2-{[2-(benzylamino)pyrimidinyl]methoxy}phenyl){[(5S )
{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furan
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (VIa) and [2-(benzylamino)pyrimidinyl]methanol
(Preparation 9at) as the appropriate alcohol, Example 254 was obtained. HRMS
calculated for C H ClN O S: 845.2762; found 423.6479 (M+2H).
45 44 7 6
Example 255 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol Example 255 was obtained. HRMS calculated for C H ClN O S: 770.2289;
39 39 6 7
found 771.2344 (M+H).
Example 256 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(cyclopropylmethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [2-(cyclopropylmethoxy)pyrimidinyl]methanol
(Preparation 9au) as the appropriate alcohol, Example 256 was obtained. HRMS
calculated for C H ClN O S: 810.2602; found 406.1380 (M+2H).
42 43 6 7
Example 257 (2R)(2-{[2-(benzyloxy)pyrimidinyl]methoxy}phenyl){[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (VIa) and (2-benzyloxypyrimidinyl)methanol as the
appropriate alcohol, Example 257 was obtained. HRMS calculated for C H ClN O S:
45 43 6 7
846.2602; found 424.1407 (M+2H).
Example 258 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 4-pyridylmethanol as the appropriate alcohol,
Example 258 was obtained. HRMS calculated for C H ClN O S: 739.2231; found
39 38 5 6
370.6187 (M+2H).
Example 259 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and pyrimidinylmethanol as the appropriate alcohol,
Example 259 was obtained. HRMS calculated for C H ClN O S: 740.2184; found
38 37 6 6
741.2259 (M+H).
Example 260 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 260 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 743.2404 (M+H).
Example 261 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propanyl)-
1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [1-(propanyl)-1H-pyrazolyl]methanol
(Preparation 9dc) as the appropriate alcohol, Example 261 was obtained. HRMS
calculated for C H ClN O S: 770.2653; found 771.2726 (M+H).
40 43 6 6
Example 262 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-cyclopentyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-cyclopentyl-1H-pyrazolyl)methanol
(Preparation 9dg) as the appropriate alcohol, Example 262 was obtained. HRMS
calculated for C H ClN O S: 796.2810; found 797.2835 (M+H).
42 45 6 6
Example 263 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-phenyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-phenyl-1H-pyrazolyl)methanol as the appropriate
alcohol, Example 263 was obtained. HRMS calculated for C H ClN O S: 804.2497;
43 41 6 6
found 805.2575 (M+H).
Example 264 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol, Example 264 was obtained. HRMS calculated for
C H ClN O S: 756.2497; found 757.2597 (M+H).
39 41 6 6
Example 265 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-
trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 265 was obtained. HRMS
calculated for C H ClF N O S: 810.2214; found 406.1175 (M+2H).
39 38 3 6 6
Example 266 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(oxetan
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and oxetanylmethanol as the appropriate alcohol,
Example 266 was obtained as a mixture of diastereoisomers. HRMS calculated for
C H ClN O S: 718.2228; found 719.2296 (M+H) and found 719.2283 (M+H).
37 39 4 7
Example 267 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
imidazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-imidazolyl)methanol as the
appropriate alcohol, Example 267 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 372.1233 (M+2H).
Example 268 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
methylpyrazinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-methylpyrazinyl)methanol as the appropriate
alcohol Example 268 was obtained. HRMS calculated for C H ClN O S: 754.2340;
39 39 6 6
found 755.2408 (M+H).
Example 269 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-chloropyrazin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-chloropyrazinyl)methanol as the appropriate
alcohol, Example 269 was obtained. HRMS calculated for C H Cl N O S: 774.1794;
38 36 2 6 6
found 775.1817 (M+H).
Example 270 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
methoxypyrazinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-methoxypyrazinyl)methanol as the appropriate
alcohol, Example 270 was obtained. HRMS calculated for C H ClN O S: 770.2289;
39 39 6 7
found 771.2329 (M+H).
Example 271 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-methylpyrimidinyl)methanol as the appropriate
alcohol, Example 271 was obtained. HRMS calculated for C H ClN O S: 754.2340;
39 39 6 6
found 755.2422 (M+H).
Example 272 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyrrolidin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and (2-pyrrolidinylpyrimidinyl)methanol as the
appropriate alcohol, Example 272 was obtained. HRMS calculated for C H ClN O S:
42 44 7 6
809.2762; found 405.6443 (M+2H).
Example 273 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (VIa) and (2-(morpholinyl)pyrimidinyl)methanol as the
appropriate alcohol, Example 273 was obtained. HRMS calculated for C H ClN O S:
42 44 7 7
825.2711; found 413.6424 (M+2H).
Example 274 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol, Example 274 was obtained. HRMS calculated for C H ClN O S: 770.2289;
39 39 6 7
found 771.2398 (M+H).
Example 275 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and pyrazinylmethanol as the appropriate alcohol,
Example 275 was obtained. HRMS calculated for C H ClN O S: 740.2184; found
38 37 6 6
741.2255 (M+H).
Example 276 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
imidazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-imidazolyl)methanol as the
appropriate alcohol, Example 276 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 372.1237 (M+2H).
Example 277 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and pyrimidinylmethanol as the appropriate alcohol,
Example 277 was obtained. HRMS calculated for C H ClN O S: 740.2184; found
38 37 6 6
741.2266 (M+H).
Example 278 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-thiazol
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 1,3-thiazolylmethanol as the appropriate alcohol,
Example 278 was obtained. HRMS calculated for C H ClN O S : 745.1796; found
37 36 5 6 2
746.1855 (M+H).
Example 279 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 279 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 372.1243 (M+2H).
Example 280 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-oxazol
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 1,3-oxazolylmethanol as the appropriate alcohol,
Example 280 was obtained. HRMS calculated for C H ClN O S: 729.2024; found
37 36 5 7
730.2116 (M+H).
Example 281 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-thiazol
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 1,3-thiazolylmethanol as the appropriate alcohol,
Example 281 was obtained. HRMS calculated for C H ClN O S : 745.1796; found
37 36 5 6 2
746.1867 (M+H).
Example 282 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-methyl-2H-
indazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (2-methyl-2H-indazolyl)methanol as the appropriate
alcohol, Example 282 was obtained. HRMS calculated for C H ClN O S: 792.2497;
42 41 6 6
found 397.1336 (M+2H).
Example 283 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(5-
phenylpyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (5-phenylpyrimidinyl)methanol as the appropriate
alcohol, Example 283 was obtained. HRMS calculated for C H ClN O S: 816.2497;
44 41 6 6
found 817.2539 (M+H).
Example 284 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(isoquinolin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and isoquinolinylmethanol as the appropriate alcohol,
Example 284 was obtained. HRMS calculated for C H ClN O S: 789.2388; found
43 40 5 6
395.6266 (M+2H).
Example 285 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(3-chloropyridin-
2-yl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (3-chloropyridyl)methanol as the appropriate
alcohol, Example 285 was obtained. HRMS calculated for C H Cl N O S: 773.1842;
39 37 2 5 6
found 774.1881 (M+H).
Example 286 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and pyrimidinylmethanol as the appropriate alcohol,
Example 286 was obtained. HRMS calculated for C H ClN O S: 740.2184; found
38 37 6 6
741.2229 (M+H).
Example 287 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-
imidazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (VIa) and (1-methyl-1H-imidazolyl)methanol as the
appropriate alcohol, Example 287 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 372.1246 (M+2H).
Example 288 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(3,3,3-
trifluoropropoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 3,3,3-trifluoropropanol as the appropriate alcohol,
Example 288 was obtained. HRMS calculated for C H ClF N O S: 744.1996; found
36 36 3 4 6
745.2037 (M+H).
Example 289 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-(pyridin
yl)ethoxy]phenyl}propanoic acid
Using General Procedure (VIa) and 2-(2-pyridyl)ethanol as the appropriate alcohol,
Example 289 was obtained. HRMS calculated for C H ClN O S: 753.2388; found
40 40 5 6
377.6280 (M+2H).
Example 290 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-methoxyethanol as the appropriate alcohol, Example
290 was obtained. HRMS calculated for C H ClN O S: 706.2228; found 707.2279
36 39 4 7
(M+H).
Example 291 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
phenoxyethoxy)phenyl]propanoic acid
Using General Procedure (VIa) and 2-phenoxyethanol as the appropriate alcohol, Example
291 was obtained. HRMS calculated for C H ClN O S: 768.2384; found 769.2459
41 41 4 7
(M+H).
Example 292 (2R){2-[2-(benzyloxy)ethoxy]phenyl}{[(5S ){3-chloromethyl
[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Using General Procedure (VIa) and 2-benzyloxyethanol as the appropriate alcohol,
Example 292 was obtained. HRMS calculated for C H ClN O S: 782.2541; found
42 43 4 7
392.1344 (M+2H).
Example 293 (2S){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
503 mg 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](2-
furyl)thieno[2,3-d]pyrimidine (Preparation 14) (1 mmol), 353 mg ethyl (2S)hydroxy
[2-[[(2R)-tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 3bm) (1.2
mmol) and 986 mg cesium carbonate (3 mmol) were dissolved in 10 mL dry tertbutanol.
The mixture was stirred at 60°C under nitrogen until no further conversion was observed.
The reaction mixture was cooled to room temperature, then 5 mL 2 M LiOH solution was
added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM.
The combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure. The crude product was purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Diastereoisomer eluting later was collected as Example 293. HRMS calculated for
C H ClN O S: 732.2384; found 733.2476 (M+H).
38 41 4 7
Example 294 (2R){2-[(1-benzyl-1H-1,2,3-triazolyl)methoxy]phenyl}{[(5S )
{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furan
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Example 295 (2R){2-[(1-benzyl-1H-1,2,3-triazolyl)methoxy]phenyl}{[(5S )
{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furan
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
To a THF solution of 310 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
propynoxyphenyl)propanoate (see Step A of Example 216) (0.433 mmol), 86 mg
benzyl azide (0.649 mmol) and 3 mg Cp*Ru(PPh ) Cl were added and the mixture was
stirred at 70°C until no further conversion was observed. Then it was concentrated under
reduced pressure and the crude product was purified via flash chromatography using DCM
and MeOH as eluents to obtain the mixture of triazole regioisomers. Then 185 mg of this
mixture (0.218 mmol) was dissolved in 5 mL dioxane / water (1:1) and 92 mg LiOH ×
H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
DCM. The combined organic phases were dried over Na SO , filtered and concentrated
under reduced pressure. The regioisomers were separated and purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents. Regioisomer eluting earlier was collected as Example 294. HRMS calculated for
C43H42ClN7O6S: 819.2606; found 410.6375 (M+2H). Regioisomer eluting later was
collected as Example 295. HRMS calculated for C H ClN O S: 819.2606; found
43 42 7 6
410.6381 (M+2H).
Example 296 (2R){[(5S ){3-chloromethyl[2-(4-methyloxidopiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
During the synthesis of Example 209, Example 296 was formed and isolated as a side
product. HRMS calculated for C H ClN O S: 678.1915; found 679.1966 (M+H).
34 35 4 7
Example 297 (2R){[(5S ){3-chloromethyl[2-(4-methyl-1,4-dioxidopiperazin-
1-yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
200 mg (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic
acid (Example 209) was dissolved in 1 mL methanol and 5 µL 50% aqueous hydrogen
peroxide solution was added. The reaction mixture was stirred at room temperature
overnight. Then water was added and the mixture was extracted with DCM. The organic
phase was dried over Na SO , filtered and concentrated under reduced pressure. The crude
product was purified via preparative reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents to obtain Example 297. HRMS calculated for
C H ClN O S: 694.1864; found 695.1911 (M+H).
34 35 4 8
General Procedure (VIIa)
Step A:
1.0 eq. of ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 6e),
2.0 eq. of the appropriate alcohol and 2.0 eq. triphenylphosphine were dissolved in dry
toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
volatiles were evaporated under reduced pressure, the crude ester was purified via flash
chromatography using DCM and MeOH as eluents.
Step B:
The obtained ester was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH ×
H O was added. The mixture was stirred at room temperature until no further conversion
was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 298 (2R){[(5S )(3-chloromethyl{[(2S)methylpyrrolidin
yl]methoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and [(2S)methylpyrrolidinyl]methanol as the
appropriate alcohol, Example 298 was obtained. HRMS calculated for C H ClN O S:
33 32 3 6
633.1700; found 634.1771 (M+H)
Example 299 (2R){[(5S )(3-chloromethyl{[(2R)methylpyrrolidin
yl]methoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and [(2R)methylpyrrolidinyl]methanol as the
appropriate alcohol, Example 299 was obtained. HRMS calculated for C H ClN O S:
33 32 3 6
633.1700; found 634.1774 (M+H)
Example 300 (2R){[(5S ){3-chloromethyl[(3R or S)-(1-methylazepan
yl)oxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and (1-methylpiperidyl)methanol as the appropriate
alcohol, Example 300 was obtained collecting only the later eluting diastereomer (absolute
configuration not confirmed). HRMS calculated for C H ClN O S: 647.1857; found
34 34 3 6
648.1916 (M+H)
Example 301 (2R){[(5S ){3-chloromethyl[((3R or S)methylpiperidin
yl)oxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
and
Example 302 (2R){[(5S ){3-chloromethyl[((3S or R)methylpiperidin
yl)oxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 1-methylpiperidinol as the appropriate alcohol
Example 301 was obtained collecting the earlier eluting diastereomer (absolute
configuration not determined) HRMS calculated for C H ClN O S: 633.1700; found
33 32 3 6
634.1771 (M+H), and Example 302 was obtained collecting the later eluting diastereomer
(absolute configuration not determined). HRMS calculated for C H ClN O S: 633.1700;
33 32 3 6
found 634.1763 (M+H)
Example 303 (2R){[(5S ){3-chloromethyl[(1-methylpyrrolidin
yl)oxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and 1-methylpyrrolidinol as the appropriate alcohol,
Example 303 was obtained. HRMS calculated for C H ClN O S: 619.1500; found
32 30 3 6
620.1544 (M+H)
Example 304 (2R){[(5S ){3-chloromethyl[(1-methylpiperidin
yl)oxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and 1-methylpiperidinol as the appropriate alcohol,
Example 304 was obtained. HRMS calculated for C H ClN O S: 633.1700; found
33 32 3 6
634.1753 (M+H)
Example 305 (2R)({(5S )[3-chloromethyl((3S or R)-pyrrolidin
yloxy)phenyl](furanyl)thieno[2,3-d]pyrimidinyl}oxy)(2-methoxyphenyl)
propanoic acid
Example 306 (2R)({(5S )[3-chloromethyl((3R or S)-pyrrolidin
yloxy)phenyl](furanyl)thieno[2,3-d]pyrimidinyl}oxy)(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and pyrrolidinol as the appropriate alcohol Example
305 was obtained collecting the earlier eluting diastereomer (absolute configuration not
confirmed) HRMS calculated for C H ClN O S: 605.1387; found 606.1472 (M+H), and
31 28 3 6
Example 306 was obtained collecting the later eluting diastereomer (absolute
configuration not confirmed). HRMS calculated for C H ClN O S: 605.1387; found
31 28 3 6
606.1461 (M+H)
Example 307 (2R)({(5S )[4-((3S or R)azabicyclo[2.2.2]octyloxy)chloro
methylphenyl](furanyl)thieno[2,3-d]pyrimidinyl}oxy)(2-
methoxyphenyl)propanoic acid
Example 308 (2R)({(5Sa)[4-((3R or S)azabicyclo[2.2.2]octyloxy)chloro
methylphenyl](furanyl)thieno[2,3-d]pyrimidinyl}oxy)(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and quinuclidinol as the appropriate alcohol, Example
307 was obtained collecting the earlier eluting diastereomer (absolute configuration not
confirmed) HRMS calculated for C H ClN O S: 645.1700; found 646.1799 (M+H), and
34 32 3 6
Example 308 was obtained collecting the later eluting diastereomer (absolute
configuration not confirmed). HRMS calculated for C H ClN O S: 645.1700; found
34 32 3 6
646.1746 (M+H)
Example 309 (2R){[(5S ){3-chloromethyl[((2S or R)methylpiperidin
yl)methoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and (1-methylpiperidyl)methanol as the appropriate
alcohol, Example 309 was obtained collecting the earlier eluting diastereomer (absolute
configuration not confirmed). HRMS calculated for C H ClN O S: 647.1857; found
34 34 3 6
648.1934 (M+H)
Example 310 (2R){[(5S ){3-chloromethyl[(1-methylpyrrolidinyl)methoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl) propanoic
acid
Using General Procedure (VIIa) and (1-methylpyrrolidinyl)methanol as the appropriate
alcohol, Example 310 was obtained. HRMS calculated for C H ClN O S: 633.1700;
33 32 3 6
found 634.1775 (M+H)
Example 311 (2R){[(5S ){3-chloromethyl[(1-methylpiperidinyl)methoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl) propanoic
acid
Using General Procedure (VIIa) and (1-methylpiperidyl)methanol as the appropriate
alcohol, Example 311 was obtained. HRMS calculated for C H ClN O S: 647.1857;
34 34 3 6
found 648.1911 (M+H)
Example 312 (2R){[(5S )(3-chloro{[1-(2-methoxyethyl)pyrrolidinyl]methoxy}
methylphenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and [1-(2-methoxyethyl)pyrrolidinyl]methanol as the
appropriate alcohol, Example 312 was obtained. HRMS calculated for C H ClN O S:
36 3 7
677.1962; found 678.2026 (M+H)
Example 313 (2R){[(5S ){3-chloro[(1,4-dimethylpiperazinyl)methoxy]
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
Using General Procedure (VIIa) and (1,4-dimethylpiperazinyl)methanol as the
appropriate alcohol, Example 313 was obtained. HRMS calculated for C H ClN O S:
34 35 4 6
662.1966; found 663.2004 (M+H)
Example 314 (2R){[(5S ){3-chloromethyl[(4-methylmorpholinyl)methoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl) propanoic
acid
Using General Procedure (VIIa) and (4-methylmorpholinyl)methanol as the appropriate
alcohol, Example 314 was obtained. HRMS calculated for C H ClN O S: 649.1649;
33 32 3 7
found 650.1710 (M+H)
Example 315 (2R)({(5S )[3-chloromethyl(morpholinylmethoxy)phenyl]
(furanyl)thieno[2,3-d]pyrimidinyl}oxy)(2-methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and morpholinylmethanol as the appropriate alcohol,
Example 315 was obtained. HRMS calculated for C H ClN O S: 635.1493; found
32 30 3 7
636.1518 (M+H)
Example 316 (2R){[(5S ){3-chloromethyl[2-(1-methylpyrrolidinyl)ethoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl) propanoic
acid
Using General Procedure (VIIa) and 2-(1-methylpyrrolidinyl)ethanol as the appropriate
alcohol, Example 316 was obtained. HRMS calculated for C H ClN O S: 647.1857;
34 34 3 6
found 648.1909 (M+H)
Example 317 (2R){[(5S ){3-chloromethyl[2-(1-methylpiperidin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(1-methylpiperidyl)ethanol as the appropriate
alcohol, Example 317 was obtained. HRMS calculated for C H ClN O S: 661.2013;
36 3 6
found 662.2056 (M+H)
Example 318 (2R){[(5S ){3-chloromethyl[2-(4-methylmorpholin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(4-methylmorpholinyl)ethanol as the appropriate
alcohol, Example 318 was obtained collecting only the later eluting diastereomer (absolute
configuration not confirmed). HRMS calculated for C H ClN O S: 663.1806; found
34 34 3 7
664.1881 (M+H)
Example 319 (2R)({(5S )[4-(2-aminoethoxy)chloromethylphenyl](furan
yl)thieno[2,3-d]pyrimidinyl}oxy)(2-methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-aminoethanol as the appropriate alcohol, Example
319 was obtained. HRMS calculated for C H ClN O S: 579.1231; found 580.1301
29 26 3 6
(M+H)
Example 320 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 320 was obtained. HRMS calculated for C H ClN O S: 607.1544; found
31 30 3 6
608.1617 (M+H)
Example 321 (2R){[(5S ){3-chloromethyl[2-(4-methyloxopiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 4-(2-hydroxyethyl)methyl-piperazinone
(Preparation 9eg) as the appropriate alcohol, Example 321 was obtained. HRMS
calculated for C H ClN O S: 676.1758; found 677.1850 (M+H)
34 33 4 7
Example 322 (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(4-ethylpiperazinyl)ethanol as the appropriate
alcohol, Example 322 was obtained. HRMS calculated for C H ClN O S: 676.2122;
37 4 6
found 677.2186 (M+H)
Example 323 (2R){[(5S ){4-[2-(4-acetylpiperazinyl)ethoxy]chloro
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
141 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-furyl)thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 6e) (0.25 mmol),
0.092 mL 2-piperazinylethanol (0.75 mmol) and 197 mg triphenylphosphine (0.75
mmol) were dissolved in 5 mL dry toluene, then 173 mg ditertbutyl azodicarboxylate (0.75
mmol) was added. The mixture was stirred at 50°C under nitrogen until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
crude ester was purified via flash chromatography using DCM and MeOH as eluents
resulting the intermediate product ethyl (2R)[(5S )[3-chloromethyl(2-piperazin-
1-ylethoxy)phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate. H NMR (500 MHz, DMSO-d ): 8.58 (s , 1H), 7.79 (dd, 1H), 7.25 (d, 1H),
7.24 (d, 1H), 7.18 (m, 1H), 6.91 (d, 1H), 6.75 (m, 1H), 6.52 (dd, 1H), 6.33 (d, 1H), 5.69
(dd, 1H), 5.41 (dd, 1H), 4.27 (m, 2H), 4.05 (m, 1H), 4.02 (m, 1H), 3.76 (s, 3H), 2.97 (dd,
1H), 2.73 (t, 2H), 2.64 (m, 4H), 2.43 (brm, 4H), 2.43 (dd, 1H), 1.94 (s, 3H), 1.06 (t, 3H).
Step B:
87 mg ethyl (2R)[(5S )[3-chloromethyl(2-piperazinylethoxy)phenyl](2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (0.13 mmol) and
0.036 mL triethylamine (0.26 mmol) were dissolved in 1 mL dry DCM at room
temperature. 0.018 mL acetyl chloride (0.26 mmol) was added and the reaction mixture
was stirred until no further conversion was observed. The reaction was quenched with
water and the mixture was extracted with DCM. The combined organic phases were
washed with water, dried with Na SO and concentrated under reduced pressure. Crude
ethyl (2R)[(5S )[4-[2-(4-acetylpiperazinyl)ethoxy]chloromethyl-phenyl]
(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate was dissolved in
a mixture of 1 mL dioxane and 1 mL water and 11 mg LiOH × H O (0.26 mmol) was
added. The mixture was stirred at room temperature until no further conversion was
observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted
with DCM, dried with Na SO , concentrated under reduced pressure and purified via
preparative reversed phase chromatography resulting Example 323. HRMS calculated for
C H ClN O S: 690.1915; found 691.1996 (M+H)
35 4 7
Example 324 (2R){[(5S )(3-chloromethyl{2-[4-(propanyl)piperazin
yl]ethoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(4-isopropylpiperazinyl)ethanol as the
appropriate alcohol, Example 324 was obtained. HRMS calculated for C H ClN O S:
36 39 4 6
690.2279; found 691.2335 (M+H)
Example 325 (2R){[(5S ){3-chloromethyl[2-(4-phenylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(4-phenylpiperazinyl)ethanol as the appropriate
alcohol, Example 325 was obtained. HRMS calculated for C H ClN O S: 724.2122;
39 37 4 6
found 725.2187 (M+H)
Example 326 (2R){[(5S )(4-{2-[4-(2-aminooxoethyl)piperazinyl]ethoxy}
chloromethylphenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
81 mg ethyl (2R)[(5S )[3-chloromethyl(2-piperazinylethoxy)phenyl](2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (as described in
Step A of Example 323) (0.12 mmol) was dissolved in 2 mL dry THF. 41 mg 2-
bromoacetamide (0.30 mmol) and 98 mg Cs CO (0.30 mmol) were added at room
temperature and the mixture was heated at 70 °C until no further conversion was observed.
The mixture was concentrated under reduced pressure and the crude product was
hydrolyzed by the addition of 3 mL NaOH solution (10 m/m%) in aqueous methanol (90%
methanol). The mixture was stirred at room temperature until no further conversion was
observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted
with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting
Example 326. HRMS calculated for C H ClN O S: 705.2024; found 706.2112 (M+H)
36 5 7
Example 327 (2R){[(5S )(3-chloromethyl{2-[4-(2,2,2-trifluoroethyl)piperazin-
1-yl]ethoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-[4-(2,2,2-trifluoroethyl)piperazinyl]ethanol
(Preparation 9eh) as the appropriate alcohol, Example 327 was obtained. HRMS
calculated for C H ClF N O S: 730.1840; found 731.1919 (M+H)
34 3 4 6
Example 328 (2R){[(5S )(3-chloro{2-[4-(2,2-difluoroethyl)piperazin
yl]ethoxy}methylphenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-[4-(2,2-difluoroethyl)piperazinyl]ethanol
(Preparation 9ei) as the appropriate alcohol, Example 328 was obtained. HRMS
calculated for C H ClF N O S: 712.1934; found 713.1978 (M+H)
35 2 4 6
Example 329 (2R){[(5S ){4-[2-(4-benzylpiperazinyl)ethoxy]chloro
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
75 mg ethyl (2R)[(5S )[3-chloromethyl(2-piperazinylethoxy)phenyl](2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (as described in
Step A of Example 323) (0.115 mmol) and 0.013 mL benzaldehyde (0.127 mmol) were
dissolved in 1 mL dry DCM. 37 mg sodium triacetoxyborohydride (0.173 mmol) was
added and the reaction mixture was stirred at room temperature until no further conversion
was observed. The reaction was quenched with NaHCO solution and extracted with DCM.
The combined organic phases were dried with Na SO and concentrated under reduced
pressure. The crude product was purified using flash chromatography eluting with DCM-
MeOH gradient.
Step B:
The ester (product of Step A) was hydrolyzed by the addition of 3 mL NaOH solution (10
m/m%) in aqueous methanol (90% methanol). The mixture was stirred at room
temperature until no further conversion was observed. The reaction mixture was diluted
with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents resulting Example 329. HRMS calculated for C H ClN O S: 738.2279;
40 39 4 6
found 739.2322 (M+H)
Example 330 (2R){[(5S )(3-chloro{2-[4-(2-methoxyethyl)piperazinyl]ethoxy}-
2-methylphenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
135 mg ethyl (2R)[(5S )[3-chloromethyl(2-piperazinylethoxy)phenyl](2-
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (as described in
Step A of Example 323) (0.20 mmol) was dissoleved in 1.5 mL dry THF. 0.040 mL 1-
bromomethoxy-ethane (0.40 mmol) and 130 mg Cs CO (0.40 mmol) were added at
room temperature and the mixture was heated at 70 °C until no further conversion was
observed. The mixture was concentrated under reduced pressure and the crude product was
purified using flash chromatography eluting with a DCM-MeOH gradient.
Step B:
The ester obtained in Step A was hydrolyzed by adding 3 mL NaOH solution (10 m/m%)
in aqueous methanol (90% methanol). The mixture was stirred at room temperature until
no further conversion was observed. The reaction mixture was diluted with brine,
neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried
with Na SO , concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents
resulting Example 330. HRMS calculated for C H ClN O S: 706.2228; found 707.2273
36 39 4 7
(M+H)
Example 331 (2R){[(5S ){3-chloromethyl[2-(methylamino)ethoxy]phenyl}
(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (VIIa) and 2-(methylamino)ethanol as the appropriate alcohol,
Example 331 was obtained. HRMS calculated for C H ClN O S: 593.1387; found
28 3 6
594.1455 (M+H)
Example 332 (2R){[(5S )(3-chloromethyl{[(4-methylpiperazin
yl)acetyl]oxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
100 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-furyl)thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 6e) (0.18 mmol) was
dissolved in 0.5 mL dioxane and a solution of 37 mg LiOH × H O (0.88 mmol) in 0.5 mL
water was added to it. The mixture was stirred at room temperature for 30 minutes,
quenched with water, acidified with dilute hydrochloric acid solution and extracted with
DCM. The combined organic phases were dried with Na SO and concentrated under
reduced pressure. The crude product was re-dissolved in 2 mL dry DCM, 64 mg 2-(4-
methylpiperazinyl)acetic acid (0.40 mmol), 208 mg PyBOP (0.40 mmol) and 0.060 mL
triethylamine (0.44 mmol) were added. The mixture was stirred at room temperature until
no further conversion was observed. Further DCM was added and the organic phase was
washed with water, dried with Na SO and concentrated under reduced pressure. The crude
product was purified with preparative HPLC resulting Example 332. HRMS calculated for
C H ClN O S: 676.1758; found 677.1846 (M+H)
34 33 4 7
Example 333 (2R){[(5R ){3-fluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 334 (2R){[(5S ){3-fluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
501 mg ethyl (2R)[5-(3-fluorohydroxymethyl-phenyl)(2-furyl)thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 11b, mixture of
diastereomers) (0.913 mmol), 198 mg 2-(4-methylpiperazinyl)ethanol (1.37 mmol) and
480 mg triphenylphosphine (1.83 mmol) were dissolved in 10 mL dry toluene, then 420
mg ditertbutyl azodicarboxylate (1.83 mmol) was added. The mixture was stirred at 50°C
under nitrogen for 45 minutes. The volatiles were evaporated under reduced pressure and
the crude ester was purified using flash chromatography (eluents: EtOAc and MeOH). The
obtained ester was dissolved in a mixture of 4 mL dioxane and 2 mL water and 200 mg
LiOH × H O was added. The reaction mixture was stirred at room temperature for 1.5
hours, quenched by the addition of brine and neutralized with 2 M HCl. The mixture was
extracted with DCM, dried with Na SO , concentrated under reduced pressure and purified
via preparative reversed phase chromatography using 25 mM aqueous NH HCO solution
and MeCN as eluents. Example 333 was obtained as the diastereoisomer eluting earlier
from the preparative HPLC column [HRMS calculated for C H FN O S: 646.2261;
34 35 4 6
found 647.2365 (M+H)], and Example 334 was obtained as the diastereoisomer eluting
later from the preparative HPLC column [HRMS calculated for C H FN O S: 646.2261;
34 35 4 6
found 647.2302 (M+H)].
Example 335 (2R){[(5S ){3-chloroethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 336 (2R){[(5R ){3-chloroethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
250 mg ethyl ((2R)[5-(3-chloroethylhydroxy-phenyl)(2-furyl)thieno[2,3-d]
pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 11a, mixture of
diastereomers) (0.40 mmol), 115 mg 2-(4-methylpiperazinyl)ethanol (0.80 mmol) and
210 mg triphenylphosphine (0.80 mmol) were dissolved in 5 mL dry toluene, then 184 mg
ditertbutyl azodicarboxylate (0.80 mmol) was added. The mixture was stirred at 50°C
under nitrogen for 1 hour. The volatiles were evaporated under reduced pressure and the
crude ester was purified using flash chromatography (eluents: EtOAc and MeOH). The
obtained ester was dissolved in a mixture of 4 mL dioxane and 2 mL water and 100 mg
LiOH × H O was added. The reaction mixture was stirred at 30 °C for 1 hour. Water was
added to the mixture and pH was set to 4-5 with 2 M HCl. The mixture was extracted with
DCM, dried with Na SO , concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents. Example 335 was obtained as the diastereoisomer eluting later from the
preparative HPLC column [HRMS calculated for C H ClN O S: 676.2122; found
37 4 6
677.2204 (M+H)], while Example 336 was obtained as the diastereoisomer eluting earlier
from the preparative HPLC column [HRMS calculated for C H ClN O S: 676.2122;
37 4 6
found 677.2181 (M+H)]
Example 337 (2R){[5-{3-chlorofluoro[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid (mixture of diastereoisomers)
503 mg ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4e) (1.00 mmol), 900 mg 1-[2-[2-chloro
fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine
(Preparation 5f) (2.20 mmol), 35 mg Ataphos (0.05 mmol) and 977 mg Cs CO (3.00
mmol) were dissolved in 10 mL dioxane and 2 mL water. It was heated to 110°C for 15
minutes via microwave irradiation. Then it was diluted with brine, extracted with DCM,
and the combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure and purified via reversed phase chromatography, using 25 mM aqueous
NH HCO solution and MeCN as eluents. The obtained ester was dissolved in a mixture of
mL dioxane and 5 mL water and 200 mg LiOH × H2O was added. The reaction mixture
was stirred at room temperature until no further conversion was observed. Water was
added to the mixture and pH was set between 4-5 with 2 M HCl. The mixture was
extracted with DCM, and the combined organic phases were dried with Na SO ,
concentrated under reduced pressure and purified via preparative reversed phase
chromatography resulting Example 337. HRMS calculated for C H ClFN O S:
33 32 4 6
666.1715; found 667.1792 (M+H)
General Procedure (VIIIa)
Step A:
1.0 eq. 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](2-
furyl)thieno[2,3-d]pyrimidine (Preparation 14), 1.2 eq. of the appropriate alcohol and 3.0
eq. cesium carbonate were dissolved in dry tertbutanol or dry DMSO (0.2 M for
Preparation 14). The mixture was stirred at 60°C under nitrogen until no further
conversion was observed. The reaction mixture was cooled to room temperature then it
was diluted with brine and extracted with DCM. The combined organic phases were dried
over MgSO and evaporated under reduced pressure. The crude product was purified via
flash chromatography using EtOAc / MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane / H O (1:1, 0.2 M for the product of Step
A) and 10 eq. LiOH × H O was added then it was stirred at room temperature until no
further conversion was observed. The reaction mixture was diluted with brine, neutralized
with 2 M HCl, and extracted with DCM. The combined organic phases were dried over
Na SO , concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 338 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(difluoromethoxy)phenyl]propanoic acid
Using General Procedure (VIIIa) and methyl (2R)[2-(difluoromethoxy)phenyl]
hydroxy-propanoate (Preparation 3aj) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 338. HRMS calculated for C H ClF N O S:
34 33 2 4 6
698.1777; found 699.1866 (M+H)
Example 339 (2R)-{[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(phenyl)ethanoic acid
Example 340 (2R)-{[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(phenyl)ethanoic acid
Using General Procedure (VIIIa) and methyl (2R)hydroxyphenyl-acetate as the
appropriate alcohol, the diastereoisomer eluting earlier was collected as Example 339 and
the diastereoisomer eluting later was collected as Example 340. HRMS calculated for
C H ClN O S: 618.1704; found 619.1766 (M+H) and 619.1768 (M+H)
32 31 4 5
Example 341 (2S){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
fluorophenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2S)(2-fluorophenyl)hydroxy-propanoate
(Preparation 3az) as the appropriate alcohol, the diastereoisomer eluting later was
collected as Example 341. HRMS calculated for C H ClFN O S: 650.1766; found
33 32 4 5
651.1825 (M+H)
Example 342 (2R,3S){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}hydroxy
phenylpropanoic acid
Example 343 (2R,3S){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}hydroxy
phenylpropanoic acid
Using General Procedure (VIIIa) and methyl (2R,3S)-2,3-dihydroxyphenyl-propanoate
as the appropriate alcohol, the diastereoisomer eluting earlier was collected as Example
342 and the diastereoisomer eluting later was collected as Example 343. HRMS calculated
for C H ClN O S: 648.1809; found 649.1879 (M+H) and 649.1875 (M+H)
33 33 4 6
Example 344 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxy
methylphenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)hydroxy(2-methoxymethyl-
phenyl)propanoate (Preparation 3at) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 344. HRMS calculated for C H ClN O S:
37 4 6
676.2122; found 677.2176 (M+H)
Example 345 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(5-fluoro
methoxyphenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)(5-fluoromethoxy-phenyl)
hydroxy-propanoate (Preparation 3ar) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 345. HRMS calculated for C H ClFN O S:
34 34 4 6
680.1872; found 681.1947 (M+H)
Example 346 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(4-fluoro
methoxyphenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)(4-fluoromethoxy-phenyl)
hydroxy-propanoate (Preparation 3as) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 346. HRMS calculated for C H ClFN O S:
34 34 4 6
680.1872; found 681.1915 (M+H)
Example 347 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(3-
methylphenyl)propanoic acid
Using General Procedure (VIIIa) and methyl (2R)hydroxy(m-tolyl)propanoate
(Preparation 3ap) as the appropriate alcohol, the diastereoisomer eluting later was
collected as Example 347. HRMS calculated for C H ClN O S: 646.2017; found
34 35 4 5
647.2073 (M+H)
Example 348 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(3-
fluorophenyl)propanoic acid
Using General Procedure (VIIIa) and methyl (2R)(3-fluorophenyl)hydroxy-
propanoate (Preparation 3ak) as the appropriate alcohol, the diastereoisomer eluting later
was collected as Example 348. HRMS calculated for C H ClFN O S: 650.1766; found
33 32 4 5
651.1818 (M+H)
Example 349 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(3-
methoxyphenyl)propanoic acid
Using General Procedure (VIIIa) and methyl (2R)hydroxy(3-
methoxyphenyl)propanoate (Preparation 3al) as the appropriate alcohol, the
diastereoisomer eluting later was collected as Example 349. HRMS calculated for
C H ClN O S: 662.1966; found 663.2043 (M+H)
34 35 4 6
Example 350 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2,3-
difluorophenyl)propanoic acid
Using General Procedure (VIIIa) and methyl (2R)(2,3-difluorophenyl)hydroxy-
propanoate (Preparation 3am) as the appropriate alcohol, the diastereoisomer eluting later
was collected as Example 350. HRMS calculated for C H ClF N O S: 668.1672; found
33 31 2 4 5
669.1729 (M+H)
Example 351 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxy
methylphenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)hydroxy(2-methoxymethyl-
phenyl)propanoate (Preparation 3au) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 351. HRMS calculated for C H ClN O S:
37 4 6
676.2122; found 677.2221 (M+H)
Example 352 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(3-fluoro
methoxyphenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)(3-fluoromethoxy-phenyl)
hydroxy-propanoate (Preparation 3aq) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 352. HRMS calculated for C H ClFN O S:
34 34 4 6
680.1872; found 681.1963 (M+H)
Example 353 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(trifluoromethyl)phenyl]propanoic acid
Using General Procedure (VIIIa) and methyl (2R)hydroxy[2-
(trifluoromethyl)phenyl]propanoate (Preparation 3an) as the appropriate alcohol, the
diastereoisomer eluting later was collected as Example 353. HRMS calculated for
C34H32ClF3N4O5S: 700.1734; found 701.1803 (M+H)
Example 354 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methylphenyl)propanoic acid
Using General Procedure (VIIIa) and methyl (2R)hydroxy(o-tolyl)propanoate
(Preparation 3ao) as the appropriate alcohol, the diastereoisomer eluting later was
collected as Example 354. HRMS calculated for C H ClN O S: 646.2017; found
34 35 4 5
647.2087 (M+H)
Example 355 (2R)[2-(aminomethyl)phenyl]{[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Step A:
252 mg 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](2-
furyl)thieno[2,3-d]pyrimidine (Preparation 14) (0.50 mmol), 196 mg ethyl (2R)[2-
[(tert-butoxycarbonylamino)methyl]phenyl]hydroxy-propanoate (Preparation 3aw)
(0.60 mmol) and 488 mg cesium carbonate (1.50 mmol) were dissolved in dry tertbutanol
(0.1 M for Preparation 14). The mixture was stirred at 60°C under nitrogen until no
further conversion was observed. The mixture was cooled to room temperature, then it was
diluted with brine and extracted with EtOAc. The combined organic phases were dried
over MgSO , filtered and concentrated, and then purified by flash chromatography on
silica gel using EtOAc / MeOH as eluents to give ethyl (2R)[2-[(tert-
butoxycarbonylamino)methyl]phenyl][5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-propanoate.
Step B:
198 mg ethyl (2R)[2-[(tert-butoxycarbonylamino)methyl]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidin
yl]oxy-propanoate (0.250 mmol) was dissolved in 10 mL dry DCM, then 1 mL TFA was
added and it was stirred at room temperature until no further conversion was observed, and
then reaction mixture was washed with saturated NaHCO . The organic layer was dried
over MgSO , filtered and the volatiles were evaporated under reduced pressure to give
ethyl (2R)[2-(aminomethyl)phenyl][5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-propanoate.
Step C:
56 mg ethyl (2R)[2-(aminomethyl)phenyl][5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-
propanoate (0.081 mmol) was dissolved in 1 mL dioxane/water (1:1) and 68 mg LiOH ×
H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
DCM. The combined organic phases were dried over Na SO , filtered, concentrated and
purified via preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents. The diastereoisomer eluting later was collected as Example
355. HRMS calculated for C H ClN O S: 661.2126; found 331.6148 (M+2H)
34 36 5 5
Example 356 (2R){2-[(acetylamino)methyl]phenyl}{[(5S ){3-chloromethyl
[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Step A:
100 mg ethyl (2R)[2-(aminomethyl)phenyl][5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-
propanoate (0.145 mmol) (Step B of Example 355) and 61 µl triethyl amine (435 µmol)
were dissolved in 5 mL DCM, and then 12 µl acetyl chloride (174 µmol) was added.
Reaction mixture was stirred at room temperature until no further conversion was
observed. The crude mixture was purified via flash chromatography using EtOAc / MeOH
as eluents to give ethyl (2R)[2-(acetamidomethyl)phenyl][5-[3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-
propanoate.
Step B:
73 mg ethyl (2R)[2-(acetamidomethyl)phenyl][5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy-
propanoate (0.10 mmol) was dissolved in 2 mL dioxane / water (1:1) and 84 mg LiOH ×
H O (2.0 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated and purified via preparative reverse phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents. The diastereoisomer eluting later was
collected as Example 356. HRMS calculated for C H ClN O S: 703.2231; found
36 38 5 6
704.231 (M+H)
Example 357 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
fluorophenyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)(2-fluorophenyl)hydroxy-propanoate
(Preparation 3ba) as the appropriate alcohol, the diastereoisomer eluting later was
collected as Example 357. HRMS calculated for C H ClFN O S: 650.1766; found
33 32 4 5
651.1827 (M+H)
Example 358 (2R){2-[(tert-butoxycarbonyl)amino]phenyl}{[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furanyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)[2-(tert-butoxycarbonylamino)phenyl]-
2-hydroxy-propanoate (Preparation 3av) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 358. HRMS calculated for C H ClN O S:
38 42 5 7
747.2493; found 748.2538 (M+H)
Example 359 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2,3-dihydro
benzofuranyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)(2,3-dihydrobenzofuranyl)
hydroxy-propanoate (Preparation 3bd) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 359. HRMS calculated for C H ClN O S:
35 4 6
674.1966; found 675.2033 (M+H)
Example 360 (2S){[(5Ra){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2,3-dihydro
benzofuranyl)propanoic acid
Using General Procedure (VIIIa) and ethyl (2S)(2,3-dihydrobenzofuranyl)
hydroxy-propanoate (Preparation 3be) as the appropriate alcohol, the diastereoisomer
eluting later was collected as Example 360. HRMS calculated for C H ClN O S:
35 4 6
674.1966; found 675.2025 (M+H)
Example 361 (2S){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2,2,2-
trifluoroethyl)sulfanyl]phenyl}propanoic acid
Using General Procedure (VIIIa) and ethyl (2S)hydroxy[2-(2,2,2-
trifluoroethylsulfanyl)phenyl]propanoate (Preparation 3ax) as the appropriate alcohol, the
diastereoisomer eluting later was collected as Example 361. HRMS calculated for
C H ClF N O S : 746.1611; found 747.1678 (M+H)
34 3 4 5 2
Example 362 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2,2,2-
trifluoroethyl)sulfanyl]phenyl}propanoic acid
Using General Procedure (VIIIa) and ethyl (2R)hydroxy[2-(2,2,2-
trifluoroethylsulfanyl)phenyl]propanoate (Preparation 3ay) as the appropriate alcohol, the
diastereoisomer eluting later was collected as Example 362 was obtained. HRMS
calculated for C35H34ClF3N4O5S2: 746.1611; found 747.1682 (M+H)
General Procedure (IXa)
Step A:
1 eq. of ethyl (2R)[6-(5-chlorofuryl)-(5S )[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8f), 2 eq. of the appropriate alcohol and 2 eq.
PPh were dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen. After no
further conversion observed the volatiles were evaporated under reduced pressure and the
crude ester was purified via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. The residue was purified via preparative reversed phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 363 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (IXa) and methanol as the appropriate alcohol, Example 363 was
obtained. HRMS calculated for C H Cl N O S: 696.1576; found 697.1656 (M+H)
34 34 2 4 6
Example 364 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (IXa) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 364 was obtained. HRMS calculated for C H Cl N O S: 766.1995;
38 40 2 4 7
found 767.2056 (M+H)
Example 365 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
214 mg ethyl (2R)[6-(5-chlorofuryl)-(5Sa)[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8f) (0.300 mmol) and 138 mg K CO (1.00 mmol) were
dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.00
mmol) was added. The mixture was stirred at room temperature under nitrogen for 7 hours.
Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was dissolved in 8 mL dioxane-water (1:1) and 126 mg LiOH
× H O (3.00 mmol) was added. The mixture was stirred at room temperature for 1 hour.
Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO , concentrated under reduced pressure
and the residue was purified via preparative reversed phase chromatography using 5 mM
aqueous NH HCO solution and MeCN as eluents to give Example 365. HRMS calculated
for C H Cl F N O S: 764.145; found 765.1523 (M+H)
33 2 3 4 6
Example 366 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IXa) and 2-pyridylmethanol as the appropriate alcohol,
Example 366 was obtained. HRMS calculated for C H Cl N O S: 773.1842; found
39 37 2 5 6
387.5992 (M+2H)
Example 367 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IXa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 367 was obtained. HRMS
calculated for C H Cl F N O S: 842.1668; found 843.175 (M+H)
39 35 2 3 6 6
Example 368 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(morpholinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IXa) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 368 was obtained. HRMS
calculated for C H Cl N O S: 859.2322; found 430.6247 (M+2H)
42 43 2 7 7
Example 369 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (IXa) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol, Example 369 was obtained. HRMS calculated for C H Cl N O S: 804.19; found
39 38 2 6 7
805.2032 (M+H)
Example 370 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IXa) and pyrimidinylmethanol as the appropriate alcohol,
Example 370 was obtained. HRMS calculated for C H Cl N O S: 774.1794; found
38 36 2 6 6
775.182 (M+H)
Example 371 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IXa) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 371 was obtained. HRMS calculated for C H Cl N O S:
38 38 2 6 6
776.1951; found 777.1999 (M+H)
Example 372 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (IXa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol, Example 372 was obtained. HRMS calculated for
C H Cl N O S: 790.2107; found 396.1113 (M+2H)
39 40 2 6 6
Example 373 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-
trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (IXa) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 373 was obtained. HRMS
calculated for C H Cl F N O S: 844.1824; found 845.186 (M+H)
39 37 2 3 6 6
Example 374 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IXa) and pyrazinylmethanol as the appropriate alcohol,
Example 374 was obtained. HRMS calculated for C H Cl N O S: 774.1794; found
38 36 2 6 6
775.1824 (M+H)
Example 375 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrimidin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IXa) and pyrimidinylmethanol as the appropriate alcohol,
Example 375 was obtained. HRMS calculated for C H Cl N O S: 774.1794; found
38 36 2 6 6
775.1869 (M+H)
Example 376 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}[2-(1,3-oxazol
ylmethoxy)phenyl]propanoic acid
Using General Procedure (IXa) and 1,3-oxazolylmethanol as the appropriate alcohol,
Example 376 was obtained. HRMS calculated for C H Cl N O S: 763.1634; found
37 35 2 5 7
764.1685 (M+H)
Example 377 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2S)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Step A:
228 mg of ethyl (2R)[6-(5-chlorofuryl)-(5S )(3-chlorohydroxymethyl-
phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2S)-tetrahydrofuran
yl]methoxy]phenyl]propanoate (Preparation 6g, 0.340 mmol), 101 mg 2-(4-
methylpiperazinyl)ethanol (0.70 mmol), and 184 mg PPh (0.700 mmol) were dissolved
in 2 mL dry toluene, then 161 mg ditertbutyl azodicarboxylate (0.700 mmol) was added.
The mixture was stirred at 50°C under nitrogen until no further conversion observed, than
the volatiles were evaporated under reduced pressure and the residue was purified via flash
chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in 6 mL dioxane-water 1:1 and 150 mg LiOH × H O
was added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM,
then the combined organic phases were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents to give Example 377. HRMS
calculated for C H Cl N O S: 766.1995; found 767.2095 (M+H)
38 40 2 4 7
General Procedure (Xa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8g), 2 eq. of the appropriate alcohol and 2 eq.
triphenyl phosphine were dissolved in dry toluene (5 mL/mmol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 378 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (Xa) and methanol as the appropriate alcohol, Example 378 was
obtained. HRMS calculated for C H ClFN O S: 720.2185; found 721.2243 (M+H).
37 38 4 6
Example 379 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-
[(2R)-tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (Xa) and [(2R)-tetrahydrofuranyl]methanol as the appropriate
alcohol, Example 379 was obtained. HRMS calculated for C H ClFN O S: 790.2603;
41 44 4 7
found 791.2670 (M+H).
Example 380 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(2,2,2-trifluoroethoxy)phenyl]propanoic acid
Step A:
221 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluoromethoxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (Preparation 8g) (0.3 mmol) and 138 mg K CO (1.0 mmol)
were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate
(1.0 mmol) was added. The mixture was stirred at room temperature under nitrogen until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, extracted with DCM. The combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure.
Step B:
The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH ×
H O (3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 380. HRMS calculated for C H ClF N O S: 788.2058; found 789.2133 (M+H).
38 37 4 4 6
Example 381 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridin
ylmethoxy)phenyl]propanoic acid
Using General Procedure (Xa) and 2-pyridylmethanol as the appropriate alcohol, Example
381 was obtained. HRMS calculated for C H ClFN O S: 797.2450; found 399.6308
42 41 5 6
(M+2H).
Example 382 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
{[2-(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Xa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 382 was obtained. HRMS
calculated for C H ClF N O S: 866.2276; found 867.2352 (M+H).
42 39 4 6 6
Example 383 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-
[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (Xa) and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol, Example 383 was obtained. HRMS calculated for C H ClFN O S: 828.2508;
42 42 6 7
found 415.1343 (M+2H).
Example 384 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-
[(1-ethyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Xa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation 9da)
as the appropriate alcohol, Example 384 was obtained. HRMS calculated for
C H ClFN O S: 814.2716; found 408.1436 (M+2H).
42 44 6 6
Example 385 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-
[(1-propyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (Xa) and (1-propyl-1H-pyrazolyl)methanol (Preparation
9db) as the appropriate alcohol, Example 385 was obtained. HRMS calculated for
C43H46ClFN6O6S: 828.2872; found 415.1536 (M+2H).
Example 386 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(pyrazinylmethoxy)phenyl]propanoic acid
Using General Procedure (Xa) and pyrazinylmethanol as the appropriate alcohol,
Example 386 was obtained. HRMS calculated for C H ClFN O S: 798.2403; found
41 40 6 6
799.2474 (M+H).
Example 387 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-
(2-methoxyethoxy)phenyl]propanoic acid
Using General Procedure (Xa) and 2-methoxyethanol as the appropriate alcohol, Example
387 was obtained. HRMS calculated for C H ClFN O S: 764.2447; found 765.2502
39 42 4 7
(M+H).
General Procedure (XIa)
Step A:
1 eq. methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i), 2 eq. of the appropriate
alcohol and 2 eq. PPh were dissolved in dry toluene (0.2 M for the phenol), then 2 eq.
ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using EtOAc
and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, and the combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIb)
Step A:
1 eq. methyl (2R)[(5R )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6n), 2 eq. of the appropriate
alcohol and 2 eq. PPh were dissolved in dry toluene (0.2 M for the phenol), then 2 eq.
ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using EtOAc
and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, and the combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIc)
Step A:
1 eq. methyl (2R)[6-ethyl-(5S )(4-hydroxymethyl-phenyl)thieno[2,3-d]pyrimidin-
4-yl]oxyphenyl-propanoate (Preparation 6j), 2 eq. of the appropriate alcohol and 2 eq.
PPh were dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using EtOAc and MeOH
as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, and the combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XId)
Step A:
1 eq. methyl (2R)[6-ethyl-(5R )(4-hydroxymethyl-phenyl)thieno[2,3-d]pyrimidin-
4-yl]oxyphenyl-propanoate (Preparation 6o), 2 eq. of the appropriate alcohol and 2 eq.
PPh were dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using EtOAc and MeOH
as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H2O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, and the combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIe)
Step A:
1 eq. phenol derivative, 2 eq. of the appropriate alcohol and 2 eq. PPh were dissolved in
dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the crude intermediate was purified
via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM, and the combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIf)
1 eq. ester was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH × H O was
added and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM,
and the combined organic phases were dried over Na SO , filtered and concentrated under
reduced pressure. If necessary it was purified via preparative reversed phase
chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
Example 388 (2R){[(5Sa)(3-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-d]
pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) was hydrolyzed according to
General Procedure (XIf) to give Example 388. HRMS calculated for C H ClN O S:
24 21 2 4
468.0911; found 469.0997 (M+H).
Example 389 (2R){[(5R )(3-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5R )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-d]
pyrimidinyl]oxyphenyl-propanoate (Preparation 6n) was hydrolyzed according to
General Procedure (XIf) to give Example 389. HRMS calculated for C H ClN O S:
24 21 2 4
468.0911; found 469.0982 (M+H).
Example 390 (2R)[((5S ){3-chloro[2-(dimethylamino)oxoethoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-hydroxy-N,N-dimethyl-acetamide as the appropriate
alcohol, Example 390 was obtained. HRMS calculated for C H ClN O S: 553.1438;
28 28 3 5
found 554.1538 (M+H).
Example 391 (2R)[((5S ){3-chloromethyl[2-oxo(pyrrolidin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-hydroxypyrrolidinyl-ethanone as the
appropriate alcohol, Example 391 was obtained. HRMS calculated for C H ClN O S:
30 3 5
579.1595; found 580.1673 (M+H).
Example 392 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)
oxoethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-hydroxy(4-methylpiperazinyl)ethanone as the
appropriate alcohol, Example 392 was obtained. HRMS calculated for C H ClN O S:
31 33 4 5
608.1860; found 609.1948 (M+H).
Example 393 (2R)[((5S ){3-chloromethyl[2-(morpholinyl)
oxoethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-hydroxy(morpholinyl)ethanone as the
appropriate alcohol, Example 393 was obtained. HRMS calculated for C H ClN O S:
30 3 6
595.1544; found 596.1626 (M+H).
Example 394 (2R)({(5S )[4-(benzyloxy)chloromethylphenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
Using General Procedure (XIa) and phenylmethanol as the appropriate alcohol, Example
394 was obtained. HRMS calculated for C H ClN O S: 558.1380; found 559.1465
31 27 2 4
(M+H).
Example 395 (2R)({(5S )[3-chloromethyl(pyridinylmethoxy)phenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
Using General Procedure (XIa) and 4-pyridylmethanol as the appropriate alcohol,
Example 395 was obtained. HRMS calculated for C H ClN O S: 559.1333; found
26 3 4
560.1396 (M+H).
Example 396 (2R)[((5S ){3-chloromethyl[2-(pyridinyl)ethoxy]phenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(3-pyridyl)ethanol as the appropriate alcohol,
Example 396 was obtained. HRMS calculated for C H ClN O S: 573.1489; found
31 28 3 4
574.1559 (M+H).
Example 397 (2R)[((5S ){3-chloromethyl[2-(pyridinyl)ethoxy]phenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(4-pyridyl)ethanol as the appropriate alcohol,
Example 397 was obtained. HRMS calculated for C H ClN O S: 573.1489; found
31 28 3 4
574.1562 (M+H).
Example 398 (2R){[(5S )(4-butoxychloromethylphenyl)ethylthieno[2,3-d]
pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XIa) and butanol as the appropriate alcohol, Example 398
was obtained. HRMS calculated for C H ClN O S: 524.1537; found 525.1619 (M+H).
28 29 2 4
Example 399 (2R)[((5S ){3-chloromethyl[3-(pyridinyl)propoxy]phenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 3-(4-pyridyl)propanol as the appropriate alcohol,
Example 399 was obtained. HRMS calculated for C H ClN O S: 587.1646; found
32 30 3 4
588.1732 (M+H).
Example 400 (2R)[((5S ){3-chloro[3-(dimethylamino)propoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 3-(dimethylamino)propanol as the appropriate
alcohol, Example 400 was obtained. HRMS calculated for C H ClN O S: 553.1802;
29 32 3 4
found 554.1891 (M+H).
Example 401 (2R)[((5S ){3-chloromethyl[3-(2-oxopyrrolidin
yl)propoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 1-(3-hydroxypropyl)pyrrolidinone as the
appropriate alcohol, Example 401 was obtained. HRMS calculated for C H ClN O S:
31 32 3 5
593.1751; found 594.1826 (M+H).
Example 402 (2R)[((5S ){3-chloromethyl[3-(4-methylpiperazin
yl)propoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 3-(4-methylpiperazinyl)propanol as the
appropriate alcohol, Example 402 was obtained. HRMS calculated for C H ClN O S:
32 37 4 4
608.2224; found 609.2304 (M+H).
Example 403 (2R)[((5S ){3-chloro[3-(1H-imidazolyl)propoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 3-(1H-imidazolyl)propanol as the appropriate
alcohol, Example 403 was obtained. HRMS calculated for C H ClN O S: 576.1598;
29 4 4
found 577.1698 (M+H).
Example 404 (2R){[(5S )(3-chloro{3-[(ethylcarbamoyl)amino]propoxy}
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XIa) and 1-ethyl(3-hydroxypropyl)urea as the appropriate
alcohol, Example 404 was obtained. HRMS calculated for C H ClN O S: 596.1860;
33 4 5
found 597.1943 (M+H).
Example 405 (2R)({(5S )[3-chloro(3-hydroxypropoxy)methylphenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
Using General Procedure (XIa) and propane-1,3-diol as the appropriate alcohol, Example
405 was obtained. HRMS calculated for C H ClN O S: 526.1329; found 527.1402
27 27 2 5
(M+H).
Example 406 (2R)[((5Sa){3-chloromethyl[3-(methylsulfonyl)propoxy]phenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 3-methylsulfonylpropanol as the appropriate
alcohol, Example 406 was obtained. HRMS calculated for C H ClN O S : 588.1156;
28 29 2 6 2
found 589.1242 (M+H).
Example 407 (2R)[((5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 407 was obtained. HRMS calculated for C H ClN O S: 539.1646; found
28 30 3 4
540.1742 (M+H).
Example 408 (2R)[((5R ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIb) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 408 was obtained. HRMS calculated for C H ClN O S: 539.1646; found
28 30 3 4
540.1744 (M+H).
Example 409 (2R)[((5S ){4-[2-(dimethylamino)ethoxy]methylphenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIc) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 409 was obtained. HRMS calculated for C H N O S: 505.2035; found
28 31 3 4
506.2096 (M+H).
Example 410 (2R)[((5R ){4-[2-(dimethylamino)ethoxy]methylphenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XId) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 410 was obtained. HRMS calculated for C H N O S: 505.2035; found
28 31 3 4
506.2109 (M+H).
Example 411 (2R){[(5S )(3-chloro{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}-
2-methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XIa) and 2-[2-hydroxyethyl(methyl)amino]ethanol as the
appropriate alcohol, Example 411 was obtained. HRMS calculated for C H ClN O S:
29 32 3 5
569.1751; found 570.1837 (M+H).
Example 412 (2R){[(5S )(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}chloro
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XIa) and 2-[bis(2-hydroxyethyl)amino]ethanol as the
appropriate alcohol, Example 412 was obtained. HRMS calculated for C H ClN O S:
34 3 6
599.1857; found 600.1939 (M+H).
Example 413 (2R)[((5S ){3-chloro[2-(4-hydroxypiperidinyl)ethoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 1-(2-hydroxyethyl)piperidinol as the appropriate
alcohol, Example 413 was obtained. HRMS calculated for C H ClN O S: 595.1908;
31 34 3 5
found 596.1976 (M+H).
Example 414 (2R)[((5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIb) and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 414 was obtained. HRMS calculated for C H ClN O S: 594.2068;
31 35 4 4
found 595.2138 (M+H).
Example 415 (2R)[((5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 415 was obtained. HRMS calculated for C H ClN O S: 594.2068;
31 35 4 4
found 595.2148 (M+H).
Example 416 (2R)[(6-ethyl-(5Ra){2-methyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XId) and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 416 was obtained. HRMS calculated for C H N O S: 560.2457; found
31 36 4 4
561.2524 (M+H).
Example 417 (2R)[(6-ethyl-(5S ){2-methyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIc) and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 417 was obtained. HRMS calculated for C H N O S: 560.2457; found
31 36 4 4
561.2536 (M+H).
Example 418 (2R)[((5S ){3-chloro[2-(1H-imidazolyl)ethoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(1H-imidazolyl)ethanol as the appropriate
alcohol, Example 418 was obtained. HRMS calculated for C H ClN O S: 562.1442;
29 27 4 4
found 563.1537 (M+H).
Example 419 (2R)[((5S ){3-chloromethyl[2-(2-oxoimidazolidin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 1-(2-hydroxyethyl)imidazolidinone as the
appropriate alcohol, Example 419 was obtained. HRMS calculated for C H ClN O S:
29 29 4 5
580.1547; found 581.1613 (M+H).
Example 420 (2R)[((5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(morpholinyl)ethanol as the appropriate alcohol,
Example 420 was obtained. HRMS calculated for C H ClN O S: 581.1751; found
32 3 5
582.1847 (M+H).
Example 421 (2R)[((5R ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIb) and 2-(morpholinyl)ethanol as the appropriate alcohol,
Example 421 was obtained. HRMS calculated for C H ClN O S: 581.1751; found
32 3 5
582.1853 (M+H).
Example 422 (2R)[((5S ){4-[2-(acetylamino)ethoxy]chloromethylphenyl}
ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and N-(2-hydroxyethyl)acetamide as the appropriate
alcohol, Example 422 was obtained. HRMS calculated for C H ClN O S: 553.1438;
28 28 3 5
found 554.1511 (M+H).
Example 423 (2R)({(5S )[3-chloro(2-hydroxyethoxy)methylphenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
Using General Procedure (XIa) and ethylene glycol as the appropriate alcohol, Example
423 was obtained. HRMS calculated for C H ClN O S: 512.1173; found 513.1256
26 25 2 5
(M+H).
Example 424 (2R)({(5Sa)[3-chloro(2-methoxyethoxy)methylphenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
Using General Procedure (XIa) and 2-methoxyethanol as the appropriate alcohol, Example
424 was obtained. HRMS calculated for C H ClN O S: 526.1329; found 527.1400
27 27 2 5
(M+H).
Example 425 (2R)[((5Sa){3-chloro[2-(2-methoxyethoxy)ethoxy]
methylphenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIa) and 2-(2-methoxyethoxy)ethanol as the appropriate
alcohol, Example 425 was obtained. HRMS calculated for C H ClN O S: 570.1591;
29 31 2 6
found 571.1690 (M+H).
Example 426 (2R){[(5S )(3-chlorohydroxymethylnitrophenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5S )(3-chlorohydroxymethylnitro-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15a) was hydrolyzed according
to General Procedure (XIf) to give Example 426. HRMS calculated for C H ClN O S:
24 20 3 6
513.0761; found 514.0840 (M+H).
Example 427 (2R){[(5S )(5-bromochlorohydroxymethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5S )(5-bromochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15f) was hydrolyzed
according to General Procedure (XIf) to give Example 427. HRMS calculated for
C H BrClN O S: 546.0016; found 547.0106 (M+H).
24 20 2 4
Example 428 (2R){[(5S )(3,5-dichlorohydroxymethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5S )(3,5-dichlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15e) was hydrolyzed according
to General Procedure (XIf) to give Example 428. HRMS calculated for C H Cl N O S:
24 20 2 2 4
502.0521; found 503.0582 (M+H).
Example 429 (2R){[(5R )(3,5-dichlorohydroxymethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
40 mg methyl (2R)[6-ethyl-(5R )(4-hydroxymethyl-phenyl)thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6o) (0.089 mmol) was dissolved
in 2 mL THF and 26 mg NCS (0.193 mmol) was added. The mixture was stirred at 55°C
until no further conversion was observed. Then the volatiles were evaporated under
reduced pressure and the crude intermediate was purified via flash chromatography using
heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to
General Procedure (XIf) to give Example 429. HRMS calculated for C H Cl N O S:
24 20 2 2 4
502.0521; found 503.0587 (M+H).
Example 430 (2R)[((5S ){3-chlorohydroxymethyl[(4-methylpiperazin
yl)methyl]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
483 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6i) (1.0 mmol) and 140 mg
hexamethylenetetramine (1.0 mmol) were dissolved in 10 mL TFA and stirred at 90°C for
3 hours. The cooled reaction mixture was poured onto 100 mL icy water and the
precipitated solid was filtered and dried. Then it was dissolved in 20 mL EtOH, 167 L 1-
methylpiperazine (1.5 mmol) and 636 mg Na(OAc) H (3.0 mmol) were added and the
mixture was stirred at room temperature until no further conversion was observed. Then it
was diluted with water, extracted with DCM, combined organic phases were dried over
Na SO , filtered and concentrated under reduced pressure. The crude intermediate was
purified via reversed phase chromatography using aqueous 0.1% TFA solution and MeCN
as eluents. The intermediate obtained in Step A was hydrolyzed according to General
Procedure (XIf) to give Example 430. HRMS calculated for C H ClN O S: 580.1911;
33 4 4
found 581.1972 (M+H).
Example 431 (2R){[(5S )(5-aminochlorohydroxymethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[(5S )(5-aminochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15b) was hydrolyzed
according to General Procedure (XIf) to give Example 431. HRMS calculated for
C H ClN O S: 483.1020; found 484.1083 (M+H).
24 22 3 4
Example 432 (2R)({(5S )[3-chlorohydroxymethyl(4-methylpiperazin
yl)phenyl]ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
1.00 g immobilized PPh (3.00 mmol) and 761 mg iodine (3.00 mmol) were dissolved in 5
mL DCM and stirred for 15 minutes, then 272 mg imidazole (4.00 mmol) was added, and
the mixture was stirred for 10 minutes. Then 115 L 2-[2-
hydroxyethyl(methyl)amino]ethanol (1.00 mmol) was added, and the mixture was stirred
for 1 hour. Then it was filtered, the filtrate was washed with saturated Na S O solution
2 2 3
and brine, dried over Na SO , filtered and concentrated under reduced pressure. To the
formed 2-iodo-N-(2-iodoethyl)-N-methyl-ethanamine 100 mg methyl (2R)[(5S )(5-
aminochlorohydroxymethyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy
phenyl-propanoate (Preparation 15b) (0.20 mmol), 42 mg NaHCO (0.50 mmol) and 2
mL EtOH were added and the mixture was stirred at reflux temperature overnight. Then it
was diluted with EtOAc, washed with water and brine. The combined organic phases were
dried over Na SO , filtered and concentrated under reduced pressure. The crude
intermediate was purified via flash chromatography, using EtOAc and MeOH as eluents.
The obtained intermediate was hydrolyzed according to General Procedure (XIf) to give
Example 432. HRMS calculated for C H ClN O S: 566.1755; found 567.1794 (M+H).
29 31 4 4
Example 433 (2R)({(5S )[3-chloro(formylamino)hydroxymethylphenyl]
ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
mg methyl (2R)[(5S )(5-aminochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15b) (0.07 mmol) was
dissolved in 0.5 mL dry toluene under N . 23 L triethyl-orthoformate (0.136 mmol) was
added and the mixture was stirred at 100°C for 2.5 hours. Then the volatiles were
evaporated under reduced pressure and the residue was purified via flash chromatography,
using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according
to General Procedure (XIf) to give Example 433. HRMS calculated for C H ClN O S:
22 3 5
511.0969; found 512.1048 (M+H).
Example 434 (2R)[((5S ){3-chloromethoxymethyl[(4-methylpiperazin
yl)methyl]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Step A:
408 mg methyl (2R)[(5S )(5-bromochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15f) (0.73 mmol) was
dissolved in 4 mL MeOH, then 444 mg immobilized PPh (1.33 mmol) and 306 mg
ditertbutyl azodicarboxylate (1.33 mmol) were added and the mixture was stirred at 50°C
under nitrogen until no further conversion was observed. Then the mixture was filtered, the
filtrate was concentrated under reduced pressure and the residue was purified via flash
chromatography using heptane and EtOAc as eluents to obtain methyl (2R)[(5S )(5-
bromochloromethoxymethyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy
phenyl-propanoate.
Step B:
195 mg of the bromo derivative (0.34 mmol) synthesized in step A was dissolved in 3 mL
THF, then 309 mg potassium 1-methyltrifluoroboratomethylpiperazine (1.70 mmol), 8
mg Pd(OAc) (0.034 mmol), 28 mg SPhos (0.068 mmol), 665 mg Cs CO (2.04 mmol) and
2 2 3
0.3 mL water were added, and the mixture was heated to 90°C for 10 minutes via
microwave irradiation. Then the volatiles were evaporated under reduced pressure, the
residue was diluted with brine, extracted DCM, and the combined organic phases were
dried over Na SO , filtered and concentrated under reduced pressure. The obtained
intermediate was hydrolyzed according to General Procedure (XIf) to give Example 434.
HRMS calculated for C H ClN O S: 594.2068; found 595.2145 (M+H).
31 35 4 4
Example 435 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]-
-nitrophenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIe), methyl (2R)[(5S )(3-chlorohydroxymethyl
nitro-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation
15a) as the phenol and 2-(4-methylpiperazinyl)ethanol as the appropriate alcohol,
Example 435 was obtained. HRMS calculated for C H ClN O S: 639.1918; found
31 34 5 6
640.1984 (M+H).
Example 436 (2R)[((5S ){3,5-dichloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIe) with methyl (2R)[(5S )(3,5-dichlorohydroxy
methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
(Preparation 15e) as the phenol and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 436 was obtained. HRMS calculated for C H Cl N O S: 628.1678;
31 34 2 4 4
found 629.1776 (M+H).
Example 437 (2R)[((5S ){5-aminochloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XIe) with methyl (2R)[(5S )(5-aminochlorohydroxy-
2-methyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate
(Preparation 15b) as the phenol and 2-(4-methylpiperazinyl)ethanol as the appropriate
alcohol, Example 437 was obtained. HRMS calculated for C H ClN O S: 609.2177;
31 36 5 4
found 610.2226 (M+H).
Example 438 (2R){[(5S )(5-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
100 mg methyl (2R)[6-ethyl-(5S )(4-hydroxymethyl-phenyl)thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 6j) (0.223 mmol) was dissolved
in 5 mL THF, then 31 mg NCS (0.234 mmol) was added. The reaction mixture was stirred
at 60°C overnight. Two monochlorinated and a dichlorinated intermediate were formed.
The volatiles were evaporated under reduced pressure and the isomers were separated via
preparative reversed phase chromatography using 40 mM aqueous NH4OAc solution (pH
was set to 4 with AcOH) and MeCN as eluents. The monochlorinated regioisomer eluting
earlier was collected. The obtained intermediate was hydrolyzed according to General
Procedure (XIf) to give Example 438. HRMS calculated for C H ClN O S: 468.0911;
24 21 2 4
found 469.0981 (M+H).
Example 439 (2R){[(5R )(5-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
105 mg methyl (2R)[6-ethyl-(5R )(4-hydroxymethyl-phenyl)thieno[2,3-d]
pyrimidinyl]oxyphenyl-propanoate (Preparation 6o) (0.234 mmol) was dissolved in
mL THF, then 34 mg NCS (0.257 mmol) was added. The mixture was stirred at 60°C
overnight. Two monochlorinated and a dichlorinated intermediate were formed. The
volatiles were evaporated under reduced pressure, and the mixture was hydrolyzed
according to General Procedure (XIf). The isomer mixture was separated via preparative
reversed phase chromatography using 40 mM aqueous NH OAc solution (pH was set to 4
with AcOH) and MeCN as eluents. The monochlorinated regioisomer eluting later was
collected as Example 439. HRMS calculated for C H ClN O S: 468.0911; found
24 21 2 4
469.0987 (M+H).
Example 440 (2R)[(6-ethyl-(5S ){2-methyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid and (2S)
[(6-ethyl-(5R ){2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}thieno[2,3-
d]pyrimidinyl)oxy]phenylpropanoic acid (racemic)
45 mg 2-(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-propanoic acid
(Preparation 4m) (0.10 mmol), 108 mg 1-methyl[2-[4-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenoxy]ethyl]piperazine (Preparation 5h) (0.30 mmol), 18 mg
Pd dba (0.02 mmol), 14 mg BuPAd (0.04 mmol) and 55 mg K CO (0.40 mmol) were
2 3 2 2 3
dissolved in 2 mL DME and 0.5 mL water. The mixture was heated to 120°C for 10
minutes via microwave irradiation. Then the mixture was cooled to room temperature,
filtered, washed with saturated NaHCO3 solution. The filtrate was washed with Et2O, then
it was acidified with 2 M HCl and extracted with DCM. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure. The
diastereomers were separated and purified via preparative reversed phase chromatography
using 40 mM aqueous NH OAc solution (pH was set to 4 with AcOH) and MeCN as
eluents. The diastereoisomer pair eluting later was collected as Example 440. HRMS
calculated for C H N O S: 560.2457; found 561.2549 (M+H).
31 36 4 4
Example 441 (2R){[(5S )(8-chloromethyloxo-3,4-dihydro-2H-1,4-benzoxazin-
6-yl)ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
100 mg methyl (2R)[(5S )(5-aminochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15b) (0.20 mmol) was
dissolved in 1 mL dry THF under N and was cooled to 0°C. Then 42 mg K CO (0.30
2 2 3
mmol) and 19 L bromoacetyl bromide (0.22 mmol) were added and the mixture was
stirred for 30 minutes, then heated to 50°C and stirred overnight. Then it was concentrated
under reduced pressure and purified via flash chromatography, using heptane and EtOAc
as eluents. The obtained ester was hydrolyzed according to General Procedure (XIf) to give
Example 441. HRMS calculated for C H ClN O S: 523.0969; found 524.1062 (M+H).
26 22 3 5
Example 442 (2R)[((5S ){7-chloro[(dimethylamino)methyl]methyl
benzofuranyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
152 mg methyl (2R)[(5S )(3-chlorohydroxyiodomethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15d) (0.25 mmol), 33
mg N,N-dimethylpropynamine (0.40 mmol), 18 mg PdCl (PPh ) (0.025 mmol) and 5
2 3 2
mg copper(I) iodide (0.025 mmol) were dissolved in 1 mL DIPA under N . The mixture
was stirred at 50°C for 30 minutes. Then it was concentrated under reduced pressure and
purified via flash chromatography, using heptane and EtOAc as eluents. The obtained
intermediate was hydrolyzed according to General Procedure (XIf) to give Example 442.
HRMS calculated for C H ClN O S: 549.1489; found 505.0959 (M+H - Me NH).
29 28 3 4 2
Example 443 (2R){[(5S )(7-chloromethylbenzofuranyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
110 mg methyl (2R)[(5S )(3-chlorohydroxyiodomethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15d) (0.18 mmol), 51
L ethynyl(trimethyl)silane (0.36 mmol), 6.3 mg PdCl (PPh ) (0.009 mmol) and 1.7 mg
2 3 2
copper(I) iodide (0.009 mmol) were dissolved in 2 mL DIPA under N . The mixture was
stirred at 50°C for 10 minutes, then 0.22 mL TBAF (1 M in THF, 0.22 mmol) was added
and the mixture was stirred for additional 20 minutes. Then the volatiles were evaporated
under reduced pressure and the residue was purified via flash chromatography, using
heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to
General Procedure (XIf) to give Example 443. HRMS calculated for C H ClN O S:
26 21 2 4
492.0911; found 493.0999 (M+H).
Example 444 (2R){[(5S )(7-chloro-2,6-dimethyl-1,3-benzoxazolyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
50 mg methyl (2R)[(5S )(5-aminochlorohydroxymethyl-phenyl)ethyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15b) (0.10 mmol) was
dissolved in 0.5 mL dry toluene under N . 27 L triethyl-orthoacetate (0.15 mmol) was
added and the mixture was stirred at 100°C for 2.5 hours. Then the volatiles were
evaporated under reduced pressure and the residue was purified via flash chromatography,
using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according
to General Procedure (XIf) to give Example 444. HRMS calculated for C H ClN O S:
26 22 3 4
507.1020; found 508.1114 (M+H).
Example 445 (2R)[((5S ){7-chloromethyl[(4-methylpiperazinyl)methyl]-
1,3-benzoxazolyl}ethylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
56 mg methyl (2R)[(5S )[7-chloro(chloromethyl)methyl-1,3-benzoxazolyl]-
6-ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15c) (0.10
mmol) was dissolved in 2 mL dry THF under N . 20 mg 4-methyl-piperazine (0.20 mmol)
was added and the mixture was stirred at room temperature for 1 hour. Then the volatiles
were evaporated under reduced pressure and the obtained crude intermediate was
hydrolyzed according to General Procedure (XIf) to give Example 445. HRMS calculated
for C H ClN O S: 605.1864; found 606.1937 (M+H).
31 32 5 4
Example 446 (2R)({(5S )[7-chloromethyl(morpholinylmethyl)-1,3-
benzoxazolyl]ethylthieno[2,3-d]pyrimidinyl}oxy)phenylpropanoic acid
56 mg methyl (2R)[(5S )[7-chloro(chloromethyl)methyl-1,3-benzoxazolyl]-
6-ethyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (Preparation 15c) (0.10
mmol) was dissolved in 2 mL dry THF under N . 18 mg morpholine (0.20 mmol) was
added and the mixture was stirred at room temperature overnight. The volatiles were
evaporated under reduced pressure and the obtained crude intermediate was hydrolyzed
according to General Procedure (XIf) to give Example 446. HRMS calculated for
C H ClN O S: 592.1547; found 593.1613 (M+H).
29 4 5
Example 447 (2R){[6-ethyl-(5S )(4-hydroxymethylphenyl)thieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[6-ethyl-(5S )(4-hydroxymethyl-phenyl)thieno[2,3-d]pyrimidinyl]
oxyphenyl-propanoate (Preparation 6j) was hydrolyzed according to General
Procedure (XIf) to give Example 447. HRMS calculated for C H N O S: 434.1300;
24 22 2 4
found 435.1358 (M+H).
Example 448 (2R){[6-ethyl-(5R )(4-hydroxymethylphenyl)thieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid
Methyl (2R)[6-ethyl-(5R )(4-hydroxymethyl-phenyl)thieno[2,3-d]pyrimidinyl]
oxyphenyl-propanoate (Preparation 6o) was hydrolyzed according to General
Procedure (XIf) to give Example 448. HRMS calculated for C H N O S: 434.1300;
24 22 2 4
found 435.1369 (M+H).
Example 449 (2R){[(5S )(3-chloromethylphenyl)ethylthieno[2,3-d]pyrimidin-
4-yl]oxy}phenylpropanoic acid and (2S){[(5R )(3-chloromethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid (racemic)
373 mg 2-(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-propanoic acid
(Preparation 4m) (0.82 mmol), 280 mg (3-chloromethyl-phenyl)boronic acid (1.64
mmol), 151 mg Pd dba (0.164 mmol), 118 mg BuPAd (0.329 mmol) and 795 mg K CO
2 3 2 2 3
(5.75 mmol) were dissolved in 15 mL DME and 3 mL water. The mixture was heated to
80°C for 30 minutes via microwave irradiation. Then it was cooled to room temperature,
filtered, washed with saturated NaHCO solution. The filtrate was washed with Et O, then
it was acidified with 2 M HCl and extracted with DCM, the combined organic phases were
dried over Na SO , filtered and concentrated under reduced pressure. The diastereomers
were separated and purified via preparative reversed phase chromatography using 40 mM
aqueous NH OAc solution (pH was set to 4 with AcOH) and MeCN as eluents.
Diastereoisomer pair eluting earlier was collected as Example 449. HRMS calculated for
C H ClN O S: 452.0961; found 453.1045 (M+H).
24 21 2 3
Example 450 (2R){[(5S )(3-chloromethylphenyl)ethylthieno[2,3-d]pyrimidin-
4-yl]oxy}phenylpropanoic acid
Example 451 (2R){[(5R )(3-chloromethylphenyl)ethylthieno[2,3-d]pyrimidin-
4-yl]oxy}phenylpropanoic acid
150 mg methyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (Preparation 4i) (0.320 mmol), 164 mg (3-chloromethyl-phenyl)boronic
acid (0.961 mmol), 74 mg Pd(PPh ) (0.064 mmol), and 265 mg Ag CO (0.961 mmol)
3 4 2 3
were dissolved in 6 mL DME. It was heated to 100°C for 10 minutes via microwave
irradiation. Then the mixture was cooled to room temperature, and the volatiles were
evaporated under reduced pressure. The diastereoisomers were separated via flash
chromatography, using heptane and EtOAc as eluents. The diastereoisomer eluting earlier
was collected and hydrolyzed according to General Procedure (XIf) to give Example 450.
HRMS calculated for C H ClN O S: 452.0961; found 453.1040 (M+H). The
24 21 2 3
diastereoisomer eluting later was collected and hydrolyzed according to General Procedure
(XIf) to give Example 451. HRMS calculated for C H ClN O S: 452.0961; found
24 21 2 3
453.1044 (M+H).
Example 452 (2R){[6-ethyl-(5S )(3-hydroxymethylphenyl)thieno[2,3-
d]pyrimidinyl]oxy}phenylpropanoic acid and (2S){[6-ethyl-(5R )(3-hydroxy
methylphenyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid (racemic)
45 mg 2-(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-propanoic acid
(Preparation 4m) (0.10 mmol), 70 mg 2-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (0.30 mmol), 18 mg Pd dba (0.02 mmol), 14 mg BuPAd (0.04
2 3 2
mmol) and 55 mg K CO (0.40 mmol) were dissolved in 2 mL DME and 0.5 mL water. It
was heated to 90°C for 30 minutes via microwave irradiation. Then the mixture was cooled
to room temperature, filtered, washed with saturated NaHCO solution. The filtrate was
washed with Et O, then it was acidified with 2 M HCl and extracted with DCM. The
combined organic phases were dried over Na SO , filtered and concentrated under reduced
pressure. The diastereomers were separated and purified via preparative reversed phase
chromatography using 40 mM aqueous NH OAc solution (pH was set to 4 with AcOH)
and MeCN as eluents. The diastereoisomer pair eluting earlier was collected as Example
452. HRMS calculated for C H N O S: 434.1300; found 435.1371 (M+H).
24 22 2 4
General Procedure (XIIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8h), 2 eq. of the appropriate alcohol and 2. eq triphenyl phosphine were
dissolved in abs. toluene (0.2 M for the phenol), then 2 eq ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using ethyl acetate and methanol as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and the residue was purified via preparative reversed phase chromatography using
25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIIb)
Step A:
1 eq. of the appropriate phenol, 2 eq. 2-(4-methylpiperazinyl)ethanol and 2 eq. triphenyl
phosphine were dissolved in abs. toluene (5 mL/mmol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced
pressure and the residue was purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 453 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-methoxyphenyl)propanoic acid
Using General Procedure (XIIa) and methanol as the appropriate alcohol, Example 453
was obtained. HRMS calculated for C H ClN O S: 624.2173; found 625.2259 (M+H)
32 37 4 5
Example 454 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy][2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Step A:
192 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8h) (0.3 mmol) and 138 mg K CO (1.0 mmol) were dissolved in
2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was
added. The mixture was stirred at room temperature under nitrogen until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM The combined organic phases were dried over Na SO and
concentrated under reduced pressure.
Step B:
The product of Step A was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH × H O
(3.57 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and the residue was purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 454. HRMS calculated for C H ClF N O S: 692.2047; found 693.2151 (M+H)
33 36 3 4 5
Example 455 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]{2-[(2-methoxypyrimidin
yl)methoxy]phenyl}propanoic acid
Using General Procedure (XIIa) and (2-methoxypyrimidinyl)methanol as the
appropriate alcohol, Example 455 was obtained. HRMS calculated for C H ClN O S:
37 41 6 6
732.2497; found 367.1311 (M+2H)
Example 456 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]{2-[(1-ethyl-1H-pyrazol
yl)methoxy]phenyl}propanoic acid
Using General Procedure (XIIa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation
9da) as the appropriate alcohol, Example 456 was obtained. HRMS calculated for
C H ClN O S: 718.2704; found 360.144 (M+2H)
37 43 6 5
Example 457 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy][2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (XIIa) and 2-methoxyethanol as the appropriate alcohol,
Example 457 was obtained. HRMS calculated for C H ClN O S: 668.2435; found
34 41 4 6
335.1297 (M+2H)
Example 458 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2,3-dihydrobenzofuran-
7-yl)propanoic acid
Using General Procedure (XIIb) and ethyl (2R)[(5Sa)(3-chlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy(2,3-dihydrobenzofuran
yl)propanoate (Preparation 17c) as the appropriate phenol, Example 458 were obtained.
HRMS calculated for C33H37ClN4O5S: 636.2173; found 637.2233 (M+H)
Example 459 (2S)[((5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2,3-dihydrobenzofuran-
7-yl)propanoic acid
Using General Procedure (XIIb) and ethyl (2S)[(5R )(3-chlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy(2,3-dihydrobenzofuran
yl)propanoate (Preparation 17d) as the appropriate phenol, Example 459 were obtained.
HRMS calculated for C H ClN O S: 636.2173; found 637.2236 (M+H)
33 37 4 5
Example 460 (2R)(1,3-benzodioxolyl)[((5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]propanoic
acid
Using General Procedure (XIIb) and ethyl (2R)(1,3-benzodioxolyl)[(5S )(3-
chlorohydroxymethyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
(Preparation 17b) as the appropriate phenol, Example 460 was obtained. HRMS
calculated for C H ClN O S: 638.1966; found 639.2067 (M+H)
32 35 4 6
Example 461 (2R)(1-benzofuranyl)[((5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]propanoic
acid
Using General Procedure (XIIb) and ethyl (2R)(benzofuranyl)[(5S )(3-chloro-
4-hydroxymethyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
(Preparation 17e) as the appropriate phenol, Example 461 was obtained. HRMS
calculated for C H ClN O S: 634.2017; found 635.2069 (M+H)
33 35 4 5
Example 462 (2S)(1-benzofuranyl)[((5R ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy]propanoic
acid
Using General Procedure (XIIb) and ethyl (2S)(benzofuranyl)[(5R )(3-chloro-
4-hydroxymethyl-phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate
(Preparation 17f) as the appropriate phenol, Example 462 was obtained. HRMS
calculated for C H ClN O S: 634.2017; found (M+H)
33 35 4 5
Example 463 (2R)[((5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-fluorophenyl)propanoic
acid
Using General Procedure (XIIb) and ethyl (2R)[(5S )(3-chlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-fluorophenyl)propanoate
(Preparation17h) as the phenol, Example 463 was obtained. HRMS calculated for
C H ClFN O S: 612.1973; found 613.205 (M+H)
31 34 4 4
Example 464 (2S)[((5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-fluorophenyl)propanoic
acid
Using General Procedure (XIIb) and ethyl (2S)[(5R )(3-chlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-fluorophenyl)propanoate
(Preparation17g) as the phenol, Example 464 was obtained. HRMS calculated for
C H ClFN O S: 612.1973; found 613.2053 (M+H)
31 34 4 4
General Procedure (XIIIa)
Step A:
1 eq. ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)propynyl-
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 6l), 2 eq.
of the appropriate alcohol and 2 eq. PPh were dissolved in dry toluene (0.2 M for the
phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at
50°C under nitrogen until no further conversion was observed. The volatiles were
evaporated under reduced pressure and the crude intermediate was purified via flash
chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and the residue was purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIIIb)
Step A:
1 eq. phenol derivative, 2 eq. of the appropriate alcohol and 2 eq. PPh were dissolved in
dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the crude intermediate was purified
via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and the residue was purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XIIIc)
1 eq. ester was dissolved in dioxane-water 1:1 (10 mL / mmol) and 10 eq. LiOH × H O
was added and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. If necessary the product was purified via preparative reversed phase
chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
Example 465 (2R){[(5S ){3-chloromethyl[2-(1-methylpiperidin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XIIIa) and 2-(1-methylpiperidyl)ethanol as the appropriate
alcohol, Example 465 was obtained. HRMS calculated for C H ClN O S: 633.2064;
34 36 3 5
found 634.2136 (M+H).
Example 466 (2R){[(5S )(3-chloro{2-[di(propanyl)amino]ethoxy}
methylphenyl)(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XIIIa) and 2-(diisopropylamino)ethanol as the appropriate
alcohol, Example 466 was obtained. HRMS calculated for C H ClN O S: 635.2221;
34 38 3 5
found 636.2310 (M+H).
Example 467 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (XIIIa) and 2-(dimethylamino)ethanol as the appropriate alcohol,
Example 467 was obtained. HRMS calculated for C H ClN O S: 579.1595; found
30 3 5
580.1663 (M+H).
Example 468 (2R){[(5S ){3-chloromethyl[2-(pyrrolidinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (XIIIa) and 2-pyrrolidinylethanol as the appropriate alcohol,
Example 468 was obtained. HRMS calculated for C H ClN O S: 605.1751; found
32 32 3 5
606.1822 (M+H).
Example 469 (2R){[(5S ){3-chloromethyl[2-(piperidinyl)ethoxy]phenyl}
(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (XIIIa) and 2-(1-piperidyl)ethanol as the appropriate alcohol,
Example 469 was obtained. HRMS calculated for C H ClN O S: 619.1908; found
33 34 3 5
620.2011 (M+H).
Example 470 (2R){[(5R )(3-chlorofluoromethoxymethylphenyl)(prop
ynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Example 471 (2R){[(5S )(3-chlorofluoromethoxymethylphenyl)(prop
ynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
522 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (1.00 mmol), 451 mg 2-(3-chlorofluoro-
4-methoxymethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 5i)
(1.50 mmol), 73 mg PdCl × dppf (0.10 mmol) and 652 mg Cs CO (2.00 mmol) were
2 2 3
dissolved in 10 mL dioxane and 2.5 mL water, and heated under nitrogen at 110°C for 10
minutes in a microwave reactor. Then reaction mixture was diluted with brine, neutralized
with 2 M HCl, and extracted with DCM. The combined organic phases were dried over
Na SO , concentrated under reduced pressure and the residue was purified via flash
chromatography, using heptane and EtOAc as eluents, then it was hydrolyzed according to
General Procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example
470. HRMS calculated for C H ClFN O S: 540.0922; found 541.0987 (M+H). The
27 22 2 5
diastereoisomer eluting later was collected as Example 471. HRMS calculated for
C H ClFN O S: 540.0922; found 541.1009 (M+H).
27 22 2 5
Example 472 (2R)({(5R )[3-chloromethoxymethyl(4-methylpiperazin
yl)phenyl](propynyl)thieno[2,3-d]pyrimidinyl}oxy)(2-
methoxyphenyl)propanoic acid
Example 473 (2R)({(5S )[3-chloromethoxymethyl(4-methylpiperazin
yl)phenyl](propynyl)thieno[2,3-d]pyrimidinyl}oxy)(2-
methoxyphenyl)propanoic acid
418 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (0.80 mmol), 381 mg 1-[3-chloro
methoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]methyl-
piperazine (Preparation 5j) (1.00 mmol), 58 mg PdCl × dppf (0.08 mmol) and 391 mg
Cs CO (1.20 mmol) were dissolved in 10 mL dioxane and 2 mL water and was heated
under nitrogen at 110°C for 10 minutes in a microwave reactor. Then reaction mixture was
diluted with brine, and extracted with DCM. The combined organic phases were dried over
Na SO , concentrated under reduced pressure and the residue was purified via flash
chromatography, using heptane and EtOAc as eluents, then it was hydrolyzed according to
General Procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example
472. HRMS calculated for C H ClN O S: 620.1860; found 621.1929 (M+H). The
32 33 4 5
diastereoisomer eluting later was collected as Example 473. HRMS calculated for
C H ClN O S: 620.1860; found 621.1929 (M+H).
32 33 4 5
Example 474 (2R){[(5R ){3-chloro-2,5-dimethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 475 (2R){[(5S ){3-chloro-2,5-dimethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XIIIb), diastereoisomer mixture of ethyl (2R)[5-(3-chloro
hydroxy-2,5-dimethyl-phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 18b) as the phenol and 2-(4-methylpiperazin
yl)ethanol as the appropriate alcohol Example 474 and Example 475 were obtained. The
diastereoisomer eluting earlier was collected as Example 474. HRMS calculated for
C H ClN O S: 648.2173; found 649.2252 (M+H). The diastereoisomer eluting later was
34 37 4 5
collected as Example 475. HRMS calculated for C H ClN O S: 648.2173; found
34 37 4 5
649.2251 (M+H).
Example 476 (2R){[(5S ){3-chlorofluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XIIIb), ethyl (2R)[(5S )(3-chlorofluorohydroxy
methyl-phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate (Preparation 18c) as the phenol and 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol Example 476 was obtained. HRMS calculated for C H ClFN O S:
33 34 4 5
652.1922; found 653.2005 (M+H).
Example 477 (2R){[(5S ){3-chloromethoxymethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
To 57 mg ethyl (2R)[(5S )(3-chlorohydroxymethoxymethyl-phenyl)prop-
1-ynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation
18a) (0.10 mmol), 29 mg 2-(4-methylpiperazinyl)ethanol (0.20 mmol) and 100 mg
immobilized PPh (0.30 mmol) 1 mL dry toluene was added followed by 52 mg 3-
(dimethylcarbamoylimino)-1,1-dimethyl-urea (0.30 mmol). The mixture was stirred at
50°C under nitrogen until no further conversion was observed. Then the mixture was
filtered, the filtrate was concentrated under reduced pressure and the residue was purified
via flash chromatography using EtOAc and MeOH as eluents. The obtained intermediate
was hydrolyzed according to General Procedure (XIIIc) to give Example 477. HRMS
calculated for C H ClN O S: 664.2122; found 665.2200 (M+H).
34 37 4 6
Example 478 (2R){[(5R ){3-chloro[3-(dimethylamino)propyl]methylphenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Example 479 (2R){[(5S ){3-chloro[3-(dimethylamino)propyl]methylphenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
522 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (1.00 mmol), 1.30 mmol 3-[2-chloro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-N,N-dimethyl-propan
amine (Preparation 5n), 71 mg AtaPhos (0.10 mmol) and 652 mg Cs CO (2.00 mmol)
were dissolved in 8 mL dioxane and 2 mL water, and heated under nitrogen at 100°C for
minutes in a microwave reactor. The reaction mixture was diluted with brine and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and the residue was purified via flash chromatography, using
EtOAc and MeOH as eluents. The obtained intermediate was hydrolyzed according to
General Procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example
478. HRMS calculated for C H ClN O S: 577.1802; found 578.1876 (M+H). The
31 32 3 4
diastereoisomer eluting later was collected as Example 479. HRMS calculated for
C H ClN O S: 577.1802; found 578.1881 (M+H).
31 32 3 4
Example 480 (2R){[(5S )(3-chlorohydroxymethylphenyl)(propyn
yl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)propynyl-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 6l) was hydrolyzed
according to General Procedure (XIIIc) to give Example 480. HRMS calculated for
C H ClN O S: 508.0860; found 509.0940 (M+H).
26 21 2 5
General Procedure (XIVa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8i), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were
dissolved in abs. toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate
was added. The mixture was stirred at 50°C under nitrogen until no further conversionwas
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and the residue was purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 481 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
ethoxyphenyl)propanoic acid
Using General Procedure (XIVa) and ethanol as the appropriate alcohol, Example 481 was
obtained. HRMS calculated for C H ClN O S: 648.2173; found 649.2249 (M+H).
34 37 4 5
Example 482 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XIVa) and [2-(2-methoxyphenyl)pyrimidinyl]methanol
(Preparation 9bp) as the appropriate alcohol, Example 482 was obtained. HRMS
calculated for C H ClN O S: 818.2653; found 410.1394 (M+2H).
44 43 6 6
Example 483 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-
methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Step A:
1.30 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
(Preparation 8i) (2.0 mmol), 0.94 g (2-methylsulfanylpyrimidinyl)methanol
(Preparation 9aa) (6.0 mmol) and 1.57 g PPh (6.0 mmol) were dissolved in 40 mL dry
toluene, then 1.38 g di-tert-butyl azodicarboxylate (6.0 mmol) was added. The mixture was
stirred at 50°C under nitrogen. If needed, the addition of (2-methylsulfanylpyrimidin
yl)methanol (Preparation 9aa) (6.0 mmol), PPh (6.0 mmol) and ditertbutyl
azodicarboxylate (6.0 mmol) can be repeated. When no further conversion was observed
the volatiles were evaporated and the residue was purified via flash chromatography using
DCM and MeOH as eluents, to obtain ethyl (2R)[(5S )[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy[2-
[(2-methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate. HRMS calculated for
C H ClN O S : 787.2498; found 787.2464 (M+H).
40 43 6 5 2
Step B:
0.572 g ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methylsulfanylpyrimidin-
4-yl)methoxy]phenyl]propanoate (0.44 mmol), 0.179 g (3-methylpyridyl)boronic acid
(1.31 mmol), 0.25 g copper(I) thiophenecarboxylate (1.31 mmol) and 51 mg Pd(PPh )
were dissolved in 5 mL dry THF heated under nitrogen at 70 °C. If needed, the addition of
reagents was repeated. When no further conversion was observed, the volatiles were
evaporated and the residue was purified via flash chromatography using DCM and MeOH
as eluents.
Step C:
The product of Step B was dissolved in 5 mL dioxane-water 1:1 and 10 eq. LiOH × H O
was added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced
pressure and the residue was purified via preparative reverse phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents to furnish Example 483. HRMS
calculated for C H ClN O S: 803.2657; found 402.6401 (M+2H).
43 42 7 5
Example 484 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XIVa) and [2-(2-methoxyethyl)pyrimidinyl]methanol
(Preparation 9bl) as the appropriate alcohol, Example 484 was obtained. HRMS
calculated for C H ClN O S: 770.2653; found 386.1410 (M+2H).
40 43 6 6
Example 485 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(morpholinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XIVa) and (2-(morpholinyl)pyrimidinyl)methanol
(Preparation 9ar) as the appropriate alcohol, Example 485 was obtained. HRMS
calculated for C H ClN O S: 797.2762; found 399.6446 (M+2H).
41 44 7 6
Example 486 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XIVa) and (2-methoxypyrimidinyl)methanol as the
appropriate alcohol, Example 486 was obtained. HRMS calculated for C H ClN O S:
38 39 6 6
742.2340; found 743.2424 (M+H).
Example 487 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XIVa) and [2-(2,2,2-trifluoroethoxy)pyrimidinyl]methanol
(Preparation 9ai) as the appropriate alcohol, Example 487 was obtained. HRMS
calculated for C H ClF N O S: 810.2214; found 811.2323 (M+H).
39 38 3 6 6
Example 488 (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propyn
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XIVa) and (1-tert-butyl-1H-pyrazolyl)methanol
(Preparation 9dt) as the appropriate alcohol, Example 488 was obtained. HRMS
calculated for C H ClN O S: 756.2861; found 379.1485 (M+2H).
40 45 6 5
Example 489 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2-
trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (XIVa) and [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol
(Preparation 9du) as the appropriate alcohol, Example 489 was obtained. HRMS
calculated for C H ClF N O S: 782.2265; found 783.2353 (M+H).
38 38 3 6 5
Example 490 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propyn
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XIVa) and (1-butyl-1H-pyrazolyl)methanol (Preparation
9dd) as the appropriate alcohol, Example 490 was obtained. HRMS calculated for
C H ClN O S: 756.2861; found 757.2953 (M+H).
40 45 6 5
Example 491 (2S)(1-benzofuranyl){[(5R ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Step A:
0.137 g ethyl (2S)(benzofuranyl)[(5R )5-(3-chlorohydroxymethyl-phenyl)
propynyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation 20b) (0.25 mmol),
0.072 g 2-(4-methylpiperazinyl)ethanol (0.5 mmol) and 0.166 g PPh (0.5 mmol) were
dissolved in 4 mL dry toluene and 0.115 g ditertbutyl azodicarboxylate (0.5 mmol) was
added and it was heated at 50°C. If needed, the addition of reagents can be repeated. When
no further conversion was observed the volatiles were evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in 10 mL dioxane-water 1:1 and 0.200 g LiOH × H O
(5.88 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and the residue was purified via preparative reverse phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to furnish
Example 491. HRMS calculated for C H ClN O S: 644.1860; found 645.1934 (M+H).
34 33 4 5
Example 492 (2R)(1-benzofuranyl){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidin
yl]oxy}propanoic acid
Step A:
0.137 g ethyl (2R)(benzofuranyl)[(5S )5-(3-chlorohydroxymethyl-phenyl)
propynyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation 20a) (0.25 mmol),
0.072 g 2-(4-methylpiperazinyl)ethanol (0.5 mmol) and 0.166 g PPh (0.5 mmol) were
dissolved in 4 mL dry toluene and 0.115 g ditertbutyl azodicarboxylate (0.5 mmol) was
added and it was heated at 50°C. If needed, the addition of reagents can be repeated. When
no further conversion was observed the volatiles were evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in 10 mL dioxane-water 1:1 and 0.200 g LiOH × H O
(5.88 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and the residue was purified via preparative reverse phase
chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to furnish
Example 492. HRMS calculated for C H ClN O S: 644.1860; found 645.1935 (M+H).
34 33 4 5
General Procedure (XVa)
Step A:
1 eq. methyl (2R)[6-bromo-(5S )(3-chlorohydroxymethyl-phenyl)thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 22), 2.5 eq. of the appropriate
boronic ester or boronic acid and 2.5 eq. Cs CO were dissolved in THF-water (4:1) (12.5
ml/mmol of Preparation 22), then 0.1 eq Pd(dppf)Cl was added. The mixture was heated
under nitrogen at 110°C in a microwave reactor until no further conversion was observed.
Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO , concentrated under reduced pressure
and the residue was purified via flash chromatography using heptane and ethyl acetate as
eluents.
Step B:
1 eq. of the product of Step A, 2 eq. 2-(4-methylpiperazinyl)ethanol and 2 eq. PPh were
dissolved in dry toluene (5 mL/mmol of the product of Step A), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step C:
The product of Step B was dissolved in dioxane-water 1:1 (10 mL/mmol product of Step
B) and 10 eq. LiOH × H O was added. The mixture was stirred at room temperature until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, and extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure and the residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XVb)
Step A:
1 eq. phenol derivative, 2 eq. 2-(4-methylpiperazinyl)ethanol and 2 eq. triphenyl
phosphine were dissolved in dry toluene (5 mL/mmol of phenol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol product of Step
A) and 10 eq. LiOH × H O was added. The mixture was stirred at room temperature until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, and extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure and the residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 493 (2R)[(6-[(1Z)-butenyl]-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic
acid
Step A:
8.45 g 4-chloro-5,6-diiodo-thieno[2,3-d]pyrimidine (Preparation 1b) (20 mmol), 5.41 g
methyl (2R)hydroxyphenyl-propanoate (Preparation 3ag) (30 mmol) and 13.03 g
Cs CO (40 mmol) were placed in a flask. 20 mL DMSO was added and the mixture was
stirred at 60°C until no further conversion was observed. It was diluted with water, the pH
was set to 5 with 2 M HCl, and then it was extracted with dichloromethane. The combined
organic layers were dried over Na SO , concentrated under reduced pressure, and purified
via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (2R)-
2-(5,6-diiodothieno[2,3-d]pyrimidinyl)oxyphenyl-propanoate. H NMR (400 MHz,
DMSO-d6): 8.49 (s, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 1H), 5.78 (dd, 1H), 3.75 (s,
3H), 3.50-3.35 (m, 2H).
Step B:
230 mg methyl (2R)(5,6-diiodothieno[2,3-d]pyrimidinyl)oxyphenyl-propanoate
(0.4 mmol), 14 mg Pd(PPh )2Cl (0.02 mmol) and 4 mg CuI (0.02 mmol) were dissolved in
3 mL DIPA, then butyne was bubbled through the reaction mixture, which was stirred at
°C until no further conversion was observed. The reaction mixture was concentrated
under reduced pressure and purified via flash chromatography using heptane and ethyl
acetate as eluents to obtain methyl (2R)(6-butynyliodo-thieno[2,3-d]pyrimidin
yl)oxyphenyl-propanoate. H NMR (400 MHz, CDCl ): 8.52 (s, 1H), 7.43 (m, 2H), 7.29
(m, 2H), 7.22 (m, 1H), 5.76 (dd, 1H), 3.73 (s, 3H), 3.49-3.35 (m, 2H), 2.54 (q, 2H), 1.31 (t,
3H).
Step C:
189 mg methyl (2R)(6-butynyliodo-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (0.383 mmol) and 155 mg 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (Preparation 5a) (0.6 mmol) were dissolved in 3 mL 2-methyl-
tetrahydrofurane, 600 µL tetrabutyl ammonium hydroxyde (1M in water, 0.6 mmol) was
added. Then 27 mg AtaPhos (0.038 mmol) was added and the reaction mixture was heated
under nitrogen at 110°C in a microwave reactor until no further conversion was observed.
Then reaction mixture was diluted with dichloromethane and brine, the pH was set to 5
with 2 M HCl, and extracted with dichloromethane. The combined organic layers were
dried over Na SO and concentrated under reduced pressure. The residue was purified via
flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer
eluting later was collected as methyl (2R)[6-butynyl-(5Sa)(2-chlorohydroxy
methyl-phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. MS: (M+H) =
507.0.
Step D:
50 mg methyl (2R)[6-butynyl-(5S )(2-chlorohydroxymethyl-
phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (0.1 mmol) and 2 mg
Pd/BaCO3 (5 m/m%) (0.001 mmol) was dissolved in 10 mL methanol. Then 2.5 mL H2
was added and the reaction mixture was stirred at room temperature until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
crude intermediate was purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN to obtain methyl (2R)[6-[(1Z)-butenyl]-
(5S )(2-chlorohydroxymethyl-phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-
propanoate. H NMR (500 MHz, DMSO-d ): 10.35 (br s, 1H), 8.54 (s, 1H), 7.15 (m, 3H),
7.07 (d, 1H), 7.01 (d, 1H), 6.65 (m, 2H), 6.31 (dt, 1H), 6.14 (d, 1H), 5.44 (dd, 1H), 3.56 (s,
3H), 2.95 (dd, 1H), 2.65 (dd, 1H), 2.16 (g, 2H), 2.00 (s, 3H), 0.96 (t, 3H). HRMS: (M+H)
= 509.1324.
Step E:
20 mg methyl (2R)[6-[(1Z)-butenyl]-(5S )(2-chlorohydroxymethyl-phenyl)
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (0.039 mmol), 12 mg 2-(4-
methylpiperazinyl)ethanol (0.08 mmol) and 26 mg triphenyl phosphine (0.08 mmol)
were dissolved in 3 mL dry toluene, then 18 mg ditertbutyl azodicarboxylate (0.08 mmol)
was added. The mixture was stirred at 40°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the residue was
purified via flash chromatography using ethyl acetate and methanol as eluents.
Step F:
The product of Step E was dissolved in 1 mL dioxane-water (1:1) and 17 mg LiOH × H O
(0.4 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated
under reduced pressure, and the residue was purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 493. HRMS calculated for C H ClN O S: 620.2224; found (M+H)
33 37 4 4
Example 494 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-methylpropenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(2-methylpropenyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 494 was obtained. HRMS
calculated for C H ClN O S: 620.2224; found 621.2287 (M+H)
33 37 4 4
Example 495 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(4-methylthienyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 495 was obtained. HRMS
calculated for C H ClN O S : 662.1788; found 663.1884 (M+H)
34 35 4 4 2
Example 496 (2R){[6-(1-benzofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 2-(benzofuranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 496 was obtained. HRMS
calculated for C H ClN O S: 682.2017; found 683.2084 (M+H)
37 35 4 5
Example 497 (2R){[6-(1-benzothiophenyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 2-(benzothiophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 497 was obtained. HRMS
calculated for C H ClN O S : 698.1788; found 699.1879 (M+H)
37 35 4 4 2
Example 498 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 498 was obtained. HRMS
calculated for C H ClFN O S: 660.1973; found 661.2042 (M+H)
34 4 4
Example 499 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-methylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(5-methylfuryl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 499 was obtained. HRMS
calculated for C H ClN O S: 646.2017; found 647.2091 (M+H)
34 35 4 5
Example 500 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(5-methylthienyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 500 was obtained. HRMS
calculated for C H ClN O S : 662.1788; found 663.1874 (M+H)
34 35 4 4 2
Example 501 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-chlorothiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and (5-chlorothienyl)boronic acid as the appropriate
boronic acid, Example 501 was obtained. HRMS calculated for C H Cl N O S :
33 32 2 4 4 2
682.1242; found 683.1308 (M+H)
Example 502 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}phenylthieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethylphenyl-1,3,2-dioxaborolane as
the appropriate boronic ester, Example 502 was obtained. HRMS calculated for
C H ClN O S: 642.2068; found 643.2135 (M+H)
35 4 4
Example 503 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1-methyl-1H-pyrrolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrrole as the appropriate boronic ester, Example 503 was obtained. HRMS
calculated for C H ClN O S: 645.2177; found 646.2222 (M+H)
34 36 5 4
Example 504 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XVa) and 2-(2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as
the appropriate boronic ester, Example 504 was obtained. HRMS calculated for
C H ClN O S: 632.186; found 633.1939 (M+H)
33 33 4 5
Example 505 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 2-thienylboronic acid as the appropriate boronic acid,
Example 505 was obtained. HRMS calculated for C H ClN O S : 648.1632; found
33 33 4 4 2
649.172 (M+H)
Example 506 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1-methyl-1H-pyrazolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole as the appropriate boronic ester, Example 506 was obtained. HRMS
calculated for C H ClN O S: 646.2129; found 647.2195 (M+H)
33 35 6 4
Example 507 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(pyridinyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridine as the appropriate boronic ester, Example 507 was obtained. HRMS calculated
for C H ClN O S: 643.202; found 644.2089 (M+H)
34 34 5 4
Example 508 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1-methyl-1H-pyrazolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole as the appropriate boronic ester, Example 508 was obtained. HRMS
calculated for C H ClN O S: 646.2129; found 647.222 (M+H)
33 35 6 4
Example 509 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Using General Procedure (XVa) and 2-(3-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as
the appropriate boronic ester Example 509 was obtained. HRMS calculated for
C H ClN O S: 632.186; found 633.196 (M+H)
33 33 4 5
Example 510 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(3-thienyl)-1,3,2-dioxaborolane
as the appropriate boronic ester, Example 510 was obtained. HRMS calculated for
C H ClN O S : 648.1632; found 649.1711 (M+H)
33 33 4 4 2
Example 511 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(2-methylthienyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 511 was obtained. HRMS
calculated for C H ClN O S : 662.1788; found 663.1864 (M+H)
34 35 4 4 2
Example 512 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1,3-thiazolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3-
thiazole as the appropriate boronic ester, Example 512 was obtained. HRMS calculated for
C H ClN O S : 649.1584; found 650.1654 (M+H)
32 32 5 4 2
Example 513 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1-methyl-1H-pyrazolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole as the appropriate boronic ester, Example 513 was obtained. HRMS
calculated for C H ClN O S: 646.2129; found 647.2199 (M+H)
33 35 6 4
Example 514 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Step A:
531 mg 4-bromomethyl-thiophene (3.0 mmol), 813 mg 2-(5,5-dimethyl-1,3,2-
dioxaborinanyl)-5,5-dimethyl-1,3,2-dioxaborinane (3.6 mmol) and 883 mg KOAc (9.0
mmol) were dissolved in 15 mL 1,4-dioxane, then 219 mg Pd(dppf)Cl (0.3 mmol) was
added. The mixture was heated under nitrogen at 120°C in a microwave reactor until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain
5,5-dimethyl(5-methylthienyl)-1,3,2-dioxaborinane. H NMR (500 MHz, CDCl ):
7.59 (d, 1H), 7.00 (dd, 1H), 3.73 (s, 4H), 2.49 (d, 3H), 1.02 (s, 6H).
Step B:
Using General Procedure (XVa) and 5,5-dimethyl(5-methylthienyl)-1,3,2-
dioxaborinane as the appropriate boronic ester, Example 514 was obtained. HRMS
calculated for C H ClN O S : 662.1788; found 663.1884 (M+H)
34 35 4 4 2
Example 515 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-methyl-1,3-thiazolyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1,3-thiazole as the appropriate boronic ester, Example 515 was obtained. HRMS
calculated for C H ClN O S : 663.1741; found 664.1823 (M+H)
33 34 5 4 2
Example 516 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(4-methylthienyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 516 was obtained. HRMS
calculated for C34H35ClN4O4S2: 662.1788; found 663.1863 (M+H)
Example 517 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-methylthiophenyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Using General Procedure (XVa) and 4,4,5,5-tetramethyl(3-methylthienyl)-1,3,2-
dioxaborolane as the appropriate boronic ester, Example 517 was obtained. HRMS
calculated for C H ClN O S : 662.1788; found 663.1882 (M+H)
34 35 4 4 2
Example 518 (2R)[(6-bromo-(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Step A:
180 mg methyl (2R)[6-bromo-(5S )(3-chlorohydroxymethyl-phenyl)thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 22) (0.335 mmol), 96 mg 2-(4-
methylpiperazinyl)ethanol (0.672 mmol) and 177 mg PPh (0.672 mmol) were dissolved
in 6 mL dry toluene, then 145 mg ditertbutyl azodicarboxylate (0.672 mmol) was added.
The mixture was stirred at 50°C under nitrogen until no further conversion was observed.
The volatiles were evaporated under reduced pressure and the residue was purified via
flash chromatography using ethyl acetate and methanol as eluents.
Step B:
The product of Step A was dissolved in 5 ml methanol and 50 mg NaOH (1.25 mmol) was
added. The mixture was stirred at 50°C until no further conversion was observed. It was
diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined
organic layers were dried over Na SO , concentrated under reduced pressure, and the
residue was purified via preparative reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents to obtain Example 518. HRMS calculated for
C H BrClN O S: 644.086; found 645.0942 (M+H)
29 30 4 4
Example 519 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic
acid
Step A:
8.45 g 4-chloro-5,6-diiodo-thieno[2,3-d]pyrimidine (Preparation 1b) (20 mmol), 5.41 g
methyl (2R)hydroxyphenyl-propanoate (Preparation 3ag) (30 mmol) and 13.03 g
Cs CO (40 mmol) were placed in a flask. 20 mL DMSO was added and the mixture was
stirred at 60°C until no further conversion was observed. The reaction mixture was diluted
with water, the pH was set to 5 with 2 M HCl, and then it was extracted with
dichloromethane. The combined organic layers were dried over Na SO , concentrated
under reduced pressure, and the residue was purified via flash chromatography using
heptane and ethyl acetate as eluents to obtain methyl (2R)(5,6-diiodothieno[2,3-
d]pyrimidinyl)oxyphenyl-propanoate. H NMR (400 MHz, DMSO-d ): 8.49 (s, 1H),
7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 1H), 5.78 (dd, 1H), 3.75 (s, 3H), 3.50-3.35 (m, 2H).
Step B:
1.132 g methyl (2R)(5,6-diiodothieno[2,3-d]pyrimidinyl)oxyphenyl-propanoate (2
mmol), 70 mg Pd(PPh ) Cl (0.1 mmol) and 38 mg CuI (0.2 mmol) were dissolved in 10
mL DIPA, then propyne was bubbled through the reaction mixture, which was stirred at
45°C until no further conversion was observed. It was concentrated under reduced pressure
and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain
methyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate. MS: (M+H) = 479.0.
Step C:
469 mg methyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxyphenyl-
propanoate (0.98 mmol) and 537 mg 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (Preparation 5a) (2.0 mmol) were dissolved in 10 mL 1,4-
dioxane, then 815 mg Cs CO (2.5 mmol) dissolved in 2 mL water was added followed by
71 mg AtaPhos (0.1 mmol) and the mixture was heated under nitrogen at 110°C in a
microwave reactor until no further conversion was observed. After dilution with
dichloromethane and brine the pH was set to 5 with 2 M HCl and the aqueous phase was
extracted with dichloromethane. The combined organic layers were dried over Na2SO4,
concentrated under reduced pressure. The diastereoisomers were separated via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected as methyl (2R)[(5S )(2-chlorohydroxymethyl-phenyl)
propynyl-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. MS: (M+H) = 493.0.
Step D:
360 mg methyl (2R)[(5S )(2-chlorohydroxymethyl-phenyl)propynyl-
thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (0.73 mmol), 211 mg 2-(4-
methylpiperazinyl)ethanol (1.46 mmol) and 487 mg triphenyl phosphine (1.46 mmol)
were dissolved in 5 mL dry toluene, then 336 mg ditertbutyl azodicarboxylate (1.46 mmol)
was added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using ethyl acetate and methanol as eluents.
Step E:
The product of Step D was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic layers were dried over Na SO , concentrated under reduced
pressure, and the residue was purified via preparative reversed phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain Example 519.
HRMS calculated for C H ClN O S: 604.1911; found 605.2 (M+H)
32 33 4 4
Example 520 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(cyclopropylethynyl)thieno[2,3-d]pyrimidinyl]oxy}
phenylpropanoic acid
Step A:
1.132 g methyl (2R)(5,6-diiodothieno[2,3-d]pyrimidinyl)oxyphenyl-propanoate
(from Step A of Example 519, 2 mmol), 152 mg ethynylcyclopropane (2.3 mmol), 70 mg
Pd(PPh ) Cl (0.1 mmol) and 38 mg CuI (0.2 mmol) were dissolved in 4 mL DIPA and the
mixture was stirred uinder nitrogen at 40°C until no further conversion was observed. The
reaction was concentrated under reduced pressure and purified via flash chromatography
using heptane and ethyl acetate as eluents to obtain methyl (2R)[6-(2-
cyclopropylethynyl)iodo-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. MS:
(M+H) = 505.0.
Step B:
968 mg methyl (2R)[6-(2-cyclopropylethynyl)iodo-thieno[2,3-d]pyrimidinyl]oxy-
3-phenyl-propanoate (1.92 mmol) and 670 mg 2-chloromethyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.5 mmol) were dissolved in 8 mL 2-
methyl-tetrahydrofurane and 2.5 mL tetrabutylammonium hydroxyde (1M in water, 2.5
mmol) was added followed by 68 mg AtaPhos (0.096 mmol). The mixture was heated
under nitrogen at 110°C in a microwave reactor until no further conversion was observed.
Then it was diluted with dichloromethane and brine, the pH was set to 5 with 2 M HCl and
the aqueous phase was extracted with dichloromethane. The combined organic layers were
dried over Na SO , concentrated under reduced pressure. The diastereoisomers were
separated via flash chromatography using heptane and ethyl acetate as eluents. The
diastereoisomer eluting later was collected as methyl (2R)[(5S )(2-chlorohydroxy-
3-methyl-phenyl)(2-cyclopropylethynyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-
propanoate. MS: (M+H) = 519.0.
Step C:
156 mg methyl (2R)[(5S )(2-chlorohydroxymethyl-phenyl)(2-
cyclopropylethynyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (0.3 mmol), 87
mg 2-(4-methylpiperazinyl)ethanol (0.6 mmol) and 158 mg triphenyl phosphine (0.6
mmol) were dissolved in 3 mL dry toluene, then 138 mg ditertbutyl azodicarboxylate (0.6
mmol) was added. The mixture was stirred at 50°C under nitrogen until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
crude intermediate was purified via flash chromatography using ethyl acetate and methanol
as eluents.
Step D:
The product of Step C was dissolved in 5 mL methanol and 200 mg LiOH × H2O (4.76
mmol) was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
DCM, dried over Na SO , filtered and concentrated under reduced pressure and purified
via preparative reversed phase chromatography using 25 mM aqueous NH HCO solution
and MeCN as eluents to obtain Example 520. HRMS calculated for C H ClN O S:
34 35 4 4
630.2068; found 631.2096 (M+H)
Example 521 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}cyanothieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Step A:
935 mg [2-chloro(4-chlorothieno[2,3-d]pyrimidinyl)methyl-phenoxy]-
triisopropyl-silane (Preparation 23a) (2.0 mmol) was dissolved in 20 mL dry THF then
cooled to -78°C under argon atmosphere. 1.2 mL lithium diisopropylamide (2.4 mmol, 2 M
in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then
471 mg p-tolylsulfonylformonitrile (2.6 mmol) was added and the mixture was allowed to
warm up to room temperature. To the reaction mixture saturated aq. NH Cl was added and
then extracted with ethyl acetate. Organic layer was dried over Mg SO , filtered and
concentrated under reduced pressure. The crude intermediate was purified via flash
chromatography using heptane and ethyl acetate as eluents to obtain 4-chloro(3-chloro-
2-methyltriisopropylsilyloxy-phenyl)thieno[2,3-d]pyrimidinecarbonitrile.
H NMR (400 MHz, DMSO-d ): 9.16 (s, 1H), 7.26 (d, 1H), 7.03 (d, 1H), 2.10 (s, 3H),
1.42-1.30 (m, 3H), 1.10 (dd, 18H).
Step B:
380 mg 4-chloro(3-chloromethyltriisopropylsilyloxy-phenyl)thieno[2,3-d]
pyrimidinecarbonitrile (0.77 mmol) was dissolved in 7 mL PrOH, 166 mg methyl (2R)-
2-hydroxyphenyl-propanoate (Preparation 3ag) (0.92 mmol) and 753 mg Cs CO (2.31
mmol) was added and the mixture was stirred at room temperature until no further
conversion was observed. It was diluted with water, the pH of the mixture was set to 4 with
2 M HCl, and extracted with DCM. The combined organic layers were dried over Na SO ,
concentrated under reduced pressure, and the residue was purified via flash
chromatography using heptane and ethyl acetate as eluents.
Step C:
The product of Step B was dissolved in 10 mL THF, 0.8 mL TBAF (1M in THF) (0.8
mmol) was added and the mixture was stirred until no further conversion was observed.
Then it was diluted with ethyl acetate, washed with water and brine. The organic layer was
dried over Na SO , filtered and concentrated under reduced pressure and purified via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected to obtain methyl (2R)[(5S )(3-chlorohydroxymethyl-
phenyl)cyano-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. MS: (M+H) =
480.0.
Step D:
Using General Procedure (XVb) and methyl (2R)[(5S )(3-chlorohydroxy
methyl-phenyl)cyano-thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate as the
appropriate phenol Example 521 was obtained. HRMS calculated for C H ClN O S:
30 5 4
591.1707; found 592.1786 (M+H)
Example 522 (2R)[(6-acetyl-(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]phenylpropanoic acid
Step A:
935 mg [2-chloro(4-chlorothieno[2,3-d]pyrimidinyl)methyl-phenoxy]-
triisopropyl-silane (Preparation 23a) (2.0 mmol) was dissolved in 20 mL dry THF then
cooled to -78°C under argon atmosphere. 1.2 mL lithium diisopropylamide (2.4 mmol, 2 M
in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then
265 mg acetic anhydride (2.6 mmol) was added and the mixture was allowed to warm up
to room temperature. To the reaction mixture saturated NH Cl was added and then
extracted with ethyl acetate. The combined organic layers were dried over Na SO ,
concentrated under reduced pressure, and the residue purified via flash chromatography,
using heptane and EtOAc as eluents to obtain 1-[4-chloro(3-chloromethyl
triisopropylsilyloxy-phenyl)thieno[2,3-d]pyrimidinyl]ethanone. H NMR (400 MHz,
CDCl ): 8.94 (s, 1H), 6.98 (d, 1H), 6.95 (d, 1H), 2.17 (s, 1H), 2.03 (s, 1H), 1.44-1.32 (m,
3H), 1.17 (d, 18H).
Step B:
278 mg 1-[4-chloro(3-chloromethyltriisopropylsilyloxy-phenyl)thieno[2,3-
d]pyrimidinyl]ethanone (0.55 mmol) was dissolved in 5 mL PrOH, 118 mg methyl
(2R)hydroxyphenyl-propanoate (Preparation 3ag) (0.65 mmol) and 538 mg Cs CO
(1.65 mmol) was added and the mixture was stirred at room temperature until no further
conversion was observed. It was diluted with water, the pH of the mixture was set to 4 with
2 M HCl, and extracted with dichloromethane. The combined organic layers were dried
over Na SO , concentrated under reduced pressure, and the residue was purified via flash
chromatography using heptane and ethyl acetate as eluents.
Step C:
The product of Step B was dissolved in 10 mL THF, 6 mL TBAF (1M in THF) (0.6 mmol)
was added and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with ethyl acetate, washed with water and brine. The organic
layer was dried over Na SO , concentrated under reduced pressure and purified via flash
chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting
later was collected to obtain methyl (2R)[6-acetyl-(5S )(3-chlorohydroxy
methyl-phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. H NMR (500 MHz,
DMSO-d ): 10.44 (br s, 1H), 8.71 (s, 1H), 7.20 (m, 3H), 7.16 (d, 1H), 7.03 (d, 1H), 6.82
(m, 2H), 5.46 (dd, 1H), 4.75 (m, 1H), 2.87 (dd, 1H), 2.64 (dd, 1H), 2.03 (s, 3H), 1.94 (s,
3H), 1.07 (d, 3H), 0.91 (d, 3H). HRMS: (M+H) = 525.1244
Step D:
Using General Procedure (XVb) and methyl (2R)[6-acetyl-(5S )(3-chlorohydroxy-
2-methyl-phenyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate as the appropriate
phenol, Example 522 was obtained. HRMS calculated for C H ClN O S: 608.186; found
31 33 4 5
609.194 (M+H)
General Procedure (XVI)
Step A:
2.5 eq. of the appropriate boronic acid was dissolved in dry dioxane (5 mL/mmol
Preparation 25), then 2.5 eq pinacol and dry acidic Amberlyst (100 mg/mmol boronic
acid) were added and the mixture was stirred at room temperature overnight, then it was
filtered (if the appropriate boronic ester was available, then it was dissolved in dioxane (5
mL /mmol Preparation 25) and this solution was used instead of the filtrate). 1 eq. ethyl
(2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate (Preparation 25), 0.1 eq. PdCl × dppf, 2.5 eq.
Cs CO and water (2.5 mL/mmol) were added to the filtrate and the mixture was heated
under nitrogen at 110°C in a microwave reactor until no further conversion was observed.
Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The residue was purified via flash chromatography using heptane and EtOAc as
eluents.
Step B:
1 eq. of the product of Step A, 2 eq. of 2-(4-methylpiperazinyl)ethanol and 2 eq. PPh
were dissolved in dry toluene (0.2 M for the product of Step A), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.
Step C:
The product of Step B was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents.
Example 523 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4,5-trifluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(3,4,5-trifluorophenyl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 523 was obtained.
HRMS calculated for C H ClF N O S: 726.1891; found 727.1963 (M+H).
36 34 3 4 5
Example 524 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4-difluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}
(2-methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3,4-difluoromethoxy-phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 524
was obtained. HRMS calculated for C H ClF N O S: 738.2090; found 739.2158 (M+H).
37 37 2 4 6
Example 525 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3,4,5-tetrafluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(2,3,4,5-tetrafluorophenyl)-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 525 was
obtained. HRMS calculated for C H ClF N O S: 744.1796; found 745.1873 (M+H).
36 33 4 4 5
Example 526 (2R){[6-(3-chlorofluorophenyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-chlorofluoro-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 526 was
obtained. HRMS calculated for C36H35Cl2FN4O5S: 724.1689; found 725.1766 (M+H).
Example 527 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,5-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 527 was obtained.
HRMS calculated for C H ClF N O S: 708.1985; found 709.2054 (M+H).
36 35 2 4 5
Example 528 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-fluoromethoxy-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 528 was
obtained. HRMS calculated for C H ClFN O S: 720.2185; found 721.2259 (M+H).
37 38 4 6
Example 529 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(4-methylfuryl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 529 was obtained.
HRMS calculated for C H ClN O S: 676.2122; found 677.2239 (M+H).
37 4 6
Example 530 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thieno[3,2-b]thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
982 mg thieno[3,2-b]thiophene (7.0 mmol) was dissolved in 40 mL dry THF and cooled to
-78°C under argon atmosphere. 11.2 mL BuLi (7.0 mmol, 1.6 M in hexanes) was added
and the mixture was stirred at -78°C for 1 hour. Then 1.6 mL 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (7.7 mmol) was added and the mixture was allowed to
warm up to room temperature, then it was quenched with saturated aq. NH Cl solution,
then extracted with THF, dried over Na SO , filtered and concentrated and purified via
flash chromatography using heptane and EtOAc as eluents to give 4,4,5,5-tetramethyl
thieno[3,2-b]thiophenyl-1,3,2-dioxaborolane. MS (EI, 70 eV) m/z (% relative intensity,
[ion]): 120 (19), 165 (25), 166 (100), 167 (44), 180 (17), 206 (22), 223 (60), 266 (68,
[M ]).
Step B:
Using General Procedure (XVI) and 4,4,5,5-tetramethylthieno[3,2-b]thiophenyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 530 was
obtained. HRMS calculated for C H ClN O S : 734.1458; found 735.1553 (M+H).
36 35 4 5 3
Example 531 (2R)[(5S )-(5-{3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-fluoro(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidin
yl)oxy](2-methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-[4-fluoro(trifluoromethyl)phenyl]-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 531
was obtained. HRMS calculated for C H ClF N O S: 758.1953; found 759.2031 (M+H).
37 35 4 4 5
Example 532 (2R){[6-(3-chlorofluorophenyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-chlorofluoro-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 532 was
obtained. HRMS calculated for C H Cl FN O S: 724.1689; found 725.1761 (M+H).
36 35 2 4 5
Example 533 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 533 was obtained.
HRMS calculated for C H ClF N O S: 708.1985; found 709.2055 (M+H).
36 35 2 4 5
Example 534 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorohydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenol as the appropriate boronic acid derivative, Example 534 was obtained. HRMS
calculated for C H ClFN O S: 706.2028; found 707.2087 (M+H).
36 36 4 6
Example 535 (2R)[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-fluoro(2,2,2-trifluoroethoxy)phenyl]thieno[2,3-d]pyrimidin
yl)oxy](2-methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-[4-fluoro(2,2,2-trifluoroethoxy)phenyl]-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 535
was obtained. HRMS calculated for C H ClF N O S: 788.2058; found 789.2125 (M+H).
38 37 4 4 6
Example 536 (2R){[6-(3-chloro-2,4-difluorophenyl)-(5S ){3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-chloro-2,4-difluoro-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 536 was
obtained. HRMS calculated for C H Cl F N O S: 742.1595; found 743.1645 (M+H).
36 34 2 2 4 5
Example 537 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3,4-trifluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(2,3,4-trifluorophenyl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 537 was obtained.
HRMS calculated for C H ClF N O S: 726.1891; found 727.1963 (M+H).
36 34 3 4 5
Example 538 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methylphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(p-tolyl)-1,3,2-dioxaborolane as
the appropriate boronic acid derivative, Example 538 was obtained. HRMS calculated for
C H ClN O S: 686.2330; found 687.2405 (M+H).
37 39 4 5
Example 539 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-chlorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 539 was obtained.
HRMS calculated for C H Cl N O S: 706.1783; found 707.1865 (M+H).
36 36 2 4 5
Example 540 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 540 was obtained.
HRMS calculated for C H ClF N O S: 708.1985; found 709.2055 (M+H).
36 35 2 4 5
Example 541 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-methylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(5-methylfuryl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 541 was obtained.
HRMS calculated for C H ClN O S: 676.2122; found 677.2198 (M+H).
37 4 6
Example 542 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[5-(dimethoxymethyl)furanyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-methoxyphenyl)propanoic acid
Using Step A and Step B of General Procedure (XVI) and (5-formylfuryl)boronic acid
as the appropriate boronic acid derivative ethyl (2R)[(5S )[3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl](5-formylfuryl)thieno[2,3-d]pyrimidinyl]
oxy(2-methoxyphenyl)propanoate was obtained. It was dissolved in methanol-water
(9:1) containing 5 m/m% NaOH (10 eq.) and the mixture was stirred at 50°C until no
further conversion was observed. Then the mixture was diluted with water and the pH was
adjusted to 6 by the addition of 2 M HCl solution. The mixture was extracted with DCM,
the combined organic phases dried over Na SO , and concentrated under reduced pressure.
The crude product was purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 542. HRMS
calculated for C H ClN O S: 736.2334; found 737.2416 (M+H).
37 41 4 8
Example 543 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-ethylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(5-ethylfuryl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 543 was obtained.
HRMS calculated for C H ClN O S: 690.2279; found 691.2343 (M+H).
36 39 4 6
Example 544 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-methoxyfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(5-methoxyfuryl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 544 was obtained.
HRMS calculated for C H ClN O S: 692.2071; found 693.2122 (M+H).
37 4 7
Example 545 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-nitrophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(3-nitrophenyl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 545 was obtained.
HRMS calculated for C H ClN O S: 717.2024; found 718.2101 (M+H).
36 36 5 7
Example 546 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-methylphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(m-tolyl)-1,3,2-dioxaborolane as
the appropriate boronic acid derivative, Example 546 was obtained. HRMS calculated for
C H ClN O S: 686.2330; found 687.2401 (M+H).
37 39 4 5
Example 547 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-ethynylphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and trimethyl-[2-[3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl]ethynyl]silane as the appropriate boronic acid derivative,
Example 547 was obtained. HRMS calculated for C H ClN O S: 696.2173; found
38 37 4 5
697.2234 (M+H).
Example 548 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-cyanophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzonitrile as the appropriate boronic acid derivative, Example 548 was obtained.
HRMS calculated for C H ClN O S: 697.2126; found 698.2188 (M+H).
37 36 5 5
Example 549 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl[3-(trifluoromethyl)phenyl]-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 549 was
obtained. HRMS calculated for C H ClF N O S: 740.2047; found 741.2125 (M+H).
37 36 3 4 5
Example 550 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-chlorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 550 was obtained.
HRMS calculated for C H Cl N O S: 706.1783; found 707.1860 (M+H).
36 36 2 4 5
Example 551 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 551 was obtained.
HRMS calculated for C36H36ClFN4O5S: 690.2079; found 691.2152 (M+H).
Example 552 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(dimethylamino)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and N,N-dimethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)aniline as the appropriate boronic acid derivative, Example 552 was
obtained. HRMS calculated for C H ClN O S: 715.2595; found 716.2681 (M+H).
38 42 5 5
Example 553 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol
as the appropriate boronic acid derivative, Example 553 was obtained. HRMS calculated
for C H ClN O S: 688.2122; found 689.2204 (M+H).
36 37 4 6
Example 554 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-methoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 554 was obtained.
HRMS calculated for C H ClN O S: 702.2279; found 703.2358 (M+H).
37 39 4 6
Example 555 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl[3-(trifluoromethoxy)phenyl]-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 555 was
obtained. HRMS calculated for C37H36ClF3N4O6S: 756.1996; found 757.2067 (M+H).
Example 556 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(4-fluorophenoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-[3-(4-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 556 was
obtained. HRMS calculated for C H ClFN O S: 782.2341; found 783.2412 (M+H).
42 40 4 6
Example 557 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-ethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-ethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 557 was obtained.
HRMS calculated for C H ClN O S: 716.2435; found 717.2505 (M+H).
38 41 4 6
Example 558 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(methylsulfanyl)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(3-methylsulfanylphenyl)-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 558 was obtained.
HRMS calculated for C H ClN O S : 718.2050; found 719.2113 (M+H).
37 39 4 5 2
Example 559 (2R){[6-(3-chlorofluorophenyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(3-chlorofluoro-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 559 was
obtained. HRMS calculated for C36H35Cl2FN4O5S: 724.1689; found 725.1765 (M+H).
Example 560 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 560 was obtained.
HRMS calculated for C H ClF N O S: 708.1985; found 709.2052 (M+H).
36 35 2 4 5
Example 561 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-fluoromethoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(2-fluoromethoxy-phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 561 was
obtained. HRMS calculated for C H ClFN O S: 720.2185; found 721.2281 (M+H).
37 38 4 6
Example 562 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[2-fluoro(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidin
yl)oxy](2-methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-[2-fluoro(trifluoromethoxy)phenyl]-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 562
was obtained. HRMS calculated for C H ClF N O S: 774.1902; found 775.1974 (M+H).
37 35 4 4 6
Example 563 (2R){[6-(1-benzofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(benzofuranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 563 was obtained.
HRMS calculated for C38H37ClN4O6S: 712.2122; found 713.2193 (M+H).
Example 564 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}phenylthieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethylphenyl-1,3,2-dioxaborolane as
the appropriate boronic acid derivative, Example 564 was obtained. HRMS calculated for
C H ClN O S: 672.2173; found 673.2258 (M+H).
36 37 4 5
Example 565 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-chlorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 565 was obtained.
HRMS calculated for C H Cl N O S: 706.1783; found 707.1860 (M+H).
36 36 2 4 5
Example 566 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 566 was obtained.
HRMS calculated for C H ClFN O S: 690.2079; found 691.2169 (M+H).
36 36 4 5
Example 567 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(pyridinyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridine as the appropriate boronic acid derivative, Example 567 was obtained. HRMS
calculated for C35H36ClN5O5S: 673.2126; found 674.2205 (M+H).
Example 568 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 4,4,5,5-tetramethyl(3-thienyl)-1,3,2-dioxaborolane
as the appropriate boronic acid derivative, Example 568 was obtained. HRMS calculated
for C H ClN O S : 678.1737; found 679.1808 (M+H).
34 35 4 5 2
Example 569 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1,3-oxazolyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3-
oxazole as the appropriate boronic acid derivative, Example 569 was obtained. HRMS
calculated for C H ClN O S: 663.1918; found 664.1997 (M+H).
33 34 5 6
Example 570 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-chlorothiophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using General Procedure (XVI) and 2-(5-chlorothienyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane as the appropriate boronic acid derivative, Example 570 was obtained.
HRMS calculated for C H Cl N O S : 712.1348; found 713.1423 (M+H).
34 34 2 4 5 2
Example 571 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thieno[3,2-b]thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
782 mg 3-bromothieno[3,2-b]thiophene (3.6 mmol), 3.626 g 4,4,5,5-tetramethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3,2-dioxaborolane (14 mmol), 0.783 g
PdCl ×dppf (1.07 mmol) and 2.102 g KOAc (21.4 mmol) were dissolved in 4 mL dioxane.
The mixture was heated to 60°C and stirred under argon atmosphere until no further
conversion was observed. The reaction mixture was cooled to room temperature and
filtered through a pad of celite. The filtrate was concentrated and purified via flash
chromatography using heptane and EtOAc as eluents to give 4,4,5,5-tetramethyl
thieno[3,2-b]thiophenyl-1,3,2-dioxaborolane. H NMR (500 MHz, DMSO-d ): 8.11 (d,
1H), 7.67 (dd, 1H), 7.45 (d, 1H), 1.32 (s, 12H). HRMS calculated for C H BO S :
12 15 2 2
266.0607, found: 267.0682 (M+H).
Step B:
Using General Procedure (XVI) and 4,4,5,5-tetramethylthieno[3,2-b]thiophenyl-
1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 571 was
obtained. HRMS calculated for C H ClN O S : 734.1458; found 735.1531 (M+H).
36 35 4 5 3
Example 572 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Using Step B and C of General Procedure (XVI) and ethyl (2R)[(5S )(3-chloro
hydroxymethyl-phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 6l) as the phenol derivative, Example 572 was
obtained. HRMS calculated for C H ClN O S: 634.2017; found 635.2082 (M+H).
33 35 4 5
Example 573 (2R){[6-(butynyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
625 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 25) (1.0 mmol), 35
mg Pd(PPh ) Cl (0.05 mmol) and 19 mg CuI (0.1 mmol) were dissolved in 4 mL DIPA,
3 2 2
then butyne was bubbled through the reaction mixture, which was stirred at 50°C until
no further conversion was observed. Then the volatiles were evaporated under reduced
pressure and the crude intermediate was purified by flash chromatography using EtOAc
and MeOH as eluents to obtain ethyl (2R)[6-butynyl-(5S )(3-chlorohydroxy
methyl-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate.
Step B:
Using Step B and C of General Procedure (XVI) and ethyl (2R)[6-butynyl-(5S )
(3-chlorohydroxymethyl-phenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate as the phenol derivative, Example 573 was obtained. HRMS
calculated for C H ClN O S: 648.2173; found 649.2251 (M+H).
34 37 4 5
Example 574 (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(dimethylcarbamoyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
and
Example 575 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(dimethylcarbamoyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
2.195 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno-[2,3-d]pyrimidine (Preparation 12) (5.02 mmol) was dissolved in 50 mL dry THF
and then it was cooled to -78°C under argon atmosphere. 5.2 mL lithium diisopropylamide
(10.4 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C
for 1 hour. Then 5.00 g dry-ice was added and the mixture was allowed to warm up to
room temperature and it was stirred until no further conversion was observed. The mixture
was quenched with saturated aq. NH Cl and extracted with DCM. The combined organic
phases were dried over Na SO and concentrated under reduced pressure. The residue was
purified via flash chromatography using DCM and MeOH as eluents to obtain 4-chloro
[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidine-
6-carboxylic acid.
Step B:
1.444 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno[2,3-d]pyrimidinecarboxylic acid (3.0 mmol), 444 mg ethyl (2R)hydroxy(2-
methoxyphenyl)propanoate (Preparation 3ad) (2.0 mmol) and 987 mg cesium carbonate
(9.0 mmol) were stirred in 30 mL dry tertbutanol at 70°C until no further conversion was
observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The crude intermediate was purified via flash
chromatography using DCM and MeOH as eluents to obtain 5-{3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}{[(2R)ethoxy(2-methoxyphenyl)
oxopropanyl]oxy}thieno[2,3-d]pyrimidinecarboxylic acid.
Step C:
669 mg 5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}{[(2R)
ethoxy(2-methoxyphenyl)oxopropanyl]oxy}thieno[2,3-d]pyrimidinecarboxylic
acid (1.0 mmol), 1 mL dimethylamine (2 mmol, 2 M in THF) and DIPA were dissolved in
mL dry DCM, then 520 mg PyBOP (1.0 mmol) was added and the mixture was stirred at
room temperature until no further conversion was observed. The volatiles were removed
under reduced pressure and the residue was purified via flash chromatography using
EtOAc and MeOH as eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl](dimethylcarbamoyl)thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate.
Step D:
Ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(dimethylcarbamoyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate was
hydrolyzed according to Step C of General Procedure (XVI). The diastereoisomer eluting
earlier was collected as Example 574. HRMS calculated for C H ClN O S: 667.2231;
33 38 5 6
found 668.2287 (M+H). The diastereoisomer eluting later was collected as Example 575.
HRMS calculated for C33H38ClN5O6S: 667.2231; found 668.2280 (M+H).
Example 576 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(1,1-difluoroethyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
4.22 g 4-chloro-5,6-diiodo-thieno[2,3-d]pyrimidine (Preparation 1b) (10.0 mmol) was
dissolved in 160 mL dry THF, then cooled to -78°C under argon atmosphere. 5 mL
ethylmagnesium chloride (2 M in THF) (10.0 mmol) was added and the mixture was
stirred at -78°C for 10 minutes. Then 1.321 g acetaldehyde (30.0 mmol) was added and the
mixture was allowed to warm up to room temperature. Saturated aq. NH Cl was added and
the mixture was extracted with ethyl acetate. The combined organic phases were dried over
Na SO and concentrated under reduced pressure. The crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain 1-(4-chloroiodo-
thieno[2,3-d]pyrimidinyl)ethanol. H NMR (400 MHz, DMSO-d ): 8.89 (s, 1H), 6.38
(d, 1H), 5.15 (m, 1H), 1.44 (d, 3H).
Step B:
2.1 g 1-(4-chloroiodo-thieno[2,3-d]pyrimidinyl)ethanol (6.17 mmol) was dissolved in
100 mL dichloromethane, then cooled to 0°C under argon atmosphere. Then 2.75 g Dess-
Martin periodinane (6.47 mmol) was added and strirred until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using DCM as eluent to obtain 1-(4-chloroiodo-
thieno[2,3-d]pyrimidinyl)ethanone. H NMR (400 MHz, DMSO-d ): 9.04 (s, 1H), 2.80
(s, 3H).
Step C:
1.02 g 1-(4-chloroiodo-thieno[2,3-d]pyrimidinyl)ethanone (3.01 mmol) was
dissolved in 25 mL dichloromethane, then 3.22 g DAST (20.0 mmol) was added. The
mixture was stirred at 50°C under argon atmosphere until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using dichloromethane as eluent to obtain 4-chloro-
6-(1,1-difluoroethyl)iodo-thieno[2,3-d]pyrimidine. H NMR (400 MHz, DMSO-d ):
9.02 (s, 1H), 2.22 (t, 3H).
Step D:
880 mg 4-chloro(1,1-difluoroethyl)iodo-thieno[2,3-d]pyrimidine (2.44 mmol), 821
mg ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad) (3.66 mmol)
and 1.59 g Cs CO (4.88 mmol) were stirred at 50°C in 2.5 mL DMSO until no further
conversion was observed. The reaction mixture was diluted with brine, then it was
extracted with EtOAc. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography
using heptane and EtOAc as eluents to obtain ethyl (2R)[6-(1,1-difluoroethyl)iodo-
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate. H NMR (400 MHz,
DMSO-d ): 8.70 (s, 1H), 7.44 (dd, 1H), 7.25 (td, 1H), 6.98 (d, 1H), 6.88 (t, 1H), 5.69 (dd,
1H), 4.10 (q, 2H), 3.80 (s, 3H), 3.41 (dd, 1H), 3.26 (dd, 1H), 2.20 (t, 3H), 1.09 (t, 3H).
Step E:
920 mg ethyl (2R)[6-(1,1-difluoroethyl)iodo-thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (1.68 mmol) and 676 mg 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (2.52 mmol) were dissolved
in 7 mL 2-Me-THF, then 2.52 mL tetrabutylammonium hydroxide (2.52 mmol, 1 M in
water) and 119 mg AtaPhos (0.168 mmol) were added and the mixture was heated under
nitrogen at 110°C in a microwave reactor until no further conversion was observed. Then it
was diluted with brine and extracted with dichloromethane. The combined organic phases
were dried over Na2SO4 and concentrated under reduced pressure, and the crude
intermediate was purified via flash chromatography using heptane and EtOAc as eluents to
obtain ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(1,1-difluoroethyl)
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate as a mixture of
diastereoisomers. H NMR (400 MHz, DMSO-d ): 10.34 (br s, 1H), 8.68 (s, 1H), 7.20 (td,
1H), 7.04 (d, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 6.81 (t, 1H), 6.55 (dd, 1H), 5.42 (dd, 1H),
3.98 (m, 2H), 3.76 (s, 3H), 2.87 (dd, 1H), 2.46 (dd, 1H), 1.93 (s, 3H), 1.72 (t, 3H), 1.00 (t,
3H).
Step F:
100 mg ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(1,1-difluoroethyl)
thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (0.178 mmol), 51 mg 2-
(4-methylpiperazinyl)ethanol (0.355 mmol) and 534 mg triphenyl phosphine (0.534
mmol) were dissolved in 4 mL dry toluene, then 123 mg ditertbutyl azodicarboxylate
(0.534 mmol) was added. The mixture was stirred at 45°C under nitrogen until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
crude intermediate was purified via flash chromatography using EtOAc and methanol as
eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](1,1-difluoroethyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate.
Step G:
The intermediate obtained in Step F was dissolved in 3 mL methanol and 100 mg LiOH ×
H O (2.38 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents. The diastereoisomer eluting later was collected as Example 576. HRMS
calculated for C H ClF N O S: 660.1985; found 661.2059 (M+H).
32 35 2 4 5
Example 577 (2R){[6-(5-bromofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
1.326 g (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic
acid (Example 209) (2 mmol) was dissolved in 20 mL chloroform, then 534 mg NBS (3
mmol) was added. The resulting mixture was stirred at 0°C until no further conversion was
observed. Then the mixture was diluted with water and the pH was adjusted to 6 by the
addition of 2 M HCl solution. The mixture was extracted with DCM, the combined organic
phases were dried over Na SO and concentrated under reduced pressure. The crude
product was purified via reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 577. HRMS calculated for
C H BrClN O S: 740.1071; found 741.1165 (M+H).
34 34 4 6
Example 578 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-ethynylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
52 mg (2R){[6-(5-bromofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid (Example 577) (0.07 mmol), 96 mg butyl-dimethyl-[2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)ethynyl]silane (0.36 mmol), 120 mg Cs CO
(0.36 mmol) and 6 mg PdCl × dppf (0.008 mmol) were dissolved in a mixture of 0.80 mL
dioxane and 0.20 mL water. The reaction mixture was stirred at 70°C until no further
conversion was observed. The reaction was quenched at room temperature with water and
the mixture was extracted with DCM. The combined organic phases were dried over
Na SO and concentrated under reduced pressure. The residue was dissolved in 0.50 mL
THF, then 50 µL TBAF (1 M in THF) was added and the reaction mixture was stirred at
room temperature until no further conversion was observed. Then the mixture was
concentrated under reduced pressure and purified via reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 578. HRMS
calculated for C H ClN O S: 686.1966; found 687.2039 (M+H).
36 35 4 6
Example 579 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-cyanofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
250 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 25) (0.40 mmol), 315
mg PPh (1.20 mmol), 276 mg ditertbutyl azodicarboxylate (1.20 mmol) and 173 mg 2-(4-
methylpiperazinyl)ethanol (1.20 mmol) were dissolved in 10 ml dry toluene and the
reaction mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The mixture was concentrated under reduced pressure and the crude product was
purified via flash chromatography using DCM and MeOH as eluents. The obtained product
was hydrolyzed in 3 mL methanol-water (9:1) containing NaOH (5m/m%) at room
temperature. The mixture was diluted with water, the pH was adjusted to 6 by the addition
of 2 M HCl solution, and it was extracted with DCM. The combined organic phases were
dried over Na SO and concentrated under reduced pressure. The crude product was
purified using reverse phase preparative HPLC resulting (2R)[(5S )[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoic acid.
Step B:
72 mg (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid (0.10 mmol),
66 mg 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)furancarbonitrile (0.30 mmol), 18
mg AtaPhos (0.025 mmol) and 98 mg Cs CO (0.30 mmol) were dissolved in a mixture of
0.75 mL THF and 0.25 mL water and heated under nitrogen at 100 °C for 10 minutes in a
microwave reactor. The crude reaction mixture was diluted with water and the pH was
adjusted to 6 by the addition of 2N HCl solution. The mixture was extracted with DCM,
the combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified via reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents to obtain Example 579. HRMS
calculated for C35H34ClN5O6S: 687.1918; found 688.2001 (M+H).
Example 580 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[5-(methoxycarbonoimidoyl)furanyl]thieno[2,3-d]pyrimidin
yl)oxy](2-methoxyphenyl)propanoic acid
222 mg (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(5-cyanofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 579) (0.032 mmol) was hydrolyzed in 3 mL methanol-water
(9:1) containing NaOH (5m/m%) at room temperature. After evaporation of the volatiles
under reduced pressure the multicomponent mixture was purified using reversed phase
chromatography with 25 mM aqueous NH HCO solution and MeCN as eluents to give
Example 580 as one of the products. HRMS calculated for C H ClN O S: 719.2180;
36 38 5 7
found 360.6152 (M+2H).
Example 581 (2R){[6-(5-carbamoylfuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Hydrolysis of (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(5-cyanofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 579) was performed as described in Example 580. Example 581
was obtained as one of the products of the multicomponent mixture following separation
by reversed phase chromatography with 25 mM aqueous NH HCO solution and MeCN as
eluents. HRMS calculated for C H ClN O S: 705.2024; found 706.2105 (M+H)
36 5 7
Example 582 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[5-(dimethylcarbamoyl)furanyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-methoxyphenyl)propanoic acid
Step A:
984 mg 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno[2,3-d]pyrimidine (Preparation 12) (2.25 mmol) was dissolved in 20 mL dry THF
under N and cooled to -78°C. 2.25 mL LDA (2 M in THF, 4.5 mmol) was added at -78°C
and the reaction mixture was stirred for 1 h at this temperature, then 9 mL
chloro(trimethyl)stannane (1 M in THF, 9 mmol) was added and stirred for 20 min at -
78°C, then the reaction mixture was allowed to warm up to room temperature. Saturated
aq. NH Cl was added and the mixture was extracted with diethyl ether. The combined
organic phases were dried over Na SO and concentrated under reduced pressure. The
residue was dissolved in 60 mL EtOAc and following the addition of 40 mL saturated aq.
NaF solution it was stirred overnight and filtered. The aqueous phase was extracted with
EtOAc and the combined organic phases were dried over Na SO , and evaporated under
reduced pressure. The crude product was purified via flash chromatography using DCM
and MeOH as eluents to obtain [4-chloro[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]-trimethyl-stannane. H NMR (500 MHz,
DMSO-d ): 8.90 (s, 1H), 7.13 (d, 1H), 7.11 (d, 1H), 4.22 (m, 2H), 2.77 (t, 2H), 2.57 (br s,
4H), 2.41 (br s, 4H), 2.21 (br s, 3H), 1.97 (s, 3H), 0.14 (s, 9H). HRMS calculated for
C H Cl N OSSn: 600.0539; found 601.0584 (M+H).
23 30 2 4
Step B:
1.91g 5-bromofurancarboxylic acid (10 mmol), 10 mL dimethylamine (2 M in THF, 20
mmol), 5.42 g PyBOP (10.4 mmol) and 3.5 mL DIPA (20 mmol) were dissolved in 20 mL
dry DCM and stirred at room temperature under N until no further conversion was
observed. The DCM was evaporated under reduced pressure and the residue was purified
via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-N,N-
dimethyl-furancarboxamide. MS: (M+H) = 218.2.
Step C:
400 mg [4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno[2,3-d]pyrimidinyl]-trimethyl-stannane (product of Step A) (0.6 mmol), 291 mg
-bromo-N,N-dimethyl-furancarboxamide (product of Step B) (1.3 mmol), 12 mg
Pd(PhCN) Cl (0.03 mmol), 13 mg CuI (0.06 mmol) and 20 mg Ph As (0.06 mmol) were
2 2 3
dissolved in 1 mL NMP and stirred at 100°C under N until no further conversion was
observed. The mixture was diluted with EtOAc and washed with saturated aq. NaF
solution. The aqueous phase was extracted with EtOAc and the combined organic phases
were dried over Na SO and evaporated under reduced pressure. The crude product was
purified via flash chromatography using DCM and MeOH as eluents to obtain 5-[4-chloro-
-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidin-
6-yl]-N,N-dimethyl-furancarboxamide. H NMR (500 MHz, DMSO-d ): 8.97 (s, 1H),
7.26 (d, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 5.80 (d, 1H), 4.24 (t, 2H), 3.13 (br s, 3H), 2.97 (br
s, 3H), 2.79 (t, 2H), 2.57 (br s, 4H), 2.35 (br s, 4H), 2.17 (s, 3H), 2.06 (s, 3H). HRMS
calculated for C27H29Cl2N5O3S: 573.1368; found 574.1463 (M+H).
Step D:
0.255 g 5-[4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno[2,3-d]pyrimidinyl]-N,N-dimethyl-furancarboxamide (0.4 mmol), 0.134 g ethyl
(2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad) (0.6 mmol) and 0.391
g Cs CO (1.2 mmol) were placed in a 100 mL flask. 35 mL propanol was added and
the mixture was stirred at 50°C under N until no further conversion was observed. 1 mL
water and 0.336 g LiOH×H O (8 mmol) were added and the mixture was stirred at 50°C
until no further conversion was observed. The reaction was diluted with water; the pH was
adjusted between 4-5 using 2 M HCl and extracted with DCM. The combined organic
phases were dried over Na SO and evaporated under reduced pressure. The diastereomers
were separated via preparative reversed phase chromatography using 20 mM aqueous
NH HCO solution and MeCN as eluents; the diastereomer eluting later was collected as
Example 582. HRMS calculated for C H ClN O S: 733.2337; found 734.2450 (M+H).
37 40 5 7
Example 583 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[5-(methoxycarbonyl)furanyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-methoxyphenyl)propanoic acid
Hydrolysis of (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(5-cyanofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 579) was performed as described in Example 580. Example 583
was obtained as one of the products of the multicomponent mixture following separation
by reversed phase chromatography with 25 mM aqueous NH HCO solution and MeCN as
eluents. HRMS calculated for C H ClN O S: 720.2021; found 721.2104 (M+H).
36 37 4 8
Example 584 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-ethenylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
27 mg (2R){[6-(5-bromofuranyl)-(5S ){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 577) (0.036 mmol), 28 mg 4,4,5,5-tetramethylvinyl-1,3,2-
dioxaborolane (0.18 mmol), 23 mg Cs CO (0.072 mmol) and 3 mg AtaPhos (0.004 mmol)
were dissolved in a mixture of 0.40 mL dioxane and 0.10 mL water. The reaction mixture
was stirred at 70 °C until no further conversion was observed. The reaction mixture was
quenched at room temperature with water and the pH was set to 5 using 2 M HCl solution.
The mixture was extracted with DCM, and the combined organic phases were dried over
Na SO and concentrated under reduced pressure. The crude product was purified via
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents to obtain Example 584. HRMS calculated for C H ClN O S: 688.2122; found
36 37 4 6
689.2178 (M+H).
Example 585 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-cyclopropylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
283 mg (2R){[6-(5-bromofuranyl)-(5S ){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 577) (0.38 mmol), 0.70 mL 2-cyclopropyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (3.8 mmol), 0.62 g Cs CO (1.9 mmol) and 29 mg PdCl × dppf (0.04
2 3 2
mmol) were dissolved in a mixture of 4 mL dioxane and 1 mL water. The mixture was
heated under nitrogen at 100 °C in a microwave reactor until no further conversion was
observed. The reaction was quenched at room temperature with water and the pH was set
to 6 using 2 M HCl solution. The mixture was extracted with DCM, the combined organic
phases were dried over Na SO and concentrated under reduced pressure. The crude
product was purified via reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 585. HRMS calculated for
C H ClN O S: 702.2279; found 703.2337 (M+H).
37 39 4 6
Example 586 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(5-phenylfuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid
200 mg (2R){[6-(5-bromofuranyl)-(5S ){3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)
propanoic acid (Example 577) (0.27 mmol), 275 mg 4,4,5,5-tetramethylphenyl-1,3,2-
dioxaborolane (1.35 mmol), 440 mg Cs CO (1.35mmol) and 19 mg AtaPhos (0.027
mmol) were dissolved in a mixture of 3 mL dioxane and 0.75 mL water. The reaction
mixture was stirred under nitrogen at 70 °C for 1 hour. The reaction was quenched at room
temperature with water and the pH was set to 5 using 2 M HCl solution. The mixture was
extracted with DCM, the combined organic phases were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 586. HRMS calculated for C H ClN O S: 738.2279; found 739.2358 (M+H).
40 39 4 6
Example 587 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-methoxyphenyl)propanoic acid
Step A:
500 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 25) (0.80 mmol), 630
mg PPh (2.40 mmol), 352 mg ditertbutyl azodicarboxylate (2.40 mmol) and 346 mg 2-(4-
methylpiperazinyl)ethanol (2.40 mmol) were dissolved in 20 ml dry toluene and the
reaction mixture was stirred at 50 °C under nitrogen atmosphere until no further
conversion was observed. The mixture was concentrated under reduced pressure and the
residue was purified via flash chromatography using DCM and MeOH as eluents to give
ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate.
Step B:
445 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (0.59
mmol), 264 mg 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (1.20 mmol), 106
mg AtaPhos (0.15 mmol) and 391 mg Cs CO (1.20 mmol) were dissolved in a mixture of
4.5 mL THF and 4.5 mL water. The mixture was heated under nitrogen at 100 °C in a
microwave reactor until no further conversion was observed. The crude reaction mixture
was diluted with water and the pH was adjusted to 6 by the addition of 2 M HCl solution.
The mixture was extracted with DCM, the combined organic phases were dried over
Na SO and concentrated under reduced pressure. The residue was purified via flash
chromatography using DCM and MeOH as eluents to give ethyl (2R)[(5S )[3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](3-hydroxyphenyl)thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate.
Step C:
72 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](3-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoate (0.10 mmol), 80 mg PPh (0.30 mmol), 70 mg ditertbutyl azodicarboxylate
(0.30 mmol) and 33 mg 4-pyridylmethanol (0.30 mmol) were dissolved in 3 ml dry toluene
and the reaction mixture was stirred under nitrogen at 50°C until no further conversion was
observed. The mixture was concentrated under reduced pressure and the crude product was
purified via flash chromatography using DCM and MeOH as eluents. The obtained product
was hydrolyzed in 3 mL methanol-water (9:1) containing NaOH (5m/m%) at room
temperature. The mixture was diluted with water and the pH was adjusted to 6 by the
addition of 2 M HCl. The mixture was extracted with DCM, the combined organic phases
were dried over Na SO and concentrated under reduced pressure. The crude product was
purified via reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents to obtain Example 587. HRMS calculated for C42H42ClN5O6S:
779.2544; found 390.6339 (M+2H).
Example 588 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{3-[2-(morpholinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-methoxyphenyl)propanoic acid
Using the same procedures as described for Example 587 and replacing 4-pyridylmethanol
with 2-(morpholinyl)ethanol in Step C, Example 588 was obtained. HRMS calculated
for C H ClN O S: 801.2963; found 401.6554 (M+2H).
42 48 5 7
Example 589 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(2-methoxyethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Using the same procedures as described for Example 587 and replacing 4-pyridylmethanol
with 2-methoxyethanol in Step C, Example 589 was obtained. HRMS calculated for
C H ClN O S: 746.2541; found 747.26 (M+H).
39 43 4 7
Example 590 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}((2S or R)-tetrahydrofuranyl)thieno[2,3-d]pyrimidinyl]oxy}
(2-methoxyphenyl)propanoic acid
and
Example 591 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}((2R or S)-tetrahydrofuranyl)thieno[2,3-d]pyrimidinyl]oxy}
(2-methoxyphenyl)propanoic acid
Step A:
To a solution of 565 mg Preparation 6e (1.00 mmol) in 90 ml EtOH 1298 mg palladium
hydroxide on carbon (Pearlman’s catalyst 20 wt. %) was added. The reaction mixture was
flushed with nitrogen, and then it was flushed with hydrogen and stirred under hydrogen
atmosphere (10 bar) at room temperature for 4 days. The reaction mixture was filtered
through a pad of Celite and the filtrate was concentrated under reduced pressure. The
residue was purified via preparative reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents to give ethyl (2R)[(5Sa)(3-chloro
hydroxymethyl-phenyl)tetrahydrofuranyl-thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate diastereomers. H NMR (500 MHz, DMSO-d ) of the
diastereomer eluted earlier: 10.26 (s, 1H), 8.54 (s, 1H), 7.18 (td, 1H), 7.02 (d, 1H), 6.97 (d,
1H), 6.90 (dd, 1H), 6,75 (t, 1H), 6.32 (dd, 1H), 5.35 (dd, 1H), 4.70 (t, 1H), 4.03-3.96 (m,
3H), 3.76 (s, 3H), 3.73 (m, 1H), 2.95 (m, 1H), 2.45 (dd, 1H), 2.07 (m, 1H), 1.99 (s, 3H),
1.96 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H), 1.05 (t, 3H).
H NMR (500 MHz, DMSO-d ) of the diastereomer eluted later: 10.26 (br s, 1H), 8.55 (s,
1H), 7.19 (td, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.91 (d, 1H), 6,77 (td, 1H), 6.46 (dd, 1H),
5.36 (dd, 1H), 4.82 (t, 1H), 4.05-3.93 (m, 3H), 3.76 (s, 3H), 3.71 (m, 1H), 2.85 (dd, 1H),
2.57 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.94 (s, 3H), 1.88 (m, 1H), 1.66 (m, 1H), 1.00 (t,
3H).
Step B:
Using the Step B and Step C of General Procedure (XVI), starting from the earlier eluted
diastereomer in Step A Example 590 was obtained. HRMS calculated for C H ClN O S:
34 39 4 6
666.2279; found 667.2349 (M+H); Starting from the later eluted diastereomer in Step A
Example 591 was obtained. HRMS calculated for C H ClN O S: 666.2279; found
34 39 4 6
667.2315 (M+H).
Example 592 (2R)[((5R ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-methoxyphenyl)propanoic acid
Step A:
649 mg 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (2.0 mmol),
538 mg ethyl (2R)hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad) (2.4
mmol) and 1.955 g cesium carbonate (6.0 mmol) were stirred at 70°C in 10 mL dry
tertbutanol until no further conversion was observed. The mixture was cooled to room
temperature, and then 10 mL water, 947 mg 1-[2-[2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine (Preparation
5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture was stirred
under nitrogen at 60°C until no further conversion was observed. Then brine was added
and the mixture was extracted with EtOAc. The combined organic phases were dried over
MgSO and concentrated under reduced pressure. The residue was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate.
Step B:
The product of Step A was hydrolyzed according to Step C of General Procedure (XVI);
the diastereoisomer eluting earlier was collected as Example 592. HRMS calculated for
C H ClN O S: 624.2173; found 625.2255 (M+H).
32 37 4 5
Example 593 (2S)[((5S )5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-methoxyphenyl)propanoic acid
Step A:
649 mg 4-chloroethyliodo-thieno[2,3-d]pyrimidine (Preparation 1d) (2.0 mmol),
538 mg ethyl (2S)hydroxy(2-methoxyphenyl)propanoate (Preparation 3bi) (2.4
mmol) and 1.955 g cesium carbonate (6.0 mmol) were stirred at 70°C in 10 mL dry
tertbutanol until no further conversion was observed. The mixture was cooled to room
temperature, and then 10 mL water, 947 mg 1-[2-[2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine (Preparation
5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture was stirred at
60°C until no further conversion was observed. Then brine was added and the mixture was
extracted with EtOAc. The combined organic phases were dried over MgSO , filtered and
concentrated under reduced pressure. The crude intermediate was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2S)[5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]ethyl-thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate.
Step B:
The product of Step A was hydrolyzed according to Step C of General Procedure (XVI);
the diastereoisomer eluting earlier was collected as Example 592. HRMS calculated for
C H ClN O S: 624.2173; found 625.2239 (M+H).
32 37 4 5
General Procedure (XVIIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorohydroxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methoxy
pyrimidinyl)methoxy]phenyl]propanoate (Preparation 28a), 2 eq. of the appropriate
alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (5 mL/mmol), then 2
eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using ethyl
acetate and methanol as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 594 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-fluoro(methoxymethyl)phenyl]thieno[2,3-d]pyrimidin
yl)oxy]{2-[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Step A:
0.801 g LiCl (19 mmol) was heated at 250°C for 10 minutes under N . Then it was cooled
to room temperature and the flask was charged with 0.911 g Mg (38 mmol) and 30 mL dry
THF. The Mg was activated with 0.15 mL iBu AlH (1 M in THF, 0.15 mmol) for 10
minutes, then it was cooled to 0°C and 3.313 g 4-bromofluoro
(methoxymethyl)benzene (15 mmol) was added. After 30 minutes stirring at 0°C 4 mL 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20 mmol) was added and the reaction
mixture was stirred for 30 minutes, then filtered through celite, diluted with EtOAc and
washed with saturated aq. NH Cl. The aqueous phase was extracted with EtOAc. The
combined organic phases were dried over Na SO , concentrated under reduced pressure
and the residue was purified via flash chromatography using heptane and EtOAc as eluents
to obtain 2-[4-fluoro(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
MS (EI, 70 eV) m/z (% relative intensity, [ion]): 59 (21), 85 (20), 134 (24), 135 (100), 136
(28), 150 (30), 165 (24), 166 (43), 167 (95), 192 (20), 251 (44, [M ]).
Step B:
3.94 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidine (Preparation 13) (7 mmol), 2.11 g 2-[4-fluoro
(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.4 mmol), 4.56 g
Cs CO (14 mmol), and 0.496 g AtaPhos (0.7 mmol) were placed in a 100 mL flask. 45
mL dioxane and 15 mL water were added, and the mixture was stirred under N at 70°C
until no further conversion was observed. Then it was diluted with brine, neutralized with 2
M HCl, and extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure, and the crude product was purified via flash
chromatography using DCM and MeOH as eluents to obtain 4-chloro[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl][4-fluoro(methoxymethyl)
phenyl]thieno[2,3-d]pyrimidine. MS: (M+H) = 575.2.
Step C:
2.615 g 4-chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl][4-
fluoro(methoxymethyl)phenyl]thieno[2,3-d]pyrimidine (4.5 mmol), 1.61 g ethyl (2R)
hydroxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 3ab-(R)) (5.5
mmol) and 4.40 g Cs2CO3 (13.5 mmol) were placed in a 100 mL flask. 50 mL tert-butanol
was added and the mixture was stirred at 80°C under N until no further conversion was
observed. The mixture was diluted with water, the pH was set to 7 with 2 M HCl, and then
it was extracted with DCM. The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl][4-fluoro(methoxymethyl)
phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
as a mixture of diastereoisomers. MS: (M+H) = 833.2.
Step D:
2.36 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
[4-fluoro(methoxymethyl)phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (28.3 mmol) was dissolved in 15 mL EtOH,
then 20 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room
temperature until no further conversion was observed. Saturated aq. NaHCO solution was
added and the reaction mixture was extracted with DCM. The combined organic layers
were dried over Na SO and concentrated under reduced pressure. The crude product was
purified via flash chromatography using DCM and MeOH as eluents to obtain ethyl (2R)-
2-[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl][4-fluoro
(methoxymethyl) phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate
as a mixture of diastereomers. MS: (M+H) =749.2.
Step E:
0.375 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-[4-fluoro(methoxymethyl)phenyl]thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate (0.5 mmol), 0.21 g (2-methoxypyrimidinyl)methanol (1.5
mmol) and 0.393 g PPh (1.5 mmol) were dissolved in 10 mL dry toluene, then 0.345 g
ditertbutyl azodicarboxylate (1.5 mmol) was added. The mixture was stirred at 50°C under
N until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using DCM and
methanol as eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl][4-fluoro(methoxymethyl)phenyl]thieno[2,3-d]pyrimidinyl]
oxy[2-[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate as a mixture of
diastereomers. MS: (M+H) = 871.2.
Step F:
The product of Step E was dissolved in 10 mL dioxane-water (1:1) and 0.21 g LiOH × H O
(5 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reverse phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents. The diastereomer eluting later
was collected as Example 594. HRMS calculated for C H ClFN O S: 842.2665; found
43 44 6 7
422.1408 (M+2H).
Example 595 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorohydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-
[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
316 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](4-fluorohydroxy-phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-
[(2-methoxypyrimidinyl)methoxy]phenyl]propanoate (Preparation 28a) (0.375 mmol)
was dissolved in 10 mL dioxane-water 1:1 and 157 mg LiOH × H O (3.75 mmol) was
added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and purified via preparative reversed phase chromatography using MeCN and 25
mM aqueous NH HCO solution as eluents to obtain Example 595. HRMS calculated for
C H ClFN O S: 814.2352; found 408.1254 (M+2H).
41 40 6 7
Example 596 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-fluoro[2-(morpholinyl)ethoxy]phenyl}thieno[2,3-
d]pyrimidinyl)oxy]{2-[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XVIIa) and 2-(morpholinyl)ethanol as the appropriate
alcohol, Example 596 was obtained. HRMS calculated for C H ClFN O S: 927.3192;
47 51 7 8
found 464.6657 (M+2H).
Example 597 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-fluoro(2-hydroxyethoxy)phenyl]thieno[2,3-d]pyrimidin
yl)oxy]{2-[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XVIIa) and ethylene glycol as the appropriate alcohol, Example
597 was obtained. HRMS calculated for C H ClFN O S: 858.2614; found 430.1402
43 44 6 8
(M+2H).
Example 598 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-fluoro(2-methoxyethoxy)phenyl]thieno[2,3-d]pyrimidin
yl)oxy]{2-[(2-methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XVIIa) and 2-methoxyethanol as the appropriate alcohol,
Example 598 was obtained. HRMS calculated for C H ClFN O S: 872.277; found
44 46 6 8
437.1468 (M+2H).
Example 599 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-methoxypropyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Step A:
3.754 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (10.0 mmol),
1198 mg 3-methoxypropyne (17.1 mmol), 702 mg Pd(PPh ) Cl (1.0 mmol), 288 mg CuI
(2.0 mmol) and 2.8 mL TEA (20 mmol) were dissolved in 50 mL THF, and the mixture
was stirred under nitrogen at room temperature until no further conversion was observed. It
was concentrated under reduced pressure and purified via flash chromatography using
heptane and ethyl acetate as eluents to obtain 5-bromochloro(3-methoxyprop
ynyl)thieno[2,3-d]pyrimidine. H NMR (400 MHz, DMSO-d ): 9.04 (s, 1H), 4.50 (s, 2H),
3.40 (s, 3H).
Step B:
2.07 g 5-bromochloro(3-methoxypropynyl)thieno[2,3-d]pyrimidine (6.517 mmol),
2.11 g ethyl (2R)hydroxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 3ab-(R)) (7.17 mmol) and 6.58 g Cs2CO3 (20 mmol) were placed in a flask.
70 mL tert-butanol was added and the mixture was stirred under nitrogen at 65°C until no
further conversion was observed. It was diluted with water and extracted with
dichloromethane. The combined organic layers were dried over Na SO and concentrated
under reduced pressure to obtain ethyl (2R)[5-bromo(3-methoxyprop
ynyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate. It
was used in next step without further purification. MS: (M+H) = 575.0.
Step C:
The product of Step B and 2.6 g 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (Preparation 5a) (9.68 mmol) were dissolved in 21 mL THF,
then 5.24 g Cs CO (16.08 mmol) dissolved in 7 mL water was added followed by 431 mg
AtaPhos (0.61 mmol), and the mixture was stirred under nitrogen at 65 °C until no further
conversion was observed. Then it was diluted with dichloromethane and brine. After phase
separation the aqueous phase was extracted with dichloromethane. The organic layers were
combined and dried over Na SO and concentrated under reduced pressure. The residue
was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain
ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(3-methoxypropynyl)thieno
[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate as a mixture of
diastereomers. MS: (M+H) = 637.2.
Step D:
2.765 g ethyl (2R)[5-(3-chlorohydroxymethyl-phenyl)(3-methoxyprop
ynyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(4.34 mmol), 1.3 g 2-(4-methylpiperazinyl)ethanol (9.0 mmol) and 2.623 g triphenyl
phosphine (10.0 mmol) were dissolved in 40 mL dry toluene, then 2.303 g ditertbutyl
azodicarboxylate (10.0 mmol) was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the residue was purified via flash chromatography using ethyl acetate and
methanol as eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl](3-methoxypropynyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) =
763.2.
Step E:
3.59 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(3-methoxypropynyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate (4.3 mmol) and 458 mg Selcat Q6 were dissolved in 50 mL
methanol, then 1.87 g tert-butylamine borane (21.5 mmol) was added. The mixture was
stirred at room temperature until no further conversion was observed. It was filtered
through a plug of celite and the volatiles were evaporated under reduced pressure to obtain
ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](3-
methoxypropyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)
propanoate as a mixture of diastereomers that was used in next step without further
purification. MS: (M+H) = 767.2.
Step F:
The product of Step E was dissolved in 20 mL EtOH, then 20 mL 1.25 M HCl in EtOH
was added and the mixture was stirred at room temperature until no further conversion was
observed. Most of the EtOH was evaporated under reduced pressure then water and
saturated aq. NaHCO solution were added and the mixture was extracted with DCM. The
combined organic layers were dried over Na SO and concentrated under reduced pressure.
The crude product was purified via flash chromatography using DCM and MeOH as
eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](3-methoxypropyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate as a mixture of diastereomers. MS: (M+H) = 683.2.
Step G:
479 mg ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-(3-methoxypropyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate (0.7
mmol), 280 mg (2-methoxypyrimidinyl)methanol (2.0 mmol) and 525 mg triphenyl
phosphine (2.0 mmol) were dissolved in 10 mL dry toluene, then 461 mg ditertbutyl
azodicarboxylate (2.0 mmol) was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using ethyl
acetate and methanol as eluents.
Step H:
The product of Step G was dissolved in 30 mL dioxane-water (1:1) and 250 mg LiOH ×
H O (5.95 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure, and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents. The
diastereoisomer eluting later was collected as Example 599. HRMS calculated for
C H ClN O S: 776.2759; found 777.2796 (M+H).
39 45 6 7
General Procedure (XVIIIa)
Step A:
1 eq. ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl-
4-[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy-
propanoate (Preparation 26c), 2 eq. of the appropriate boronic acid derivative and 2.5 eq.
Cs CO were dissolved in THF-water (1:1) (0.1 M for Preparation 26c), then 0.1 eq.
PdCl ×dppf was added. The mixture was heated under nitrogen at 100°C in a microwave
reactor until no further conversion was observed. Then it was diluted with brine and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via flash chromatography using EtOAc and MeOH as
eluents.
Step B:
The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and purified via preparative reversed phase chromatography using 25 mM
aqueous NH4HCO3 solution and MeCN as eluents separating the diastereoisomers.
Example 600 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
cyanophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (4-cyanophenyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 600.
HRMS calculated for C H ClN O S: 819.2970; found 410.6565 (M+2H).
44 46 7 5
Example 601 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
ethylphenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (4-ethylphenyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 601.
HRMS calculated for C H ClN O S: 822.3330; found 412.1729 (M+2H).
45 51 6 5
Example 602 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (4-hydroxyphenyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 602.
HRMS calculated for C H ClN O S: 810.2966; found 406.1541 (M+2H).
43 47 6 6
Example 603 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
methoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (4-methoxyphenyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 603.
HRMS calculated for C44H49ClN6O6S: 824.3123; found 413.1648 (M+2H).
Example 604 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-ethoxyphenyl)thieno
[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (4-ethoxyphenyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 604.
HRMS calculated for C H ClN O S: 838.3279; found 420.1700 (M+2H).
45 51 6 6
Example 605 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[6-(6'-chloro-2,3'-
bipyridinyl)-(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Example 606 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(6-chloropyridin
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (6-chloropyridyl)boronic acid as the appropriate
boronic acid derivative Example 606 was collected as the secondly eluting
diastereoisomer. HRMS calculated for C H Cl N O S: 829.2580; found 415.6359
42 45 2 7 5
(M+2H). Overreaction at the Suzuki coupling was also observed and the later eluting
diastereoisomer of this side product was collected as Example 605. HRMS calculated for
C H Cl N O S: 906.2845; found 454.1481 (M+2H).
47 48 2 8 5
Example 607 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5Sa){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(6-fluoropyridin
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (6-fluoropyridyl)boronic acid as the appropriate
boronic acid derivative, the diastereoisomer eluting later was collected as Example 607.
HRMS calculated for C H ClFN O S: 813.2875; found 407.6496 (M+2H).
42 45 7 5
Example 608 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(6-methoxypyridin
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and (6-methoxypyridyl)boronic acid as the
appropriate boronic acid derivative, the diastereoisomer eluting later was collected as
Example 608. HRMS calculated for C H ClN O S: 825.3075; found 413.6608 (M+2H).
43 48 7 6
Example 609 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(pyridinyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and 3-pyridylboronic acid as the appropriate boronic
acid derivative, the diastereoisomer eluting later was collected as Example 609. HRMS
calculated for C H ClN O S: 795.2970; found 398.6572 (M+2H).
42 46 7 5
Example 610 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(1-methyl-1H-pyrazol
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (XVIIIa) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyrazole as the appropriate boronic acid derivative, the diastereoisomer
eluting later was collected as Example 610. HRMS calculated for C H ClN O S:
41 47 8 5
798.3079; found 400.1599 (M+2H).
Example 611 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}ethynylthieno[2,3-
d]pyrimidinyl)oxy]propanoic acid
Step A:
437 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidin
yl]oxy-propanoate (Preparation 26c) (0.5 mmol), 139 µL ethynyl(trimethyl)silane (1.0
mmol), 35 mg Pd(PPh ) Cl (0.05 mmol) and 19 mg copper(I) iodide (0.1 mmol) were
3 2 2
dissolved in 5 mL DIPA, then the mixture was stirred under nitrogen at 60°C until no
further conversion was observed. The reaction mixture was cooled to room temperature
and 600 µl TBAF (0.6 mmol, 1 M in THF) was added and it was stirred for 30 minutes.
Then the volatiles were evaporated under reduced pressure and the crude product was
purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)-
3-[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]ethynyl-thieno[2,3-d]pyrimidinyl]oxy-
propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 611. HRMS calculated for
C H ClN O S: 742.2704; found 743.2789 (M+H).
39 43 6 5
Example 612 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[6-(butyn
yl)-(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Step A:
437 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]
oxy-propanoate (Preparation 26c) (0.5 mmol), 35 mg Pd(PPh3)2Cl2 (0.05 mmol) and 19
mg copper(I) iodide (0.1 mmol) were dissolved in 5 mL DIPA, then butyne was bubbled
through the reaction mixture, which was stirred at 60°C until no further conversion was
observed. Then the volatiles were evaporated under reduced pressure and the crude product
was purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl
(2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][6-butynyl[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]thieno[2,3-d]pyrimidinyl]oxy-
propanoate.
Step B:
The obtained intermediate was hydrolyzed according to Step B of General Procedure
(XVIIIa) and the diastereoisomer eluting later was collected as Example 612. HRMS
calculated for C H ClN O S: 770.3017; found 386.1594 (M+2H).
41 47 6 5
Example 613 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(3-methoxypropyn
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Step A:
437 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidin
yl]oxy-propanoate (Preparation 26c) (0.5 mmol), 70 mg 3-methoxypropyne (1.0
mmol), 35 mg Pd(PPh ) Cl (0.05 mmol) and 19 mg CuI (0.1 mmol) were dissolved in 5
3 2 2
mL DIPA and stirred under nitrogen at 60°C until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the crude product was purified by
flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[2-[(1-
butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl](3-methoxypropynyl)thieno[2,3-d]pyrimidinyl]oxy-
propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa);
the diastereoisomer eluting later was collected as Example 613. HRMS calculated for
C H ClN O S: 786.2966; found 787.3040 (M+H).
41 47 6 6
Example 614 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}cyanothieno[2,3-
d]pyrimidinyl)oxy]propanoic acid
Step A:
437 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]
oxy-propanoate (Preparation 26c) (0.5 mmol) and 224 mg CuCN (2.5 mmol) were stirred
at 100°C in 5 mL dry DMF until no further conversion was observed. Brine was added and
the mixture was extracted with DCM. The combined organic phases were washed with
brine, then dried over MgSO and concentrated under reduced pressure. The residue was
purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)-
3-[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]cyano-thieno[2,3-d]pyrimidinyl]oxy-
propanoate.
Step B:
The obtained intermediate was hydrolyzed according to Step B of General Procedure
(XVIIIa) and the diastereoisomer eluting later was collected as Example 614. HRMS
calculated for C H ClN O S: 743.2657; found 372.6390 (M+2H).
38 42 7 5
Example 615 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(trifluoromethyl)
thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Step A:
437 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]
oxy-propanoate (Preparation 26c) (0.75 mmol), 28.2 mg 1,10-phenanthroline (0.156
mmol), 29.7 mg copper(I) iodide (0.156 mmol), 130 mg potassium fluoride (2.23 mmol),
330 µL trimethyl(trifluoromethyl)silane (2.23 mmol) and 250 µL trimethyl borate (2.23
mmol) were dissolved in 5 mL dry DMSO and the mixture was stirred at room temperature
overnight under argon atmosphere. Then brine was added and the mixture was extracted
with DCM. The combined organic phases were washed with brine, dried over MgSO , and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[2-[(1-butyl-
1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy] phenyl](trifluoromethyl)thieno[2,3-d]pyrimidinyl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 615. HRMS calculated for
C H ClF N O S: 786.2578; found 394.1372 (M+2H).
38 42 3 6 5
Example 616 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}{4-[2-(morpholin
yl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]propanoic acid
Step A:
420 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](4-hydroxyphenyl)thieno[2,3-
d]pyrimidinyl]oxy-propanoate (see Step A of Example 602) (0.5 mmol), 182 µl 2-
(morpholinyl)ethanol (1.5 mmol) and 393 mg triphenylphosphine (3.0 mmol) were
dissolved in 10 mL dry toluene, then 261 mg ditertbutyl azodicarboxylate (3.0 mmol) was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. Then the volatiles were evaporated under reduced pressure and the residue was
purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (2R)
[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl][4-(2-(morpholinyl)ethoxy)phenyl]thieno[2,3-
d]pyrimidinyl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 616. HRMS calculated for
C H ClN O S: 923.3807; found 462.6977 (M+2H).
49 58 7 7
Example 617 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(3-
methoxypropyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
350 mg ethyl (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(3-methoxypropyn
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid (Example 613) (0.43 mmol) and 46
mg Selcat Q6 were dissolved in 5 mL methanol, then 187 mg tert-butylamine borane (2.2
mmol) was added and the mixture was stirred at room temperature until no further
conversion was observed. The mixture was filtered through celite, then the filtrate was
diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined
organic phases were dried over Na SO and concentrated under reduced pressure. The
residue was purified via preparative reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents to obtain Example 617. HRMS calculated for
C H ClN O S: 790.3279; found 791.3329 (M+H).
41 51 6 6
Example 618 (2R){[6-(6-aminopyridinyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-butyl-1H-
pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (XVIIIa) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridinamine as the appropriate boronic acid derivative; the diastereoisomer eluting
later was collected as Example 618. HRMS calculated for C H ClN O S: 810.3079;
42 47 8 5
found 811.3129 (M+H).
Example 619 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}[6-(morpholin
yl)pyridinyl]thieno[2,3-d]pyrimidinyl)oxy]propanoic acid
Step A:
250 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](6-fluoropyridyl)thieno[2,3-
d]pyrimidinyl]oxy-propanoate (see Step A of Example 607) (0.29 mmol) and 258 µL
morpholine (2.90 mmol) were heated at 150°C in a microwave reactor until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
residue was purified via flash chromatography using EtOAc and MeOH as eluents to give
ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl](6-morpholinopyridyl)thieno[2,3-
d]pyrimidinyl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 619. HRMS calculated for
C H ClN O S: 880.3497; found 441.1825 (M+2H).
46 53 8 6
Example 620 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}{6-[(2-
methoxyethyl)amino]pyridinyl}thieno[2,3-d]pyrimidinyl)oxy]propanoic acid
Step A:
300 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](6-fluoropyridyl)thieno[2,3-
d]pyrimidinyl]oxy-propanoate (see Step A of Example 607) (0.35 mmol) and 258 µL 2-
methoxyethanamine (3.50 mmol) were heated at 150°C in a microwave reactor until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude product was purified via flash chromatography using EtOAc and MeOH as
eluents to give ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro-
2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl][6-(2-methoxyethylamino)
pyridyl]thieno[2,3-d]pyrimidinyl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 620. HRMS calculated for
C H ClN O S: 868.3497; found 435.1839 (M+2H).
45 53 8 6
Example 621 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}{6-[2-(morpholin
yl)ethoxy]pyridinyl}thieno[2,3-d]pyrimidinyl)oxy]propanoic acid
Step A:
260 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](6-fluoropyridyl)thieno[2,3-
d]pyrimidinyl]oxy-propanoate (Step A of Example 607) (0.31 mmol), 405 mg 2-
(morpholinyl)ethanol (3.10 mmol) and 293 mg cesium carbonate (0.93 mmol) were
stirred at 60°C in 10 mL dry tert-butanol until no further conversion was observed. Brine
was added and the mixture was extracted with DCM. The combined organic phases were
washed with brine, then dried over MgSO , and concentrated under reduced pressure. The
residue was purified via flash chromatography using EtOAc and MeOH as eluents to give
ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl][6-(2-morpholinoethoxy)pyridyl]thieno[2,3-
d]pyrimidinyl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 621. HRMS calculated for
C H ClN O S: 924.3759; found 463.1961 (M+2H).
48 57 8 7
Example 622 (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}[((5S ){3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}[6-(2-methoxyethoxy)
pyridinyl]thieno[2,3-d]pyrimidinyl)oxy]propanoic acid
Step A:
200 mg ethyl (2R)[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](6-fluoropyridyl)thieno[2,3-d]
pyrimidinyl]oxy-propanoate (see Step A of Example 607) (0.24 mmol), 56 µL 2-
methoxyethanol (0.72 mmol) and 232 mg cesium carbonate (0.72 mmol) were stirred at
70°C in 5 mL dry tert-butanol until no further conversion was observed. Brine was added
and the mixture was extracted with DCM. The combined organic phases were washed with
brine, then dried over MgSO , and concentrated under reduced pressure. The residue was
purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (2R)
[2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl][5-[3-chloromethyl[2-(4-methyl
piperazinyl)ethoxy]phenyl][6-(2-methoxyethoxy)pyridyl]thieno[2,3-d]pyrimidin-
4-yl]oxy-propanoate.
Step B:
The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa)
and the diastereoisomer eluting later was collected as Example 622. HRMS calculated for
C H ClN O S: 869.3337; found 435.6737 (M+2H).
45 52 7 7
General Procedure (XXa)
The appropriate acid was dissolved in ethanol (20 mL/g) containing 1% cc. sulfuric acid
and the mixture was stirred at 70°C until no further conversion was observed. Water was
added to the mixture and it was neutralized with NaHCO , extracted with DCM, the
combined organic phases were dried with Na SO and concentrated under reduced
pressure. The crude ester was purified via preparative reversed phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents.
Example 623 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(propanyl)-1H-pyrazolyl]methoxy}phenyl)propanoate
Starting from Example 182 using General Procedure (XXa), Example 623 was obtained.
HRMS calculated for C H ClFN O S: 816.2872; found 409.1516 (M+2H)
42 46 6 6
Example 624 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan-
2-yl)-1H-pyrazolyl]methoxy}phenyl)propanoate
Starting from Example 71 using General Procedure (XXa), Example 624 was obtained.
HRMS calculated for C H ClFN O S: 826.3079; found 414.1627 (M+2H)
44 48 6 5
Example 625 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoate
Starting from Example 176 using General Procedure (XXa), Example 625 was obtained.
HRMS calculated for C H ClFN O S: 816.2508; found 817.2629 (M+H)
41 42 6 7
Example 626 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoate
Starting from Example 54 using General Procedure (XXa), Example 626 was obtained.
HRMS calculated for C H ClFN O S: 826.2716; found 414.1440 (M+2H)
43 44 6 6
Example 627 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxy
phenyl)propanoate
Starting from Example 209 using General Procedure (XXa), Example 627 was obtained.
HRMS calculated for C H ClN O S: 690.2279; found 691.2347 (M+H)
36 39 4 6
Example 628 ethyl (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoate
Starting from Example 2 using General Procedure (XXa), Example 628 was obtained.
HRMS calculated for C H ClFN O S: 788.2811; found 789.2875 (M+H)
42 46 4 6
Example 629 ethyl (2R){[(5Sa){3-chloromethyl[2-(morpholin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoate
Starting from Example 648 using General Procedure (XXa), Example 629 was obtained.
HRMS calculated for C H ClFN O S: 775.2494; found 776.2560 (M+H)
41 43 3 7
Example 630 ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoate
Starting from Example 126 using General Procedure (XXa), Example 630 was obtained.
HRMS calculated for C H ClFN O S: 733.2389; found 734.2469 (M+H)
39 41 3 6
Example 631 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoate
Starting from Example 91 using General Procedure (XXa), Example 631 was obtained.
HRMS calculated for C H ClFN O S: 796.2610; found 797.2695 (M+H)
42 42 6 5
Example 632 ethyl (2R){[(5S ){3-chloromethyl[2-(morpholin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazin
ylmethoxy)phenyl]propanoate
Starting from Example 148 using General Procedure (XXa), Example 632 was obtained.
HRMS calculated for C H ClFN O S: 783.2294; found 784.2387 (M+H)
41 39 5 6
Example 633 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(thiophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoate
Starting from Example 568 using General Procedure (XXa), Example 633 was obtained.
HRMS calculated for C H ClN O S : 706.2050; found 707.2111 (M+H)
36 39 4 5 2
Example 634 ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoate
Starting from Example 127 using General Procedure (XXa), Example 634 was obtained.
HRMS calculated for C H ClF N O S: 731.1844; found 732.1929 (M+H)
36 34 4 3 5
Example 635 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoate
Starting from Example 3 using General Procedure (XXa), Example 635 was obtained.
HRMS calculated for C H ClF N O S: 786.2266; found 787.2334 (M+H)
39 39 4 4 5
Example 636 ethyl (2R){[(5S )(3-chlorohydroxymethylphenyl)(thiophen
yl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoate
Starting from Example 715 using General Procedure (XXa), Example 636 was obtained.
HRMS calculated for C H ClN O S : 580.0893; found 581.0953 (M+H)
29 25 2 5 2
Example 637 ethyl (2R){[(5S ){3-chloromethyl[2-(morpholin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoate
Starting from Example 657 using General Procedure (XXa), Example 637 was obtained.
HRMS calculated for C H ClF N O S: 773.1949; found 774.2023 (M+H)
38 36 4 3 6
Example 638 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2-
trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoate
Starting from Example 58 using General Procedure (XXa), Example 638 was obtained.
HRMS calculated for C H ClF N O S: 894.2589; found 895.2688 (M+H)
44 43 4 6 6
Example 639 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Starting from Example 30 using General Procedure (XXa), Example 639 was obtained.
HRMS calculated for C H ClFN O S: 902.3029; found 452.1594 (M+2H)
49 48 6 6
Example 640 2,3-dihydro-1H-indenyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-methoxyphenyl)propanoate
69 mg (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid
(Example 1) (0.10 mmol), 20 mg 2,3-dihydro-1H-indenol (0.15 mmol), 0.028 mL
triethylamine (0.20 mmol) and 78 mg PyBOP (0.15 mmol) were dissolved in 3 mL DCM
and the reaction mixture was stirred at room temperature until no further conversion was
observed. Water was added and the mixture was extracted with DCM, and the combined
organic phases were dried with Na SO and concentrated under reduced pressure. The
crude ester was purified via preparative reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents resulting Example 640. HRMS
calculated for C H ClFN O S: 806.2705; found 807.2820 (M+H)
45 44 4 5
Example 641 2,2,2-trifluoroethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-methoxyphenyl)propanoate
69 mg (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid
(Example 1) (0.10 mmol), 0.011 mL trifluoroethanol (0.15 mmol), 0.028 mL triethylamine
(0.20 mmol) and 78 mg PyBOP (0.15 mmol) were dissolved in 3 mL DCM and the
reaction mixture was stirred at room temperature until no further conversion was observed.
Water was added and the mixture was extracted with DCM, and the combined organic
phases were dried with Na SO and concentrated under reduced pressure. The crude ester
was purified via preparative reversed phase chromatography using 25 mM aqueous
NH HCO solution and MeCN as eluents resulting Example 641. HRMS calculated for
C H ClF N O S: 772.2109; found 773.2188 (M+H)
38 37 4 4 5
Example 642 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoate
Starting from Example 1 using General Procedure (XXa), Example 642 was obtained.
HRMS calculated for C H ClFN O S: 718.2392; found 719.2475 (M+H)
38 40 4 5
Example 643 {[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoyl]oxy}methyl 2,2-dimethylpropanoate
69 mg (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid
(Example 1) (0.10 mmol), 15 mg chloromethyl 2,2-dimethylpropanoate (0.10 mmol), 30
mg sodium iodide (0.20 mmol) and 65 mg Cs CO (0.20 mmol) were dissolved in 1 mL
DMF and the reaction mixture was stirred at room temperature until no further conversion
was observed. Water was added and the mixture was extracted with DCM, and the
combined organic phases were dried with Na SO and concentrated under reduced
pressure. The crude ester was purified via preparative reversed phase chromatography
using 25 mM aqueous TFA solution and MeCN as eluents resulting Example 643. HRMS
calculated for C42H46ClFN4O7S: 804.2760; found 805.2822 (M+H)
Example 644 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoate
69 mg (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid
(Example 1) (0.10 mmol), 15 mg 4-(chloromethyl)methyl-1,3-dioxolone (0.10
mmol), 30 mg sodium iodide (0.20 mmol) and 65 mg Cs CO (0.20 mmol) were dissolved
in 1 mL DMF and the reaction mixture was stirred at room temperature until no further
conversion was observed. Water was added and the mixture was extracted with DCM, and
the combined organic phases were dried with Na SO and concentrated under reduced
pressure. The crude ester was purified via preparative reversed phase chromatography
using 25 mM aqueous TFA solution and MeCN as eluents resulting Example 644. HRMS
calculated for C H N O FSCl: 802.2239; found 803.2298 (M+H)
41 40 4 8
General Procedure (XXIa)
Step A:
1 eq. phenol derivative, 2 eq. of the appropriate alcohol and 2 eq. PPh were dissolved in
dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the crude intermediate was purified
via flash chromatography using EtOAc and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via preparative reversed phase chromatography using
mM aqueous NH4HCO3 solution and MeCN as eluents.
General Procedure (XXIb)
1 eq. ester was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOH × H O was
added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure. If necessary the crude product was purified via preparative reversed phase
chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
Example 645 (2R){[(5S )(4-{2-[4-(4-aminobutyl)piperazinyl]ethoxy}chloro
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (XXIa), ethyl (2R)[(5S )(3-chlorohydroxymethyl-
phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2R)-tetrahydrofuran
yl]methoxy]phenyl]propanoate (Preparation 6r) as the phenol and 2-[4-(4-
aminobutyl)piperazinyl]ethanol as the appropriate alcohol, Example 645 was obtained.
HRMS calculated for C H ClFN O S: 817.3076; found 818.3129 (M+H).
43 49 5 6
Example 646 (2R){[(5S ){3-bromomethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
531 mg ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4n) (1.00 mmol), 598 mg [2-bromomethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]-triisopropyl-silane (Preparation
5o) (1.27 mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg Cs CO (2.00 mmol) were
dissolved in 8 mL dioxane and 2 mL water. The mixture was heated under nitrogen at
110°C for 15 minutes in a microwave reactor. Then 1.2 mL TBAF (1.20 mmol in 1 M
THF) was added and the mixture was stirred for 5 minutes at room temperature. Then it
was diluted with water, acidified to pH 4 with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude intermediate was purified via flash chromatography using heptane and
EtOAc as eluents and the diastereoisomer eluting later was collected as ethyl (2R)[(5S )-
-(3-bromohydroxymethyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-methoxyphenyl)propanoate.
Step B:
Using the product of Step A as the phenol and 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol in General Procedure (XXIa), Example 646 was obtained. HRMS
calculated for C H BrFN O S: 734.1574; found 735.1637 (M+H).
36 36 4 5
Example 647 (2R){[(5S ){2,3-dichloro[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
266 mg ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4n) (0.50 mmol), 298 mg 1-[2-[2,3-dichloro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine
(Preparation 5p) (0.70 mmol), 35 mg AtaPhos (0.05 mmol) and 489 mg Cs CO (1.50
mmol) were dissolved in 4 mL dioxane and 1 mL water, and the mixture was heated under
nitrogen at 110°C for 8 minutes in a microwave reactor. Then it was diluted with brine and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents.
Step B:
The product of Step A was hydrolyzed according to General Procedure 21b and the
diastereoisomer eluting later was collected as Example 647. HRMS calculated for
C H Cl FN O S: 710.1533; found 711.1604 (M+H).
33 2 4 5
Example 648 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-tetrahydrofuran
ylmethoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chlorohydroxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2R)-
tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 6r) as the phenol and 2-
(morpholinyl)ethanol as the appropriate alcohol, Example 648 was obtained. HRMS
calculated for C H ClFN O S: 747.2181; found 748.2237 (M+H).
39 39 3 7
Example 649 (2R){[(5S ){3-chloromethyl[(1-methylpyrrolidin
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid (mixture of diastereoisomers)
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chlorohydroxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2R)-
tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 6r) as the phenol and (1-
methylpyrrolidinyl)methanol as the appropriate alcohol, Example 649 was obtained.
HRMS calculated for C H ClFN O S: 731.2232; found 732.2297 (M+H).
39 39 3 6
Example 650 (2R){[(5S ){3-chloromethyl[((3 R or S)methylpiperidinyl)
oxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2R)-
tetrahydrofuranylmethoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5Sa)(3-chlorohydroxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[(2R)-
tetrahydrofuranyl]methoxy]phenyl]propanoate (Preparation 6r) as the phenol and 1-
methylpiperidinol as the appropriate alcohol, Example 650 was obtained as a single
diastereoisomer (the absolute configuration of the 1-methylpiperidinyl moiety was not
determined). HRMS calculated for C H ClFN O S: 731.2232; found 732.2319 (M+H).
39 39 3 6
Example 651 (2R){[(5Ra){5-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]pyridinyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[5-[5-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-hydroxyphenyl)propanoate (Preparation 8j) as the phenol and (2-
methoxypyrimidinyl)methanol as the appropriate alcohol, Example 651 was obtained as
the later eluting diastereoisomer. HRMS calculated for C H ClFN O S: 799.2355; found
40 39 7 6
400.6259 (M+2H).
Example 652 (2R){[(5R ){5-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]pyridinyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-
ethyl-1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[5-[5-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]pyridyl](4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy(2-hydroxyphenyl)propanoate (Preparation 8j) as the phenol and (1-ethyl-1H-
pyrazolyl)methanol (Preparation 9da) as the appropriate alcohol, Example 652 was
obtained as the later eluting diastereoisomer. HRMS calculated for C H ClFN O S:
40 41 7 5
785.2562; found 393.6355 (M+2H).
Example 653 (2R){[(5S ){3-chloromethyl[3-(4-methylpiperazin
yl)propyl]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 654 (2R){[(5R ){3-chloromethyl[3-(4-methylpiperazin
yl)propyl]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
531 mg ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4n) (1.00 mmol), 393 mg 1-[3-[2-chloro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]propyl]methyl-piperazine
(Preparation 5r) (1.00 mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg Cs CO (2.00
mmol) were dissolved in 8 mL dioxane and 2 mL water, and the mixture was heated under
nitrogen at 110°C for 7 minutes in a microwave reactor. Then it was diluted with brine and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents.
Step B:
The product of Step B was hydrolyzed according to General Procedure 21b. The
diastereoisomer eluting earlier was collected as Example 654. HRMS calculated for
C H ClFN O S: 688.2286; found 689.2396 (M+H).
37 38 4 4
The diastereoisomer eluting later was collected as Example 653. HRMS calculated for
C H ClFN O S: 688.2286; found 689.2358 (M+H).
37 38 4 4
Example 655 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(3-
methoxypropyl)phenyl]propanoic acid
Step A:
1.00 g ethyl (2R)[(5S )-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8a) (1.41 mmol) and 594 L TEA (4.25 mmol) were dissolved in
mL dry DCM, then 477 L trifluoromethylsulfonyl trifluoromethanesulfonate (2.00
mmol) was added and the mixture was stirred at room temperature for 10 minutes. Then it
was concentrated under reduced pressure and the residue was dissolved in 10 mL dry
DMSO. 156 mg PdCl ×dppf (0.21 mmol), 81 mg copper(I) iodide (0.42 mmol), 1.17 mL
3-methoxypropyne (14.2 mmol) and 903 mg K PO (3.00 mmol) were added and the
mixture was stirred under nitrogen at 80°C for 8 hours. Then it was diluted with EtOAc
and filtered through celite. The filtrate was washed with brine, dried over MgSO , and
concentrated under reduced pressure. The residue was purified via flash chromatography
using EtOAc and MeOH as eluents to obtain ethyl (2R)[(5S )[3-chloromethyl
[2-(4-methylpiperazinyl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]
oxy[2-(3-methoxypropynyl)phenyl] propanoate.
Step B:
326 mg ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(3-methoxypropynyl)
phenyl]propanoate (0.43 mmol) and 46 mg Selcat Q6 were dissolved in 5 mL methanol,
then 187 mg tert-butylamine borane (2.2 mmol) was added and the mixture was stirred at
room temperature until no further conversion was observed. The mixture was filtered
through celite and the filtrate was concentrated under reduced pressure.
Step C:
The product of Step B was hydrolyzed according to General Procedure (XXIb) to give
Example 655. HRMS calculated for C H ClFN O S: 732.2548; found 733.2614 (M+H).
39 42 4 5
Example 656 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(3-
methoxypropynyl)phenyl]propanoic acid
Ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(3-methoxypropynyl)phenyl]
propanoate (see Step A of Example 655) was hydrolyzed according to General Procedure
(XXIb) to give Example 656. HRMS calculated for C39H38ClFN4O5S: 728.2235; found
729.2301 (M+H).
Example 657 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[5-(3-chlorohydroxymethyl-
phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(2,2,2-trifluoroethoxy)
phenyl]propanoate (Preparation 6s) as the phenol and 2-(morpholinyl)ethanol as the
appropriate alcohol, Example 657 was obtained as the secondly eluting diastereoisomer.
HRMS calculated for C H ClF N O S: 745.1636; found 746.1686 (M+H).
36 32 4 3 6
Example 658 (2R){[(5S ){3-chloromethyl[((2 S or R)methylpyrrolidin
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid (single diastereoisomer)
and
Example 659 (2R){[(5S ){3-chloromethyl[((2 R or S)methylpyrrolidin
yl)methoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid (single diastereoisomer)
Using General Procedure (XXIa) with ethyl (2R)[5-(3-chlorohydroxymethyl-
phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-(2,2,2-trifluoroethoxy)
phenyl]propanoate (Preparation 6s) as the phenol and 1-methylpiperidinol as the
appropriate alcohol, a rearrangement was observed during the Mitsunobu coupling.
Example 658 and Example 659 were isolated as the thirdly and fourthly eluting
diastereoisomers differing in the absolute configuration of the 1-methylpyrrolidinyl
moiety, which was not determined. Example 658 HRMS calculated for C H ClF N O S:
36 32 4 3 5
729.1687; found 730.1762 (M+H) and 730.1716 (M+H). Example 659 HRMS calculated
for C H ClF N O S: 729.1687; found 730.1716 (M+H).
36 32 4 3 5
Example 660 (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(dimethylamino)pyrimidin
yl]methoxy}phenyl)propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chloromethoxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8l) as the phenol and [2-(dimethylamino)pyrimidin
yl]methanol (Preparation 9an) as the appropriate alcohol, Example 660 was obtained.
HRMS calculated for C36H31ClFN5O5S: 699.1718; found 700.1805 (M+H).
Example 661 (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-(4-methylpiperazin
yl)ethoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chloromethoxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8l) as the phenol and 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol, Example 661 was obtained. HRMS calculated for C H ClFN O S:
36 36 4 5
690.2079; found 691.2141 (M+H).
Example 662 (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[2-
(dimethylamino)ethoxy]phenyl}propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chloromethoxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8l) as the phenol and 2-(dimethylamino)ethanol as the
appropriate alcohol, Example 662 was obtained. HRMS calculated for C H ClFN O S:
33 31 3 5
635.1657; found 636.1770 (M+H).
Example 663 (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({1-[2-(dimethylamino)ethyl]-1H-
pyrazolyl}methoxy)phenyl]propanoic acid
Using General Procedure (XXIa) with ethyl (2R)[(5S )(3-chloromethoxy
methyl-phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8l) as the phenol and {1-[2-(dimethylamino)ethyl]-1H-pyrazol
yl}methanol (Preparation 9dj) as the appropriate alcohol, Example 663 was obtained.
HRMS calculated for C H ClFN O S: 715.2031; found 716.2157 (M+H).
37 35 5 5
Example 664 (2R){[(5Sa){3-chlorofluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
and
Example 665 (2R){[(5R ){3-chlorofluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
531 mg ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-
methoxyphenyl)propanoate (Preparation 4n) (1.00 mmol), 380 mg 2-chlorofluoro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5m) (1.33
mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg Cs CO (2.00 mmol) were dissolved in 8
mL dioxane and 2 mL water. The mixture was heated under nitrogen at 110°C for 10
minutes in a microwave reactor. Then it was diluted with brine, neutralized with 2 M HCl,
and extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via flash chromatography,
using heptane and EtOAc as eluents to obtain a mixture of diastereoisomers.
Step B:
Using the product of Step A as the phenol and 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol in General Procedure (XXIa) the diastereoisomer eluting earlier was
collected as Example 665. HRMS calculated for C H ClF N O S: 708.1985; found
36 35 2 4 5
709.2042 (M+H). The diastereoisomer eluting later was collected as Example 664. HRMS
calculated for C H ClF N O S: 708.1985; found 709.2037 (M+H).
36 35 2 4 5
General Procedure (XXIIa)
Step A:
1 eq. ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(2-furyl)thieno[2,3-
d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate (Preparation 6d), 2
eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene
(5 ml/mmol), then 2 eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at
50°C under nitrogen until no further conversion was observed. The volatiles were
evaporated under reduced pressure and the crude intermediate was purified via flash
chromatography using ethyl acetate and methanol as eluents.
Step B:
The product of Step A was dissolved in ethanol (5 mL/mmol), then HCl (1.25 M in
ethanol) was added (5 mL/mmol) and the mixture was stirred at room temperature until no
further conversion was observed. Most of the ethanol was evaporated under reduced
pressure. The reaction mixture was treated carefully with saturated aq. NaHCO solution
and extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure.
Step C:
1 eq. of the product of Step B, 2 eq. of the appropriate alcohol and 2 eq. triphenyl
phosphine were dissolved in dry toluene (5 mL/mmol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the residue was purified via flash chromatography using ethyl acetate and methanol as
eluents.
Step D:
The product of Step C was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH
× H O was added. The mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced
pressure, and purified via preparative reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents.
Example 666 (2R){[(5S )(3-chloromethylphenyl)(furanyl)thieno[2,3-
d]pyrimidinyl]oxy}{2-[2-(4-methylpiperazinyl)ethoxy]phenyl}propanoic acid
Step A:
251 mg 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (0.668
mmol), 270 mg ethyl (2R)hydroxy[2-[2-(4-methylpiperazin
yl)ethoxy]phenyl]propanoate (Preparation 3bk) (0.8 mmol) and 871 mg Cs CO (2.67
mmol) were placed in a flask. 7 mL tert-butanol was added and the mixture was stirred at
60°C until no further conversion was observed. Then it was concentrated under reduced
pressure and purified via flash chromatography using ethyl acetate and methanol as eluents
to obtain ethyl (2R)(5-bromoiodo-thieno[2,3-d]pyrimidinyl)oxy[2-[2-(4-
methylpiperazinyl)ethoxy]phenyl]propanoate.
Step B:
420 mg ethyl (2R)(5-bromoiodo-thieno[2,3-d]pyrimidinyl)oxy[2-[2-(4-methyl
piperazinyl)ethoxy]phenyl]propanoate (0.62 mmol), 360 mg 2-(2-furyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1.86 mmol), 606 mg cesium carbonate (1.86 mmol), and
74 mg Pd(dppf)Cl (0.124 mmol) were placed in a flask. 8 mL 1,4-dioxane and 2 mL water
were added, and the mixture was stirred at 40°C under argon until no further conversion
was observed. The reaction mixture was concentrated under reduced pressure and purified
via preparative reversed phase chromatography using 5 mM aqueous NH HCO solution
and MeCN as eluents to obtain ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidin
yl]oxy[2-[2-(4-methylpiperazinyl)ethoxy]phenyl]propanoate. MS: (M+H) = 615.0.
Step C:
189 mg ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy[2-[2-(4-
methylpiperazinyl)ethoxy]phenyl]propanoate (0.3 mmol) and 146 mg 2-(3-chloro
methyl-phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (0.6 mmol) were dissolved in 2.5 mL
1,4-dioxane, then 195 mg Cs2CO3 (0.6 mmol) dissolved in 0.6 mL water was added
followed by 21 mg AtaPhos (0.021 mmol), and the mixture was heated under nitrogen at
110°C in a microwave reactor until no further conversion was observed. Then it was
diluted with brine and extracted with dichloromethane. The combined organic phases were
dried over Na SO , concentrated under reduced pressure, and purified via flash
chromatography using dichloromethane and methanol as eluents.
Step D:
The product of Step C was dissolved in 4 mL dioxane-water (1:1) and 126 mg LiOH ×
H O (3.0 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
The diastereoisomer eluting later was collected to obtain Example 666. HRMS calculated
for C H ClN O S: 632.1860; found 633.1962 (M+H)
33 33 4 5
Example 667 (2S){[(5R )(3-chloromethylphenyl)(furanyl)thieno[2,3-d]
pyrimidinyl]oxy}{2-[2-(4-methylpiperazinyl)ethoxy]phenyl}propanoic acid
Step A:
260 mg 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (0.69 mmol),
280 mg ethyl (2S)hydroxy[2-[2-(4-methylpiperazinyl)ethoxy]phenyl]propanoate
(Preparation 3bo) (0.83 mmol) and 899 mg Cs CO (2.76 mmol) were placed in a flask. 7
mL tert-butanol was added and the mixture was stirred at 60°C until no further conversion
was observed. Then it was concentrated under reduced pressure and purified via flash
chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2S)(5-
bromoiodo-thieno[2,3-d]pyrimidinyl)oxy[2-[2-(4-methylpiperazinyl)ethoxy]
phenyl]propanoate.
Step B:
420 mg ethyl (2S)(5-bromoiodo-thieno[2,3-d]pyrimidinyl)oxy[2-[2-(4-
methylpiperazinyl)ethoxy]phenyl]propanoate (0.62 mmol), 360 mg 2-(2-furyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1.86 mmol), 606 mg cesium carbonate (1.86 mmol), and
74 mg Pd(dppf)Cl (0.124 mmol) were placed in a flask. 8 mL 1,4-dioxane and 2 mL water
were added, and the mixture was stirred at 40°C under argon until no further conversion
was observed. The reaction mixture was concentrated under reduced pressure and purified
via preparative reversed phase chromatography using 5 mM aqueous NH HCO solution
and MeCN as eluents to obtain. ethyl (2S)[5-bromo(2-furyl)thieno[2,3-d]pyrimidin-
4-yl]oxy[2-[2-(4-methylpiperazinyl)ethoxy]phenyl]propanoate. MS: (M+H) = 615.0.
Step C:
189 mg ethyl (2S)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy[2-[2-(4-
methylpiperazinyl)ethoxy]phenyl]propanoate (0.3 mmol) and 146 mg 2-(3-chloro
methyl-phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (0.6 mmol) were dissolved in 2.5 mL
1,4-dioxane, then 195 mg Cs CO (0.6 mmol) dissolved in 0.6 mL water was added
followed by 21 mg AtaPhos (0.021 mmol), and the mixture was heated under nitrogen at
110°C in a microwave reactor until no further conversion was observed. Then it was
diluted with brine and extracted with dichloromethane. The combined organic phases were
dried over Na SO , concentrated under reduced pressure, and purified via flash
chromatography using dichloromethane and methanol as eluents.
Step D:
The product of Step C was dissolved in 4 mL dioxane-water (1:1) and 126 mg LiOH ×
H O (3.0 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
The diastereoisomer eluting later was collected to obtain Example 667. HRMS calculated
for C H ClN O S: 632.1860; found 633.1959 (M+H)
33 33 4 5
Example 668 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl-1H-pyrazol
yl)methoxy]phenyl}propanoic acid
Using General Procedure (XXIIa) with 2-(dimethylamino)ethanol as the appropriate
alcohol in Step A and (1-methyl-1H-pyrazolyl)methanol as the appropriate alcohol in
Step C, Example 668 was obtained. HRMS calculated for C H ClN O S: 687.1918;
34 5 6
found 688.1996 (M+H)
Example 669 (2R){[(5Sa){3-chloro[2-(4-ethylpiperazinyl)ethoxy]
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (XXIIa) with 2-(4-ethylpiperazinyl)ethanol as the appropriate
alcohol in Step A and 2-methoxyethanol as the appropriate alcohol in Step C, Example
669 was obtained. HRMS calculated for C H ClN O S: 720.2384; found 721.2455
37 41 4 7
(M+H)
Example 670 (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]
methylphenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXIIa) with 2-(4-ethylpiperazinyl)ethanol as the appropriate
alcohol in Step A and (2-methoxypyrimidinyl)methanol as the appropriate alcohol in
Step C, Example 670 was obtained. HRMS calculated for C H ClN O S: 784.2446;
40 41 6 7
found 393.1312 (M+2H)
Example 671 (2R){[(5S )(3-chloromethyl{2-[4-(propanyl)piperazin
yl]ethoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-
methoxyethoxy)phenyl]propanoic acid
Using General Procedure (XXIIa) with 2-(4-isopropylpiperazinyl)ethanol as the
appropriate alcohol in Step A and 2-methoxyethanol as the appropriate alcohol in Step C,
Example 671 was obtained. HRMS calculated for C H ClN O S: 734.2541; found
38 43 4 7
735.2639 (M+H)
Example 672 (2R){[(5S )(3-chloromethyl{2-[4-(propanyl)piperazin
yl]ethoxy}phenyl)(furanyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXIIa) with 2-(4-isopropylpiperazinyl)ethanol as the
appropriate alcohol in Step A and (2-methoxypyrimidinyl)methanol as the appropriate
alcohol in Step C, Example 672 was obtained. HRMS calculated for C H ClN O S:
41 43 6 7
798.2602; found 799.2644 (M+H)
Example 673 (2R)[(5S )[2,3-dimethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-(2-furyl)thieno[2,3-d]pyrimidinyl]oxy[2-(2,2,2-trifluoroethoxy)phenyl]propanoic
acid
Step A:
574 mg ethyl (2R)[5-bromo(2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-
tetrahydropyranyloxyphenyl)propanoate (Preparation 4d) (1.0 mmol), 562 mg 1-[2-
[2,3-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-
piperazine (Preparation 5s) (1.5 mmol), 71 mg AtaPhos (0.1 mmol) and 652 mg Cs CO
(2.0 mmol) were dissolved in a mixture of 5 mL THF and 5 mL water. The reaction was
heated under nitrogen at 110°C in a microwave reactor until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
dichloromethane. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via flash chromatography, using ethyl acetate and
methanol as eluents.
Step B:
The product of Step A was dissolved in 5 mL ethanol, then 20 mL HCl solution (1.25 M in
ethanol) was added and it was stirred at room temperature until no further conversion was
observed. Saturated aq. NaHCO solution was added carefully and it was extracted with
dichloromethane. The combined organic phases were dried over Na2SO4, concentrated
under reduced pressure, and purified via flash chromatography using ethyl acetate and
methanol as eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate as mixture of diastereoisomers. MS: (M+H) = 641.4.
Step C:
The product of Step B was dissolved in 5 mL DMF, 276 mg K2CO3 (2.00 mmol) and 232
mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.00 mmol) were added and the mixture
was stirred at room temperature until no further conversion was observed. It was diluted
with brine and extracted with DCM. The combined organic phases were dried over
Na SO , concentrated under reduced pressure, and purified via flash chromatography using
ethyl acetate and methanol as eluents.
Step D:
The product of Step C was dissolved in 12 mL dioxane-water (1:1) and 300 mg LiOH ×
H O (7.14 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
The diastereoisomer eluting later was collected as Example 673. HRMS calculated for
C H F N O S: 710.2386; found 711.2442 (M+H)
36 37 3 4 6
Example 674 (2R){[(5S )(3-chlorohydroxymethylphenyl)(furan
yl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyridinylmethoxy)phenyl]propanoic acid
Step A:
488 mg 5-bromochloro(2-furyl)thieno[2,3-d]pyrimidine (Preparation 2c) (1.3
mmol), 471 mg ethyl ethyl (2R)hydroxy[2-(2-pyridylmethoxy)phenyl]propanoate
(Preparation 3bn) (1.56 mmol) and 1.27 g Cs CO (3.9 mmol) were placed in a flask. 20
mL tert-butanol was added and the mixture was stirred at 70°C until no further conversion
was observed. The solvent was evaporated under reduced pressure, the residue was diluted
with water, the pH was set to 8 with 2 M HCl, and then it was extracted with DCM. The
combined organic layers were dried over Na SO , concentrated under reduced pressure,
and purified via flash chromatography using heptane and ethyl acetate as eluents.
Step B:
The product of Step A and 83.27 mg 2-chloromethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (Preparation 5a) (0.31 mmol) were dissolved in 2 mL THF,
then 252 mg Cs CO (0.78 mmol) dissolved in 2 mL water was added followed by 18 mg
AtaPhos (0.03 mmol), and the mixture was heated under nitrogen at 100°C in a microwave
reactor until no further conversion was observed. It was diluted with ethyl acetate and
brine, the organic layer was dried over Na SO and concentrated under reduced pressure.
The residue was purified via flash chromatography using heptane and ethyl acetate as
eluents. MS: (M+H) = 641.4.
Step C:
The product of Step B was dissolved in 4 mL dioxane-water (1:1) and 59 mg LiOH × H O
(1.4 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using MeCN and 25 mM aqueous NH HCO solution as eluents.
The diastereoisomer eluting later was collected as Example 674. HRMS calculated for
C H ClN O S: 613.1074; found 614.1152 (M+H).
32 24 3 6
General Procedure (XXIIIa)
To 1 eq. of the appropriate ester in MeOH (24 mL/mmol) 28 eq. LiOH×H O (5.96 mmol)
was added and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with
DCM. The combined organic phases were dried over Na SO , concentrated under reduced
pressure and purified via preparative reversed phase chromatography using 0.1% aqueous
TFA solution and MeCN as eluents
Example 675 (2R)(1,3-benzodioxolyl){[(5S )(3-chlorohydroxy
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Ethyl (2R)(1,3-benzodioxolyl)[(5S )(3-chlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation 17b) in General
Procedure (XXIIIa) gave Example 675. HRMS calculated for C H ClN O S: 512.0809;
21 2 6
found 513.0869 (M+H)
Example 676 (2S)(1,3-benzodioxolyl){[(5S )(3-chlorohydroxy
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Ethyl (2S)(1,3-benzodioxolyl)[(5S )(3-chlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation 17i) in General Procedure
(XXIIIa) gave Example 676. HRMS calculated for C H ClN O S: 512.0809; found
21 2 6
513.0877 (M+H)
Example 677 (2S)(1,3-benzodioxolyl){[(5R )(3-chlorohydroxy
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Ethyl (2S)(1,3-benzodioxolyl)[(5R )(3-chlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation 17j) in General Procedure
(XXIIIa) gave Example 677. HRMS calculated for C H ClN O S: 512.0809; found
21 2 6
513.089 (M+H)
Example 678 (2R)(1,3-benzodioxolyl){[(5R )(3-chlorohydroxy
methylphenyl)ethylthieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Ethyl (2R)(1,3-benzodioxolyl)[(5R )(3-chlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxy-propanoate (Preparation17a) in General Procedure
(XXIIIa) gave Example 678. HRMS calculated for C H ClN O S: 512.0809; found
21 2 6
513.0868 (M+H)
Example 679 (2S){[(5R )(3-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Example 680 (2S){[(5Sa)(3-chlorohydroxymethylphenyl)ethylthieno[2,3-d]
pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Step A:
0.61 g ethyl (2S)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-methoxyphenyl)
propanoate (Preparation 4r) (1.19 mmol), 0.480 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (1.79 mmol), 0.218 g
Pd (dba) (0.24 mmol), 0.171 g BuPAd (0.48 mmol), 1.79 mL Bu NOH solution (1.79
2 3 2 4
mmol, 1 M in water) and 7 mL 2-Me-THF were heated with stirring at 110°C under argon
for 10 mins in a microwave reactor. The pH of the mixture was set to 6 with 2 M HCl, and
then it was extracted with MTBE. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure, and purified via flash chromatography using heptane
and EtOAc as eluents, yielding ethyl (2S)[5-(3-chlorohydroxymethyl-phenyl)
ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate as a mixture of
diastereomers. MS: (M+H) = 527.2.
Step B:
To 0.529 g of the product of Step A (1.0 mmol) dissolved in 6 mL THF-water (1:1) 0.250g
LiOH×H O (5.96 mmol) was added and the mixture was stirred at room temperature until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, and extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure and purified via preparative reverse phase
chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain
Example 680 as the product eluting earlier [HRMS calculated for C H ClN O S:
23 2 5
498.1016; found 499.1079 (M+H)], and Example 679 as the product eluting later [HRMS
calculated for C H ClN O S: 498.1016; found 499.1097 (M+H)].
23 2 5
Example 681 (2R){[(5S )5-(3-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Example 682 (2R){[(5R )(3-chlorohydroxymethylphenyl)ethylthieno[2,3-
d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Step A:
0.50 g ethyl (2R)(6-ethyliodo-thieno[2,3-d]pyrimidinyl)oxy(2-methoxyphenyl)
propanoate (Preparation 4q) (0.98 mmol), 0.393 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (1.46 mmol), 0.179 g
Pd (dba) (0.2 mmol), 0.140 g BuPAd (0.39 mmol), 1.46 mL Bu NOH solution (1.46
2 3 2 4
mmol, 1 M in water) and 5 mL 2-Me-THF were heated under nitrogen with stirring at
110°C for 10 mins in a microwave reactor. The pH of the mixture was set to 6 with 2 M
HCl, and then it was extracted with MTBE. The combined organic phases were dried over
Na SO , concentrated under reduced pressure and purified via flash chromatography using
heptane and EtOAc as eluents to yield ethyl (2R)[5-(3-chlorohydroxymethyl-
phenyl)ethyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate as a
mixture of diastereomers. MS: (M+H) = 527.2.
Step B:
To 0.454g of the product of Step A (0.86 mmol) dissolved in 6 mL THF-water (1:1)
0.250g LiOH×H O (5.96 mmol) was added and the mixture was stirred at room
temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were
dried over Na SO , concentrated under reduced pressure, and purified via preparative
reverse phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents to
obtain Example 682 as the product eluting earlier [HRMS calculated for C H ClN O S:
23 2 5
498.1016; found 499.1091 (M+H) ], and Example 681 as the product eluting later [HRMS
calculated for C H ClN O S: 498.1016; found 499.1074 (M+H) ].
23 2 5
Example 683 (2S)[(5R )-(5-{3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}ethylthieno[2,3-d]pyrimidinyl)oxy](2-
methoxyphenyl)propanoic acid
Step A:
0.2 g (2S){[(5R )(3-chlorohydroxymethylphenyl)ethylthieno[2,3-d]
pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid (Example 679) (0.4 mmol) was
dissolved in 2 mL dry methanol and 20 µL concentrated sulfuric acid was added and it was
stirred at room temperature until no further conversion was observed. Then the mixture
was concentrated, the residue was dissolved in EtOAc and it was washed with saturated aq.
NaHCO solution. The organic layer was dried over Na SO and concentrated under
3 2 4
reduced pressure to give methyl (2S){[(5R )(3-chlorohydroxymethylphenyl)
ethylthieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoate, which was used
without further purification.
Step B:
The mixture of 0.232 g of the product of Step A (0.45 mmol), 0.13 g 2-(4-methylpiperazin-
1-yl)ethanol (0.9 mmol), 0.208 g ditertbutyl azodicarboxylate (0.9 mmol) and 0.301 g resin
bound triphenylphosphine (3 mmol/g, 0.9 mmol) was stirred in 3 mL dry toluene at 50°C
until no further conversion was observed. Then the mixture was filtered through a pad of
Celite, the pad was washed with EtOAc and the filtrate was concentrated under reduced
pressure. The residue was dissolved in 4 mL methanol and 0.108 g LiOH×H O (2.57
mmol) was added and the mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reverse phase chromatography using
40 mM aqueous NH OAc solution (pH set to 4 with AcOH) and MeCN as eluents to obtain
Example 683. HRMS calculated for C H ClN O S: 624.2173; found 625.2253 (M+H) .
32 37 4 5
General Procedure (XXIVa)
Step A:
1 eq. phenol derivative, 2 eq. of the appropriate alcohol and 2 eq. PPh were dissolved in
dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under nitrogen until no further conversion was observed. The
volatiles were evaporated under reduced pressure and the residue was purified via flash
chromatography using EtOAc and MeOH as eluents.
Step B:
The obtained intermediate was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH×H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 684 (2R){[(5S ){3-chloromethyl[2-(piperazinyl)ethoxy]phenyl}
(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (XXIVa), ethyl (2R)[(5S )(3-chlorohydroxymethyl-
phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate
(Preparation 6l) as the phenol and 2-piperazinylethanol as the appropriate alcohol,
Example 684 was obtained. HRMS calculated for C H ClN O S: 620.1860; found
32 33 4 5
621.1944 (M+H).
Example 685 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Using General Procedure (XXIVa), ethyl (2R)[(5S )(3-chlorohydroxymethyl-
phenyl)propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate
(Preparation 6l) as the phenol and 2-(morpholinyl)ethanol as the appropriate alcohol,
Example 685 was obtained. HRMS calculated for C H ClN O S: 621.1700; found
32 32 3 6
622.1776 (M+H).
Example 686 (2R){[(5R ){3-fluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 687 (2R){[(5S ){3-fluoromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
522 mg ethyl (2R)(5-iodopropynyl-thieno[2,3-d]pyrimidinyl)oxy(2-
methoxyphenyl)propanoate (Preparation 4k) (1.00 mmol), 378 mg 2-fluoromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5g) (1.50 mmol), 73 mg
PdCl ×dppf (0.10 mmol) and 489 mg Cs CO (1.50 mmol) were dissolved in 8 mL
2 2 3
dioxane and 2 mL water. The mixture was heated under nitrogen at 110°C for 10 minutes
in a microwave reactor. The reaction was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via flash chromatography, using heptane and EtOAc
as eluents to give a mixture of diastereoisomers.
Step B:
Using General Procedure (XXIVa) with the product of Step A as the phenol and 2-(4-
methylpiperazinyl)ethanol as the appropriate alcohol Example 686 and Example 687
were obtained. The diastereoisomer eluting earlier was collected as Example 686. HRMS
calculated for C H FN O S: 618.2312; found 619.2398 (M+H). The diastereoisomer
33 35 4 5
eluting later was collected as Example 687. HRMS calculated for C H FN O S:
33 35 4 5
618.2312; found 619.2396 (M+H).
Example 688 (2R){[(5R ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-trifluoroethoxy)
phenyl]propanoic acid
Step A:
667 mg of ethyl (2R)[(5R )(3-chlorohydroxymethyl-phenyl)(5-fluoro
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6q) (1.00 mmol), 262 mg 2-(morpholinyl)ethanol (2.00 mmol), and 525
mg PPh (2.00 mmol) were dissolved in 5 mL dry toluene, then 461 mg ditertbutyl
azodicarboxylate (2.00 mmol) was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the residue was purified via flash chromatography using EtOAc and methanol
as eluents to give ethyl (2R)[(5R )[3-chloromethyl(2-morpholinoethoxy)
phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyran
yloxyphenyl)propanoate.
Step B:
The product of Step A was dissolved in 35 mL HCl (1.25 M in EtOH) and the mixture was
stirred at 60°C for 2h. Saturated aq. NaHCO solution was added to the reaction mixture,
and it was extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure and purified via flash chromatography using DCM
and methanol as eluents to give ethyl (2R)[(5R )[3-chloromethyl(2-(morpholin-
4-yl)ethoxy)phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(2-
hydroxyphenyl)propanoate.
Step C:
The product of Step B (232 mg, 0.34 mmol) was dissolved in 2 ml DMF, 138 mg K CO
(1.0 mmol) and 77 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) were
added. The mixture was stirred at room temperature under nitrogen for 7 hours. Then it
was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined
organic phases were dried over Na SO and concentrated under reduced pressure. The
obtained ester was dissolved in 5 mL dioxane-water (1:1) and 142 mg LiOH×H O (3.40
mmol) was added. The mixture was stirred at room temperature for 1 hour, then it was
diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined
organic phases were dried over Na SO , concentrated under reduced pressure and purified
via preparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution
and MeCN as eluents to give Example 688. HRMS calculated for C H ClF N O S:
34 30 4 3 7
735.1429; found 736.1469 (M+H)
Example 689 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2-
trifluoroethoxy)phenyl]propanoic acid
Starting from ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(5-fluoro
furyl)thieno[2,3-d]pyrimidinyl]oxy(2-tetrahydropyranyloxyphenyl)propanoate
(Preparation 6c) and using the same steps as described for Example 688 gave Example
689. HRMS calculated for C H ClF N O S: 735.1429; found 736.1501 (M+H).
34 30 4 3 7
Example 690 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[4-fluoro
(methoxymethoxy)phenyl]propanoic acid
Step A:
2.816 g 4-Chloro[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidine (Preparation 13) (5.00 mmol), 1.634 g ethyl (2R)[4-
fluoro(methoxymethoxy)phenyl]hydroxy-propanoate (Preparation 3bf) (6.00 mmol)
and 4.88 g Cs CO (15.0 mmol) were placed in a 50 mL flask. 15 mL tert-butanol was
added and the mixture was stirred at 35°C under N for 16 hours. The reaction mixture was
diluted with water, the pH was set to 7 with 2 M HCl, and it was extracted with DCM. The
combined organic phases were dried over Na SO , concentrated under reduced pressure
and purified via flash chromatography using EtOAc and methanol as eluents to obtain
ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]iodo-
thieno[2,3-d]pyrimidinyl]oxy[4-fluoro(methoxymethoxy)phenyl]propanoate as a
mixture of diastereoisomers.
Step B:
1.075 g of the product of Step A (1.35 mmol), 0.856 g 2-(5-fluorofuryl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (4.04 mmol), 0.880 g cesium carbonate (2.70 mmol), and
99 mg [1,1'-bis(diphenylphoshino)ferrocene]dichloropalladium(II) (0.135 mmol) were
dissolved in 12 mL dioxane and 3 mL water, and the mixture was heated under argon at
110°C for 15 min in a microwave reactor. The reaction mixture was diluted with EtOAc
and washed with brine. The organic layer was dried over Na SO and concentrated. The
residue was purified via flash chromatography using EtOAc and methanol as eluents to
obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy[4-fluoro(methoxymethoxy)
phenyl]propanoate. HRMS calculated for C H ClF N O S: 756.2196044; found
37 39 2 4 7
757.2255 (M+H).
Step C:
To the solution of 350 mg of the product of Step A (0.462 mmol) in 10 ml methanol 200
mg LiOH×H O (4.77 mmol) was added. The mixture was stirred at room temperature until
no further conversion was observed. Then it was diluted with brine, neutralized with 2 M
HCl, and extracted with EtOAc. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
The diastereomer eluting later was collected as Example 690. HRMS calculated for
C H ClF N O S: 728.1883; found 729.1955 (M+H)
35 2 4 7
Example 691 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[4-fluoro
(pyrazinylmethoxy)phenyl]propanoic acid
Step A:
mL HCl (1.25 M in EtOH) was added to 396 mg ethyl (2R)[5-[3-chloromethyl
[2-(4-methylpiperazinyl)ethoxy]phenyl](5-fluorofuryl)thieno[2,3-d]pyrimidin
yl]oxy[4-fluoro(methoxymethoxy)phenyl]propanoate (0.522 mmol, product of Step
B of Example 690) and the mixture was stirred at room temperature for 48h. Saturated aq.
NaHCO solution was added to the reaction mixture, and it was extracted with EtOAc. The
combined organic layers were dried over Na SO and concentrated. The residue was
purified via flash chromatography using DCM and methanol as eluents to give ethyl (2R)-
2-[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](5-fluorofuryl)
thieno[2,3-d]pyrimidinyl]oxy(4-fluorohydroxyphenyl)propanoate. HRMS
calculated for C H ClF N O S: 712.1933897; found 713.2005 (M+H).
35 2 4 6
Step B:
200 mg of the product of Step A (0.281 mmol), 61.8 mg pyrazinylmethanol (0.562
mmol) and 147 mg PPh3 (0.562 mmol) were dissolved in 2 mL dry toluene, then 129 mg
ditertbutyl azodicarboxylate (0.562 mmol) was added. The mixture was stirred at 50°C
under nitrogen until no further conversion was observed. The volatiles were evaporated
under reduced pressure and the crude intermediate was purified via flash chromatography
using EtOAc and MeOH as eluents.
Step C:
The product of Step B was dissolved in 4 mL dioxane-water (1:1) and 109 mg LiOH×H O
(2.60 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with EtOAc. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
The diastereomer eluting later was collected as Example 691. HRMS calculated for
C H ClF N O S: 776.1995; found 777.209 (M+H)
38 35 2 6 6
Example 692 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(4-fluoro
methoxyphenyl)propanoic acid
Step A:
200 mg ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-(5-fluorofuryl)thieno[2,3-d]pyrimidinyl]oxy(4-fluorohydroxyphenyl)
propanoate (Step A of Example 691, 0.281 mmol), 22.7 l methanol (0.562 mmol) and
147 mg PPh (0.562 mmol) were dissolved in 2 mL dry toluene, then 129 mg ditertbutyl
azodicarboxylate (0.562 mmol) was added. The mixture was stirred at 50°C under nitrogen
until no further conversion was observed. The volatiles were evaporated under reduced
pressure and the crude intermediate was purified via flash chromatography using EtOAc
and MeOH as eluents.
Step B:
The product of Step A was dissolved in 4 mL dioxane-water (1:1) and 109 mg LiOH×H O
(2.60 mmol) was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with EtOAc. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
The diastereomer eluting later was collected as Example 692. HRMS calculated for
C H ClF N O S: 698.1777; found 699.1846 (M+H)
34 33 2 4 6
Example 693 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(6-fluoropyridinyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Step A:
2.88 g ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate (Preparation 26b)
(4 mmol), 1.80 g [1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methanol (Preparation 9du)
(10 mmol) and 2.62 g PPh were dissolved in dry toluene (0.2 M for Preparation 26b),
then 2.30 g ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under
argon atmosphere. After reaching appropriate conversion the volatiles were evaporated
under reduced pressure and the crude ester was purified via flash chromatography using
EtOAc and MeOH as eluents to obtain ethyl (2R)[5-[3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl]iodo-thieno[2,3-d]pyrimidinyl]oxy[2-[[1-
(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy]phenyl]propanoate.
Step B:
1.35 g of the product of Step A (1.5 mmol), 254 mg (6-fluoropyridyl)boronic acid (1.8
mmol), 110 mg Pd(dppf)Cl (0.15 mmol) and 1.59 g cesium carbonate (4.5 mmol) were
dissolved in 10 mL THF-water (1:1). The mixture was heated under nitrogen at 100°C in a
microwave reactor until no further conversion was observed. Then it was diluted with brine
and extracted with DCM. The combined organic phases were dried over Na SO , filtered
and concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[5-[3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl](6-fluoropyridyl)thieno[2,3-d]
pyrimidinyl]oxy[2-[[2-(2,2,2-trifluoroethyl)pyrazolyl]methoxy]phenyl]
propanoate.
Step C:
250 mg of the product of Step B (0.29 mmol) was dissolved in 3 mL dioxane-water (1:1,
mL/mmol) and 122 mg LiOH × H O (2.9 mmol, 10 eq.) was added. The mixture was
stirred at room temperature until no further conversion was observed. Then it was diluted
with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic
phases were dried over Na SO and concentrated. The residue was purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents. The diastereoisomer eluting later was collected as Example 693. HRMS
calculated for C H ClF N O S: 839.2280; found 840.2366 (M+H)
40 38 4 7 5
Example 694 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[6-(2-methoxyethoxy)pyridinyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Step A:
416 mg ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-(6-fluoropyridyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-trifluoroethyl)-1H-
pyrazolyl]methoxy]phenyl]propanoate (product of Step B of Example 693) (0.48
mmol), 112 µL 2-methoxyethanol (1.44 mmol) and 464 mg cesium carbonate (1.44 mmol)
were stirred at 70°C in 5 mL dry tert-butanol until no further conversion was observed.
Brine was added and the mixture was extracted with DCM. The combined organic phases
were washed with brine, then dried over MgSO and concentrated under reduced pressure.
The residue was purified via flash chromatography using EtOAc and MeOH as eluents to
obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
[6-(2-methoxyethoxy)pyridyl]thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-
trifluoroethyl)-1H-pyrazolyl]methoxy]phenyl]propanoate.
Step B:
The product of Step A was hydrolyzed according to Step C of Example 693; the
diastereoisomer eluting later was collected as Example 694. HRMS calculated for
C H ClF N O S: 895.2742; found 896.2801 (M+H)
43 45 3 7 7
Example 695 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[6-(2,2,2-trifluoroethoxy)pyridinyl]thieno[2,3-d]pyrimidin
yl)oxy](2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Step A:
434 mg ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]-
6-(6-fluoropyridyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-trifluoroethyl)-1H-
pyrazolyl]methoxy]phenyl]propanoate (product of Step B of Example 693) (0.50
mmol), 510 µL 2,2,2-trifluoroethanol (7.0 mmol) and 489 mg cesium carbonate (1.5
mmol) were stirred at 70°C in 5 mL dry BuOH until no further conversion was observed.
Brine was added and the mixture was extracted with DCM. The organic phase was washed
with brine, then dried over MgSO and concentrated under reduced pressure. The residue
was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl
(2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl][6-(2,2,2-
trifluoroethoxy)pyridyl]thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-trifluoroethyl)-
1H-pyrazolyl]methoxy]phenyl]propanoate.
Step B:
The product of Step A was hydrolyzed according to Step C of Example 693; the
diastereoisomer eluting later was collected as Example 695. HRMS calculated for
C H ClF N O S: 919.2353; found 920.2414 (M+H)
42 40 6 7 6
Example 696 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(6-methoxypyridinyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-
(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Step A:
450 mg (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]
methoxy]phenyl]propanoate (product of Step A of Example 693) (0.5 mmol), 92 mg (6-
methoxypyridyl)boronic acid (0.6 mmol), 37 mg Pd(dppf)Cl (0.05 mmol) and 530 mg
cesium carbonate (1.5 mmol) were dissolved in 5 mL THF-water (1:1) and the mixture was
heated under nitrogen at 100°C in a microwave reactor until no further conversion was
observed. Then it was diluted with brine and extracted with DCM. The combined organic
phases were dried over Na SO and concentrated under reduced pressure. The crude
product was purified via flash chromatography using EtOAc and MeOH as eluents to
obtain ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(6-methoxypyridyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[1-(2,2,2-trifluoroethyl)-1H-
pyrazolyl]methoxy]phenyl]propanoate
Step B:
The product of Step A was hydrolyzed according to Step C of Example 693; the
diastereoisomer eluting later was collected as Example 696. HRMS calculated for
C H ClF N O S: 851.2480; found 852.2514 (M+H)
41 41 3 7 6
General Procedure (XXVIIa)
Step A:
1 eq. ethyl (2R)[5-(3-chloromethoxymethyl-phenyl)(4-fluorohydroxy-
phenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methoxypyrimidinyl)methoxy]phenyl]
propanoate (Preparation 28b), 2 eq. of the appropriate alcohol and 2 eq. PPh were
dissolved in dry toluene (0.2 M for the phenol), then 2 eq. ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under nitrogen until no further conversion was
observed. The volatiles were evaporated under reduced pressure and the crude intermediate
was purified via flash chromatography using DCM and MeOH as eluents.
Step B:
The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH×H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic layers were dried over Na SO and
concentrated under reduced pressure. The residue was purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
The diastereoisomers were separated at this stage.
Example 697 (2R){[(5R )(3-chloromethoxymethylphenyl){4-fluoro[2-
(4-methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol, Example 697 was obtained as the diastereomer eluting earlier. HRMS
calculated for C H ClFN O S: 828.2508; found 415.1324 (M+2H)
42 42 6 7
Example 698 (2R){[(5S )(3-chloromethoxymethylphenyl){4-fluoro[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(4-methylpiperazinyl)ethanol as the
appropriate alcohol, Example 698 was obtained as the diastereomer eluting later. HRMS
calculated for C H ClFN O S: 828.2508; found 415.1343 (M+2H)
42 42 6 7
Example 699 (2R){[(5R )(3-chloromethoxymethylphenyl){4-fluoro[2-
(morpholinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(morpholinyl)ethanol as the
appropriate alcohol, Example 699 was obtained as the diastereomer eluting earlier. HRMS
calculated for C41H39ClFN5O8S: 815.2192; found 408.6163 (M+2H)
Example 700 (2R){[(5S )(3-chloromethoxymethylphenyl){4-fluoro[2-
(morpholinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(morpholinyl)ethanol as the
appropriate alcohol, Example 700 was obtained as the diastereomer eluting later. HRMS
calculated for C H ClFN O S: 815.2192; found 408.6173 (M+2H)
41 39 5 8
Example 701 (2R){[(5R )(3-chloromethoxymethylphenyl){3-[2-
(dimethylamino)ethoxy]fluorophenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(dimethylamino)ethanol as the
appropriate alcohol, Example 701 was obtained as the diastereomer eluting earlier. HRMS
calculated for C H ClFN O S: 773.2086; found 387.6122 (M+2H)
39 37 5 7
Example 702 (2R){[(5S )(3-chloromethoxymethylphenyl){3-[2-
(dimethylamino)ethoxy]fluorophenyl}thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXVIIa) starting from 2-(dimethylamino)ethanol as the
appropriate alcohol, Example 702 was obtained as the diastereomer eluting later. HRMS
calculated for C H ClFN O S: 773.2086; found 387.6114 (M+2H)
39 37 5 7
General Procedure (XXXIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8m), 3 eq. of the appropriate alcohol and 3 eq. triphenyl
phosphine were dissolved in dry toluene (20 mL/mmol), then 3 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under N until no further
conversion was observed. The volatiles were evaporated under reduced pressure and the
residue was purified via flash chromatography using DCM and methanol as eluents.
Step B:
The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH×H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combibed organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reverse phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 703 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXXIa) and (2-methoxypyrimidinyl)methanol as the
appropriate alcohol, Example 703 was obtained. HRMS calculated for C H ClF N O S:
41 39 2 6 6
816.2308; found 817.2434 (M+H).
Example 704 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXXIa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation
9da) as the appropriate alcohol, Example 704 was obtained. HRMS calculated for
C H ClF N O S: 802.2516; found 803.2607 (M+H).
41 41 2 6 5
Example 705 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 705 was obtained. HRMS
calculated for C H ClF N O S: 854.2077; found 855.2121 (M+H).
41 36 5 6 5
General Procedure (XXXIIa)
Step A:
1 eq. ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8k), 2 eq. of the appropriate alcohol and 2 eq. triphenyl
phosphine were dissolved in abs. toluene (5 ml/mmol), then 2 eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents.
Step B:
The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq.
LiOH×H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure and purified via preparative reversed phase chromatography using
mM aqueous NH HCO solution and MeCN as eluents.
Example 706 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-
methoxypyrimidinyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXXIIa) and (2-methoxypyrimidinyl)methanol as the
appropriate alcohol, Example 706 was obtained. HRMS calculated for C H ClF N O S:
41 39 2 6 6
816.2308; found 817.2389 (M+H)
Example 707 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(trifluoromethyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIa) and [2-(trifluoromethyl)pyrimidinyl]methanol
(Preparation 9bj) as the appropriate alcohol, Example 707 was obtained. HRMS
calculated for C H ClF N O S: 854.2077; found 855.2146 (M+H)
41 36 5 6 5
Example 708 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3,4-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-ethyl-
1H-pyrazolyl)methoxy]phenyl}propanoic acid
Using General Procedure (XXXIIa) and (1-ethyl-1H-pyrazolyl)methanol (Preparation
9da) as the appropriate alcohol, Example 708 was obtained. HRMS calculated for
C H ClF N O S: 802.2516; found 803.2561 (M+H)
41 41 2 6 5
Example 709 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(propan
yloxy)phenyl]propanoic acid
Step A:
3.75 g 5-bromochloroiodo-thieno[2,3-d]pyrimidine (Preparation 1a) (10 mmol),
2.44 g 2-(3-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11 mmol), 8.15 g
Cs2CO3 (25 mmol), and 366 mg Pd(dppf)Cl2 (0.5 mmol) were placed in a 250 mL flask. 40
mL THF and 40 mL water were added, and then stirred overnight at 70°C under N . To the
reaction mixture brine was added, the pH was set to 6 with 2 M HCl and it was extracted
with DCM. The combined organic layers were dried over Na SO and concentrated under
reduced pressure. The crude product was purified via flash chromatography using heptane
and EtOAc as eluents to obtain 5-bromochloro(3-fluorophenyl)thieno[2,3-
d]pyrimidine. H NMR (500 MHz, DMSO-d ): 9.04 (s, 1H), 7.66-7.60 (m, 2H), 7.56 (d,
1H), 7.44 (td, 1H).
HRMS calculated for C H ClFBrN S: 341.9029; found 342.9093 (M+H).
12 5 2
Step B:
2.62 g of the product of Step A (7.6 mmol), 3.78 g ethyl (2R)hydroxy[2-[(4-
methoxyphenyl)methoxy]phenyl]propanoate (Preparation 3ae) (11.5 mmol) and 7.46 g
Cs CO (22.9 mmol) were placed in a 250 mL flask. 150 mL tert-butanol was added and
the mixture was stirred at 60°C under N until no further conversion was observed. Water
was added to the mixture and it was extracted with DCM. The combined organic layers
were dried over Na SO , concentrated, and purified via flash chromatography using
heptane and EtOAc as eluents to obtain ethyl (2R)[5-bromo(3-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl] propanoate. H
NMR (500 MHz, DMSO-d ): 8.67 (s, 1H), 7.62-7.54 (m, 3H), 7.40 (m, 4H), 7.22 (td, 1H),
7.08 (d, 1H), 6.90 (d, 2H), 6.88 (td, 1H), 5.71 (dd, 1H), 5.10 (d, 1H), 5.06 (d, 1H), 4.11 (m,
2H), 3.74 (s, 3H), 3.45 (dd, 1H), 3.21 (dd, 1H), 1.10 (t, 3H).
HRMS calculated for C H BrFN O S: 636.0730; found 637.0815 (M+H).
31 26 2 5
Step C:
0.152 g of the product of Step B (0.24 mmol), 0.160 g 2-chloromethyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenol (Preparation 5a) (0.60 mmol), and 0.017 g
Ataphos (0.024 mmol) were dissolved in 1.7 mL 2-Me-THF, and 0.6 mL
tetrabutylammonium hydroxide (1M in H O, 0.6 mmol) was added. The mixture was
heated under nitrogen at 110 °C for 10 min in a microwave reactor. The reaction was
diluted with water, the pH was adjusted to 4 by the addition of 2 M HCl, and it was
extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The mixture of diastereomers was separated via flash
chromatography using heptane and EtOAc as eluents. The diastereomer eluting later was
collected as ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(3-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl]
propanoate. H NMR (500 MHz, DMSO-d ): 10.28 (s, 1H), 8.62 (s, 1H), 7.41-7.39 (m,
3H), 7.20-7.12 (m, 4H), 7.01-6.96 (m, 3H), 6.90 (d, 2H), 6.71 (td, 1H), 6.33 (dd, 1H), 5.43
(dd, 1H), 5.05 (d, 1H), 5.01 (d, 1H), 4.03 (q, 2H), 3.73 (s, 3H), 3.04 (dd, 1H), 2.46 (dd,
1H), 1.79 (s, 3H), 1.04 (t, 3H).
HRMS calculated for C H ClFN O S: 698.1654; found 699.1754 (M+H).
38 32 2 6
Step D:
0.966 g of the product of Step C (1.4 mmol), 0.60 g 2-(4-methylpiperazinyl)ethanol (4.1
mmol) were dissolved in 20 mL dry toluene, then 1.38 g PPh polymer (3 mmol/g, 4.1
mmol) and 0.95 g di-tert-butyl azodicarboxylate (4.1 mmol) was added. The mixture was
stirred at 50°C under N until no further conversion was observed. The polymer was
filtered off, toluene was evaporated under reduced pressure and the residue was purified
via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[(5S )-
-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](3-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy[2-[(4-methoxyphenyl)methoxy]phenyl]propanoate. H
NMR (500 MHz, DMSO-d ): 8.64 (s, 1H), 7.41-7.38 (m, 3H), 7.29 (d, 1H), 7.20-7.12 (m,
4H), 7.03-7.01 (m, 2H), 6.90 (d, 2H), 6.70 (t, 1H), 6.31 (dd, 1H), 5.42 (dd, 1H), 5.04 (d,
1H), 5.00 (d, 1H), 4.19 (m, 2H), 4.02 (q, 2H), 3.73 (s, 3H), 2.99 (dd, 1H), 2.70 (t, 2H), 2.50
(dd, 1H), 2.46 (br s, 4H), 2.22 (br s, 4H), 2.08 (s, 3H), 1.82 (s, 3H), 1.02 (t, 3H).
HRMS calculated for C H ClFN O S: 824.2811; found 825.2899 (M+H).
45 46 4 6
Step E:
0.20 g of the product of Step D (0.24 mmol) was dissolved in 0.5 mL DCM and cooled to
0°C. 4 mL HBr (33 % solution in acetic acid) was added and the mixture was stirred for 10
min. Water was added and the pH was adjusted to 4 by the addition of saturated aq.
NaHCO solution. The mixture was extracted with DCM, the combined organic phases
were dried over Na SO and concentrated under reduced pressure. The crude product was
dissolved in 20 mL EtOH and 0.2 mL cc. H SO was added. The reaction mixture was
stirred at 50°C until no further conversion was observed. Brine was added and the mixture
was extracted with DCM. The combined organic phases were dried over Na SO and
concentrated under reduced pressure. The crude product was purified via flash
chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)[(5S )[3-
chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](3-fluorophenyl)thieno
[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)propanoate. HRMS calculated for
C H FN O S: 704.2235; found 705.2307 (M+H).
37 46 4 6
Step F:
95 mg of the product of Step E (0.13 mmol), 94 mg PPh (0.39 mmol), 96 mg ditertbutyl
azodicarboxylate (0.39 mmol) and 32 µL propanol (0.39 mmol) were dissolved in 2 ml
dry toluene and the reaction mixture was stirred at 50°C under N until no further
conversion was observed. The mixture was concentrated under reduced pressure. The
residue was dissolved in 5 mL MeOH, 252 mg LiOH×H O (6.0 mmol) was added and it
was stirred at room temperature until no further conversion was observed. The methanol
was evaporated under reduced pressure, water was added to the residue, the pH was
adjusted to 4 by the addition of 2 M HCl solution, and it was extracted with DCM. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified via preparative reverse phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain Example 709.
HRMS calculated for C H ClFN O S: 718.2392; found 719.2469 (M+H).
38 40 4 5
Example 710 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}(3-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(4-methoxybenzyl)
oxy]phenyl}propanoic acid
100 mg of the product of Step D in Example 709 (0.12 mmol) was dissolved in 5 mL
MeOH. 252 mg LiOH×H O (6 mmol) was added and the mixture was stirred at room
temperature until no further conversion was observed. The methanol was evaporated under
reduced pressure, water was added, and the pH was adjusted to 4 by the addition of 2 M
HCl. The precipitated crude product was filtered, dried and purified via preparative reverse
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to
obtain Example 710. HRMS calculated for C43H42ClFN4O6S: 796.2498; found 797.2565
(M+H).
Example 711 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
hydroxyphenyl)propanoic acid
100 mg of the product of Step E in Example 709 (0.14 mmol) was dissolved in 5 mL
MeOH, 252 mg LiOH×H O (6 mmol) was added and the mixture was stirred at room
temperature until no further conversion was observed. The methanol was evaporated under
reduced pressure, water was added, and the pH was adjusted to 4 by the addition of 2 M
HCl. The precipitated crude product was filtered, dried and purified via preparative reverse
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to
obtain Example 711. HRMS calculated for C H ClFN O S: 676.1922; found 677.2005
34 4 5
(M+H).
Example 712 (2R){[(5S ){3-chloromethyl[2-(morpholinyl)ethoxy]phenyl}-
6-(1-methyl-1H-pyrazolyl)thieno[2,3-d]pyrimidinyl]oxy}phenylpropanoic acid
Step A:
266 mg methyl (2R)[6-bromo-(5S )(3-chlorohydroxymethyl-phenyl)thieno[2,3-
d]pyrimidinyl]oxyphenyl-propanoate (Preparation 22) (0.50 mmol), 312 mg 1-
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrazole (1.50 mmol), 488 mg
Cs CO (1.50 mmol), and 54 mg Pd(dppf)Cl (0.075 mmol) were dissolved in a mixture of
2 3 2
8 mL 2-Me-THF and 1 mL water and the mixture was heated under nitrogen at 100 °C for
minutes in a microwave reactor. The reaction was diluted with water, the pH was
adjusted between 3-4 by the addition of 2 M HCl, and the mixture was extracted with
DCM. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. The residue was purified via flash chromatography using DCM and
MeOH as eluents to give methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)
(1-methylpyrazolyl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate. HRMS
calculated for C H ClN O S: 534.1129; found 535.1210 (M+H).
27 23 4 4
Step B:
99 mg methyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(1-methylpyrazol-
4-yl)thieno[2,3-d]pyrimidinyl]oxyphenyl-propanoate (0.185 mmol), 97 mg PPh
(0.37 mmol), 85 mg ditertbutyl azodicarboxylate (0.37 mmol) and 53 mg 2-(morpholin
yl)ethanol (0.37 mmol) were dissolved in 3 ml dry toluene and the reaction mixture was
stirred at 50 °C under nitrogen atmosphere for 2 hours. The mixture was concentrated
under reduced pressure and the residue was purified via flash chromatography using DCM
and MeOH as eluents.
Step C:
The product of Step B was hydrolyzed at room temperature in 5 mL methanol-water (9:1)
containing NaOH (5m/m%). After completion the mixture was diluted with water, the pH
was adjusted to 6 by the addition of 2 M HCl, and the mixture was extracted with DCM.
The combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude product was purified using reverse phase preparative HPLC resulting
Example 712. HRMS calculated for C H ClN O S: 633.1813; found 634.1894 (M+H).
32 32 5 5
Example 713 (2R){[(5S )(3-chloromethoxymethylphenyl){3-[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
250 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 25) (0.40 mmol), 315
mg PPh (1.20 mmol) and 276 mg ditertbutyl azodicarboxylate (1.20 mmol) were
dissolved in 3 mL methanol. The mixture was stirred at 50 °C under nitrogen atmosphere
for 30 minutes. The mixture was concentrated under reduced pressure and the crude
product was purified via flash chromatography using heptane and EtOAc as eluents to give
ethyl (2R)[(5S )(3-chloromethoxymethyl-phenyl)iodo-thieno[2,3-d]
pyrimidinyl]oxy(2-methoxyphenyl)propanoate. HRMS calculated for
C H ClIN O S: 638.0139; found 639.0222 (M+H).
26 24 2 5
Step B:
291 mg of the product of Step A (0.40 mmol), 352 mg 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenol (1.60 mmol), 652 mg Cs CO (2.00 mmol) and 19 mg
Pd(dppf)Cl (0.04 mmol) were dissolved in a mixture of 2.4 mL dioxane and 1.2 mL water,
and the mixture was heated under nitrogen at 110 °C for 10 minutes in a microwave
reactor. The reaction was diluted with water, the pH was adjusted between 3-4 by the
addition of 2 M HCl, and the mixture was extracted with DCM. The combined organic
phases were dried over Na SO and concentrated under reduced pressure. The residue was
purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2R)-
2-[(5S )(3-chloromethoxymethyl-phenyl)(3-hydroxyphenyl)thieno[2,3-d]
pyrimidinyl]oxy(2-methoxyphenyl)propanoate. HRMS calculated for
C H ClN O S: 604.1435; found 605.1518 (M+H).
32 29 2 6
Step C:
146 mg of the product of Step B (0.24 mmol), 197 mg PPh (0.75 mmol), 152 mg
ditertbutyl azodicarboxylate (0.75 mmol) and 108 mg 2-(4-methylpiperazinyl)ethanol
(0.75 mmol) were dissolved in 4 ml dry toluene and the reaction mixture was stirred at 50
°C under nitrogen for 30 minutes. The mixture was concentrated under reduced pressure
and the obtained crude product was hydrolyzed at room temperature in 5 mL methanol-
water (9:1) containing NaOH (5m/m%). After completion the mixture was diluted with
water, the pH was adjusted to 6 by the addition of 2 M HCl, and the mixture was extracted
with DCM. The combined organic phases were dried over Na SO and concentrated under
reduced pressure. The crude product was purified using reverse phase preparative HPLC
resulting Example 713. HRMS calculated for C H ClN O S: 702.2279; found 703.2362
37 39 4 6
(M+H).
Example 714 (2R){[6-(5-chlorofuranyl)-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(5-chloro
methoxyphenyl)propanoic acid
A mixture of 200 mg (2R)[(5Sa)[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl](2-furyl)thieno[2,3-d]pyrimidinyl]oxy(2-methoxyphenyl)
propanoic acid (Example 209) (0.30 mmol) and 300 mg NCS (2.25 mmol) in 5 mL
chloroform was stirred overnight under nitrogen at room temperature. The mixture was
diluted with water and extracted with DCM. The combined organic phases were dried over
Na SO and concentrated under reduced pressure. The crude product was purified using
reverse phase preparative HPLC to give Example 714. HRMS calculated for
C34H33Cl3N4O6S: 730.1186; found 731.1251 (M+H).
Example 715 (2R){[(5S )(3-chlorohydroxymethylphenyl)(thiophen
yl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
Step A:
462 mg ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)iodo-thieno[2,3-
d]pyrimidinyl]oxy(2-methoxyphenyl)propanoate (Preparation 25) (0.8 mmol), 336
mg 4,4,5,5-tetramethyl(3-thienyl)-1,3,2-dioxaborolane (1.6 mmol), 58 mg Pd(dppf)Cl
(0.08 mmol), and 521 mg cesium carbonate (1.6 mmol) was dissolved in 8 mL dioxane and
2 mL water and it was heated under nitrogen at 110°C for 7 min in a microwave reactor.
Water was added to the reaction, the pH was adjusted between 4-5 with 2 M HCl, and it
was extracted with DCM. The combined organic phases were dried over Na2SO4,
concentrated under reduced pressure, and purified via flash chromatography using heptane
and ethyl acetate as eluents.
Step B:
140 mg of the product of Step A (0.24 mmol) was dissolved in 10 mL MeOH, 202 mg
LiOH×H O (4.80 mmol) was added and it was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and
extracted with DCM. The combined organic phases were dried over Na SO , concentrated
under reduced pressure, and purified via preparative reversed phase chromatography using
40 mM aqueous NH OAc solution (pH set to 4 with AcOH) and MeCN as eluents to obtain
Example 715. HRMS calculated for C H ClN O S : 552.0580; found 553.0647 (M+H).
27 21 2 5 2
Example 716 (2R){[(5R ){3-chloromethyl[3-(4-methylpiperazinyl)prop
ynyl]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Example 717 (2R){[(5S ){3-chloromethyl[3-(4-methylpiperazinyl)prop
ynyl]phenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoic acid
Step A:
297 mg 4-chloroiodo-thieno[2,3-d]pyrimidine (Preparation 1c) (1.00 mmol), 398 mg
2-(4-bromochloromethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Preparation 5t) (1.20 mmol), 73 mg PdCl × dppf (0.10 mmol) and 978 mg Cs CO (3.00
2 2 3
mmol) were dissolved in 10 mL dioxane and 2.5 mL water, and heated under nitrogen at
60°C for 90 minutes in a microwave reactor. The reaction mixture was concentrated under
reduced pressure and purified via flash chromatography, using heptane and EtOAc as
eluents to obtain 5-(4-bromochloromethyl-phenyl)chloro-thieno[2,3-d]pyrimidine.
Step B:
192 mg of the product of Step A (0.51 mmol) was dissolved in 5 mL dry THF under N
and was cooled to -78°C with dry ice-aceton. 308 L LDA (0.62 mmol in 2 M THF, EtPh)
was added and it was stirred for 1 hour, then 163 mg iodine (0.64 mmol) was added and
the mixture was allowed to warm up to room temperature. It was diluted with Et O,
washed with saturated Na S O solution, dried over Na SO , filtered and concentrated
2 2 3 2 4
under reduced pressure and purified via flash chromatography using heptane and EtOAc as
eluents to obtain 5-(4-bromochloromethyl-phenyl)chloroiodo-thieno[2,3-d]
pyrimidine.
Step C:
50 mg of the product of Step B (0.1 mmol) was dissolved in 2 mL dioxane, then 72 mg 2-
(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.30 mmol), 7.3 mg
Pd(dppf)Cl (0.01 mmol), 98 mg Cs CO (0.30 mmol) and 0.5 mL water were added. The
2 2 3
mixture was heated under nitrogen to 60°C for 30 minutes in a microwave reactor. Then it
was concentrated under reduced pressure and purified via flash chromatography, using
heptane and EtOAc as eluents to obtain 5-(4-bromochloromethyl-phenyl)chloro
(2,3-difluorophenyl)thieno[2,3-d]pyrimidine.
Step D:
165 mg of the product of Step C was dissolved in 2 mL isopropanol. 112 mg ethyl (2R)
hydroxy(2-methoxyphenyl)propanoate (Preparation 3ad) (0.50 mmol) and 326 mg
Cs CO (1.00 mmol) were added and the mixture was stirred at 50°C for 2 hours. Then it
was diluted with water, neutralized with 2 M HCl, and extracted with DCM. The combined
organic phases were dried over Na SO and concentrated under reduced pressure. Then it
was dissolved in 5 mL MeOH, 141 mg LiOH×H O (3.35 mmol) was added and it was
stirred at room temperature for 1 hour. Then it was diluted with brine, neutralized with 2 M
HCl, and extracted with DCM. The combined organic phases were dried over Na SO ,
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 40 mM aqueous NH OAc solution (pH set to 4 with AcOH) and
MeCN as eluents to obtain (2R)[5-(4-bromochloromethyl-phenyl)(2,3-
difluorophenyl)thieno[2,3-d] pyrimidinyl]oxy(2-methoxyphenyl)propanoic acid as a
mixture of diastereomers.
Step E:
To 77 mg of the product of Step D (0.12 mmol), 82 mg 1-methylpropynyl-piperazine
(0.60 mmol), 2.7 mg Pd(OAc) (0.012 mmol), 8.5 mg BuPAd (0.024 mmol), and 2.3 mg
copper(I) iodide (0.012 mmol) 1 mL DIPA wase added and the mixture was heated under
nitrogen to 120°C for 40 minutes in a microwave reactor. The reaction mixture was
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 40 mM aqueous NH OAc solution (pH was set to 4 with AcOH)
and MeCN as eluents to obtain Example 716 and Example 717. The diastereoisomer
eluting earlier was collected as Example 716. HRMS calculated for C H ClF N O S:
37 33 2 4 4
702.1879; found 703.1963 (M+H). The diastereoisomer eluting later was collected as
Example 717. HRMS calculated for C H ClF N O S: 702.1879; found 703.1947 (M+H).
37 33 2 4 4
Example 718 (2R){[6-(5-chlorofuranyl)-(5Sa){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl]oxy}(4-fluoro
methoxyphenyl)propanoic acid
Step A:
700 mg 5-bromochloro(5-chlorofuryl)thieno[2,3-d]pyrimidine (Preparation 2d)
(2.0 mmol), 581 mg ethyl (2R)(4-fluoromethoxy-phenyl)hydroxy-propanoate
(Preparation 3as) (2.4 mmol) and 1.955 g cesium carbonate (6.0 mmol) were stirred at
70°C in 10 mL dry tertbutanol until no further conversion was observed. The mixture was
cooled to room temperature, and then 10 mL water, 947 mg 1-[2-[2-chloromethyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine
(Preparation 5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture
was stirred under nitrogen at 60°C until no further conversion was observed. Then brine
was added and the mixture was extracted with EtOAc. The combined organic phases were
dried over MgSO and concentrated under reduced pressure. The crude intermediate was
purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)-
2-[6-(5-chlorofuryl)[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
thieno[2,3-d]pyrimidinyl]oxy(4-fluoromethoxy-phenyl)propanoate.
Step B:
560 mg of the product of Step A (0.75 mmol) was dissolved in 20 mL dioxane-water (1:1)
and 632 mg LiOH×H O (15.1 mmol) was added. The mixture was stirred at room
temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were
dried over Na SO , filtered and concentrated. The residue was purified via preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents; the diastereoisomer eluting later was collected as Example 718. HRMS calculated
for C H Cl FN O S: 714.1482; found 715.1553 (M+H).
34 33 2 4 6
Example 719 (2R){[(5R )(3-chloromethylphenyl)(propenyl)thieno[2,3-d]
pyrimidinyl]oxy}phenylpropanoic acid
Example 720 (2R){[(5Sa)(3-chloromethylphenyl)(propenyl)thieno[2,3-d]
pyrimidinyl]oxy}phenylpropanoic acid
Step A:
The mixture of 0.421 g 4-Chloro(3-chloromethyl-phenyl)iodo-thieno[2,3-
d]pyrimidine (Preparation 24b) (1.0 mmol), 0.207 mL 2-isopropenyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (1.1 mmol), 0.303 g Ag CO (1.1 mmol), 0.173 g Pd(PPh ) (0.15
2 3 3 4
mmol), and 5 mL 2-MeTHF was heated under nitrogen at 100°C for 15 min in a
microwave reactor. The reaction was diluted with 50 mL DCM and it was filtered through
a pad of celite. The celite was washed with DCM and the filtrate was evaporated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to give 4-chloro(3-chloromethyl-phenyl)isopropenyl-thieno[2,3-
d]pyrimidine. H NMR (500 MHz, DMSO-d ): 8.95 (s, 1H), 7.56 (dd, 1H), 7.31 (t, 1H),
7.25 (dd, 1H), 5.33 (m, 1H), 5.22 (m, 1H), 2.08 (s, 3H), 1.77 (m 1H).
Step B:
The mixture of 0.12 g product of Step A (0.36 mmol), 0.193 g methyl (2R)hydroxy
phenyl-propanoate (Preparation 3ag) (1.07 mmol), 0.466 g Cs CO (1.43 mmol), and 4
mL dry DMSO was heated at 80°C until no further conversion was observed. The mixture
was cooled to room temperature, it was diluted with DCM and brine, neutralized with 2 M
HCl, and it was extracted with DCM. The combined organic layers were dried over
Na SO and evaporated under reduced pressure. The obtained crude material was dissolved
in 10 mL MeOH-THF (1:1), 227 mg LiOH×H O (5.5 mmol) was added and the mixture
was stirred at 45 °C until no further conversion was observed. Then it was diluted with
brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases
were dried over Na SO and concentrated under reduced pressure. The residue was
purified via preparative reverse phase chromatography using 0.1% aqueous TFA solution
and MeCN as eluents to obtain Example 719, as the diastereomer eluting earlier [HRMS
calculated for C H ClN O S: 464.0961; found 465.1054 (M+H)], and Example 720, as
21 2 3
the diastereomer eluting later [HRMS calculated for C H ClN O S: 464.0961; found
21 2 3
465.1028 (M+H)].
Example 721 (2R){[(5Sa)(3-chloromethylphenyl)ethenylthieno[2,3-d]
pyrimidinyl]oxy}phenylpropanoic acid
Step A:
The mixture of 550 mg 4-chloro(3-chloromethyl-phenyl)iodo-thieno[2,3-
d]pyrimidine (Preparation 24b) (1.3 mmol), 0.245 mL 4,4,5,5-tetramethylvinyl-1,3,2-
dioxaborolane (1.43 mmol), 0.397 g Ag CO (1.43 mmol), 0.227 g Pd(PPh ) (0.195
2 3 3 4
mmol), and 6 mL 2-MeTHF was heated under nitrogen at 100°C for 15 min in a
microwave reactor. The mixture was diluted with 50 mL DCM and it was filtered through
a pad of celite. The celite was washed with DCM and the filtrate was evaporated under
reduced pressure. The residue was purified via flash chromatography using heptane and
EtOAc as eluents to give 4-chloro(3-chloromethyl-phenyl)vinyl-thieno[2,3-
d]pyrimidine. H NMR (500 MHz, DMSO-d ): 8.94 (s, 1H), 7.59 (dm, 1H), 7.35 (t, 1H),
7.24 (dm, 1H), 6.44 (dd, 1H), 5.90 (d, 1H), 5.54 (d, 1H), 2.04 (s, 3H).
Step B:
The mixture of 150 mg product of Step A (0.47 mmol), 0.252 g methyl (2R)hydroxy
phenyl-propanoate (Preparation 3ag) (1.4 mmol), 0.456 g Cs CO (1.40 mmol), and 5 mL
dry DMSO was heated at 80°C until no further conversion was observed. The mixture was
cooled to room temperature, it was diluted with DCM and brine, neutralized with 2 M HCl,
and the phases were separated. The aqueous layer was extracted with DCM, the combined
organic layers were dried over Na SO , and evaporated under reduced pressure. The crude
product was dissolved in 10 mL MeOH-THF (1:1), 0.196 g LiOH×H O (4.67 mmol) was
added and the mixture was stirred at 45°C until no further conversion was observed. Then
it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The
combined organic phases were dried over Na SO and concentrated under reduced
pressure. The residue was purified via preparative reverse phase chromatography using
0.1% aqueous TFA solution and MeCN as eluents to obtain Example 721 as the
diastereomer eluting later. HRMS calculated for C H ClN O S: 450.0805; found
24 19 2 3
451.0893 (M+H).
General Procedure (XXb)
The appropriate acid was dissolved in the appropriate alcohol (20 mL/g) containing 1% cc.
sulfuric acid and the mixture was stirred at 70°C until no further conversion was observed.
Water was added to the mixture and it was neutralized with NaHCO , extracted with DCM,
the combined organic phases were dried over Na SO and concentrated under reduced
pressure. The crude ester was purified via preparative reversed phase chromatography
using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XXc)
1 eq. from the appropriate acid was dissolved in DMF (10 mL / mmol), then 1.1 eq. from
the appropriate alkyl halide, 2eq. NaI and 2 eq. Cs CO were added. The mixture was
stirred at room temperature under N atmosphere until no further conversion was observed.
Then it was diluted with water and extracted with dichloromethane. The combined organic
phases were dried over Na SO , filtered and concentrated under reduced pressure and
purified via preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents.
General Procedure (XXXIIIa)
1 eq. ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]
methoxy]phenyl]propanoate (Preparation 30), 1.5 eq. boronic acid, 2eq. cesium
carbonate, 0.05 eq. Pd(OAc) , and 0.05 eq. BuX-Phos were placed in a flask. 8 mL/mmol
THF and 2 mL/mmol water were added, and then the mixture was stirred at 70°C under
argon atmosphere until no further conversion was observed. Volatiles were evaporated
under reduced pressure. The residue was purified via flash chromatography using DCM
and MeOH as eluents to obtain the appropriate intermediate as a mixture of diastereomers.
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq.
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure. Diastereomers were separated by
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents.
General Procedure (XXXIIIb):
1eq. ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-hydroxyphenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidin-
4-yl]methoxy]phenyl]propanoate (Preparation 31), 2eq. of the appropriate alcohol and
2eq. PPh were dissolved in dry toluene (4 mL /mmol), then 2eq. ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under N until no further
conversion was observed. Volatiles were evaporated under reduced pressure. The residue
was purified via flash chromatography using EtOAc and MeOH as eluents. The obtained
intermediate was dissolved in dioxane-water 1:1 (25 ml/mmol) and 10eq. LiOH × H O was
added. The mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XXXIIIc)
1eq. ethyl (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
iodo-thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidinyl]
methoxy]phenyl]propanoate (Preparation 30), 3eq. of the appropriate alkyne, 0.1 eq. CuI,
0.05 eq bis(triphenylphosphine) palladium(II) dichloride and DIPA (4 mL/0.1 mmol) were
stirred under N at room temperature until no further conversion was observed. The
volatiles were removed in vacuo, the residue was purified via flash chromatography.
Product was dissolved in dioxane : H O = 1:1 (25 ml/mmol), and 10 eq. LiOH x H O was
added. The mixture was stirred until no further conversion was observed. Then it was
diluted with brine, acidified with 2M HCl and extracted with dichloromethane. The
combined organic phases were dried over Na SO , filtered and concentrated under reduced
pressure and purified via preparative reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents.
Genaral Procedure (XXXIV)
1eq. ethyl (2R)[5-bromo(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-
(2-methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate (Preparation 4v), 1.2 eq.
of the appropriate boronic acid derivative, 3 eq. cesium carbonate and 0.1 eq. AtaPhos
were placed in a flask. 2.5 mL dioxane and 2.5 mL water were added, and the mixture was
stirred at 70°C under argon atmosphere until no further conversion was observed. The
mixture was diluted with water and extracted with EtOAc. The combined organic layers
were dried over Na SO , filtered and concentrated under reduced pressure. The crude
product was purified via flash chromatography using EtOAc and MeOH as eluents. The
obtained intermediate was dissolved in dioxane:water 1:1 (8ml/mmol), 5eq. NaOH was
added, and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, acidified with 2 M HCl and extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XXXV)
1 eq. ethyl (2R)[(5S )(3-chlorohydroxymethyl-phenyl)(4-fluorophenyl)
thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-fluorophenyl)pyrimidinyl]methoxy]phenyl]
propanoate (Preparation 6u), 3eq. of the appropriate alcohol, and 3eq. PPh were
dissolved in dry toluene (20 mL / mmol), then 3eq. ditertbutyl azodicarboxylate was
added. The mixture was stirred at 50°C under N until no further conversion was observed.
The toluene was evaporated under reduced pressure and the residue was purified via flash
chromatography using DCM and MeOH as eluents. To this intermediate 10 eq. LiOH x
H O, and dioxane:H O 1:1 (15 mL / mmol) were added and the mixture was stirred at
room temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents.
General Procedure (XXXVI)
1 eq. ethyl (2R)[(5Sa)[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-chloropyrimidin
yl)methoxy]phenyl]propanoate (0.24 mmol Preparation 29), 2 eq. of the appropriate
boronic acid derivative, 0.04 eq. bis(triphenylphosphine)palladium(II) dichloride, 2M
Na CO solution (2.5 mL/ mmol) and dioxane (2.5 mL/ mmol) were stirred under N
2 3 2
atmosphere at 90 C until no further conversion was observed. Then LiOH x H O (416
mg/mmol) was added and the mixture was stirred until no further conversion was
observed. Then it was diluted with brine, acidified with 2M HCl and extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents.
General Procedure (XXXVII)
1 eq. paraformaldehyde and 3 eq. NaI were dissolved in DCM (10 ml/mmol
paraformaldehyde) and 2.5 eq. from the appropriate alkanoyl-chloride was added
(dissolved in 1 ml/ mmol DCM). The mixture was stirred at room temperature until no
further conversion was observed. Mixture was then filtered and concentrated in vacuo.
General Procedure (XXXVIII)
1 eq. from the appropriate phenol derivative, 3 eq. of the appropriate alcohol, and 3 eq.
PPh were dissolved in dry toluene (20 ml / mmol), then 3 eq. ditertbutyl azodicarboxylate
was added. The mixture was stirred at 50°C under N until no further conversion was
observed. The toluene was evaporated under reduced pressure and the residue was purified
via flash chromatography using DCM and MeOH as eluents. To this intermediate 10 eq.
LiOH x H O, and dioxane:H O 1:1 (15 ml / mmol) were added and the mixture was stirred
at room temperature until no further conversion was observed. Then it was diluted with
brine, neutralized with 2 M HCl, extracted with dichloromethane. The combined organic
phases were dried over Na SO , filtered and concentrated under reduced pressure and
purified via preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents.
General Procedure (XXXIX)
1 eq. Preparation 38, 3 eq. of the appropriate alcohol, and 3 eq. PPh were dissolved in
dry toluene (20 ml / mmol), then 3 eq. ditertbutyl azodicarboxylate was added. The
mixture was stirred at 50°C under N2 until no further conversion was observed. The
toluene was evaporated under reduced pressure and the residue was purified via flash
chromatography using DCM and MeOH as eluents. To this intermediate 10 eq. LiOH x
H O, and dioxane:H O 1:1 (15 ml / mmol) were added and the mixture was stirred at room
temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and
MeCN as eluents.
Example 722 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
hydroxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
220 mg (0.25 mmol) Example 30 was dissolved in 5 ml DCM and treated with BBr
(0.625 ml, 1M in DCM) at 40 C until no further conversion was observed. The mixture
was diluted with water, pH was adjusted to 7 with saturated NaHCO solution and
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 722. HRMS calculated for C H ClFN O S: 860.2559; found 431.1340
46 42 6 6
(M+2H).
Example 723 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(propanyloxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ib) and 2-isopropoxyphenylboronic acid as the appropriate
boronic acid derivative, Example 723 was obtained. HRMS calculated for
C H ClFN O S: 902.3029; found 452.1607 (M+2H).
49 48 6 6
Example 724 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-
methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ib) and 2-(2-methoxyethoxy)phenylboronic acid as the
appropriate boronic acid derivative, Example 724 was obtained. HRMS calculated for
C H ClFN O S: 918.2978; found 460.1564 (M+2H).
49 48 6 7
Example 725 (2R)[2-({2-[2-(benzyloxy)phenyl]pyrimidinyl}methoxy)phenyl]
{[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (Ib) and 2-benzyloxyphenylboronic acid as the appropriate
boronic acid derivative, Example 725 was obtained. HRMS calculated for
C H ClFN O S: 950.3029; found 476.1587 (M+2H).
53 48 6 6
Example 726 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
ethylphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and 2-ethylphenylboronic acid as the appropriate boronic
acid derivative, Example 726 was obtained. HRMS calculated for C H ClFN O S:
48 46 6 5
872.2923; found 437.1541 (M+2H).
Example 727 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(trifluoromethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ib) and 2-(trifluoromethyl)phenylboronic acid as the appropriate
boronic acid derivative, Example 727 was obtained. HRMS calculated for
C H ClF N O S: 912.2484; found 913.2554 (M+H).
47 41 4 6 5
Example 728 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ib) and 2-(hydroxymethyl)phenylboronic acid as the appropriate
boronic acid derivative, Example 728 was obtained. HRMS calculated for
C H ClFN O S: 874.2716; found 875.2804 (M+H).
47 44 6 6
Example 729 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4-
methoxy(trifluoromethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (Ia) and [2-[4-methoxy(trifluoromethyl)phenyl]pyrimidin
yl]methanol (Preparation 9ej) as the appropriate alcohol, Example 729 was obtained.
HRMS calculated for C H ClF N O S: 942.2589; found 943.2636 (M+H).
48 43 4 6 6
Example 730 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-
methoxypyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVI) and 3-methoxypyridineboronic acid as the
appropriate boronic acid derivative, Example 730 was obtained. HRMS calculated for
C H ClFN O S: 875.2668; found 438.6420 (M+2H).
46 43 7 6
Example 731 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,5-
dimethylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVI) and 2,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine as the appropriate boronic acid derivative, Example 731 was
obtained. HRMS calculated for C H ClFN O S: 873.2875; found 437.6516 (M+2H).
47 45 7 5
Example 732 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(5,6-
dimethylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVI) and 2,3-dimethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine as the appropriate boronic acid derivative, Example 732 was
obtained. HRMS calculated for C H ClFN O S: 873.2875; found 473.6524 (M+2H).
47 45 7 5
Example 733 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,4-
dimethoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ib) and 2,4-dimethoxyphenylboronic acid as the appropriate
boronic acid derivative, Example 733 was obtained. HRMS calculated for
C H ClFN O S: 904.2821; found 453.1494 (M+2H).
48 46 6 7
Example 734 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(5-
methoxymethylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVI) and 5-methoxymethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine as the appropriate boronic acid derivative, Example 734 was
obtained. HRMS calculated for C H ClFN O S: 889.2825; found 445.6481 (M+2H).
47 45 7 6
Example 735 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxypyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVI) and 2-methoxypyridineboronic acid as the
appropriate boronic acid derivative, Example 735 was obtained. HRMS calculated for
C H ClFN O S: 875.2668; found 438.6420 (M+2H).
46 43 7 6
Example 736 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(pyridin-
4-ylmethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(4-pyridylmethyl)pyrazolyl]methanol
(Preparation 9ek) as the appropriate alcohol, Example 736 was obtained. HRMS
calculated for C H ClFN O S: 847.2719; found 424.6432 (M+2H).
45 43 7 5
Example 737 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxyphenyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2-methoxyphenyl)pyrazolyl]methanol
(Preparation 9el) as the appropriate alcohol, Example 737 was obtained. HRMS
calculated for C H ClFN O S: 862.2716; found 863.2783 (M+H).
46 44 6 6
Example 738 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxyphenyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-(2-methoxyphenyl)pyrazolyl]methanol
(Preparation 9em) as the appropriate alcohol, Example 738 was obtained. HRMS
calculated for C H ClFN O S: 862.2716; found 863.2807 (M+H).
46 44 6 6
Example 739 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxybenzyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [[1-[(2-methoxyphenyl)methyl]pyrazolyl]methanol
(Preparation 9en) as the appropriate alcohol, Example 739 was obtained. HRMS
calculated for C H ClFN O S: 876.2872; found 439.1519 (M+2H).
47 46 6 6
Example 740 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-
methoxybenzyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
Using General Procedure (Ia) and [1-[(2-methoxyphenyl)methyl]pyrazolyl]methanol
(Preparation 9eo) as the appropriate alcohol, Example 740 was obtained. HRMS
calculated for C H ClFN O S: 876.2872; found 439.1490 (M+2H).
47 46 6 6
Example 741 (2R){[(5S ){3-chloroethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIV) and 1-[2-[2-chloroethyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine (Preparation 5u) as the
appropriate boronic acid derivative, Example 741 was obtained as the diastereomer eluting
later. HRMS calculated for C H ClFN O S: 888.2872; found 445.1515 (M+2H).
48 46 6 6
Example 742 (2R){[(5S ){2-bromochloro[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIV) and 1-[2-[3-bromochloro(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenoxy]ethyl]methyl-piperazine (Preparation 5v) as the
appropriate boronic acid derivative, Example 742 was obtained as the diastereomer eluting
later. HRMS calculated for C H BrClFN O S: 938.1664; found 470.0914 (M+2H).
46 41 6 6
Example 743 (2R){[(5S ){2,3-dichloro[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIV) and 1-[2-[2,3-dichloro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenoxy]ethyl]methyl-piperazine (Preparation 5w) as the
appropriate boronic acid derivative, Example 743 was obtained as the diastereomer eluting
later. HRMS calculated for C46H41Cl2FN6O6S: 894.2169; found 448.1157 (M+2H).
Example 744 (2R){[(5S ){3-chloromethyl[2-(piperazinyl)ethoxy]phenyl}
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin-
4-yl]methoxy}phenyl)propanoic acid
657 mg (0.95 mmol) ethyl (2R)[(5S )-[3-chloromethyl[2-(piperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8o), 411 mg (1.9 mmol) 2[2-(2-methoxyphenyl)pyrimidinyl]
methanol (Preparation 9bp) and 498 mg (1.9 mmol) triphenyl phosphine were dissolved
in 25 ml abs. toluene, then 437 mg (1.9 mmol) ditertbutyl azodicarboxylate was added.
The mixture was stirred at 50°C under nitrogen until no further conversion was observed.
The volatiles were evaporated under reduced pressure and the crude intermediate was
purified via flash chromatography using ethyl acetate and methanol as eluents. The
obtained intermediate was dissolved in 10 ml dioxane-water 1:1 and 420 mg (10mmol)
LiOH × H O was added. The mixture was stirred at room temperature until no further
conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to
obtain Example 744. HRMS calculated for C H N O FSCl: 860.2559; found 431.1368
46 42 6 6
(M+2H).
Example 745 (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
470 mg (0.55 mmol) ethyl (2R)[(5S )-[3-chloromethyl[2-(4-ethylpiperazin
yl)ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-
methylsulfanylpyrimidinyl)methoxy]phenyl]propanoate (Preparation 10d), 231 mg
(1.65 mmol) 2-fluorophenylboronic acid and 315 mg (1.65 mmol) copper(I)
thiophenecarboxylate were dissolved in 10 ml dry THF, then 95 mg (0.0825 mmol)
Pd(PPh ) was added. The mixture was stirred at 70°C under nitrogen until no further
conversion was observed. Then it was concentrated under reduced pressure and the crude
intermediate was purified via flash chromatography using dichloromethane and methanol
as eluents. The obtained intermediate was dissolved in 5 ml dioxane-water 1:1 and 231 mg
(5.5 mmol) LiOH × H O was added. The mixture was stirred at room temperature until no
further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 745. HRMS calculated for C H ClF N O S: 876.2672; found 439.1426
47 43 2 6 5
(M+2H).
Example 746 (2R){[(5S ){3-chloro[2-(diethylamino)ethoxy]methylphenyl}
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluorophenyl)pyrimidin
yl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXV) and N,N-diethylethanolamine as the appropriate
alcohol, Example 746 was obtained. HRMS calculated for C H ClF N O S: 835.2407;
45 40 2 5 5
found 836.2482 (M+H).
Example 747 (2R){[(5S )(3-chloro{2-[ethyl(methyl)amino]ethoxy}
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXV) and 2-(N-methyl-ethylamino)ethanol as the appropriate
alcohol, Example 747 was obtained. HRMS calculated for C H ClF N O S: 821.225;
44 38 2 5 5
found 822.2324 (M+H).
Example 748 (2R){[(5S )(3-chloro{2-[cyclopropyl(methyl)amino]ethoxy}
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXV) and 2-(cyclopropyl(methyl)amino)ethanol as the
appropriate alcohol, Example 748 was obtained. HRMS calculated for C H ClF N O S:
45 38 2 5 5
833.225; found 834.2344 (M+H).
Example 749 (2R){[(5S ){3-chloromethyl[2-(piperazinyl)ethoxy]phenyl}
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-hydroxyphenyl)pyrimidin-
4-yl]methoxy}phenyl)propanoic acid
244 mg (0.283 mmol) Example 30 was dissolved in 6 ml DCM and treated with 0.71 ml
BBr (1M in DCM) at 40 C until no further conversion was observed. The mixture was
diluted with water, the pH was adjusted to 7 with saturated NaHCO solution and extracted
with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 749. HRMS calculated for C H ClFN O S: 846.2403; found 424.1281
45 40 6 6
(M+2H).
Example 750 (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
Using General Procedure (IIa) and (1-tert-butyl-1H-pyrazolyl)methanol (Preparation
9dt) as the appropriate alcohol, Example 750 was obtained. HRMS calculated for
C H ClFN O S: 757.2501; found 379.6326 (M+2H).
40 41 5 5
Example 751 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,5-dimethylpyridin
yl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and 2,5-dimethylpyridineboronic acid pinacol ester as
the appropriate boronic acid derivative, Example 751 was obtained. HRMS calculated for
C H ClFN O S: 818.2454; found 410.1319 (M+2H).
44 40 6 5
Example 752 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propanyl)-1H-pyrazol
yl]methoxy}phenyl)propanoic acid
Using General Procedure IIa and [1-(propanyl)-1H-pyrazolyl]methanol as the
appropriate alcohol, Example 752 was obtained. HRMS calculated for C H ClFN O S:
39 39 5 5
743.2344; found 744.2422 (M+H).
Example 753 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-
methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
Using General Procedure (IIb) and 2-(2-methoxyethoxy)phenylboronic acid as the
appropriate boronic acid derivative, Example 753 was obtained. HRMS calculated for
C H ClFN O S: 863.2556; found 864.2656 (M+H).
46 43 5 7
Example 754 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2-ethoxyethyl)-1H-pyrazol-
-yl]methoxy}phenyl)propanoic acid
Using General Procedure (IIa) and [1-(2-ethoxyethyl)pyrazolyl]methanol (Preparation
9ep) as the appropriate alcohol, Example 754 was obtained. HRMS calculated for
C H ClFN O S: 773.245; found 774.2551 (M+H).
40 41 5 6
Example 755 (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-
chloro[2-(dimethylamino)ethoxy]methylphenyl}(2,3-difluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoic acid
212 mg (0.317 mmol) ethyl (2R)[(5S )[3-chloromethyl[2-
dimethylaminoethoxy]phenyl](2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy
(2-hydroxyphenyl)propanoate (Preparation 8n), 147 mg (0.95 mmol) (1-tert-butyl-1H-
pyrazolyl)methanol (Preparation 9dt) and 249 mg (0.95 mmol) triphenyl phosphine
were dissolved in 10 ml abs. toluene, then 222 mg (0.96 mmol) ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no
further conversion was observed. The volatiles were evaporated under reduced pressure
and the crude intermediate was purified via flash chromatography using ethyl acetate and
methanol as eluents. The obtained intermediate was dissolved in 7 ml dioxane and 7 ml
water and 133 mg (3.17 mmol) LiOH × H O was added. The mixture was stirred at room
temperature until no further conversion was observed. Then it was diluted with brine,
neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents to obtain Example 755. HRMS calculated for C H ClF N O S:
40 40 2 5 5
775.2407; found 776.2498 (M+H).
Example 756 Ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (IIa) Step A and [2-(2-methoxyphenyl)pyrimidinyl]methanol
(Preparation 9bp) as the appropriate alcohol, Example 756 was obtained. HRMS
calculated for C H ClFN O S: 847.2607; found 424.6386 (M+2H).
46 43 5 6
Example 757 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluorophenyl)pyrimidin-
4-yl]methoxy}phenyl)propanoic acid
Using General Procedure (IIb) and 2-fluorophenylboronic acid as the appropriate boronic
acid derivative, Example 757 was obtained. HRMS calculated for C H ClF N O S:
43 36 2 5 5
807.2094; found 808.2171 (M+H).
Example 758 (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-phenoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
and
Example 759 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-phenoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIa) and 4-phenoxyphenylboronic acid as the appropriate
boronic acid derivative, the diastereomer eluting earlier was isolated as Example 758
[HRMS calculated C H ClN O S: 948.3072; found 475.1602 (M+2H)] and the
53 49 6 7
diastereomer eluting later as Example 759 [HRMS calculated C H ClN O S: 948.3072;
53 49 6 7
found 475.1602 (M+2H)].
Example 760 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Example 761 (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-methoxyphenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIa) and 4-methoxyphenylboronic acid as the appropriate
boronic acid derivative, the diastereomer eluting earlier was isolated as Example 760
[HRMS calculated C H ClN O S: 886.2915; found 444.1536 (M+2H)] and the
48 47 6 7
diastereomer eluting later as Example 761 [HRMS calculated C H ClN O S: 886.2915;
48 47 6 7
found 444.1525 (M+2H)].
Example 762 (2R)[(6-[4-(benzyloxy)phenyl]-(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIa) and 4-benzyloxyphenylboronic acid as the
appropriate boronic acid derivative, the diastereomer eluting later was isolated as Example
762. HRMS calculated C H ClN O S: 962.3228; found 482.1698 (M+2H).
54 51 6 7
Example 763 (2R)[((5Ra){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[2-(morpholinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
and
Example 764 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[2-(morpholinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and N-(2-hydroxyethyl)morpholine as the appropriate
alcohol, the diastereomer eluting earlier was isolated as Example 763 [HRMS calculated
C H ClN O S: 985.3600; found 493.6883 (M+2H)] and the diastereomer eluting later as
53 56 7 8
Example 764 [HRMS calculated C H ClN O S: 985.3600; found 493.6876 (M+2H)].
53 56 7 8
Example 765 (2R)[((5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(2-phenylethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Example 766 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(2-phenylethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2-
{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 2-phenylethanol as the appropriate alcohol, the
diastereomer eluting earlier was isolated as Example 765 [HRMS calculated
C H ClN O S: 976.3385; found 489.1787 (M+2H] and the diastereomer eluting later as
55 53 6 7
Example 766 [HRMS calculated C55H53ClN6O7S: 976.3385; found 489.1743 (M+2H)].
Example 767 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[(2-methylbenzyl)oxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 2-methylbenzyl alcohol as the appropriate
alcohol, Example 767 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O S: 976.3385; found 489.1774 (M+2H)
55 53 6 7
Example 768 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[(4-methylbenzyl)oxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 4-methylbenzyl alcohol as the appropriate
alcohol, Example 768 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O S: 976.3385; found 489.1775 (M+2H).
55 53 6 7
Example 769 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 2-pyridinemethanol as the appropriate alcohol,
Example 769 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O7S: 963.3181; found 482.6681 (M+2H).
53 50 7
Example 770 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[(4-methoxybenzyl)oxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 4-methoxybenzylalcohol as the appropriate
alcohol, Example 770 was obtained as the diastereomer eluting later. HRMS calculated
C55H53ClN6O8S: 992.3334; found 497.1725 (M+2H).
Example 771 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}{4-[(1-methyl-1H-pyrazolyl)methoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 771 was obtained as the diastereomer eluting later. HRMS
calculated C H ClN O S: 966.329; found 484.1700 (M+2H)
52 51 8 7
Example 772 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 3-pyridinemethanol as the appropriate alcohol,
Example 772 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O S: 963.3181; found 482.6673 (M+2H).
53 50 7 7
Example 773 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}{4-[(3-methylbenzyl)oxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 3-methylbenzyl alcohol as the appropriate
alcohol, Example 773 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O S: 976.3385; found 489.1780 (M+2H).
55 53 6 7
Example 774 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]
(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 4-pyridinemethanol as the appropriate alcohol
Example 774 was obtained as the diastereomer eluting later. HRMS calculated
C53H50ClN7O7S: 963.3181; found 482.6644 (M+2H).
Example 775 (2R)[(6-{4-[(4-chlorobenzyl)oxy]phenyl}-(5S ){3-chloromethyl
[2-(4-methylpiperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 4-chlorobenzyl alcohol as the appropriate
alcohol, Example 775 was obtained as the diastereomer eluting later. HRMS calculated
C H Cl N O S: 996.2839; found 499.1510 (M+2H).
54 50 2 6 7
Example 776 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}{4-[(1-methyl-1H-pyrazolyl)methoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and (1-methyl-1H-pyrazolyl)methanol as the
appropriate alcohol, Example 776 was obtained as the diastereomer eluting later. HRMS
calculated C H ClN O S: 966.329; found 484.1727 (M+2H).
52 51 8 7
Example 777 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(thiophenylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 2-thiophenemethanol as the appropriate alcohol,
Example 777 was obtained as the diastereomer eluting later. HRMS calculated
C H ClN O S : 968.2793; found 485.1469 (M+2H).
52 49 6 7 2
Example 778 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(thiophenylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIb) and 3-thiophenemethanol as the appropriate alcohol,
Example 778 was obtained as the diastereomer eluting later. HRMS calculated
C52H49ClN6O7S2: 968.2793; found 485.1450 (M+2H).
Example 779 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}{4-[(1-methyl-1H-pyrazolyl)methoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy](2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid
216 mg (0.25 mmol) Preparation 32, 84 mg (0.75 mmol) (1-methyl-1H-pyrazol
yl)methanol and 197 mg (0.75 mmol) PPh3 were dissolved in 5 ml toluene, then 173 mg
(0.75 mmol) ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C
under N until no further conversion was observed. The toluene was evaporated under
reduced pressure and the residue was purified via flash chromatography using DCM and
MeOH. To this intermediate 105 mg LiOH x H O (2.5 mmol), 5 ml dioxane and 5 ml H O
were added and the mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents Example
779 was obtained as the diastereomer eluting later. HRMS calculated for
C H ClF N O S: 930.2902; found 466.1531 (M+2H).
46 46 3 8 6
Example 780 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl}{4-[(1-methyl-1H-pyrazolyl)methoxy]phenyl}thieno[2,3-d]pyrimidin
yl)oxy][2-(2,2,2-trifluoroethoxy)phenyl]propanoic acid
215 mg (0.27 mmol) Preparation 33, 92 mg (0.82 mmol) (1-methyl-1H-pyrazol
yl)methanol and 215 mg (0.82 mmol) PPh were dissolved in 5 ml toluene, then 189 mg
(0.82 mmol) ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C
under N until no further conversion was observed. The toluene was evaporated under
reduced pressure and the residue was purified via flash chromatography using DCM and
MeOH. To this intermediate 113 mg LiOH x H O (2.7 mmol), 5 ml dioxane and 5 ml H O
were added and the mixture was stirred at room temperature until no further conversion
was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 780. HRMS calculated for C H ClF N O S: 850.2527; found 426.1333
42 42 3 6 6
(M+2H).
Example 781 (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-phenylbutynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and 4-phenylbutyne as the appropriate alkyne,
Example 781 was obtained as the diastereomer eluting later. HRMS calculated for
C H ClN O S: 908.3123; found 455.1646 (M+2H).
51 49 6 6
Example 782 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-phenoxypropynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and phenyl propargyl ether as the appropriate alkyne,
Example 782 was obtained as the diastereomer eluting later. HRMS calculated for
C H N O SCl: 910.2915; found 456.1537 (M+2H).
50 47 6 7
Example 783 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(5-phenylpentynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and 5-phenylpentyne as the appropriate alkyne,
Example 783 was obtained as the diastereomer eluting later. HRMS calculated for
C H ClN O S: 922.3279; found 462.1712 (M+2H).
52 51 6 6
Example 784 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-methoxypropynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and methyl propargyl ether as the appropriate alkyne,
Example 784 was obtained as the diastereomer eluting later. HRMS calculated for
C45H45ClN6O7S: 848.2759; found 425.1431 (M+2H).
Example 785 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[4-(morpholinyl)butynyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and 4-(3-butynyl)-morpholine as the appropriate
alkyne, Example 785 was obtained as the diastereomer eluting later. HRMS calculated for
C H ClN O S: 917.3337; found 459.6732 (M+2H).
49 52 7 7
Example 786 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}[3-(morpholinyl)propynyl]thieno[2,3-d]pyrimidinyl)oxy]-
3-(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIIIc) and 4-(propynyl)morpholine as the appropriate
alkyne, Example 786 was obtained as the diastereomer eluting later. HRMS calculated for
C H ClN O S: 903.3181; found 452.6657 (M+2H).
48 50 7 7
Example 787 methyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXb) with Example 30 as the appropriate acid and MeOH as
the appropriate alcohol, Example 787 was obtained. HRMS calculated for
C H ClFN O S: 888.2872; found 889.2942 (M+H).
48 46 6 6
Example 788 propanyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin-
1-yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXb) with Example 30 as the appropriate acid and 2-propanol
as the appropriate alcohol, Example 788 was obtained. HRMS calculated for
C50H50ClFN6O6S: 916.3185; found 459.1679 (M+2H).
Example 789 2-methoxyethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXb) with Example 30 as the appropriate acid and 2-
methoxyethanol as the appropriate alcohol, Example 789 was obtained. HRMS calculated
for C H ClFN O S: 932.3134; found 467.1658 (M+2H).
50 50 6 7
Example 790 ethyl (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 745 as the appropriate acid, Example 790
was obtained. HRMS calculated for C H ClF N O S: 904.2985; found 905.3029 (M+H).
49 47 2 6 5
Example 791 ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S )-
-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXa) and Example 70 as the appropriate acid, Example 791
was obtained. HRMS calculated for C H ClFN O S: 840.3236; found 841.3319 (M+H).
45 50 6 5
Example 792 ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5Sa)-
-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propyn
yl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
260 mg (0.4 mmol) ethyl (2R)[(5S )[3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl]propynyl-thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8i), 185 mg (1.2 mmol) (1-tert-butyl-1H-pyrazolyl)methanol
(Preparation 9dt) and 276 mg (1.2 mmol) triphenyl phosphine were dissolved in 7ml abs.
toluene then 315 mg (1.2 mmol) ditertbutyl azodicarboxylate was added. The mixture was
stirred at 50°C under nitrogen until no further conversion was observed. Volatiles were
evaporated under reduced pressure and the crude intermediate was purified via flash
chromatography using DCM and methanol as eluents to obtain Example 792. HRMS
calculated for C H ClN O S: 756.2861; found 393.1677 (M+2H).
42 49 6 5
Example 793 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
hydroxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 722 as the appropriate acid, Example 793
was obtained. HRMS calculated for C H ClFN O S: 888.2872; found 889.2902
48 46 6 6
Example 794 ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S )-
-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXa) with Example 750 as the appropriate acid, Example 794
was obtained. HRMS calculated for C H ClFN O S: 785.2814; found 393.6469 (M+2H).
42 45 5 5
Example 795 ethyl (2R){[(5S ){3-chloromethyl[2-(piperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
657 mg (0.95 mmol) ethyl (2R)[(5Sa)-[3-chloromethyl[2-(piperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy(2-hydroxyphenyl)
propanoate (Preparation 8o), 411 mg (1.9 mmol) 2-[2-(2-methoxyphenyl)pyrimidinyl]
methanol (Preparation 9bp) and 498 mg (1.9 mmol) triphenyl phosphine were dissolved
in 25 ml abs. toluene, then 437 mg (1.9 mmol) ditertbutyl azodicarboxylate was added.
The mixture was stirred at 50°C under nitrogen until no further conversion was observed.
The volatiles were evaporated under reduced pressure and the crude intermediate was
purified via flash chromatography using ethyl acetate and methanol as eluents to obtain
Example 795. HRMS calculated for C H ClFN O S: 888.2872; found 445.1502
48 46 6 6
(M+2H).
Example 796 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-
methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (XXa) with Example 724 as the appropriate acid, Example 796
was obtained. HRMS calculated for C H ClFN O S: 946.3291; found 474.1723 (M+2H).
51 52 6 7
Example 797 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 114 as the appropriate acid, Example 797
was obtained. HRMS calculated for C H ClF N O S: 890.2829; found 446.1503
48 45 2 6 5
(M+2H).
Example 798 ethyl (2R){[(5S ){3-chloromethyl[2-(piperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
hydroxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 749 as the appropriate acid, Example 798
was obtained. HRMS calculated for C H ClFN O S: 874.2716; found 875.2812 (M+H).
47 44 6 6
Example 799 2-methoxyethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 757 as the appropriate acid and 2-
bromoethyl methyl ether as the appropriate alkyl halide, Example 799 was obtained.
HRMS calculated for C46H42ClF2N5O6S: 865.2512; found 866.2581 (M+H).
Example 800 2-methoxyethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-
methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (XXb) with Example 753 as the appropriate acid and 2-
methoxyethanol as the appropriate alcohol, Example 800 was obtained. HRMS calculated
for C H ClFN O S: 921.2974; found 461.6576 (M+2H).
49 49 5 8
Example 801 ethyl (2R){[(5S )(3-chloro{2-[ethyl(methyl)amino]ethoxy}
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 747 as the appropriate acid, Example 801
was obtained. HRMS calculated for C H ClF N O S: 849.2563; found 850.2645 (M+H).
46 42 2 5 5
Example 802 2-methoxyethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}-
2-{[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) with Example 750 as the appropriate acid and 2-
bromoethyl methyl ether as the appropriate alkyl halide, Example 802 was obtained.
HRMS calculated for C H ClFN O S: 815.2919; found 816.3029 (M+H).
43 47 5 6
Example 803 2-methoxyethyl (2R){[(5S )(3-chloro{2-
[ethyl(methyl)amino]ethoxy}methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 747 as the appropriate acid and 2-
bromoethyl methyl ether as the appropriate alkyl halide, Example 803 was obtained.
HRMS calculated for C47H44ClF2N5O6S: 879.2669; found 880.2722 (M+H).
Example 804 ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S )-
-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(2,3-
difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXa) with Example 755 as the appropriate acid, Example 804
was obtained. HRMS calculated for C H ClF N O S: 803.272; found 804.2792 (M+H).
42 44 2 5 5
Example 805 2-methoxyethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}-
2-{[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(2,3-
difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) with Example 755 as the appropriate acid and 2-
bromoethyl methyl ether as the appropriate alkyl halide, Example 805 was obtained.
HRMS calculated for C H ClF N O S: 833.2825; found 834.2926 (M+H).
43 46 2 5 6
Example 806 ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2-
methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (XXa) with Example 753 as the appropriate acid, Example 806
was obtained. HRMS calculated for C H ClFN O S: 891.2869; found 446.6493 (M+2H).
48 47 5 7
Example 807 ethyl (2R){[(5Sa){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXa) with Example 757 as the appropriate acid, Example 807
was obtained. HRMS calculated for C H ClF N O S(.HCl): 835.2407; found 836.2449
45 40 2 5 5
(M+H).
Example 808 2,2,2-trifluoroethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
250 mg (0.286 mmol) Example 30 was dissolved in 10 ml DCM, then 41 L (0.572
mmol) 2,2,2-trifluoroethanol, 223 mg (0.429 mmol) PyBOP and 80 l (0.572 mmol)
triethylamine were added. The mixture was stirred at room temperature under N
atmosphere until no further conversion was observed. Then it was diluted with water and
extracted with dichloromethane. The combined organic phases were dried over Na SO ,
filtered and concentrated under reduced pressure and purified via preparative reversed
phase chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to
obtain Example 808. HRMS calculated for C H ClF N O S: 956.2746; found 957.2821
49 45 4 6 6
(M+H).
Example 809 2,3-dihydro-1H-indenyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
438 mg (0.5 mmol) Example 30, 134 mg (1 mmol) 5-indanol, and 140 l (1 mmol)
triethylamine were dissolved in 10 ml DCM, then 520 mg (1 mmol) PyBOP was added at 0
C. The mixture was stirred at room temperature under N atmosphere until no further
conversion was observed. Then it was diluted with water and extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 809. HRMS calculated for C H ClFN O S: 990.3342; found 496.1739
56 52 6 6
(M+2H).
Example 810 {[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)
ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy
phenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}methyl 2,2-dimethylpropanoate
Using General Procedure (XXc) with Example 30 as the appropriate acid and
chloromethyl pivalate as the appropriate alkyl halide, Example 810 was obtained. HRMS
calculated for C H ClFN O S: 988.3396; found 495.175 (M+2H).
53 54 6 8
Example 811 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]
pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)
propanoate
Using General Procedure (XXc) with Example 30 as the appropriate acid and 4-
chloromethylmethyl-1,3-dioxolone as the appropriate alkyl halide, Example 811 was
obtained. HRMS calculated for C H ClFN O S: 986.2876; found 494.1504 (M+2H).
52 48 6 9
Example 812 2-(dimethylamino)oxoethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 30 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 812 was obtained.
HRMS calculated for C H ClFN O S: 959.3243; found 480.6699 (M+2H).
51 51 7 7
Example 813 2-(dimethylamino)ethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
500 mg (0.571 mmol) Example 30 was dissolved in 3 ml DCM, then 102 mg (1.142
mmol) N,N-dimethylethanolamine, 594 mg (1.142 mmol) PYBOP and 160 l (1.142
mmol) triethylamine were added. The mixture was stirred at room temperature under N
atmosphere until no further conversion was observed. Then it was diluted with water,
treated with NaHCO and extracted with dichloromethane. The combined organic phases
were dried over Na SO , filtered and concentrated under reduced pressure and purified via
preparative reversed phase chromatography using 25 mM aqueous NH HCO solution and
MeCN as eluents to obtain Example 813. HRMS calculated for C H ClFN O S:
51 53 7 6
945.3451; found 473.6805 (M+2H).
Example 814 2-(2-methoxyethoxy)ethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 30 as the appropriate acid and 1-bromo
(2-methoxyethoxy)ethane as the appropriate alkyl halide, Example 814 was obtained.
HRMS calculated for C H ClFN O S: 976.3396; found 489.1763 (M+2H).
52 54 6 8
Example 815 octyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and
1-bromooctane as the appropriate alkyl-halide, Example 815 was obtained. HRMS
calculated for C H N O FSCl: 986.3968, found: 987.4025 (M+H)
55 60 6 6
Example 816 2-(dimethylamino)oxoethyl (2R){[(5S ){3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 114 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 816 was obtained.
HRMS calculated for C H ClF N O S: 947.3043; found 948.3137 (M+H).
50 48 2 7 6
Example 817 2-(dimethylamino)oxoethyl (2R){2-[(1-tert-butyl-1H-pyrazol
yl)methoxy]phenyl}{[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) and Example 750 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 817 was obtained.
HRMS calculated for C H ClFN O S: 842.3029; found 422.1599 (M+2H).
44 48 6 6
Example 818 2-(dimethylamino)oxoethyl (2R){[(5S ){3-chloro[2-
(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 757 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 818 was obtained.
HRMS calculated for C H ClF N O S: 892.2621; found 893.2671 (M+H).
47 43 2 6 6
Example 819 2-(dimethylamino)oxoethyl (2R){[(5S ){3-chloro[2-(dimethyl
amino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}
[2-({2-[2-(2-methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (XXc) with Example 753 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 819 was obtained.
HRMS calculated for C H ClFN O S: 948.3083; found 475.1624 (M+2H).
50 50 6 8
Example 820 (5-methyloxo-1,3-dioxolyl)methyl (2R){2-[(1-tert-butyl-1H-
pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) with Example 750 as the appropriate acid and 4-
chloromethylmethyl-1,3-dioxolone as the appropriate alkyl halide, Example 820 was
obtained. HRMS calculated for C H ClFN O S: 869.2661; found 870.2700 (M+H).
45 45 5 8
Example 821 {[(2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S )
{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}propanoyl]oxy}methyl 2,2-dimethylpropanoate
Using General Procedure (XXc) with Example 750 as the appropriate acid and
chloromethyl pivalate as the appropriate alkyl halide, Example 821 was obtained. HRMS
calculated for C H ClFN O S: 871.3182; found 872.3248 (M+H).
46 51 5 7
Example 822 2-(dimethylamino)oxoethyl (2R){[(5S )(3-chloro{2-
[ethyl(methyl)amino]ethoxy}methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 747 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 822 was obtained.
HRMS calculated for C H ClF N O S: 906.2778; found 907.2874 (M+H).
48 45 2 6 6
Example 823 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S )(3-chloro{2-
[ethyl(methyl)amino]ethoxy}methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) with Example 747 as the appropriate acid and 4-
chloromethylmethyl-1,3-dioxolone as the appropriate alkyl halide, Example 823 was
obtained. HRMS calculated for C H ClF N O S: 933.2411; found 934.2522 (M+H).
49 42 2 5 8
Example 824 (5-methyloxo-1,3-dioxolyl)methyl (2R){2-[(1-tert-butyl-1H-
pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) with Example 755 as the appropriate acid and 4-
chloromethylmethyl-1,3-dioxolone as the appropriate alkyl halide, Example 824 was
obtained. HRMS calculated for C H ClF N O S: 887.2567; found 888.2638 (M+H).
45 44 2 5 8
Example 825 2-(dimethylamino)oxoethyl (2R){2-[(1-tert-butyl-1H-pyrazol
yl)methoxy]phenyl}{[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(2,3-difluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoate
Using General Procedure (XXc) with Example 755 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl halide, Example 825 was obtained.
HRMS calculated for C H ClF N O S: 860.2935; found 861.2966 (M+H).
44 47 2 6 6
Example 826 (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
1 eq. ethyl (2R)[(5R )[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]
phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methylsulfanyl
pyrimidinyl)methoxy]phenyl]propanoate (Preparation 10e), 3.0 eq. [2-(2-methoxy
phenyl)pyrimidinyl]methanol (Preparation 9bp) and 3.0 eq. copper(I)
thiophenecarboxylate were dissolved in dry THF (0.1 M for Preparation 10e), then 0.15 eq.
Pd(PPh ) was added. The mixture was stirred at 70°C under nitrogen until no further
conversion was observed. Then it was concentrated under reduced pressure and the crude
intermediate was purified via flash chromatography using dichloromethane and methanol
as eluents. The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol)
and 10 eq LiOH × H O was added. The mixture was stirred at room temperature until no
further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 826. HRMS calculated for C H ClFN O S: 874.2716; found 438.1443
47 44 6 6
(M+2H).
Example 827 (2S){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Example 828 (2S){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
1 eq. ethyl (2S)[(5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl]
(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[(2-methylsulfanylpyrimidin
yl)methoxy]phenyl]propanoate (Preparation 10f), 3.0 eq. [2-(2-
methoxyphenyl)pyrimidinyl]methanol (Preparation 9bp) and 3.0 eq. copper(I)
thiophenecarboxylate were dissolved in dry THF (0.1 M for Preparation 10f), then 0.15 eq.
Pd(PPh ) was added. The mixture was stirred at 70°C under nitrogen until no further
conversion was observed. Then it was concentrated under reduced pressure and the crude
intermediate was purified via flash chromatography using dichloromethane and methanol
as eluents. The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol)
and 10 eq LiOH × H O was added. The mixture was stirred at room temperature until no
further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl,
extracted with DCM. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 5 mM aqueous NH HCO solution and MeCN as eluents. The
diastereomer eluated later was isolated as Example 827. HRMS calculated for
C H ClFN O S: 874.2716; found 438.1437 (M+2H).
47 44 6 6
The diastereomer eluated earlier was isolated as Example 828. HRMS calculated for
C H ClFN O S: 874.2716; found 438.1422 (M+2H).
47 44 6 6
Example 829 ethyl (2S){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Starting from Example 827 and using General Procedure (XXa), Example 829 was
obtained. HRMS calculated for C H ClFN O S: 902.3029; found 452.1575 (M+2H).
49 48 6 6
Example 830 ethyl (2R){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Starting from Example 826 and using General Procedure (XXa), Example 830 was
obtained. HRMS calculated for C H ClFN O S: 902.3029; found 452.1574 (M+2H).
49 48 6 6
Example 831 ethyl (2S){[(5R ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Starting from Example 828 and using General Procedure (XXa), Example 831 was
obtained. HRMS calculated for C H ClFN O S: 902.3029; found 903.3066 (M+H).
49 48 6 6
Example 832 (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}-
6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid
1 eq. Example 857 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10 ml/mmol)
and stirred at room temperature until no further conversion was observed. Mixture was
then acidified with 1M HCl solution and extracted with EtOAc. Organic phases were dried
over Na SO and concentrated in vacuo. Crude product was purified using preparative
reversed phase chromatography using 25 mM aqueous NH HCO solution and MeCN as
eluents to obtain Example 832. HRMS calculated for C H ClFN O S: 819.2294, found:
44 39 5 6
820.2373 (M+H).
Example 833 (2R){[(5S ){3-chloromethyl[2-(6-methyl-2,6-
diazaspiro[3.3]heptyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
319 mg (0.41 mmol) Preparation 6v, 256 mg (1.64 mg) Preparation 34, and 323 mg
(1.23 mmol) PPh were dissolved in 4 ml dry toluene, then 283 mg (1.23 mmol) ditertbutyl
azodicarboxylate was added. The mixture was stirred at 50°C under N until no further
conversion was observed. The toluene was evaporated under reduced pressure and the
residue was purified via flash chromatography using DCM and MeOH as eluents. To this
intermediate 10 eq. LiOH x H O, and dioxane:H O 1:1 (15 ml / mmol) were added and the
mixture was stirred at room temperature until no further conversion was observed. Then it
was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane. The
combined organic phases were dried over Na SO , filtered and concentrated under reduced
pressure and purified via preparative reversed phase chromatography using 25 mM
aqueous NH HCO solution and MeCN as eluents to obtain Example 833 as the earlier
eluated diastereomer. HRMS calculated for C H ClFN O S: 886.2715., found: 444.1449
48 44 6 6
(M+H).
Example 834 (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}iodothieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
1 eq. Preparation 30 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10
ml/mmol)and stirred at room temperature until no further conversion was observed.
Mixture was then acidified with 1M HCl solution and extracted with EtOAc. Organic
phases were dried over Na SO and concentrated in vacuo. Crude product was purified
using preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 834 as the later eluated diastereomer.
HRMS calculated for C H ClIN O S: 906.1463, found: 454.0789 (M+2H).
41 40 6 6
Example 835 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(2-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
90.7 mg Example 834 (0.1 mmol), 26.6 mg 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (0.12 mmol), 97.7 mg cesium carbonate (0.3 mmol), 1.12 mg Pd(OAc) (5
mol%) and 4.25 mg BuX-Phos (10 mol%) were placed in a 4 mL vial. 0.5 mL dioxane and
0.5 mL water were added, and then stirred for 40 min at 70°C under argon atmosphere.
Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane,
the combined organic phases were dried over Mg SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 835. HRMS
calculated for C H N O FSCl: 874.2715, found: 438.1430 (M+2H).
47 44 6 6
Example 836 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(3-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
90.7 mg Example 834 (0.1 mmol), 26.6 mg 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (0.12 mmol), 97.7 mg cesium carbonate (0.3 mmol), 1.12 mg Pd(OAc) (5
mol%) and 4.25 mg BuX-Phos (10 mol%) were placed in a 4 mL vial. 0.5 mL dioxane and
0.5 mL water were added, and then stirred for 40 min at 70°C under argon atmosphere.
Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane,
the combined organic phases were dried over Mg SO , filtered and concentrated under
reduced pressure and purified via preparative reversed phase chromatography using 25
mM aqueous NH HCO solution and MeCN as eluents to obtain Example 836. HRMS
calculated for C H N O FSCl: 874.2715, found: 438.1443 (M+2H).
47 44 6 6
Example 837 (2R){[5-{3-chloromethoxy[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIX) and methanol as the appropriate alcohol, Example 837
was obtained. HRMS calculated for C H N O FSCl: 890.2665, found: 446.1408 and
47 44 6 7
446.1416 for the two diastereoisomers.
Example 838 (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-
[( H )methyloxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid
1 eq. Example 839 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10
ml/mmol)and stirred at room temperature until no further conversion was observed.
Mixture was then acidified with 1M HCl solution and extracted with EtOAc. Organic
phases were dried over Na SO and concentrated in vacuo. Crude product was purified
using preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 838. HRMS calculated for
C H ClD FN O S: 877.2904, found: 878.2997 (M+H).
47 41 3 6 6
Example 839 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-
[( H )methyloxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoate
Using General Procedure (Ib - Step A) and Preparation 9er as the appropriate alcohol,
Example 839 was obtained. HRMS calculated for C H ClD FN O S: 905.3217, found:
49 45 3 6 6
906.3288 (M+H).
Example 840 (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoic acid
1 eq. Example 842 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10
ml/mmol)and stirred at room temperature until no further conversion was observed.
Mixture was then acidified with 1M HCl solution and extracted with EtOAc. Organic
phases were dried over Na SO and concentrated in vacuo. Crude product was purified
using preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 840. HRMS calculated for
C H ClFN O S: 578.1078, found: 579.1140 (M+H).
24 2 5
Example 841 (2R){[(5Sa)(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin
yl]methoxy}phenyl)propanoic acid
1 eq. Example 843 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10
ml/mmol)and stirred at room temperature until no further conversion was observed.
Mixture was then acidified with 1M HCl solution and extracted with EtOAc. Organic
phases were dried over Na2SO4 and concentrated in vacuo. Crude product was purified
using preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 841. HRMS calculated for
C H ClFN O S: 762.1715, found: 763.1787 (M+H).
41 32 4 6
Example 842 ethyl (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoate
1.40 g (2.36 mmol) Preparation 8l, 1.55 g (5.90 mmol) PPh , 250 µl MeOH and 20 ml
toluene were cooled to 0 C and 1.36 g (5.90 mmol) di-tert-butyl azodicarboxylate was
added. Mixture was stirred at 60 C for 2hs. Mixture was then concentrated and purified
via flash chromatography using heptane-EtOAc-MeOH as eluents to obtain Example 842.
HRMS calculated for C H ClFN O S: 606.1392, found: 607.1479 (M+H).
32 28 2 5
Example 843 ethyl (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin
yl]methoxy}phenyl)propanoate
1.40 g (2.36 mmol) Preparation 8l, 1.55 g (5.90 mmol) PPh , 1.27 g (5.90 mmol)
Preparation 9bp and 20 ml toluene were cooled to 0 C and 1.36 g (5.90 mmol) di-tert-
butyl azodicarboxylate was added. Mixture was stirred at 60 C for 2hs. Mixture was then
concentrated and purified via flash chromatography using heptane-EtOAc-MeOH as
eluents to obtain Example 843. HRMS calculated for C H ClFN O S: 790.2028, found:
43 36 4 6
791.2123 (M+H).
Example 844 2-(dimethylamino)oxoethyl (2R){[(5Sa){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-methoxyphenyl)propanoate
Using General Procedure (XXc) and Example 1 as the appropriate acid and 2-chloro-N,N-
dimethylacetamide as the appropriate alkyl-halide, Example 844 was obtained. HRMS
calculated for C H N O FSCl: 775.2607, found: 776.2689 (M+H).
40 43 5 6
Example 845 2-(dimethylamino)oxoethyl (2R){[(5S )(3-chloromethoxy
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoate
Using General Procedure (XXc) and Example 840 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl-halide, Example 845 was obtained.
HRMS calculated for C H ClFN O S: 663.1606, found: 664.1709 (M+H).
34 31 3 6
Example 846 {[(2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoyl]oxy}methyl 2,2-dimethylpropanoate
Using General Procedure (XXc) and Example 840 as the appropriate acid and
chloromethyl pivalate as the appropriate alkyl-halide, Example 846 was obtained. HRMS
calculated for C H ClFN O S: 692.1759, found: 693.1793 (M+H).
36 34 2 7
Example 847 octyl (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin
yl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 841 as the appropriate acid and
1-bromo-octane as the appropriate alkyl-halide, Example 847 was obtained. HRMS
calculated for C H ClFN O S: 874.2967, found: 875.3002 (M+H).
49 48 4 6
Example 848 2-(dimethylamino)oxoethyl (2R){[(5Sa)(3-chloromethoxy
methylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 841 as the appropriate acid and 2-chloro-
N,N-dimethylacetamide as the appropriate alkyl-halide, Example 848 was obtained.
HRMS calculated for C H ClFN O S: 847.2243, found: 848.2276 (M+H).
45 39 5 7
Example 849 {[(2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin
yl]methoxy}phenyl)propanoyl]oxy}methyl 2,2-dimethylpropanoate
Using General Procedure (XXc) and Example 841 as the appropriate acid and
chloromethyl pivalate as the appropriate alkyl-halide, Example 849 was obtained. HRMS
calculated for C H ClFN O S: 876.2396, found: 877.2450 (M+H).
47 42 4 8
Example 850 octyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoate
Using General Procedure (XXc) and Example 1 as the appropriate acid and
1-bromo-octane as the appropriate alkyl-halide, Example 850 was obtained. HRMS
calculated for C H ClFN O S: 802.3331, found: 803.3381 (M+H).
44 52 4 5
Example 851 octyl (2R){[(5S )(3-chloromethoxymethylphenyl)(4-
fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl)propanoate
Using General Procedure (XXc) and Example 840 as the appropriate acid and
1-bromo-octane as the appropriate alkyl-halide, Example 851 was obtained. HRMS
calculated for C H ClFN O S: 690.2330, found: 691.2373 (M+H).
38 40 2 5
Example 852 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S )(3-chloro
methoxymethylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-
methoxyphenyl)propanoate
Using General Procedure (XXc) and Example 840 as the appropriate acid and
4-chloromethylmethyl-1,3-dioxolone as the appropriate alkyl-halide, Example 852
was obtained. HRMS calculated for C H ClFN O S: 690.1239, found: 691.1323 (M+H).
28 2 8
Example 853 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5Sa)(3-chloro
methoxymethylphenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-
(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 841 as the appropriate acid and
4-chloromethylmethyl-1,3-dioxolone as the appropriate alkyl-halide, Example 853
was obtained. HRMS calculated for C H ClFN O S: 874.1876, found: 875.1976 (M+H).
46 36 4 9
Example 854 {[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}methyl 2,2-
dimethylpropanoate
Using General Procedure (XXc) and Example 114 as the appropriate acid and
chloromethyl pivalate as the appropriate alkyl-halide, Example 854 was obtained. HRMS
calculated for C H ClF N O S: 976.3196, found: 977.3262 (M+H).
52 51 2 6 7
Example 855 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloro
methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy}(2-{[2-(2-fluorophenyl)pyrimidin
yl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 114 as the appropriate acid and
4-chloromethylmethyl-1,3-dioxolone as the appropriate alkyl-halide, Example 855
was obtained. HRMS calculated for C H ClF N O S: 974.2676, found: 488.1406
51 45 2 6 8
(M+2H).
Example 856 ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (Ib) and 2-(hydroxymethyl)phenylboronic acid as the appropriate
boronic acid Example 856 was obtained. HRMS calculated for C49H48ClFN6O6S:
902.3029, found: 903.3076 (M+H).
Example 857 ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]
methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-
(hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoate
Using General Procedure (IIb) and 2-(hydroxymethyl)phenylboronic acid as the
appropriate boronic acid Example 857 was obtained. HRMS calculated for
C H CFN O S: 847.2607, found: 848.2649 (M+H).
46 43 5 6
Example 858 1-(acetyloxy)ethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and 1-iodoethyl
acetate (Preparation 35a) as the appropriate alkyl-halide, Example 858 was obtained.
HRMS calculated for C H ClFN O S: 960.3083, found: 481.1627 and 481.1617 for the
51 50 6 8
two diastereomers (M+2H).
Example 859 1-{[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}ethyl 2,2-
dimethylpropanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and 1-iodoethyl
2,2-dimethylpropanoate (Preparation 35b) as the appropriate alkyl-halide, Example 859
was obtained. HRMS calculated for C H ClFN O S: 1002.3553, found: 502.1852
54 56 6 8
(M+2H).
Example 860 1-(propanoyloxy)ethyl (2R){[(5S ){3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and 1-iodoethyl
propanoate (Preparation 35c) as the appropriate alkyl-halide, Example 860 was obtained.
HRMS calculated for C H ClFN O S: 974.324, found: 488.1701 and 488.1717 for the
52 52 6 8
two diastereomers (M+2H).
Example 861 1-[(2-methylpropanoyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-
(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and 1-iodoethyl
2-methylpropanoate (Preparation 35d) as the appropriate alkyl-halide, Example 861 was
obtained. HRMS calculated for C H ClFN O S: 988.3397, found: 495.1767 and
53 54 6 8
495.1793 for the two diastereomers (M+2H).
Example 862 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloro[2-
(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}[2-({2-[2-(2-methoxyethoxy)phenyl]pyrimidin
yl}methoxy)phenyl]propanoate
Using General Procedure (XXc) and Example 753 as the appropriate acid and
4-chloromethylmethyl-1,3-dioxolone as the appropriate alkyl-halide, Example 862
was obtained. HRMS calculated for C H ClFN O S: 975.2716, found: 488.6412
51 47 5 10
(M+2H).
Example 863 (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloro[2-
(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-fluorophenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 757 as the appropriate acid and
4-chloromethylmethyl-1,3-dioxolone as the appropriate alkyl-halide, Example 863
was obtained. HRMS calculated for C H ClF N O S: 919.2254, found: 920.2332 (M+H).
48 40 2 5 8
Example 864 1-[(methoxyacetyl)oxy]ethyl (2R){[5-{3-chloromethyl[2-(4-
methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin
yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate
Using General Procedure (XXc) and Example 30 as the appropriate acid and Preparation
35e as the appropriate alkyl-halide, Example 864 was obtained. HRMS calculated for
C H ClFN O S: 990.3189, found: 496.1674 and 496.1678 for the two diastereoisomers
52 52 6 9
(M+2H).
Example 865 (2R){[5-{3-chloroethoxy[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIX) and ethanol as the appropriate alcohol, Example 865
was obtained. HRMS calculated for C H ClFN O S: 904.2821, found: 453.1487 and
48 46 6 7
453.1491 for the two diastereoisomers.
Example 866 (2R){[5-{3-chloro[2-(4-methylpiperazinyl)ethoxy](propan
yloxy)phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXIX) and isopropanol as the appropriate alcohol, Example
866 was obtained. HRMS calculated for C H ClFN O S: 918.2978, found: 460.1568 and
49 48 6 7
460.1573 for the two diastereomers.
Example 867 (2R){[5-{3-chlorohydroxy[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
1 eq. Preparation 38, 10 eq. LiOH x H O, and dioxane : H O 1 : 1 (15 ml / mmol) were
added and the mixture was stirred at room temperature until no further conversion was
observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with
dichloromethane. The combined organic phases were dried over Na SO , filtered and
concentrated under reduced pressure and purified via preparative reversed phase
chromatography using 25 mM aqueous NH HCO solution and MeCN as eluents to obtain
Example 867. HRMS calculated for C H ClFN O S: 876.2509, found: 439.1343
46 42 6 7
(M+2H).
Example 868 (2R){[5-{3-chlorocyano[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVIII) and Preparation 36 as the appropriate phenol
derivative and 2-(4-methylpiperazinyl)ethanol as the appropriate alcohol,
diastereoisomer eluting earlier was collected as Example 868. HRMS calculated for
C H ClFN O S: 885.2512; found 443.6351 (M+2H).
47 41 7 6
Example 869 (2R){[5-{3-chlorocyano[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Using General Procedure (XXXVIII) and Preparation 36 as the appropriate phenol
derivative and 2-(4-methylpiperazinyl)ethanol as the appropriate alcohol, the
diastereoisomer eluting later was collected as Example 869. HRMS calculated for
C H ClFN O S: 885.2512; found 443.6339 (M+2H).
47 41 7 6
Example 870 (2R){[5-{3-chloro(methoxymethoxy)[2-(4-methylpiperazin
yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
1 eq. Preparation 37 and 10 eq. LiOH x H O were dissolved in H O : dioxane (10
ml/mmol) and stirred at room temperature until no further conversion was observed.
Mixture was then acidified with 1M HCl solution and extracted with EtOAc. Organic
phases were dried over Na SO and concentrated in vacuo. Crude product was purified
using preparative reversed phase chromatography using 25 mM aqueous NH HCO
solution and MeCN as eluents to obtain Example 870. HRMS calculated for
C H ClFN O S: 920.2770, found: 461.1445 and 461.1460 for the two diastereomers.
48 46 6 8
Example 871 (2R){[(5S )(3-chloromethyl{2-[4-( H )methylpiperazin
yl]ethoxy}phenyl)(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-
methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid
Step A:
To the solution of 144 mg (0.162 mmol) of Example 795 and 66 mg (0.202 mmol, 1.25
eq) Cs CO in 1 mL DMF 162 µL (0.162 mmol, 1.0 eq) 1 M solution of ( H )iodomethane
2 3 3
in DMF was added and it was stirred at room temperature for 16h. Reaction mixture was
filtered and purified on prep HPLC using water (5 mM NH HCO ) and acetonitrile as
eluents to give ethyl (2R)[(5S )[3-chloromethyl[2-[4-( H )methyl-piperazin
yl]ethoxy]phenyl](4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy[2-[[2-(2-
methoxyphenyl)pyrimidinyl]methoxy]phenyl]propanoate as white crystals.
Step B:
To the solution of 76 mg (1.0 eq, 0.08384 mmol) ethyl (2R)[(5S )[3-chloromethyl-
4-[2-[4-( H3)methyl-piperazinyl]ethoxy]phenyl](4-fluorophenyl)thieno[2,3-
d]pyrimidinyl]oxy[2-[[2-(2-methoxyphenyl)pyrimidin
yl]methoxy]phenyl]propanoate in 2 mL dioxan and 1.25 mL water, 35.2 mg (10.0 eq,
0.838 mmol) LiOH x H O was added and the reaction mixture was stirred at room
temperature until full conversion. The pH of the reaction mixture was adjusted to 6 using
1N HCl, then it was filtered and purified on reversed phase preparative HPLC using water
(5 mM NH HCO ) and acetonitrile as eluents to give Example 871.
HRMS calculated for C47H41ClD3FN6O6S: 877.2904; found 439.6534 (M+2H).
PHARMACOLOGICAL STUDY
EXAMPLE A: Inhibition of Mcl-1 by the fluorescence polarisation technique
The relative binding potency of each compound was determined via Fluorescence
Polarisation (FP). The method utilised a Fluorescein labelled ligand (Fluorescein-βAla-
Ahx-A-REIGAQLRRMADDLNAQY-OH ; mw 2,765) which binds to the Mcl-1 protein
(such that Mcl-1 corresponds to the UniProtKB primary accession number: Q07820)
leading to an increased anisotropy measured in milli-polarisation (mP) units using a reader.
The addition of a compound which binds competitively to the same site as the ligand will
result in a greater proportion of unbound ligand in the system indicated by a decrease in
mP units.
Method 1: An 11 point serial dilution of each compound was prepared in DMSO and 2µl
transferred into flat bottomed, low binding, 384-well plate (final DMSO concentration
%). 38µl of buffer (10 mM 4-(2-hydroxyethyl)piperazineethanesulfonic acid [HEPES],
150 mM NaCl, 0.05% Tween 20, pH 7.4), containing the Fluorescein labelled ligand (final
concentration 1nM) and Mcl-1 protein (final concentration 5nM) was then added.
Assay plates were incubated ~2 hours at room temperature before FP was measured on a
Biomek Synergy2 reader (Ex. 528nm, Em. 640nm, Cut off 510nm) and mP units
calculated. The binding of increasing doses of test compound was expressed as a
percentage reduction in mP compared to a window established between ‘5% DMSO only’
and ‘100% inhibition’ (10µM Example 38) controls. 11-point dose response curves were
plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal Dose-
Response Model) and the inhibitory concentrations that gave a 50% reduction in mP
(IC50) were determined. Results obtained using Method 1 are presented in Table 1 below;
IC of Mcl-1 inhibition obtained using Method 1 are not underlined.
Method 2: An 11 point serial dilution of each compound was prepared in DMSO and 2µl
transferred into flat bottomed, low binding, 384-well plate (final DMSO concentration
%). 38µl of buffer (20 mM Na PO , 1mM EDTA, 50mM NaCl , pH 7.4), containing the
2 4 2
Fluorescein labelled ligand (final concentration 10nM) and Mcl-1 protein (final
concentration 10nM) was then added.
Assay plates were incubated ~2 hours at room temperature before FP was measured on a
Biomek Synergy2 reader (Ex. 528nm, Em. 640nm, Cut off 510nm) and mP units
calculated. The binding of increasing doses of test compound was expressed as a
percentage reduction in mP compared to a window established between ‘5% DMSO only’
and ‘100% inhibition’ controls (50µM unlabelled ligand). 11-point dose response curves
were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal Dose-
Response Model) and the inhibitory concentrations that gave a 50% reduction in mP
(IC50) were determined. Results obtained using Method 2 are presented in Table 1 below;
IC of Mcl-1 inhibition obtained using Method 2 are underlined.
The results show that the compounds of the invention inhibit interaction between the Mcl-1
protein and the fluorescent peptide described hereinbefore.
EXAMPLE B: In vitro cytotoxicity
The cytotoxicity studies were carried out on the H929 multiple myeloma tumour line.
The cells are distributed onto microplates and exposed to the test compounds for 48 hours.
The cell viability is then quantified by a colorimetric assay, the Microculture Tetrazolium
Assay (Cancer Res., 1987, 47, 939-942).
The results are expressed in IC (the concentration of compound that inhibits cell viability
by 50%) and are presented in Table 1 below.
The results show that the compounds of the invention are cytotoxic.
Table 1: IC of Mcl-1 inhibition (fluorescence polarisation test)
and of cytotoxicity for H929 cells
Note: IC of Mcl-1 inhibition obtained using Method 2 are underlined.
IC (M) Mcl-1 FP IC (µM) MTT H929 IC (M) Mcl-1 FP IC (µM) MTT H929
50 50 50 50
Example 1 8.0E-08 0.16 Example 29 3.3E-09 0.007
Example 2 1.2E-08 0.136 Example 30 2.8E-09 0.003
Example 3 8.9E-09 0.114 Example 31 5.6E-09 0.012
Example 4 1.6E-08 0.192 Example 32 4.8E-09 0.006
Example 5 6.2E-09 0.418 Example 33 7.8E-09 0.017
Example 6 4.9E-09 0.332 Example 34 3.3E-09 0.004
8.6E-09 0.066 4.8E-09 0.027
Example 7 Example 35
Example 8 1.6E-08 0.145 Example 36 1.1E-08 0.015
Example 9 9.3E-09 0.363 Example 37 6.0E-09 0.014
Example 10 9.7E-09 0.275 Example 38 1.9E-09 0.016
4.4E-08 0.13 4.8E-09 0.015
Example 11 Example 39
1.6E-08 0.076 5.6E-09 0.008
Example 12 Example 40
Example 13 2.2E-08 0.146 Example 41 2.9E-09 0.007
Example 14 1.3E-08 0.168 Example 42 3.2E-09 0.012
3.7E-08 0.494 9.8E-09 0.465
Example 15 Example 43
.9E-09 0.095 4.8E-09 0.006
Example 16 Example 44
Example 17 1.2E-08 0.062 Example 45 6.7E-09 0.009
Example 18 8.3E-09 0.076 Example 46 7.3E-09 0.024
Example 19 4.4E-09 0.064 Example 47 7.8E-09 0.005
Example 20 6.4E-09 0.08 Example 48 1.1E-08 0.122
Example 21 1.6E-08 0.162 Example 49 2.5E-09 0.012
Example 22 8.3E-09 0.092 Example 50 7.6E-09 0.076
Example 23 2.4E-08 0.054 Example 51 3.5E-09 0.038
Example 24 8.1E-09 0.012 Example 52 5.6E-09 0.014
Example 25 5.6E-09 0.074 Example 53 3.4E-09 0.015
Example 26 1.1E-08 0.028 Example 54 5.7E-09 0.024
Example 27 6.6E-09 0.045 Example 55 5.8E-09 0.007
4.5E-09 0.021 4.4E-09 0.022
Example 28 Example 56
IC (M) Mcl-1 FP IC (µM) MTT H929 IC (M) Mcl-1 FP IC (µM) MTT H929
50 50 50 50
Example 57 5.0E-09 0.008 Example 88 4.2E-09 0.062
Example 58 4.0E-09 0.01 Example 89 6.5E-09 0.027
Example 59 4.0E-09 0.021 Example 90 3.2E-09 0.058
Example 60 2.4E-09 0.17 Example 91 7.3E-09 0.042
Example 61 6.7E-09 0.01 Example 92 1.2E-08 ND
Example 62 3.9E-09 0.008 Example 93 1.4E-08 0.087
Example 63 4.5E-09 0.009 Example 94 1.9E-09 0.085
Example 64 4.4E-09 0.018 Example 95 4.2E-09 0.022
Example 65 1.0E-08 0.043 Example 96 3.8E-09 0.034
Example 66 4.6E-09 0.037 Example 97 3.3E-09 0.075
Example 67 3.4E-09 0.03 Example 98 3.3E-07 0.118
9.1E-09 0.035 2.0E-08 ND
Example 68 Example 99
Example 69 9.7E-08 0.114 Example 100 1.2E-08 ND
Example 70 1.6E-09 0.018 Example 101 8.0E-09 0.398
Example 71 9.4E-09 0.032 Example 102 9.5E-09 ND
9.3E-09 0.04 2.4E-08 0.214
Example 72 Example 103
Example 73 8.3E-09 0.122 Example 104 7.5E-09 0.386
Example 74 1.6E-08 0.365 Example 105 1.2E-08 0.251
Example 75 4.0E-09 0.11 Example 106 1.2E-08 0.195
1.6E-08 0.044 5.3E-09 0.007
Example 76 Example 107
Example 77 5.9E-09 0.042 Example 108 3.5E-09 0.007
Example 78 6.6E-09 0.033 Example 109 8.4E-09 0.108
Example 79 1.3E-08 0.168 Example 110 4.3E-09 0.022
4.5E-09 0.035 3.3E-09 0.008
Example 80 Example 111
Example 81 7.6E-09 0.034 Example 112 5.6E-09 0.011
Example 82 5.1E-09 0.078 Example 113 2.6E-09 0.005
Example 83 5.1E-09 0.016 Example 114 2.1E-09 0.005
3.8E-09 0.018 2.6E-09 0.003
Example 84 Example 115
Example 85 3.6E-09 0.063 Example 116 2.9E-09 0.007
Example 86 2.9E-09 0.063 Example 117 6.1E-09 0.008
Example 87 7.0E-09 0.274 Example 118 5.5E-09 0.006
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (nM) Mcl-1 FP IC50 (µM) MTT H929
Example 119 4.8E-09 0.02 Example 150 9.3E-09 0.027
Example 120 3.8E-09 0.003 Example 151 3.6E-09 0.309
Example 121 5.6E-09 0.015 Example 152 9.9E-09 0.19
Example 122 3.8E-09 0.01 Example 153 5.0E-09 0.146
Example 123 4.3E-09 0.002 Example 154 6.6E-09 0.1
Example 124 4.3E-09 0.024 Example 155 7.6E-09 0.189
Example 125 7.3E-09 0.354 Example 156 7.0E-09 0.092
Example 126 1.4E-08 0.7 Example 157 7.0E-09 0.286
Example 127 2.0E-08 0.558 Example 158 4.6E-09 0.033
4.0E-09 0.018 9.8E-09 0.246
Example 128 Example 159
Example 129 2.2E-09 0.069 Example 160 5.0E-09 0.021
Example 130 3.4E-09 0.065 Example 161 3.9E-09 0.081
7.9E-09 0.039 9.9E-09 0.027
Example 131 Example 162
4.8E-09 0.102 1.2E-08 0.047
Example 132 Example 163
Example 133 3.4E-09 0.099 Example 164 8.2E-09 0.046
Example 134 1.3E-08 0.193 Example 165 1.6E-06 ND
Example 135 8.6E-09 0.005 Example 166 6.0E-09 0.036
7.7E-09 0.015 4.6E-09 0.01
Example 136 Example 167
Example 137 5.5E-09 0.007 Example 168 2.8E-09 0.025
Example 138 8.9E-09 0.013 Example 169 9.0E-09 0.009
Example 139 8.5E-08 0.636 Example 170 5.3E-09 0.006
2.2E-08 0.205 4.1E-09 0.003
Example 140 Example 171
Example 141 3.1E-08 0.27 Example 172 3.0E-09 0.004
Example 142 4.2E-08 1.67 Example 173 3.1E-09 0.004
Example 143 2.6E-08 1.61 Example 174 2.3E-09 0.005
1.6E-08 1.6 3.9E-09 0.003
Example 144 Example 175
Example 145 1.1E-08 0.293 Example 176 3.1E-09 0.016
Example 146 3.5E-08 1.16 Example 177 2.8E-09 0.005
Example 147 2.4E-08 0.787 Example 178 6.3E-09 0.002
3.1E-08 ND 5.0E-09 0.03
Example 148 Example 179
1.2E-08 0.092 8.9E-09 0.042
Example 149 Example 180
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 181 4.8E-09 0.008 Example 212 1.6E-08 0.616
Example 182 4.4E-09 0.013 Example 213 1.8E-08 ND
Example 183 5.7E-09 0.012 Example 214 9.3E-09 0.897
Example 184 6.0E-09 0.022 Example 215 8.0E-09 0.203
Example 185 4.8E-09 0.012 Example 216 8.5E-09 0.217
Example 186 4.3E-09 0.013 Example 217 5.3E-09 1.48
Example 187 2.8E-09 0.02 Example 218 6.5E-09 0.805
Example 188 6.4E-09 0.005 Example 219 9.9E-09 0.191
Example 189 5.5E-09 0.034 Example 220 9.0E-09 0.277
7.5E-09 0.037 6.3E-09 0.059
Example 190 Example 221
Example 191 6.5E-09 0.063 Example 222 7.4E-09 0.314
Example 192 7.7E-09 0.848 Example 223 1.4E-08 0.346
.4E-09 0.116 3.7E-09 0.049
Example 193 Example 224
8.0E-09 0.058 8.4E-09 0.105
Example 194 Example 225
Example 195 5.5E-09 0.311 Example 226 2.4E-08 0.311
Example 196 5.6E-09 0.076 Example 227 2.0E-08 0.192
Example 197 5.4E-09 0.07 Example 228 2.2E-08 0.166
7.7E-09 0.002 4.5E-09 0.134
Example 198 Example 229
Example 199 6.6E-09 0.28 Example 230 1.2E-08 0.312
Example 200 6.1E-09 0.106 Example 231 1.0E-08 0.116
Example 201 5.8E-09 0.027 Example 232 9.0E-09 0.046
3.5E-09 0.009 3.4E-09 0.099
Example 202 Example 233
Example 203 9.1E-09 0.005 Example 234 1.1E-08 0.135
Example 204 4.9E-09 0.034 Example 235 5.1E-09 0.098
Example 205 3.8E-09 0.028 Example 236 7.4E-09 0.137
8.0E-09 0.135 1.5E-08 0.186
Example 206 Example 237
Example 207 6.5E-09 0.186 Example 238 5.9E-09 0.077
Example 208 5.5E-09 0.571 Example 239 1.1E-08 0.55
Example 209 9.8E-09 0.115 Example 240 7.2E-09 0.225
1.0E-08 0.406 5.5E-09 0.074
Example 210 Example 241
.2E-09 0.063 7.3E-09 0.09
Example 211 Example 242
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 243 5.6E-09 0.211 Example 274 7.7E-09 0.131
Example 244 8.6E-09 0.205 Example 275 4.5E-09 0.051
Example 245 5.8E-09 0.099 Example 276 6.2E-09 ND
Example 246 9.1E-09 0.324 Example 277 4.8E-09 0.07
Example 247 8.0E-09 0.022 Example 278 6.7E-09 0.202
Example 248 6.9E-09 0.015 Example 279 8.0E-09 0.406
Example 249 4.0E-09 0.023 Example 280 4.0E-09 0.071
Example 250 3.6E-09 0.499 Example 281 7.9E-09 0.081
Example 251 6.3E-09 0.035 Example 282 4.0E-08 0.601
4.2E-09 0.009 2.6E-08 0.25
Example 252 Example 283
Example 253 3.1E-09 0.041 Example 284 4.8E-08 1.79
Example 254 3.3E-09 0.044 Example 285 1.7E-08 0.588
7.5E-09 0.018 7.6E-09 0.508
Example 255 Example 286
4.8E-09 0.006 8.3E-09 0.667
Example 256 Example 287
Example 257 5.0E-09 0.019 Example 288 1.2E-08 0.086
Example 258 6.6E-09 0.069 Example 289 1.4E-08 0.18
Example 259 5.2E-09 0.07 Example 290 5.8E-09 0.097
6.7E-09 0.033 3.8E-08 1.3
Example 260 Example 291
Example 261 1.7E-09 0.018 Example 292 9.3E-09 0.192
Example 262 3.9E-09 0.023 Example 293 8.9E-07 ND
Example 263 2.0E-09 0.126 Example 294 1.6E-08 0.886
9.1E-09 0.034 4.7E-09 0.021
Example 264 Example 295
Example 265 3.5E-09 0.016 Example 296 9.3E-09 ND
Example 266 5.7E-09 0.093 Example 297 6.6E-09 ND
Example 267 8.8E-09 1.6 Example 298 1.2E-08 1.14
8.2E-09 0.086 1.6E-08 1.03
Example 268 Example 299
Example 269 1.1E-08 0.069 Example 300 3.7E-08 ND
Example 270 1.2E-08 0.068 Example 301 1.2E-08 0.108
Example 271 1.6E-08 0.197 Example 302 1.4E-08 1.59
2.2E-08 0.822 9.3E-09 0.998
Example 272 Example 303
9.2E-09 0.905 1.1E-08 1.7
Example 273 Example 304
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 305 6.9E-08 1.64 Example 336 43.2% @ 10 uM ND
Example 306 1.4E-08 1.12 Example 337 3.8E-08 1.87
Example 307 8.3E-09 0.998 Example 338 3.0E-08 1.04
Example 308 5.9E-09 1.5 Example 339 18.85% @ 10 uM ND
Example 309 1.0E-08 1.48 Example 340 6.7E-07 ND
Example 310 1.4E-08 0.26 Example 341 3.5E-08 0.706
Example 311 1.5E-08 1.59 Example 342 3.5E-07 ND
Example 312 8.9E-09 1 Example 343 2.5E-07 ND
Example 313 1.0E-08 0.886 Example 344 1.6E-08 0.22
6.9E-09 1.82 8.6E-09 0.322
Example 314 Example 345
Example 315 2.2E-08 ND Example 346 1.7E-08 0.063
Example 316 7.7E-09 1.46 Example 347 1.4E-08 0.25
1.8E-08 0.852 2.1E-08 0.346
Example 317 Example 348
3.0E-08 ND 2.7E-08 2.46
Example 318 Example 349
Example 319 1.5E-08 0.834 Example 350 2.8E-08 ND
Example 320 6.5E-09 0.471 Example 351 1.5E-08 0.526
Example 321 6.0E-09 ND Example 352 1.4E-08 0.91
4.3E-09 0.113 2.8E-08 ND
Example 322 Example 353
Example 323 8.8E-09 ND Example 354 1.1E-08 0.544
Example 324 1.5E-08 0.254 Example 355 3.0E-08 ND
Example 325 5.2E-08 ND Example 356 1.1E-08 ND
7.9E-09 ND 5.5E-07 3.39
Example 326 Example 357
Example 327 1.5E-08 ND Example 358 9.5E-09 1.61
Example 328 5.0E-09 3.03 Example 359 6.6E-09 0.336
Example 329 6.0E-08 3.31 Example 360 2.0E-07 ND
8.3E-09 1.17 7.1E-07 ND
Example 330 Example 361
Example 331 6.0E-09 0.394 Example 362 2.6E-08 1
Example 332 1.3E-08 ND Example 363 7.7E-09 0.071
Example 333 7.9E-07 ND Example 364 5.1E-09 0.052
1.4E-08 0.968 5.9E-09 0.026
Example 334 Example 365
1.2E-08 0.217 8.6E-09 0.346
Example 335 Example 366
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 367 3.2E-09 0.015 Example 398 1.5E-06 23.8
Example 368 1.4E-08 0.005 Example 399 1.4E-08 ND
Example 369 5.1E-09 0.009 Example 400 8.4E-08 14.4
Example 370 8.7E-09 0.018 Example 401 4.9E-08 22.3
Example 371 5.6E-09 0.027 Example 402 6.6E-08 10.4
Example 372 9.7E-09 0.018 Example 403 1.4E-08 ND
Example 373 4.6E-09 0.012 Example 404 5.7E-08 21.6
Example 374 9.2E-09 0.038 Example 405 7.4E-09 ND
Example 375 5.6E-09 0.081 Example 406 3.5E-08 21.9
2.0E-09 0.076 1.1E-07 7.33
Example 376 Example 407
Example 377 3.8E-09 0.047 Example 408 26.25% @ 10 uM 15.9
Example 378 3.2E-09 0.202 Example 409 2.0E-07 ND
1.3E-08 0.174 2.2E-06 ND
Example 379 Example 410
1.1E-08 0.162 3.4E-08 19
Example 380 Example 411
Example 381 1.3E-08 0.119 Example 412 5.1E-08 28.7
Example 382 7.1E-09 0.033 Example 413 1.3E-08 15.8
Example 383 5.6E-09 0.03 Example 414 21.35% @ 10 uM 27.2
3.8E-09 0.053 5.0E-08 6.41
Example 384 Example 415
Example 385 3.5E-09 0.048 Example 416 7.0E-07 ND
Example 386 1.0E-08 0.075 Example 417 1.5E-07 ND
Example 387 4.0E-09 0.202 Example 418 5.6E-08 13.3
2.3E-08 ND 3.4E-08 21.5
Example 388 Example 419
Example 389 1.2E-06 ND Example 420 4.0E-08 15.6
Example 390 4.0E-08 20 Example 421 38.1% @ 10 uM ND
Example 391 3.7E-08 22.1 Example 422 1.4E-08 14.4
3.0E-08 17.1 5.3E-08 ND
Example 392 Example 423
Example 393 4.1E-08 16.6 Example 424 9.6E-08 ND
Example 394 3.4E-08 ND Example 425 9.6E-09 ND
Example 395 1.6E-08 ND Example 426 4.6E-09 ND
9.9E-08 16.1 4.7E-09 ND
Example 396 Example 427
8.0E-09 15.7 7.5E-09 ND
Example 397 Example 428
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 429 5.3E-08 ND Example 460 1.3E-07 6.82
Example 430 1.4E-07 15.5 Example 461 8.5E-08 4.86
Example 431 3.2E-08 ND Example 462 3.7E-05 ND
Example 432 6.8E-08 13.6 Example 463 4.6E-08 5.11
Example 433 ND ND Example 464 3.9E-07 ND
Example 434 1.7E-07 11.3 Example 465 2.5E-08 2.06
Example 435 3.2E-07 11.1 Example 466 3.9E-08 3.35
Example 436 2.9E-08 15.1 Example 467 1.1E-08 0.502
Example 437 4.5E-08 20.3 Example 468 8.6E-09 2.02
8.5E-08 ND 1.5E-08 3.06
Example 438 Example 469
Example 439 2.5E-07 ND Example 470 4.8E-07 ND
Example 440 3.0E-07 ND Example 471 6.3E-09 ND
2.7E-08 ND 13.05% @ 10 uM ND
Example 441 Example 472
1.1E-07 20.4 5.0E-08 ND
Example 442 Example 473
Example 443 1.8E-08 ND Example 474 5.5E-07 ND
Example 444 1.2E-08 ND Example 475 6.8E-09 1.12
Example 445 1.3E-07 21 Example 476 2.0E-08 1.03
1.1E-07 25.7 5.6E-08 2.57
Example 446 Example 477
Example 447 6.8E-08 ND Example 478 5.3E-07 ND
Example 448 4.4E-07 ND Example 479 1.1E-08 ND
Example 449 2.8E-08 ND Example 480 2.8E-08 ND
2.6E-08 ND 5.4E-09 0.643
Example 450 Example 481
Example 451 5.8E-07 ND Example 482 7.4E-09 0.004
Example 452 3.0E-07 ND Example 483 5.2E-09 0.003
Example 453 2.6E-08 3 Example 484 3.4E-09 0.014
1.2E-08 ND 4.3E-09 0.012
Example 454 Example 485
Example 455 6.2E-09 0.339 Example 486 1.9E-09 0.146
Example 456 8.0E-09 0.513 Example 487 6.5E-09 0.004
Example 457 3.4E-08 ND Example 488 5.4E-09 0.014
3.2E-08 2.73 1.2E-09 0.026
Example 458 Example 489
3.7E-06 ND 3.0E-09 0.018
Example 459 Example 490
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 491 28.3% @ 10 uM ND Example 522 7.5E-08 ND
Example 492 9.0E-08 2.19 Example 523 1.8E-09 0.532
Example 493 5.0E-09 ND Example 524 3.1E-08 0.417
Example 494 4.4E-08 2.56 Example 525 3.3E-09 0.755
Example 495 3.6E-08 1.19 Example 526 4.1E-09 0.835
Example 496 2.0E-07 3.39 Example 527 7.1E-08 0.272
Example 497 9.1E-07 5.95 Example 528 1.6E-08 0.334
Example 498 7.4E-08 ND Example 529 1.3E-08 0.308
Example 499 1.0E-07 1.5 Example 530 1.2E-07 1.59
8.0E-08 2.25 3.5E-09 1.22
Example 500 Example 531
Example 501 2.8E-07 2.84 Example 532 5.9E-08 0.323
Example 502 1.9E-08 0.766 Example 533 2.8E-08 0.201
.0E-07 7.02 1.6E-08 0.413
Example 503 Example 534
2.9E-08 0.324 1.3E-07 1.84
Example 504 Example 535
Example 505 5.8E-08 0.954 Example 536 7.7E-08 0.797
Example 506 7.5E-08 8.29 Example 537 4.3E-08 0.208
Example 507 2.2E-07 ND Example 538 4.7E-08 0.672
3.7E-07 ND 7.2E-08 0.731
Example 508 Example 539
Example 509 6.2E-08 1.46 Example 540 3.2E-09 0.311
Example 510 3.9E-08 0.639 Example 541 2.9E-08 0.329
Example 511 4.8E-07 ND Example 542 4.3E-07 ND
1.3E-07 7.42 4.2E-08 0.766
Example 512 Example 543
Example 513 3.7E-07 ND Example 544 1.4E-08 0.274
Example 514 9.6E-08 1.7 Example 545 3.9E-08 1.1
Example 515 8.4E-08 2.95 Example 546 1.7E-08 0.416
1.3E-07 5.07 3.3E-08 0.475
Example 516 Example 547
Example 517 5.1E-07 6.09 Example 548 1.8E-08 0.497
Example 518 3.5E-08 9.18 Example 549 1.3E-07 1.5
Example 519 2.3E-08 0.523 Example 550 4.8E-08 0.203
4.1E-08 1.13 2.8E-08 0.201
Example 520 Example 551
2.4E-07 ND 4.1E-08 0.784
Example 521 Example 552
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 553 1.1E-08 0.585 Example 584 2.9E-08 0.902
Example 554 2.4E-08 0.177 Example 585 8.5E-08 2.92
Example 555 3.9E-07 ND Example 586 1.4E-06 ND
Example 556 1.2E-08 ND Example 587 2.6E-08 0.539
Example 557 4.5E-09 0.475 Example 588 8.0E-09 0.256
Example 558 5.9E-08 0.742 Example 589 8.7E-09 0.233
Example 559 5.2E-09 0.293 Example 590 8.4E-08 ND
Example 560 1.1E-08 0.128 Example 591 6.5E-08 1.67
Example 561 2.7E-08 0.61 Example 592 2.4E-06 ND
.1E-07 ND 1.9E-06 ND
Example 562 Example 593
Example 563 7.4E-08 1.16 Example 594 6.1E-09 0.13
Example 564 8.5E-10 0.202 Example 595 6.2E-09 0.114
4.8E-07 1.96 2.7E-09 0.12
Example 565 Example 596
3.0E-08 0.233 6.2E-09 0.449
Example 566 Example 597
Example 567 2.1E-08 1.04 Example 598 7.8E-09 0.097
Example 568 2.5E-08 0.22 Example 599 1.1E-08 ND
Example 569 3.9E-08 1.73 Example 600 4.1E-09 0.031
2.0E-08 0.324 1.2E-08 0.133
Example 570 Example 601
Example 571 4.4E-08 0.559 Example 602 3.7E-09 0.156
Example 572 1.9E-08 0.394 Example 603 5.0E-09 0.036
Example 573 1.1E-08 0.366 Example 604 5.7E-09 0.064
24.3% @ 10 uM ND 8.2E-09 0.254
Example 574 Example 605
Example 575 46.8% @ 10 uM ND Example 606 4.0E-09 0.064
Example 576 6.2E-08 1.51 Example 607 3.5E-09 0.04
Example 577 7.6E-09 0.119 Example 608 4.2E-09 0.021
3.8E-08 0.347 3.5E-09 0.063
Example 578 Example 609
Example 579 8.5E-09 0.463 Example 610 3.5E-09 0.091
Example 580 3.7E-08 ND Example 611 3.9E-09 0.23
Example 581 4.2E-07 ND Example 612 3.5E-09 0.02
8.4E-08 ND 3.5E-09 0.158
Example 582 Example 613
1.1E-07 ND 8.4E-09 ND
Example 583 Example 614
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 615 8.0E-10 0.292 Example 646 2.1E-08 0.298
Example 616 4.0E-09 0.07 Example 647 2.3E-08 0.498
Example 617 5.4E-09 0.277 Example 648 1.4E-08 ND
Example 618 5.6E-09 ND Example 649 2.3E-08 0.341
Example 619 7.0E-09 0.336 Example 650 5.1E-08 ND
Example 620 5.9E-09 0.532 Example 651 6.8E-09 0.282
Example 621 5.3E-09 0.095 Example 652 4.7E-09 0.059
Example 622 1.1E-08 0.109 Example 653 1.6E-08 ND
Example 623 67.8% @ 10 uM ND Example 654 4.0E-08 2.08
26.95% @ 10 uM ND 2.6E-08 ND
Example 624 Example 655
Example 625 74.85% @ 10 uM 0.62 Example 656 6.1E-08 0.523
Example 626 39.45% @ 10 uM ND Example 657 2.1E-08 ND
4.9E-07 ND 1.8E-08 1.71
Example 627 Example 658
33.2% @ 10 uM ND 2.2E-08 ND
Example 628 Example 659
Example 629 14.95% @ 10 uM ND Example 660 5.1E-08 ND
Example 630 27.95% @ 10 uM ND Example 661 1.0E-07 ND
Example 631 56% @ 10 uM ND Example 662 2.7E-07 ND
41.8% @ 10 uM ND 2.5E-08 ND
Example 632 Example 663
Example 633 40.2 %@ 10 uM ND Example 664 3.86E-08 2.08
Example 634 10.7% @ 10 uM ND Example 665 3.9E-06 ND
Example 635 50.75% @ 10 uM ND Example 666 7.7E-08 ND
71.7 %@ 1000 uM ND 2.1E-06 ND
Example 636 Example 667
Example 637 5.9% @ 10 uM ND Example 668 1.1E-08 0.13
Example 638 34.5% @ 10 uM ND Example 669 4.9E-09 0.108
Example 639 66.25% @ 10 uM ND Example 670 3.2E-09 0.027
42.4% @ 10 uM ND 6.9E-09 0.107
Example 640 Example 671
Example 641 9.6E-07 ND Example 672 4.3E-09 0.019
Example 642 11% @ 10 uM ND Example 673 1.1E-08 0.576
Example 643 6.6E-07 0.303 Example 674 2.1E-08 ND
3.7E-07 0.248 2.2E-08 ND
Example 644 Example 675
2.2E-08 ND 3.6E-05 ND
Example 645 Example 676
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 677 2.2E-06 ND Example 708 9.6E-09 0.055
Example 678 1.8E-06 ND Example 709 3.2E-08 0.518
Example 679 8.9E-07 ND Example 710 2.4E-09 0.384
Example 680 2.8E-05 ND Example 711 3.7E-09 0.591
Example 681 6.7E-09 ND Example 712 4.1E-07 ND
Example 682 5.1E-07 ND Example 713 1.6E-08 ND
Example 683 3.3E-06 ND Example 714 3.4E-08 0.188
Example 684 1.9E-08 2.23 Example 715 1.6E-09 ND
Example 685 1.2E-08 ND Example 716 1.5E-06 ND
1.0E-06 ND 2.7E-08 0.865
Example 686 Example 717
Example 687 2.9E-08 3.66 Example 718 1.2E-08 0.082
Example 688 3.3E-07 ND Example 719 2.7E-06 ND
8.5E-09 0.657 4.4E-08 ND
Example 689 Example 720
2.3E-08 0.178 7.6E-08 ND
Example 690 Example 721
Example 691 9.6E-09 0.037 Example 722 1.4E-09 0.023
Example 692 1.0E-08 0.079 Example 723 1.18E-09 0.004
Example 693 9.3E-10 0.101 Example 724 9.48E-10 0.002
6.4E-09 0.183 1.46E-09 0.01
Example 694 Example 725
Example 695 1.6E-08 0.268 Example 726 1.18E-09 0.011
Example 696 9.6E-09 0.05 Example 727 1.32E-09 0.013
Example 697 45.55% @ 1 uM ND Example 728 1.18E-09 0.003
7.3E-09 ND 1.24E-09 0.009
Example 698 Example 729
Example 699 28.5% @ 1 uM ND Example 730 9.48E-10 0.005
Example 700 1.2E-08 ND Example 731 9.48E-10 0.005
Example 701 40.75% @ 1 uM ND Example 732 1.27E-09 0.013
9.4E-09 ND 9.48E-10 0.005
Example 702 Example 733
Example 703 9.3E-09 0.03 Example 734 9.48E-10 0.006
Example 704 9.9E-09 0.025 Example 735 9.48E-10 0.007
Example 705 1.7E-08 0.02 Example 736 2.58E-09 ND
3.6E-09 0.04 1.43E-08 ND
Example 706 Example 737
1.4E-08 0.042 3.78E-09 0.103
Example 707 Example 738
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 739 2.32E-09 0.093 Example 770 1.01E-09 0.010
Example 740 5.04E-09 ND Example 771 1.04E-09 0.019
Example 741 9.48E-10 0.002 Example 772 9.48E-10 0.010
Example 742 9.48E-10 0.002 Example 773 1.25E-09 0.017
Example 743 9.48E-10 0.005 Example 774 9.48E-10 0.009
Example 744 9.48E-10 0.042 Example 775 3.55E-09 0.039
Example 745 9.48E-10 0.003 Example 776 9.48E-10 0.007
Example 746 3.5E-09 0.111 Example 777 1.12E-09 0.008
Example 747 3.6E-09 0.0263 Example 778 1.09E-09 0.013
1.21E-08 ND 1.86E-09 0.056
Example 748 Example 779
Example 749 8.24E-09 ND Example 780 7.26E-09 ND
Example 750 1.33E-09 0.035 Example 781 9.48E-10 0.033
9.48E-10 0.008 1.68E-09 0.057
Example 751 Example 782
.5E-09 0.084 1.06E-09 0.037
Example 752 Example 783
Example 753 3.0E-09 0.005 Example 784 9.48E-10 0.023
Example 754 4.7E-09 0.089 Example 785 3.85E-09 ND
Example 755 4.65E-09 0.032 Example 786 4.95E-09 ND
.6.89E-07 ND 4.71E-07 0.245
Example 756 Example 787
Example 757 3.95E-09 0.013 Example 788 6.74E-07 0.494
Example 758 3.53E-07 ND Example 789 3.82E-07 0.206
Example 759 9.06E-09 0.054 Example 790 1.91E-06 ND
1.18E-09 0.004 2.26E-06 ND
Example 760 Example 791
Example 761 1.07E-07 0.148 Example 792 6.44E-06 ND
Example 762 1.88E-09 0.014 Example 793 5.37E-06 ND
Example 763 9.05E-08 ND Example 794 5.35E-06 ND
1.35E-09 0.019 8.5E-07 ND
Example 764 Example 795
Example 765 6.58E-07 ND Example 796 5.16E-07 ND
Example 766 3.66E-09 0.037 Example 797 2.75E-06 ND
Example 767 1.73E-09 0.050 Example 798 5.15E-06 ND
1.04E-09 0.039 59.6% @ 10 uM ND
Example 768 Example 799
9.48E-10 0.010 1.39E-06 ND
Example 769 Example 800
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 801 4.37E-06 ND Example 832 3.15E-09 0.004
Example 802 2.88E-06 ND Example 833 3.35E-09 ND
Example 803 3.14E-06 ND Example 834 ND ND
Example 804 4.68E-05 ND Example 835 2.9E-09 0.002
Example 805 53.5% @ 10 uM ND Example 836 2.8E-09 0.002
Example 806 1.63E-06 ND Example 837 2.35E-09 0.003
Example 807 52.45% @ 10 uM ND Example 838 3.15E-09 0.002
Example 808 1.72E-07 0.010 Example 839 6.91E-07 ND
Example 809 6.91E-07 0.047 Example 840 1.28E-07 ND
4.2E-07 0.001 4.8E-09 ND
Example 810 Example 841
Example 811 8.55E-09 0.002 Example 842 7.65% @ 10uM ND
Example 812 6.51E-07 0.103 Example 843 23.05% @ 10uM ND
.47E-09 0.011 1.67E-06 ND
Example 813 Example 844
6.39E-07 0.314 7.85% @ 10uM ND
Example 814 Example 845
Example 815 19.95%@ 10 uM ND Example 846 25.1% @ 10uM ND
Example 816 1.72E-07 ND Example 847 3.55% @ 10uM ND
Example 817 4.75E-07 ND Example 848 46.7% @ 10uM ND
1.12E-06 ND 61.35% @ 10uM ND
Example 818 Example 849
Example 819 1.57E-07 ND Example 850 29.4% @ 10uM ND
Example 820 1.29E-08 ND Example 851 7.85% @ 10uM ND
Example 821 3.61E-07 ND Example 852 ND ND
2.4E-06 ND ND ND
Example 822 Example 853
Example 823 1.98E-08 ND Example 854 1.72E-07 ND
Example 824 3.82E-08 ND Example 855 ND ND
Example 825 5.82E-07 ND Example 856 9.79E-07 ND
7.35E-08 ND 77.85% @ 10uM ND
Example 826 Example 857
Example 827 ND ND Example 858 2.11E-07 ND
Example 828 2.4E-07 ND Example 859 1.13E-06 ND
Example 829 ND ND Example 860 2.04E-07 ND
-11.9% @ 10uM ND 5.77E-07 ND
Example 830 Example 861
ND ND ND ND
Example 831 Example 862
IC50 (M) Mcl-1 FP IC50 (µM) MTT H929 IC50 (M) Mcl-1 FP IC50 (µM) MTT H929
Example 863 ND ND Example 868 ND ND
Example 864 2.7E-08 ND Example 869 ND ND
Example 865 ND ND Example 870 ND ND
Example 866 ND ND Example 871 ND ND
Example 867 ND ND
ND: not determined
For partial inhibitors, the percentage fluorescence polarisation inhibition for a given
concentration of the test compound is indicated. Accordingly, 45.1% @10 µM means that
45.1% fluorescence polarisation inhibition is observed for a concentration of test
compound equal to 10 µM.
EXAMPLE C: Quantification of the cleaved form of PARP in vivo
The ability of the compounds of the invention to induce apoptosis, by measuring cleaved
PARP levels, is evaluated in a xenograft model of AMO-1 multiple myeloma cells.
1.10 AMO-1 cells are grafted sub-cutaneously into immunosuppressed mice (SCID
strain). 12 to 14 days after the graft, the animals are treated by intraveinous or oral routes
with the various compounds. After treatment, the tumour masses are recovered and lysed,
and the cleaved form of PARP is quantified in the tumour lysates.
The quantification is carried out using the "Meso Scale Discovery (MSD) ELISA
platform" test, which specifically assays the cleaved form of PARP. It is expressed in the
form of an activation factor corresponding to the ratio between the quantity of cleaved
PARP in the treated mice divided by the quantity of cleaved PARP in the control mice.
The results (presented in Table 2 below) show that the compounds of the invention are
capable of inducing apoptosis in AMO-1 tumour cells in vivo.
Table 2: Quantification of the cleaved form of PARP in vivo
PARP fold PARP fold PARP fold
Example 30 285.3 Example 158 125.1 Example 723 191.2
Example 31 138.6 Example 167 230.1 Example 724 188.9
Example 32 216.7 Example 168 179.2 Example 726 112.5
Example 41 288.1 Example 170 144 Example 729 221
Example 44 180.4 Example 171 207.4 Example 731 175.5
Example 45 194.3 Example 172 175.3 Example 734 126.49
Example 47 101.1 Example 174 170.3 Example 741 244
180.5 155.4 267.2
Example 49 Example 175 Example 742
Example 52 211.4 Example 176 133.4 Example 743 147.3
Example 53 178.7 Example 177 233.8 Example 750 181.6
188.4 238.8 117
Example 55 Example 180 Example 756
Example 57 198.3 Example 181 152.6 Example 757 135.6
Example 58 181.9 Example 182 242.5 Example 762 136.9
391.6 308.8 104.8
Example 62 Example 185 Example 774
Example 63 177.8 Example 188 121.6 Example 781 113.3
Example 70 184.1 Example 198 280 Example 787 131.5
Example 71 128.3 Example 202 153.8 Example 788 144.8
Example 77 178.2 Example 209 120.7 Example 789 135.2
Example 83 187.6 Example 256 125.1 Example 790 282.9
105.5 121 125.6
Example 91 Example 290 Example 794
Example 95 156.8 Example 483 411 Example 808 155
Example 113 189.8 Example 485 110.8 Example 810 122.4
158.2 141.4 117.6
Example 114 Example 487 Example 811
Example 115 136 Example 488 175.5 Example 812 136
Example 117 188.7 Example 489 233.2 Example 814 118.5
159.8 275.4
Example 118 Example 490
Example 120 206.8 Example 623 441.5
Example 123 243.8 Example 638 136.7
293.3 195.7
Example 135 Example 639
Example 138 333.9 Example 722 296.6
EXAMPLE D: Anti-tumour activity in vivo
The anti-tumour activity of the compounds of the invention is evaluated in a xenograft
model of AMO-1 multiple myeloma cells.
1x10 AMO-1 cells are grafted sub-cutaneously into immunosuppressed mice (SCID
strain).
6 to 8 days after the graft, when the tumour mass has reached about 150 mm , the mice are
treated with the various compounds in a daily schedule (5-day treatment). The tumour
mass is measured twice weekly from the start of treatment.
The compounds of the invention have anti-tumour activities (tumour regression) in the
AMO-1 multiple myeloma model with ΔT/C (qualification parameter of the activity of a
product, which is defined as the ratio tumour volume of the treated group / tumour volume
of the untreated control group) ranging from -26 to -100%. The results obtained show that
the compounds of the invention induce significant tumour regression during the treatment
period.
EXAMPLE E: Pharmaceutical composition: Tablets
EXAMPLE E: Pharmaceutical composition: Tablets
1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 871 ........ 5 g
Wheat starch ................................................................................................................................. 20 g
Maize starch.................................................................................................................. 20 g
Lactose ......................................................................................................................... 30 g
Magnesium stearate ........................................................................................................ 2 g
Silica............................................................................................................................... 1 g
Hydroxypropylcellulose .................................................................................................. 2 g
Claims (61)
1. Compound of formula (I): wherein: 5 A represents a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 branched (C -C )alkoxy group, -S-(C -C )alkyl group, a linear or branched 1 6 1 6 (C -C )polyhaloalkyl, a hydroxy group, a cyano, -NR R ’, -Cy or an halogen 1 6 10 10 6 atom, 10 R , R , R , R and R independently of one another represent a hydrogen atom, a 1 2 3 4 5 halogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 branched (C -C )polyhaloalkyl, a hydroxy group, a linear or branched (C -C )alkoxy group, -S-(C -C )alkyl group, a cyano, a nitro group, 1 6 1 6 15 -alkyl(C -C )-NR R ’, -O-Cy , -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , 0 6 8 8 1 0 6 1 2 6 1 -alkynyl(C -C )-Cy , -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, 2 6 1 1 6 9 8 8 8 8 -NR -C(O)-R ’, -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, 8 8 8 8 1 6 8 8 2 8 8 -SO2-alkyl(C1-C6), or the substituents of one of the pairs (R , R ), (R , R ), (R , R ), (R , R ) when 1 2 2 3 1 3 4 5 20 grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from one to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (C -C )alkyl group, -NR R ’, 1 6 10 10 -alkyl(C -C )-Cy or an oxo, 0 6 1 5 X represents a carbon or a nitrogen atom, R represents a hydrogen, a linear or branched (C -C )alkyl group, an aryl, an 6 1 8 heteroaryl group, an arylalkyl(C -C ) group, an heteroarylalkyl(C -C ) group, 1 6 1 6 R represents a linear or branched (C -C )alkyl group, a linear or branched 7 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , 2 6 2 6 3 10 -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , -Cy -Cy , 1 6 3 2 6 3 2 6 3 3 4 -alkynyl(C -C )-O-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , an halogen atom, a 2 6 3 3 0 6 0 6 4 cyano, -C(O)-R , -C(O)-NR R ’, 11 11 11 R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, or -alkyl(C -C )-Cy , 1 6 0 6 1 15 or (R , R ’) form together with the nitrogen atom carrying them an aromatic or non- aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched 20 (C -C )alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated, R represents -Cy , -Cy -alkyl(C -C )-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , 9 1 1 0 6 2 1 0 6 0 6 2 -Cy1-alkyl(C0-C6)-NR8-alkyl(C0-C6)-Cy2, -Cy1-Cy2-O-alkyl(C0-C6)-Cy5, -NR8R8’, -C(O)-NR R ’, -OR ,-NR -C(O)-R ’, -O-alkyl(C -C )-OR , -SO -R , -C(O)-OR , 8 8 8 8 8 1 6 8 2 8 8 25 -NH-C(O)-NH-R , R , R ’, R and R ’ independently of one another represent a hydrogen atom or 10 10 11 11 an optionally substituted linear or branched (C -C )alkyl group, R represents a hydrogen or a hydroxy group, Cy , Cy , Cy , Cy , Cy and Cy independently of one another, represent a 1 2 3 4 5 6 30 cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, n is an integer equal to 0 or 1, it being understood that: - "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, - "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 5 heteroatoms selected from oxygen, sulphur and nitrogen, - "cycloalkyl" means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, - “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms 10 selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (C1-C6)alkyl, optionally 15 substituted linear or branched (C -C )alkenyl group, optionally substituted linear or branched (C -C )alkynyl group, optionally substituted linear or branched (C -C )alkoxy, optionally substituted (C -C )alkyl-S-, hydroxy, oxo (or N-oxide where 1 6 1 6 appropriate), nitro, cyano, -C(O)-OR’, -O-C(O)-R’, -CO-NR’R’’, -NR’R’’, -(C=NR’)-OR’’, linear or branched (C -C )polyhaloalkyl, trifluoromethoxy, or 20 halogen, it being understood that R’ and R’’ independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C -C )alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with 25 a pharmaceutically acceptable acid or base.
2. Compounds according to claim 1 wherein at least one of the groups selected from R , R and R does not represent a hydrogen atom.
3. Compounds according to claim 1 wherein n is an integer equal to 1.
4. Compounds according to claim 1 wherein A represents a linear or branched (C -C )alkyl group or a halogen atom.
5. Compounds according to claim 1 wherein X represents a carbon atom.
6. Compounds according to claim 1 wherein R represents a hydrogen atom. 5
7. Compounds according to claim 1 wherein : represents , wherein A, R8 and R8’ are as defined in claim 1.
8. Compounds according to claim 1 wherein : represents , 10 wherein R and R ’ are as defined in claim 1.
9. Compounds according to claim 1 wherein R represents an optionally substituted linear or branched (C -C )alkoxy group or a -O-alkyl(C -C )-R group. 1 6 1 6 9
10. Compounds according to claim 1 wherein R represents a hydrogen atom.
11. Compounds according to claim 1 wherein : represents , 5 wherein R is as defined in claim 1.
12. Compounds according to claim 1 wherein R represents a hydrogen atom, a optionally substituted linear or branched (C -C )alkyl group or an heteroarylalkyl(C -C ) group. 1 8 1 6
13. Compounds according to claim 1 wherein R represents a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched 10 (C -C )alkynyl group, an aryl or an heteroaryl group.
14. Compounds according to claim 1 wherein R and R ’ independently of one another represent a linear or branched (C -C )alkyl group, or (R , R ’) form together with the 1 6 8 8 nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 15 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C -C )alkyl group.
15. Compounds according to claim 1 wherein R represents -Cy , -Cy -alkyl(C -C )-Cy , 9 1 1 0 6 2 or -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy . 1 0 6 0 6 2 20
16. Compounds according to claim 15 wherein Cy1 represents a heteroaryl group.
17. Compounds according to claim 15 wherein Cy represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group or a cyclopropyl group.
18. Compounds according to claim 15 wherein R represents -Cy -Cy in which Cy 9 1 2 1 5 represents a pyrimidinyl group and Cy represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group, or a cyclopropyl group.
19. Compounds according to claim 1, which are: - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-methoxyphenyl) 10 propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2-methoxyethoxy) phenyl] propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(2,2,2- trifluoroethoxy)phenyl]propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-(pyrazinyl methoxy)phenyl]propanoic acid, 20 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(1-methyl- 1H-pyrazolyl)methoxy]phenyl}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan 25 yl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan- 2-yl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 30 phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (trifluoromethyl) pyridinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-ethoxy pyrimidinyl)methoxy]phenyl}propanoic acid, 5 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(propan yloxy)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin 10 yl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy ethyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}(furanyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(cyclopropyl methoxy)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl) thieno[2,3-d]pyrimidinyl]oxy}propanoic acid, 20 - (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno [2,3-d]pyrimidinyl]oxy}propanoic acid, - (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro- 2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl) 25 thieno[2,3-d]pyrimidinyl]oxy}propanoic acid, - ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propan- 2-yl)-1H-pyrazolyl]methoxy}phenyl)propanoate, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 30 phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2- cyclopropylpyrimidinyl)methoxy]phenyl}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(furanyl) pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-propyl 5 pyrimidinyl)methoxy]phenyl}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2- trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 10 phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2- trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (thiophenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 15 - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholin- 4-yl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin- 20 4-yl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-ethoxy pyrimidinyl)methoxy]phenyl}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 25 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy ethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2- methoxyethyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 30 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(1H- pyrazolyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-methoxy pyridinyl)methoxy]phenyl}propanoic acid, - (2R){2-[(1-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro 5 methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno [2,3-d]pyrimidinyl]oxy}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methyl pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 10 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){2-[(1-butyl-1H-1,2,3-triazolyl)methoxy]phenyl}{[(5S ){3- chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl) 15 thieno[2,3-d]pyrimidinyl]oxy}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-methyl pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 20 phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (morpholinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2- trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid, 25 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[(2-methoxy ethyl)amino]pyrimidinyl}methoxy)phenyl]propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methyl 30 phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(2,2,2- trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholinyl) pyrimidinyl]methoxy}phenyl)propanoic acid, 5 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(morpholin- 4-yl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-ethoxy 10 phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methyl pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3,3,3- trifluoropropoxy)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-methyl pyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 20 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(methoxy methyl) pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3- 25 methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-methylpyridinyl) pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4- 30 fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2- trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoic acid, - ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,2,2- 5 trifluoroethoxy)pyrimidinyl]methoxy}phenyl)propanoate, - ethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy phenyl)pyrimidinyl]methoxy}phenyl)propanoate, - 2,2,2-trifluoroethyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazin- 10 1-yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate, - propanyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl) ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate, 15 - 2-methoxyethyl (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazin yl) ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate, - ethyl (2R){[(5S ){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) 20 pyrimidinyl]methoxy}phenyl)propanoate, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(pyridin yl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 25 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(ethoxy methyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro- 2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl) thieno[2,3-d]pyrimidinyl]oxy}propanoic acid, 30 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluoro phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-methoxy pyrimidinyl)methoxy]phenyl}propanoic acid, - (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro- 5 2-methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(propynyl) thieno[2,3-d]pyrimidinyl]oxy}propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-hydroxy phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 10 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(propan- 2-yloxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2- 15 methoxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-ethyl phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 20 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4-methoxy- 2-(trifluoromethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2,5- dimethylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 25 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(5-methoxy- 2-methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloroethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) 30 pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){2-bromochloro[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){2,3-dichloro[2-(4-methylpiperazinyl)ethoxy]phenyl} (4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid, 5 - (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[(5S ){3-chloro- 4-[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}propanoic acid, - (2R){[(5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluorophenyl) 10 pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R)[(6-[4-(benzyloxy)phenyl]-(5S ){3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}thieno[2,3-d]pyrimidinyl)oxy](2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R)[((5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}[4-(pyridinylmethoxy)phenyl]thieno[2,3-d]pyrimidinyl)oxy](2- {[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-phenylbutynyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid, 20 - methyl (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl) ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate, - ethyl (2R){[(5S ){3-chloro[2-(4-ethylpiperazinyl)ethoxy]methyl phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-fluoro 25 phenyl)pyrimidinyl]methoxy}phenyl)propanoate, - ethyl (2R){2-[(1-tert-butyl-1H-pyrazolyl)methoxy]phenyl}{[5(5S )-{3- chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl) thieno[2,3-d]pyrimidinyl]oxy}propanoate, - {[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 30 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxy phenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}methyl 2,2-dimethyl propanoate, - (5-methyloxo-1,3-dioxolyl)methyl (2R){[(5S ){3-chloromethyl [2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl) propanoate, 5 - 2-(dimethylamino)oxoethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate, - 2-(2-methoxyethoxy)ethyl (2R){[(5Sa){3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl] 10 oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate.
20. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(3,3,3-trifluoropropoxy)pyrimidinyl]methoxy}phenyl)propanoic acid. 15
21. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[1-(propanyl)-1H-pyrazolyl]methoxy}phenyl) propanoic acid.
22. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- 20 (4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[2-(trifluoromethyl)pyridinyl]methoxy}phenyl) propanoic acid.
23. A compound according to claim 1, which is ethyl (2R){[(5S ){3-chloro methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl) 25 thieno[2,3-d]pyrimidinyl]oxy}(2-{[1-(propanyl)-1H-pyrazolyl]methoxy} phenyl)propanoate.
24. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl) propanoic acid.
25. A compound according to claim 1, which is (2R){2-[(1-butyl-1H-pyrazol 5 yl)methoxy]phenyl}{[(5S ){3-chloromethyl[2-(4-methylpiperazinyl) ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid.
26. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl]methoxy}phenyl)propanoic 10 acid.
27. A compound according to claim 1, which is (2R){[(5S ){3-chloro[2- (dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}(2-{[2-(4-methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid. 15
28. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[2-(3-methylpyridinyl)pyrimidinyl]methoxy}phenyl) propanoic acid.
29. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- 20 (4-methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(3-methylpyridinyl)pyrimidinyl]methoxy}phenyl)propanoic acid.
30. A compound according to claim 1, which is (2R){[(5S ){3-chloromethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin 25 yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid.
31. A compound according to claim 1, which is (2R){[(5S ){3-chloro[2- (dimethylamino)ethoxy]methylphenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid. 5
32. A compound according to claim 1, which is (2R){[(5S ){3-chloroethyl[2- (4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid.
33. A compound according to claim 1, which is (2R){[(5S ){2-bromochloro[2- (4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin 10 yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid.
34. A compound according to claim 1, which is (2R){[(5S ){2,3-dichloro[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid.
35. Process for the preparation of a compound of formula (I) according to claim 1, 15 characterised in that there is used as starting material the compound of formula (II-a): (II-a) wherein R is as defined for formula (I), which compound of formula (II-a) is subjected to coupling with a compound of formula (III): (III) wherein R , R , R and n are as defined for formula (I), and Alk represents a linear or 4 5 12 branched (C -C )alkyl group, to yield the compound of formula (IV): (IV) wherein R , R , R , R and n are as defined for formula (I) and Alk is as defined 4 5 7 12 before, compound of formula (IV) which is further subjected to coupling with compound of formula (V): wherein R , R , R , X and A are as defined for formula (I), and R and R represent 1 2 3 B1 B2 a hydrogen, a linear or branched (C -C ) alkyl group, or R and R form with the 1 6 B1 B2 oxygen carrying them an optionally methylated ring, 5 to yield the compound of formula (VI): (VI) wherein R , R , R , R , R , R , R , X, A and n are as defined for formula (I) and Alk 1 2 3 4 5 7 12 is as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to 10 yield the carboxylic acid, which may optionally be optionally be reacted with an alcohol of formula R OH wherein R is as defined in formula (I), to yield the compound of formula (I), which may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and 5 functionalized, as required by the synthesis.
36. Process for the preparation of a compound of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (II-b): (II-b) which compound of formula (II-b) is converted into compound of formula (II-c): (II-c) which compound of formula (II-c) is subjected to coupling with a compound of formula (V): wherein R , R , R , X and A are as defined for formula (I), and R and R represent 1 2 3 B1 B2 15 a hydrogen, a linear or branched (C -C ) alkyl group, or R and R form with the 1 6 B1 B2 oxygen carrying them an optionally methylated ring, to yield the compound of formula (VII): (VII) wherein R , R , R , A and X are as defined in formula (I), 1 2 3 5 which compound of formula (VII) is further subjected to the action of I in the presence of lithium diisopropylamide to yield compound of formula (VIII): (VIII) wherein R , R , R , A and X are as defined in formula (I), 1 2 3 which compound of formula (VIII) is further subjected to coupling with a compound 10 of formula (IX): (IX) wherein R is as defined for formula (I), and R and R represent a hydrogen, a 7 B3 B4 linear or branched (C -C ) alkyl group, or R and R form with the oxygen carrying 1 6 B3 B4 them an optionally methylated ring, to yield compound of formula (X): 5 wherein R , R , R , A, X and R are as defined in formula (I), 1 2 3 7 which compound of formula (X) is further subjected to coupling with a compound of formula (III): (III) wherein R , R , R and n are as defined for formula (I), and Alk represents a linear or 4 5 12 10 branched (C -C )alkyl group, to yield the compound of formula (VI): (VI) wherein R , R , R , R , R , R , R , X, A and n are as defined for formula (I) and Alk 1 2 3 4 5 7 12 is as defined before, the ester function of which compound of formula (VI) is hydrolysed to yield the 5 carboxylic acid, which may optionally be optionally be reacted with an alcohol of formula R OH wherein R is as defined in formula (I), to yield the compound of formula (I), which may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into 10 its isomers according to a conventional separation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis. 15
37. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 34 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
38. Pharmaceutical composition according to claim 37 for use as pro-apoptotic agents.
39. Pharmaceutical composition according to claim 38 for use in the treatment of cancers and of auto-immune and immune system diseases.
40. Pharmaceutical composition according to claim 39 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the 5 colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non- small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
41. Use of a pharmaceutical composition according to claim 37 in the manufacture of medicaments for use as pro-apoptotic agents. 10
42. Use of a pharmaceutical composition according to claim 37 in the manufacture of medicaments for use in the treatment of cancers and of auto-immune and immune system diseases.
43. Use of a pharmaceutical composition according to claim 37 in the manufacture of medicaments for use in the treatment of cancers of the bladder, brain, breast and 15 uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
44. Compound of formula (I) according to any one of claims 1 to 34, or an addition salt 20 thereof with a pharmaceutically acceptable acid or base, for use as pro-apoptotic agents.
45. Compound of formula (I) according to any one of claims 1 to 34, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers and of auto-immune and immune system diseases. 25
46. Compound of formula (I) according to any one of claims 1 to 34, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian 5 cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
47. Use of a compound of formula (I) according to any one of claims 1 to 34 or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use as pro-apoptotic agents. 10
48. Use of a compound of formula (I) according to any one of claims 1 to 34 or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use in the treatment of cancers and of auto-immune and immune system diseases.
49. Use of a compound of formula (I) according to any one of claims 1 to 34 or an 15 addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, 20 prostate cancer, pancreatic cancer and small-cell lung cancer.
50. Combination of a compound of formula (I) according to any one of claims 1 to 34 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
51. Pharmaceutical composition comprising a combination according to claim 50 in 25 combination with one or more pharmaceutically acceptable excipients.
52. Combination according to claim 50 for use in the treatment of cancers.
53. Use of a combination according to claim 50 in the manufacture of medicaments for use in the treatment of cancers.
54. Compound of formula (I) according to any one of claims 1 to 34 for use in the treatment of cancers requiring radiotherapy. 5
55. Compound according to any one of claims 1 to 34 substantially as herein described with reference to any example thereof.
56. Process according to claim 35 or 36 substantially as herein described with reference to any example thereof.
57. Compound of formula (I) according to claim 1 when prepared by a process according 10 to any one of claims 35, 36 and 56.
58. Pharmaceutical composition according to any one of claims 37 to 40 and 51 substantially as herein described with reference to any example thereof.
59. Use according to any one of claims 41 to 43, 47 to 49 and 53 substantially as herein described with reference to any example thereof. 15
60. Compound according to any one of claims 1 to 34 for use according to any one of claims 44 to 46 and 54 substantially as herein described with reference to any example thereof.
61. Combination according to claim 50 or 52 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR1363500A FR3015483B1 (en) | 2013-12-23 | 2013-12-23 | NOVEL THIENOPYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
FR13/63500 | 2013-12-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ702851A NZ702851A (en) | 2016-05-27 |
NZ702851B true NZ702851B (en) | 2016-08-30 |
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