TW201718537A - 做為人類免疫缺陷病毒複製抑制劑之吡啶－３－基乙酸衍生物 - Google Patents
做為人類免疫缺陷病毒複製抑制劑之吡啶－３－基乙酸衍生物 Download PDFInfo
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- TW201718537A TW201718537A TW105125347A TW105125347A TW201718537A TW 201718537 A TW201718537 A TW 201718537A TW 105125347 A TW105125347 A TW 105125347A TW 105125347 A TW105125347 A TW 105125347A TW 201718537 A TW201718537 A TW 201718537A
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- Prior art keywords
- alkyl
- alkoxy
- group
- phenyl
- halo
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims description 26
- 241000725303 Human immunodeficiency virus Species 0.000 title description 27
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical class OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 title 1
- 230000029812 viral genome replication Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 679
- 125000003545 alkoxy group Chemical group 0.000 claims description 322
- 239000000203 mixture Substances 0.000 claims description 301
- -1 tetrahydroisoquinolyl group Chemical group 0.000 claims description 295
- 125000005843 halogen group Chemical group 0.000 claims description 111
- 229910052739 hydrogen Inorganic materials 0.000 claims description 108
- 239000001257 hydrogen Substances 0.000 claims description 108
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 98
- 125000001188 haloalkyl group Chemical group 0.000 claims description 96
- 150000002431 hydrogen Chemical class 0.000 claims description 85
- 125000001424 substituent group Chemical group 0.000 claims description 63
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 50
- 125000003566 oxetanyl group Chemical group 0.000 claims description 50
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 50
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 46
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 41
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 40
- 125000002393 azetidinyl group Chemical group 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 29
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 28
- 125000002757 morpholinyl group Chemical group 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 18
- 208000031886 HIV Infections Diseases 0.000 claims description 15
- 208000037357 HIV infectious disease Diseases 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 15
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 15
- 238000001321 HNCO Methods 0.000 claims description 14
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 14
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 14
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 14
- 125000006769 halocycloalkoxy group Chemical group 0.000 claims description 14
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 14
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 14
- 125000001425 triazolyl group Chemical group 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 11
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 11
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 10
- 239000002777 nucleoside Substances 0.000 claims description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 9
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- LLSRLLPHUVVLQJ-UHFFFAOYSA-N 1-cycloheptyldiazepane Chemical group C1CCCCCC1N1NCCCCC1 LLSRLLPHUVVLQJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 7
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical group C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 claims description 6
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 6
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 6
- 229940099797 HIV integrase inhibitor Drugs 0.000 claims description 6
- 239000003084 hiv integrase inhibitor Substances 0.000 claims description 6
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 6
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 5
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 5
- 230000034303 cell budding Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 230000035800 maturation Effects 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 2
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000707 boryl group Chemical group B* 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 229960002542 dolutegravir Drugs 0.000 claims description 2
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical group C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 claims description 2
- 125000002073 methionyl group Chemical group 0.000 claims description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 21
- 125000003010 ionic group Chemical group 0.000 claims 2
- 125000004193 piperazinyl group Chemical group 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 24
- 208000030507 AIDS Diseases 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 108010002459 HIV Integrase Proteins 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 841
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 459
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 288
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 225
- 235000019439 ethyl acetate Nutrition 0.000 description 218
- 238000005481 NMR spectroscopy Methods 0.000 description 172
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 170
- 239000000243 solution Substances 0.000 description 156
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 150
- 238000002953 preparative HPLC Methods 0.000 description 142
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 239000011734 sodium Substances 0.000 description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000012267 brine Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 229910000104 sodium hydride Inorganic materials 0.000 description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 229940011051 isopropyl acetate Drugs 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 10
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- JSZYYGMAPAQDIG-UHFFFAOYSA-N propan-2-yl 2-[(2-methylpropan-2-yl)oxy]acetate Chemical compound CC(C)OC(=O)COC(C)(C)C JSZYYGMAPAQDIG-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- IECMOFZIMWVOAS-UHFFFAOYSA-N 4,4-dimethylpiperidine Chemical compound CC1(C)CCNCC1 IECMOFZIMWVOAS-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 229940124522 antiretrovirals Drugs 0.000 description 6
- 239000003903 antiretrovirus agent Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- ICFPOEFXKAERSU-UMSFTDKQSA-N (2S)-2-[6-(aminomethyl)-4-(4,4-dimethylpiperidin-1-yl)-5-[2-[(4-fluoro-2-methylphenyl)methyl]-3,4-dihydro-1H-isoquinolin-6-yl]-2-methylpyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetic acid Chemical compound CC1=C(CN2CCC3=C(C2)C=CC(=C3)C2=C(CN)N=C(C)C([C@H](OC(C)(C)C)C(O)=O)=C2N2CCC(C)(C)CC2)C=CC(F)=C1 ICFPOEFXKAERSU-UMSFTDKQSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
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- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 4
- HFPBZWYVEVSCJI-YTTGMZPUSA-N (2S)-2-[4-(4,4-dimethylpiperidin-1-yl)-5-[4-[2-(4-fluorophenyl)ethoxy]phenyl]-2-methyl-6-(methylaminomethyl)pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetic acid Chemical compound C(C)(C)(C)O[C@H](C(=O)O)C=1C(=NC(=C(C=1N1CCC(CC1)(C)C)C1=CC=C(C=C1)OCCC1=CC=C(C=C1)F)CNC)C HFPBZWYVEVSCJI-YTTGMZPUSA-N 0.000 description 3
- CHVHRJZHOHXNDI-YTTGMZPUSA-N (2S)-2-[4-(4,4-dimethylpiperidin-1-yl)-5-[4-[2-(4-fluorophenyl)ethoxy]phenyl]-2-methyl-6-(methylsulfonylmethyl)pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetic acid Chemical compound C(C)(C)(C)O[C@H](C(=O)O)C=1C(=NC(=C(C=1N1CCC(CC1)(C)C)C1=CC=C(C=C1)OCCC1=CC=C(C=C1)F)CS(=O)(=O)C)C CHVHRJZHOHXNDI-YTTGMZPUSA-N 0.000 description 3
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Abstract
本文揭示式I化合物(包括醫藥上可接受之鹽)、包含該等化合物之醫藥組合物、製備該等化合物之方法及其於抑制HIV整合酶及治療彼等感染HIV或AIDS者之用途。□
Description
本申請案主張於2015年8月12日提出申請之美國臨時申請案第62/204,239號之權益。
本發明係關於化合物、組合物及用於治療人類免疫缺陷病毒(HIV)感染之方法。更特定而言，本發明提供HIV之新穎抑制劑、含有該等化合物之醫藥組合物及使用該等化合物治療HIV感染之方法。本發明亦係關於製備下文所述化合物之方法。
人類免疫缺陷病毒(HIV)鑑別為負責獲得性免疫缺陷症候群(AIDS)(一種特徵在於免疫系統破壞及不能抵抗威脅生命之伺機性感染之致命疾病)之致病因子。最近統計學指示，世界範圍內估計3530萬人感染該病毒(UNAIDS：Report on the Global HIV/AIDS Epidemic,2013)。除已感染之大量個體外，該病毒繼續傳播。來自2013之估計指向僅當年即有接近340萬新感染。在同一年，存在約160萬例與HIV及AIDS相關之死亡。
HIV感染之個體之當前療法由經核准抗反轉錄病毒試劑之組合組成。目前兩打以上藥物核准做為單一藥劑或做為固定劑量組合或單一錠劑方案用於HIV感染，後兩個含有2至4種核准藥劑。該等藥劑屬多
個不同種類，其靶向病毒酶或病毒複製循環期間之病毒蛋白之功能。因此，藥劑分類為核苷酸反轉錄酶抑制劑(NRTI)、非核苷酸反轉錄酶抑制劑(NNRTI)、蛋白酶抑制劑(PI)、整合酶抑制劑(INI)或進入抑制劑(一者馬拉維洛(maraviroc)靶向宿主CCR5蛋白，而另一者恩夫韋肽(enfuvirtide)係靶向病毒gp160蛋白之gp41區之肽)。另外，無抗病毒活性之藥物動力學增強子(即，科比司他(cobicistat)，以商品名TYBOSTTM(科比司他)錠劑購自Gilead Sciences)最近經核准與可受益於加強之某些抗反轉錄病毒藥劑(ARV)組合使用。
在美國，其中組合療法廣泛可用，HIV相關死亡之數目顯著下降(Palella,F.J.；Delany,K.M.；Moorman,A.C.；Loveless,M.O.；Furher,J.；Satten,G.A.；Aschman,D.J.；Holmberg,S.D.N.Engl.J.Med.1998,338,853-860)。
不幸的是，並非所有患者皆有反應且大量對此療法失敗。事實上，初始研究表明，約30-50%患者最終對抑制組合中之至少一種藥物失敗。在大部分情形下，治療失敗係由病毒抗性之出現引起。病毒抗性又係由以下引起：感染過程期間之HIV-1之複製速率、以及與病毒聚合酶相關之相對高病毒突變速率及缺乏服用處方醫藥之HIV感染個體之黏著性。顯然，需要較佳具有抵抗已對目前核准之藥物具有抗性之病毒的活性之新抗病毒藥劑。其他重要因子包括較目前核准之藥物中之許多者改良安全性及更便利投藥方案。
已揭示抑制HIV複製之化合物。參見(例如)以下專利申請案：WO2007131350、WO2009062285、WO2009062288、WO2009062289、WO2009062308、WO2010130034、WO2010130842、WO2011015641、WO2011076765、WO2012033735、WO2013123148、WO2013134113、WO2014164467、WO2014159959及WO2015126726。
業內現在需要新穎且可用於治療HIV之額外化合物。另外，該等化合物可期望地為醫藥使用提供優點，例如，關於其作用機制、結合、抑制效能、靶選擇性、溶解性、安全性概況或生物利用度中之一或多者。亦需要新調配物及利用該等化合物之治療方法。
本發明涵蓋式I化合物(包括醫藥上可接受之鹽)、以及醫藥組合物、及其於抑制HIV及治療感染HIV或AIDS之彼等中之用途。
由於本發明，現可提供新穎且可用於治療HIV之化合物。另外，該等化合物可為醫藥使用提供優點，例如，關於其作用機制、結合、抑制效能、靶選擇性、溶解性、安全性概況或生物利用度中之一或多者。
本發明亦提供包含本發明化合物(包括其醫藥上可接受之鹽)及醫藥上可接受之載劑、賦形劑及/或稀釋劑之醫藥組合物。
另外，本發明提供治療HIV感染之方法，其包含向患者投與治療有效量之本發明化合物。
另外，本發明提供抑制HIV整合酶之方法。
根據本發明，亦提供製備本發明化合物之方法。
本發明係關於下文闡述之該等以及其他重要目的。
除非另有說明，否則該等術語具有以下含義。
「烷基」意指包括1至10個碳、且較佳1至6個碳之直鏈或具支鏈飽和烴。
「烯基」意指包括2至10個碳及至少一個雙鍵且視情況經0至3個鹵基或烷氧基取代之直鏈或具支鏈烷基。
「炔基」意指包括2至10個碳、較佳2至6個碳、含有至少一個三鍵且視情況經0至3個鹵基或烷氧基取代之直鏈或具支鏈烷基。
「芳基」意指包括1至3個稠合及/或鍵結且至少一個或其組合係芳香族之環的碳環基團。非芳香族碳環部分(若存在)包括C3至C7烷基。芳香族基團之實例包括(但不限於)二氫茚基、茚基、萘基、苯基、四氫萘基及環丙基苯基。芳基可經由基團中之任何可取代之碳原子附接至母體結構。
「芳基烷基」係經由烷基部分附接至1至2個芳基且連接至母體結構之C1-C5烷基。實例包括(但不限於)-(CH2)nPh(其中n=1-5)、-CH(CH3)Ph、-CH(Ph)2。
「芳基氧基」係藉由氧附接至母體結構之芳基。
「環烷基」意指由3至7個碳構成之單環狀環系統。
「鹵基」包括氟、氯、溴及碘。
「鹵代烷基」及「鹵代烷氧基」包括自單鹵基至全鹵基之所有鹵化異構物。
「雜芳基」係如下文所定義雜環基之亞組且包括1至3個環，其中至少一個或其組合係芳香族且芳香族基團含有至少一個選自氧、氮或硫之群之原子。
「雜環基或雜環」意指1至3個包括碳及至少一個獨立地選自氧、氮及硫之其他原子之環的環狀基團。環可經由直接或螺附接橋接、稠合及/或鍵結，選擇係一個或其組合為芳香族。實例包括(但不限於)氮雜吲哚、氮雜吲哚啉、氮雜環丁烷、苯并咪唑、苯并二氧雜環戊烯基、苯并異噻唑、苯并噻唑、苯并噻二唑、苯并噻吩、苯并噁唑、咔唑、烷、二鹵基苯并二氧雜環戊烯基、二氫苯并呋喃、二氫-苯并[1,4]噁嗪、1,3-二氫苯并[c]噻吩2,2-二氧化物、2,3-二氫苯并[d]異噻唑1,1-二氧化物、3,4-二氫-2H-吡啶并[3,2-b][1,4]噁嗪、2,3-二氫-
1H-吡咯并[3,4-c]吡啶及其區域異構物變體、6,7-二氫-5H-吡咯并[2,3-b]吡嗪及其區域異構物變體、呋喃基苯基、咪唑、咪唑并[1,2-a]吡啶、吲唑、吲哚、吲哚啉、異喹啉、異喹啉酮、異噻唑啶1,1-二氧化物、嗎啉、2-氧雜-5-氮雜二環[2.2.1]庚烷、噁二唑-苯基、噁唑、苯基氮雜環丁烷、苯基吲唑、苯基六氫吡啶、苯基六氫吡嗪、苯基噁唑、苯基吡咯啶、六氫吡啶、吡啶、吡啶基苯基、吡啶基吡咯啶、嘧啶、嘧啶基苯基、吡唑-苯基、吡咯啶、吡咯啶-2-酮、1H-吡唑并[4,3-c]吡啶及其區域異構物變體、吡咯、5H-吡咯并[2,3-b]吡嗪、7H-吡咯并[2,3-d]嘧啶及其區域異構物變體、喹唑啉、喹啉、喹喏啉、四氫異喹啉、1,2,3,4-四氫-1,8-萘啶、四氫喹啉、4,5,6,7-四氫噻吩并[3,2-c]吡啶、1,2,5-噻二唑啶1,1-二氧化物、噻吩、噻吩基苯基、三唑或三唑酮。除非另外明確闡述，否則雜環基可經由產生穩定化合物之基團中之任何適宜原子附接至母體結構。
應理解，所注意雜環實例之亞組涵蓋區域異構物。例如，「氮雜吲哚」係指以下區域異構物中之任一者：1H-吡咯并[2,3-b]吡啶、1H-吡咯并[2,3-c]吡啶、1H-吡咯并[3,2-c]吡啶及1H-吡咯并[3,2-b]吡啶。另外，如(例如)「5H-吡咯并[2,3-b]吡嗪及其區域異構物變體」中之「區域異構物變體」記號亦可涵蓋7H-吡咯并[2,3-d]嘧啶、7H-吡咯并[2,3-c]嗒嗪、1H-吡咯并[2,3-d]嗒嗪、5H-吡咯并[3,2-c]嗒嗪及5H-吡咯并[3,2-d]嘧啶。類似地，6,7-二氫-5H-吡咯并[2,3-b]吡嗪及其區域異構物變體可涵蓋6,7-二氫-5H-吡咯并[2,3-d]嘧啶及6,7-二氫-5H-吡咯并[2,3-c]嗒嗪。亦應理解，無「區域異構物變體」記號並不以任何方式將申請專利範圍之範疇限於僅所述實例。
「雜環基烷基」係經由C1-C5烷基附接至母體結構之雜環基部分。實例包括(但不限於)-(CH2)n-RZ或-CH(CH3)-(RZ)，其中n=1-5且RZ選自苯并咪唑、咪唑、吲唑、異噁唑、苯基-吡唑、吡啶、喹啉、
噻唑、三唑、三唑酮、噁二唑。
具有烴部分(例如烷氧基)之術語包括具有指示數目之碳原子之烴部分之直鏈及具支鏈異構物。
鍵結及位置鍵結關係係如由有機化學之從業人員所理解穩定之彼等。
括號內及多括號內術語意欲向熟習此項技術者闡明鍵結關係。舉例而言，諸如((R)烷基)等術語意指進一步經取代基R取代之烷基取代基。
化學圖式圖解說明為在可變位置處鍵結於多環系統(例如二環系統)上之取代基意欲鍵結至繪示其所附加之環。括號內及多括號內術語意欲向熟習此項技術者闡明鍵結關係。舉例而言，諸如((R)烷基)等術語意指進一步經取代基R取代之烷基取代基。
在提及式I化合物與至少一種抗HIV藥劑之投與時「組合」、「共投與」、「並行」及類似術語意指組份係組合抗反轉錄病毒療法或高度活性抗反轉錄病毒療法(「HAART」)之部分，如由AIDS及HIV感染領域中之從業人員所瞭解。
「治療有效」意指為患者提供益處所需藥劑之量，如AIDS及HIV感染領域中之從業人員所瞭解。一般而言，治療之目標係抑制病毒負荷、恢復及保存免疫功能、改良生活品質及降低HIV相關之發病率及死亡率。
「患者」意指感染HIV病毒之人。
如AIDS及HIV感染之領域中之從業人員所瞭解來使用「治療」、「療法」、「方案」、「HIV感染」、「ARC」、「AIDS」及相關術語。
本文中未明確闡述之彼等術語將具有業內通常瞭解及接受之含義。
本發明包括化合物之所有醫藥上可接受之鹽形式。醫藥上可接
受之鹽係抗衡離子並不顯著有助於化合物之生理活性或毒性且由此用作藥理學等效物之彼等。該等鹽可根據採用市售試劑之常見有機技術製得。一些陰離子鹽形式包括乙酸鹽、醋硬脂酸鹽、苯磺酸鹽、溴化物、氯化物、檸檬酸鹽、富馬酸鹽、葡糖醛酸鹽、氫溴酸鹽、鹽酸鹽、氫碘酸鹽、碘化物、乳酸鹽、馬來酸鹽、甲磺酸鹽、硝酸鹽、雙羥萘酸鹽、磷酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽及昔萘酸鹽。一些陽離子鹽形式包括銨鹽、鋁鹽、苄星青黴素(benzathine)鹽、鉍鹽、鈣鹽、膽鹼鹽、二乙胺鹽、二乙醇胺鹽、鋰鹽、鎂鹽、葡甲胺鹽、4-苯基環己胺鹽、六氫吡嗪鹽、鉀鹽、鈉鹽、胺基丁三醇鹽及鋅鹽。
本發明化合物中之一些以立體異構物形式存在。本發明包括化合物之所有立體異構物形式，包括鏡像異構物及非鏡像異構物。製備及分離立體異構物之方法為業內已知。本發明包括化合物之所有互變異構物形式。本發明包括阻轉異構物及旋轉異構物。
本發明意欲包括出現於本發明化合物中之原子之所有同位素。同位素包括具有相同原子序數但具有不同質量數之彼等原子。概括舉例而言但不加以限制，氫之同位素包含氘及氚。碳之同位素包括13C及14C。同位素標記之本發明化合物通常可藉由彼等熟習此項技術者已知之習用技術來製備，或可藉由與本文中所述方法類似之方法使用適當同位素標記試劑代替原本採用之未標記試劑來製備。該等化合物可具有多種潛在應用，例如做為測定生物學活性之標準及試劑。在穩定同位素之情形下，該等化合物可具有有利地改良生物學、藥理學或藥物動力學性質之潛力。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷
基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；或R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；或(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；或(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；
或其醫藥上可接受之鹽。
在本發明之態樣中，R1係氫且R5係氫、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基。
在本發明之態樣中，R1係烷基且R5係氫、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基。
在本發明之態樣中，R2係經1個R7取代基及0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基。
在本發明之態樣中，R2係四氫異喹啉基且經1個R7取代基取代。
在本發明之態樣中，R3係0至3個鹵基或烷基取代基取代之六氫吡啶基。
在本發明之態樣中，R1或R5中之一者係烷基。
在本發明之態樣中，R2係鹵基。在其中R2係鹵基之本發明之態樣中，R1或R5中之一者係烷基。
在本發明之態樣中，R4選自烷基或鹵代烷基。在其中R4選自烷基或鹵代烷基之本發明之態樣中，R1或R5中之一者係烷基。
在本發明之態樣中，R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO。
在本發明之態樣中，R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基。
在本發明之態樣中，R9選自氫或烷基。
在本發明之態樣中，(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代。
在本發明之態樣中，R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基。
在本發明之態樣中，(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧
基；條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；或(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；
或(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧
基；條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；或(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；
或(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧
基；條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；或R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；或(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶
基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；
條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；或R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；或(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎
啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；條件係在R2係鹵基時，R1及R5並不同時為烷基；
R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；或R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；或(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；R10選自氫、烷基或烷氧基烷基；R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基；
Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
在本發明之態樣中，提供式I化合物：
其中：R1選自氫、鹵基、烷基、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、((環烷基)烷氧基)烷基、(環烷氧基)烷基、鹵代烷氧基烷基、(鹵代烷氧基)烷氧基烷基、((鹵代環烷基)烷氧基)烷基、(鹵代環烷氧基)烷基、(鹵代苯氧基)烷基、(Ar1)烷基、(Ar2)烷基、((R10)(R11)N)烷基、(三烷基銨)烷基、(R6)烷基、烯基、(烷氧基)烯基、羥基、烷氧基、(Ar1)烷氧基、(R10)(R11)N、CO2R10、CON(R10)(R11)、((Ar1)烷基)咪唑基或鹵代苯并咪唑基；條件係在R1係氫時，R5不為烷基；R2選自鹵基、苯基或四氫異喹啉基且經1個R7取代基及0至3個選自以下之取代基取代：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；條件係在R2係鹵基時，R1及R5並不同時為烷基；R3選自經0至3個鹵基或烷基取代基取代之氮雜環丁基、吡咯啶基、六氫吡啶基、六氫吡嗪基或高碳六氫吡啶基；R4選自烷基或鹵代烷基；
R5選自氫、烷基、鹵代烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基；條件係R1及R5並不同時為烷基；R6選自(氧雜環丁基)烷基、((氧雜環丁基)烷氧基)烷基、(四氫吡喃基氧基)烷基、(四氫吡喃基)烷氧基)烷基、((吡咯啶酮基)烷氧基)烷基、(Ar1O)烷基、((Ar1)烷氧基)烷基、((Ar2)烷氧基)烷基、(氧雜環丁基)氧基、((R8)(R9)N)烷氧基、烷硫基、烷基磺醯基或(R8)(R9)N；R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO；或R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基；R8選自氫、烷基、(環烷基)烷基、烷氧基烷基、(四氫吡喃基)烷基、四氫吡喃基或烷氧基苯基；R9選自氫或烷基；或(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代；(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代；Ar1係經0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基；且Ar2選自吡唑基、噁唑基、噻唑基、三唑基、噁二唑基或吡啶
基，且經0至3個鹵基或烷基取代基取代；或其醫藥上可接受之鹽。
對於特定式I化合物，可變取代基(包括R1,R2,R3,R4,R5,R6,R7,R8,R9,R10,R11,Ar1及Ar2)之任何情況之範疇可獨立於可變取代基之任何其他情況之範疇使用。因此，本發明包括不同態樣之組合。
在本發明之態樣中，提供可用於治療HIV感染之組合物，其包含有效量之式I化合物及醫藥上可接受之載劑。在本發明之態樣中，組合物進一步包含治療有效量之至少一種用於治療AIDS或HIV感染之選自以下之其他藥劑及醫藥上可接受之載劑：核苷HIV反轉錄酶抑制劑、非核苷HIV反轉錄酶抑制劑、HIV蛋白酶抑制劑、HIV融合抑制劑、HIV附接抑制劑、CCR5抑制劑、CXCR4抑制劑、HIV出芽或成熟抑制劑及HIV整合酶抑制劑。在本發明之態樣中，其他藥劑係德羅格韋(dolutegravir)。
在本發明之態樣中，提供治療HIV感染之方法，其包含向有需要之患者投與治療有效量之式I化合物或其醫藥上可接受之鹽。在本發明之態樣中，該方法進一步包含投與治療有效量之至少一種用於治療AIDS或HIV感染之選自以下之其他藥劑：核苷HIV反轉錄酶抑制劑、非核苷HIV反轉錄酶抑制劑、HIV蛋白酶抑制劑、HIV融合抑制劑、HIV附接抑制劑、CCR5抑制劑、CXCR4抑制劑、HIV出芽或成熟抑制劑及HIV整合酶抑制劑。在本發明之態樣中，其他藥劑係德羅格韋。在本發明之態樣中，其他藥劑係在式I化合物之前、同時或之後投與患者。
根據本發明之較佳化合物包括以下：(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯
乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(二氟甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(氟甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((4-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((環戊基氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((環戊基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯
乙氧基)苯基)-2-甲基-6-((噁唑-2-基甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((3-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(((3-氯苄基)氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基磺醯基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(((4,5-二甲基噻唑-2-基)甲氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(((1-(第三丁氧基羰基)氮雜環丁-3-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-((氮雜環丁-3-基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(6-((2-(二乙基胺基)乙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-嗎啉基乙氧基)甲基)吡啶-3-基)乙酸；
(S)-2-(第三丁氧基)-2-(6-(((3,5-二甲基-1H-吡唑-1-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((2-側氧基吡咯啶-1-基)甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-(六氫吡啶-1-基)乙氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-(1,1-二氧離子基硫嗎啉基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((環丁基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(((3,3-二氟環丁基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((3-甲基-4H-1,2,4-三唑-4-基)甲基)吡啶-3-基)乙酸；
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基-5-苯基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2,5-二甲基吡啶-3-基)乙酸；(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-5-(第三丁氧基(羧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((2-甲氧基乙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺甲醯基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基((四氫-2H-吡喃-4-基)甲基)胺甲醯基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((環己基甲基)(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(丁基(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(6-氯-1H-苯并[d]咪唑-2-基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(5-(4-氟苄基)噁唑-2-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(6-乙醯胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基磺醯胺基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-羥基-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲氧基-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-氯-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基)吡啶-3-基)乙酸；(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸；(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙基)-2-甲基吡啶-3-基)乙酸；(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙基)-2-甲基吡啶-3-基)乙酸；
(S)-2-(第三丁氧基)-2-(6-(3-(二甲基胺基)丙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(4-甲氧基苄基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸；(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((異丙基胺基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-羥基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(嗎啉基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((乙基胺
基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-((苄基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((苯基胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((氧雜環丁-3-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((噁唑-4-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((1,1-二氧
離子基硫嗎啉基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-甲氧基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-羥基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((3,4-二氫喹啉-1(2H)-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基苯基)胺基)甲基)-2-甲基吡啶-3-基)乙酸；(2S)-2-(第三丁氧基)-2-(6-((2,6-二甲基嗎啉基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；
(S)-2-(6-((雙(2-甲氧基乙基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-2-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸；(S)-2-(6-((苄基(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(2S)-2-(6-((3-苄基-3,6-二氮雜二環[3.1.1]庚-6-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-N-甲基-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；
(S)-2-(第三丁氧基)-2-(6-((N,5-二甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲醯胺基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基-2-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-(2-乙氧基乙氧基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸；(S)-2-(2-((3-(苄基氧基)丙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(2-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸；
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(嗎啉基甲基)吡啶-3-
基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((1,1-二氧離子基硫嗎啉基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-N-((5-(第三丁氧基(羧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-甲基吡啶-2-基)甲基)-N,N-二乙基乙銨；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-3-基甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((3,3-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-
甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((3-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((S)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((R)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-羥基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸；
(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((3-甲基-4H-1,2,4-三唑-4-基)甲基)吡啶-3-基)乙酸；(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙
酸；(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(6-甲基嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸；(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(1-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)吡啶-3-基)乙酸；(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-
甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(丙-1-yn-1-基)吡啶-3-基)乙酸；(S)-2-(6-胺基-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-胺基-5-(2-(苯并呋喃并[3,2-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯
乙氧基)苯基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)乙酸；(S)-2-(5-(2-(苯并呋喃并[3,2-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(4-氟苄基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(環己-1-烯-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-(環己基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環己基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-((二環[1.1.1]戊-1-基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(6-(氮雜環丁-1-基甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸；(S)-2-(6-((6-氮雜螺[2.5]辛-6-基)甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-
基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸；(S)-2-(6-((7-氮雜螺[3.5]壬-7-基)甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸；(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)吡啶-3-基)乙酸；及(S)-2-(第三丁氧基)-2-(6-(氯甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)吡啶-3-基)乙酸；及其醫藥上可接受之鹽。
本文所述之本發明化合物通常可以醫藥組合物形式投與。該等組合物包括治療有效量之式I化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑，且可含有習用賦形劑及/或稀釋劑。治療有效量係提供有意義之患者益處所需之量。醫藥上可接受之載劑係具有可接受之安全性概況之彼等習用已知載劑。組合物涵蓋所有常用固體及液體形式，包括膠囊、錠劑、菱形錠劑及粉末、以及液體懸浮液、糖漿、酏劑及溶液。組合物係使用可用調配技術及通常用於組合物中之賦形劑(例如結合及潤濕劑)及媒劑(例如水及醇)來製得。參見(例如)Remington’s Pharmaceutical Sciences，第17版，Mack Publishing Company,Easton,PA(1985)。
通常以每個劑量提供約1至1000毫克(「mg」)活性成份之劑量單位及組合物調配之固體組合物係典型的。劑量之一些實例係1mg、10mg、100mg、250mg、500mg及1000mg。通常，其他抗反轉錄病毒藥劑可以類似於臨床上使用之該種類之藥劑之單位範圍存在。通常，其係約0.25-1000mg/單位。
液體組合物通常在劑量單位範圍內。通常，液體組合物在約1-100毫克/毫升(「mg/mL」)之單位劑量範圍內。劑量之一些實例係1mg/mL、10mg/mL、25mg/mL、50mg/mL及100mg/mL。通常，其他抗反轉錄病毒藥劑可以類似於臨床上使用之該種類之藥劑之單位範圍存在。通常，其係約1-100mg/mL。
本發明涵蓋所有習用投與模式；經口及非經腸方法較佳。通常，劑量方案可類似於臨床上使用之其他抗反轉錄病毒藥劑。通常，日劑量為每日約1-100毫克/公斤(「mg/kg」)體重。通常，經口需要更多化合物且非經腸需要較少。然而，具體劑量方案將藉由醫師使用合理醫學判斷來確定。
本發明化合物期望地具有抵抗HIV之活性。因此，本發明之另一態樣係治療人類患者之HIV感染之方法，其包含投與治療有效量之式I化合物或其醫藥上可接受之鹽與醫藥上可接受之載劑、賦形劑及/或稀釋劑。
本發明亦涵蓋以組合療法給出該化合物之方法。亦即，可結合但與可用於治療AIDS及HIV感染之其他藥劑分開使用該化合物。該化合物亦可用於組合療法中，其中該化合物及一或多種其他藥劑在物理上一起呈固定劑量組合(FDC)。該等藥劑中之一些包括HIV附接抑制劑、CCR5抑制劑、CXCR4抑制劑、HIV細胞融合抑制劑、HIV整合酶抑制劑、HIV核苷反轉錄酶抑制劑、HIV非核苷反轉錄酶抑制劑、HIV蛋白酶抑制劑、出芽及成熟抑制劑、HIV衣殼抑制劑、抗感染劑
及免疫調節劑，例如PD-1抑制劑、PD-L1抑制劑、抗體及諸如此類。在該等組合方法中，通常會結合其他藥劑以約1-100mg/kg體重之日劑量給予式I化合物。通常會以治療使用量給予其他藥劑。然而，具體劑量方案將藉由醫師使用合理醫學判斷來確定。
核苷HIV反轉錄酶抑制劑之實例包括阿巴卡韋(abacavir)、去羥肌苷(didanosine)、恩曲他濱(emtricitabine)、拉米夫定(lamivudine)、司他夫定(stavudine)、泰諾福韋(tenofovir)、紮昔他濱(zalcitabine)及齊多夫定(zidovudine)。
非核苷HIV反轉錄酶抑制劑之實例包括地拉韋定(delavirdine)、依法韋侖(efavirenz)、依曲韋林(etrivirine)、奈韋拉平(nevirapine)及利匹韋林(rilpivirine)。
HIV蛋白酶抑制劑之實例包括安普那韋(amprenavir)、阿紮那韋(atazanavir)、達如那韋(darunavir)、呋山那韋(fosamprenavir)、英地那韋(indinavir)、洛匹那韋(lopinavir)、奈非那韋(nelfinavir)、利托那韋(ritonavir)、沙奎那韋(saquinavir)及替拉那韋(tipranavir)。
HIV融合抑制劑之實例係恩夫韋肽或T-1249。
HIV進入抑制劑之實例係馬拉維洛。
HIV整合酶抑制劑之實例包括德羅格韋、埃替格韋(elvitegravir)或雷特格韋(raltegravir)。
HIV附接抑制劑之實例係福特賽韋(fostemsavir)。
HIV成熟抑制劑之實例係BMS-955176，其具有以下結構：
因此，如上文所述，本文涵蓋式I化合物以及一或多種可用於治療AIDS之藥劑之組合。例如，無論在暴露前及/或暴露後之時期，本發明之化合物可有效地與有效量之AIDS抗病毒劑、免疫調節劑、抗感染劑或疫苗組合投與，例如以下非限制性表中之彼等：
抗病毒劑
合成方法
本發明化合物可藉由業內已知之各種方法(包括以下方案之彼等及具體實施例部分中)來製備。合成方案中所示之結構編號及變量編號不同於申請專利範圍或說明書之其餘部分中之結構或變量編號，且不應與其混淆。方案中之變量僅意欲說明如何製備本發明之一些化合物。本揭示內容並不限於上述闡釋性實例，實例應在所有方面視為說明性的而非限制性的，參照隨附申請專利範圍而非上述實例，且因此本發明意欲涵蓋屬申請專利範圍之等效內容之含義及範圍內的所有變
化。
方案及實例中所用之縮寫通常遵循業內所用之慣例。說明書及實例中所用之化學縮寫係如下定義：「KHMDS」為雙(三甲基矽基)醯胺鉀；「DMF」為N,N-二甲基甲醯胺；「HATU」為六氟磷酸O-(第三-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓，「MeOH」為甲醇；「Ar」為芳基；「TFA」為三氟乙酸，「DMSO」為二甲亞碸；「h」為小時；「rt」為室溫或滯留時間(上下文將指示)；「min」為分鐘；「EtOAc」為乙酸乙酯；「THF」為四氫呋喃；「Et2O」為二乙醚；「DMAP」為4-二甲基胺基吡啶；「DCE」為1,2-二氯乙烷；「ACN」為乙腈；「DME」為1,2-二甲氧基乙烷；「HOBt」為1-羥基苯并三唑水合物；且「DIEA」為二異丙基乙胺。
如本文所用之某些其他縮寫係如下定義：「1 x」為一次，「2 x」為兩次，「3 x」為三次，「℃」為攝氏度，「eq」為當量(equivalent或equivalents)，「g」為克(gram或grams)，「mg」為毫克(milligram或milligrams)，「L」為升(liter或liters)，「mL」為毫升(milliliter或milliliters)，「μL」為微升(microliter或microliters)，「N」為當量濃度，「M」為莫耳濃度，「mmol」為毫莫耳(millimole或millimoles)，「atm」為大氣壓，「psi」為磅/平方英吋，「conc.」為濃縮，「sat」或「sat’d」為飽和的，「MW」為分子量，「mp」為熔點，「ee」為鏡像異構物過量，「MS」或「Mass Spec」為質譜，「ESI」為電噴霧電離質譜，「HR」為高解析度，「HRMS」為高解析度質譜，「LCMS」為液相層析質譜，「HPLC」為高壓液相層析，「RP HPLC」為反相HPLC，「TLC」或「tlc」為薄層層析，「NMR」為核磁共振譜，「1H」為質子，「δ」為德爾塔(δ)，「s」為單峰，「d」為雙重峰，「t」為三重峰，「q」為四重峰，「m」為多重峰，「br」為寬峰，「Hz」為赫茲(hertz)，且「α」、「β」、「R」、「S」、「E」及「Z」係熟習此項技術
者所熟悉之立體化學符號。
一些化合物可根據方案I自經適當取代之雜環I-1合成，化合物I-1及I-6有市售或藉由業內熟知之反應合成。用溴處理化合物I-1提供二溴中間體I-2，藉由與POCl3反應將其轉化成氯吡啶I-3。中間體I-3使用熟習此項技術者熟知之條件便捷地轉變成酮酯I-5，該等條件包括使I-3與Grignard試劑在催化性溴化銅(I)二甲亞碸錯合物及之後在2-氯-2-乙醛酸烷基酯存在下反應。胺1-5與中間體1-6在有機鹼(例如休尼格鹼(Hunig’s base)存在下偶合提供中間體I-7。手性路易斯酸(Lewis acid)(例如I-8)介導利用兒茶酚硼烷還原酮酯I-7，提供手性醇I-9。藉由熟知條件之醇I-9之第三丁基化包括(但不限於)乙酸第三丁基酯及高氯酸，產生中間體I-10。使用業內熟知之條件(包括(但不限於)中間體I-10與R6B(OR)2之間之鈴木偶合(Suzuki coupling))將中間體I-10便捷地轉變成中間體I-11。業內熟知之硼酸酯或酸偶合劑有市售或係藉由熟習此項技術者熟知之反應製備。藉由熟習此項技術者熟知之條件使中間體I-11水解，提供羧酸I-12。
使用業內熟知之條件(包括(但不限於)中間體I-10與II-1之間之鈴
木偶合)將中間體I-10便捷地轉變成中間體II-2。II-2中之保護基團之解離提供酚II-3。藉由使用熟習此項技術者熟知之條件(包括(但不限於)Mitshunobu反應)達成酚II-3之烷基化以提供中間體II-4。藉由使用文獻中熟知之條件水解中間體II-4，提供羧酸II-5。
在又一方法中，本發明之一些化合物可根據方案III合成。
在又一方法中，本發明之一些化合物可根據方案IV合成。在方案IV中，吡啶IV-1可使用類似於先前方案中所述之彼等方法之方法來產生。此中間體可根據多個路徑實施至最終產物。在一種中，C2及C6烷基可經氧化以提供中間體IV-3及/或IV-4，其可藉由若干路徑進一步轉變成最終化合物IV-9或IV-10。
藉由熟習此項技術者熟知之方法藉由矽膠管柱上正相管柱層析使用所述適當溶劑系統純化本文所述化合物。在Sunfire Prep C18 ODB管柱(5μm；19或30×100mm)或Waters Xbridge C18管柱(5μM；19×200或30×100mm)或Water Atlantis(5μm；19或30×100mm)上使用以下移動相對此實驗部分中提及之製備型HPLC純化實施梯度溶析。移動相A：9：1 H2O/乙腈，具有10mM NH4OAc，且移動相B：A：9：1乙腈/H2O，具有10mM NH4OAc；或移動相A：9：1 H2O/乙腈，具有0.1% TFA，且移動相B：A：9：1乙腈/H2O，具有0.1% TFA；或移動相A：水/MeOH(9：1)，具有20mM NH4OAc，且移動相B：95：5 MeOH/H2O，具有20mM NH4OAc或移動相A：水/MeOH(9：1)，具有0.1% TFA，且移動相B：95：5 MeOH/H2O，具有0.1% TFA或移動相A：5：95乙腈：水，具有10-mM乙酸銨；移動相B：95：5乙腈：水，具有10-mM乙酸銨。
所有液相層析(LC)數據皆係在Shimadzu LC-10AS或LC-20AS液相層析儀上使用SPD-10AV或SPD-20A UV-Vis檢測器記錄，且質譜(MS)
數據係使用用於LC之Micromass Platform以電噴霧模式測定。
將藉由製備型HPLC純化之化合物稀釋於甲醇(1.2mL)或DMF中並使用Shimadzu LC-8A或LC-10A自動化製備型HPLC系統純化。
3,5-二溴-2,6-二甲基吡啶-4-醇：向配備有機械攪拌器、加料漏斗及冷凝器之3頸圓底燒瓶中裝入2,6-二甲基吡啶-4-醇(100g,812mmol)、CH2Cl2(1000mL)及MeOH(120mL)。向所得淺褐色或黃褐色溶液中添加tert-BuNH2(176ml,1665mmol)，在維持於5℃至10℃中之水浴(冰水)中冷卻並經70min逐滴添加Br2(84ml,1624mmol)。在添加完成後，移除冷浴並於rt下攪拌1.5h。隨後，過濾淺橙色漿液並將濾餅用醚(250mL)洗滌並乾燥，以得到白色固體狀3,5-二溴-2,6-二甲基吡啶-4-醇、氫溴酸鹽(280.75g,776mmol,96%產率)，其不經進一步純化即用於下一步驟。1H NMR(500MHz,DMSO-d6)δ 12.08(br.s.,1H),2.41(s,6H)。LCMS(M+H)=281.9。
替代程序：經60min經由加料漏斗向2,6-二甲基吡啶-4-醇(87g,706mmol)及4-甲基嗎啉(156mL,1.4mol)於二氯甲烷(1L)及甲醇(100mL)中之機械攪拌冷(冰水浴)溶液中添加溴(72.8mL,1.4mol)且隨後於rt下攪拌2h。基於藉由LCMS之監測添加額外溴(約15mL)。將產物過濾，用醚洗滌，並在真空下乾燥，以產生176.8g 3,5-二溴-2,6-二甲基吡啶-4-醇(88%)。
3,5-二溴-4-氯-2,6-二甲基-吡啶：向3,5-二溴-2,6-二甲基吡啶-4-醇(58g,206mmol)及氧氯化磷(57.7mL,619mmol)於氯仿(450mL)中之氮吹掃之溶液中添加三乙胺(28.8mL,206mmol)並於rt下攪拌1h，
隨後於80℃下攪拌3h。自加熱移除反應物並立刻在外罩真空下濃縮；隨後在高真空下濃縮。外觀係奶油色固體，將其與甲苯(2×100mL)共沸；用冰(200g)處理10min並用NaHCO3(粉末)及1N NaOH溶液小心中和，並用DCM(2×400mL)萃取。將合併之有機層乾燥(MgSO4)，濃縮，且獲得米色固體，將其用己烷洗滌並在高真空下乾燥，以產生52.74g 3,5-二溴-4-氯-2,6-二甲基-吡啶(85.1%)。濃縮己烷，產生3.5g較不純之產物。1H NMR(500MHz,CDCl3)δ 2.59(s,6H)。LCMS(M+H)=300.0。
2-氯-2-乙醛酸異丙基酯：經15min向冷(0℃)之氮吹掃之乙二醯二氯溶液(101g,799mmol)中逐滴添加丙-2-醇(38.2mL,499mmol)並將反應物於室溫下攪拌2.5h。隨後裝備回流冷凝器並施加輕微真空約1h直至移除HCl氣體(藉由NaHCO3之飽和溶液捕獲HCl)。移除回流冷凝器並向燒瓶裝備短路徑蒸餾頭。藉由在外罩真空下蒸餾(加熱至65℃之油浴)移除過量試劑，且隨後將溫度升至介於85℃至95℃且蒸餾產物(注意：棄去約5mL之第1部分)，以提供52.62g 2-氯-2-乙醛酸異丙基酯(70%)。
2-(5-溴-4-氯-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯：經20min向3,5-二溴-4-氯-2,6-二甲基吡啶(48g,160mmol)及溴化銅(I)-二甲硫錯合物(1.65g,8.02mmol)於THF(240mL)中之冷(-70℃)之氮吹掃之溶液中逐滴添加2M異丙基氯化鎂溶液(84mL,168mmol)，隨後經60min使其升溫至-10℃。經由套管將反應混合物轉移至含有維持於-60℃下之THF(160mL)中之2-氯-2-乙醛酸異丙基酯(26.6g,176mmol)之
1L圓底燒瓶中，且將反應再攪拌2.5h，同時使其升溫至-10℃。在用10% NH4Cl溶液(80mL)於醚(320mL)中之混合物稀釋後淬滅反應。將有機層用160mL飽和NaHCO3/10% NH4Cl溶液(1：1)、鹽水洗滌，並乾燥(Na2SO4)。將粗產物填裝(DCM溶液)至330g ISCO矽膠柱並使用Isolera層析站梯度溶析(5-20% EtOAc/己烷)，產生40.38g 2-(5-溴-4-氯-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯(76%)。1H NMR(500MHz,CDCl3)δ 5.28-5.21(m,1H),2.77(s,3H),2.47(s,3H),1.40(d,J=6.3Hz,6H)。LCMS(M+H)=336.04。
2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯：向2-(5-溴-4-氯-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯(7.2g,21.52mmol)及DIEA(4.13mL,23.67mmol)於無水乙腈(15mL)中之攪拌溶液中添加乙腈(15mL)中之4,4-二甲基六氫吡啶(2.68g,23.67mmol)。將所得溶液放置於75℃下之預加熱之油浴中。在加熱(75-78℃)24h後，將溫度升至85℃並持續24h。添加另一份乙腈(3mL)中之DIEA(3.5mL,20.04mmol)及4,4-二甲基六氫吡啶(0.27g,2.4mmol)並於85℃下加熱一天。將反應混合物用醚(100mL)稀釋，用水(100mL)、鹽水(50mL)洗滌，乾燥(MgSO4)，過濾，濃縮並藉由ISCO 120g柱(EtOAc/hex：0至20%)純化，以得到2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯(6.8g,16.53mmol,77%產率。1H NMR(500MHz,CDCl3)δ 5.25-5.11(m,1H),3.17(br.s.,4H),2.71(s,3H),2.41(s,3H),1.42-1.37(m,10H),1.00(s,6H)。)。LCMS(M+H)=413.3。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-羥基乙酸異丙基酯：於-50℃下經5min向2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-乙醛酸異丙基酯(7.7g,18.72mmol)及(R)-1-甲基-3,3-二苯基六氫吡咯并[1,2-c][1,3,2]氧氮硼雜環戊烯(7.5mL,7.50mmol)於無水甲苯(100mL)中之黃色溶液中逐滴添加50%兒茶酚硼烷/甲苯(6mL,28.0mmol)。隨後，經1h將反應混合物緩慢升溫至-30℃並在冷凍機(-20℃)中靜置3天。隨後，將反應混合物用EtOAc(100mL)及20mL 1M Na2CO3稀釋，並劇烈攪拌30min。分離水層並用飽和Na2CO3(2×25mL)洗滌有機層，每次劇烈攪拌15，隨後乾燥(MgSO4)，過濾並濃縮，以產生淺紫色膏糊狀粗產物，藉由急速層析使用0至40% EtOAc/hex對其進行純化，以得到無色稠膏糊狀(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-羥基乙酸異丙基酯(6.7g,15.72mmol,84%產率)。1H NMR(500MHz,CDCl3)δ 5.85(d,J=5.7Hz,1H),5.59(d,J=7.4Hz,1H),5.08(dt,J=12.5,6.3Hz,1H),3.98-3.88(m,1H),3.88-3.78(m,1H),2.76-2.68(m,1H),2.67(s,3H),2.64-2.58(m,1H),2.57(s,3H),1.73(td,J=12.8,4.8Hz,1H),1.65-1.59(m,1H),1.47-1.35(m,2H),1.27(d,J=6.3Hz,3H),1.17(d,J=6.1Hz,3H),1.09(s,3H),1.04(s,3H)。LCMS(M+H)=414.6。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-羥基乙酸異丙基酯(6.7g,16.21mmol)及70% HClO4(2.2mL,25.6mmol)於二氯甲烷(400mL)中之經攪拌冰冷黃色混合物用異丁烯氣體藉由鼓泡通過反應混合物(10min)來飽和。將反應混合物渾濁密封於密封管中，於rt下攪拌24h。將反應混合物在-10℃浴中再冷卻，鼓泡額外異丁烯(約15min)。反應混合物此時變為澄清溶液。將管密封並於rt下攪拌16h。此時之LCM顯示不完全反應。因此，將反應混合物冷卻至-30℃並鼓泡異丁烯(約15min)。24h後，將反應混合物用飽和Na2CO3(20mL)中和，分離有機層並將水層用CH2Cl2(25mL)萃取。將合併之有機層乾燥(MgSO4)，過濾，濃縮並在ISCO 120g管柱(EtOAc/hex：0至40%)上純化，以得到黏性油狀(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(5.43g,9.83mmol,60.7%產率)。1H NMR(500MHz,CDCl3)δ 6.26(br.s.,1H),5.09-4.97(m,1H),4.06(br.s.,1H),3.51(br.s.,1H),2.90(br.s.,1H),2.65(s,3H),2.56(s,3H),1.72-1.54(m,3H),1.47(br.s.,1H),1.37(br.s.,1H),1.23-1.20(m,12H),1.15(d,J=6.1Hz,3H),1.09(br.s.,3H),1.04(br.s.,3H)。LCMS(M+H)=471.3。
於rt下向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(1.81g,3.86mmol)於DCM(25mL)中之攪拌溶液中添加mCPBA(1.296g,5.78mmol)。2h後，將反
應混合物用飽和Na2CO3(3×10mL)洗滌，乾燥(MgSO4)，過濾並濃縮，以產生淺黃色發泡體狀(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶1-氧化物(1.854g,3.82mmol,99%產率)，其不經純化即用於下一步驟。LCMS(M+H)=487.1。
於rt下向(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2,6-二甲基吡啶1-氧化物(1.874g,3.86mmol)於無水DCM(20mL)中之攪拌溶液中添加三氟乙酸酐(1.090ml,7.72mmol)且隨後回流2.5h。隨後，添加MeOH(1mL)及Et3N(0.7mL,5mmol)並攪拌30min。隨後，冷卻，用飽和Na2CO3(10mL)洗滌，乾燥(MgSO4)，過濾，濃縮並藉由急速層析使用5%及10% EtOAc/hex純化，以得到兩種化合物。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：1.3311g(71%)黏性無色油，其隨時間變為白色固體。1H NMR(500MHz,CDCl3)δ 6.25(br.s.,1H),5.06(spt,J=6.3Hz,1H),4.75-4.79(m,1H),4.74-4.62(m,2H),4.02-4.12(br.s.,1H),3.54-3.46(m,1H),2.93(d,J=11.5Hz,1H),2.70-2.63(m,1H),2.61(s,3H),1.65-1.56(m,2H),1.50-1.43(m,1H),1.35-1.40(m,1H),1.23(d,J=6.2Hz,3H),(1.22(s,9H),1.16(d,J=6.3Hz,3H),1.09(s,3H),1.05(s,3H)。LCMS(M+H)=485.35及487.2。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：淺黃色膏糊，0.2762g
(15%)。1H NMR(500MHz,CDCl3)δ 6.21(br.s.,1H),5.03(spt,J=6.3Hz,1H),4.95(d,J=15.1Hz,1H),4.64(dd,J=15.3,5.0Hz,1H),4.50(br.s.,1H),4.05-3.97(m,1H),3.57(td,J=12.1,2.5Hz,1H),2.84(d,J=11.8Hz,1H),2.69(s,3H),2.62(d,J=11.8Hz,1H),1.66-1.55(m,2H),1.47(dd,J=13.2,2.0Hz,1H),1.40-1.34(m,1H),1.23(d,J=6.3Hz,3H),1.22(s,9H),1.16(d,J=6.1Hz,3H),1.09(s,3H),1.05(s,3H)。LCMS(M+H)=485.2及487.05。
1-溴-4-(4-氟苯乙氧基)苯：經20min向於冰水浴中冷卻之4-溴酚(81.7g,472mmol)、2-(4-氟苯基)乙醇(79g,567mmol)及Ph3P(149g,567mmol)於THF(100mL)中之攪拌溶液中逐滴添加DEAD(93ml,590mmol)。注意：反應放熱且且高度建議在起始大規模反應之前進行有效冷卻。1h後，移除冷浴並於rt下攪拌過夜(17h)。隨後，濃縮反應混合物，將所得殘餘物與己烷一起研磨，過濾並將濾餅用10%醚/己烷(2升)洗滌。將濾液濃縮並藉由急速層析(矽膠管柱3"×11")使用4升己烷及2升2% EtOAc/Hex純化，以得到無色液體狀1-溴-4-(4-氟苯乙氧基)苯(142g,469mmol,99%產率)(藉由1HNMR顯示經約2.5% Ph3P污染)。1H NMR(500MHz,CDCl3)δ 7.41-7.36(m,2H),7.28-7.22(m,2H),7.05-6.99(m,2H),6.82-6.76(m,2H),4.14(t,J=6.9Hz,2H),3.08(t,J=6.9Hz,2H)。
(4-(4-氟苯乙氧基)苯基) 酸：於-78℃下經15min向1-溴-4-(4-氟苯乙氧基)苯(142g,469mmol)於THF(1000mL)中之攪拌溶液中添加2M n-BuLi/環己烷(293ml,586mmol)。1.5h後，經5min向淺粉色反
應混合物中添加硼酸三異丙基酯(131ml,563mmol)並於-78℃下攪拌2h。隨後，藉由小心添加3M HCl(375mL)淬滅反應，將冷浴更換為水浴，攪拌1h，用醚(500mL)稀釋，分離水層並用水(2×200mL)洗滌有機層。將合併之水層用醚(200mL)萃取並將合併之醚層用鹽水(100mL)洗滌，乾燥(MgSO4)，過濾並濃縮至200mL。向此中添加250mL己烷並濃縮至約300mL並於rt下靜置。將沈澱固體與己烷一起研磨並過濾，以產生白色固體，其不經純化即用於下一步驟。1H NMR(500MHz,CDCl3)δ 8.18-8.15(m,2H),7.32-7.28(m,2H),7.07-7.00(m,4H),4.26(t,J=6.9Hz,2H),3.14(t,J=6.9Hz,2H)。
2-(4-(4-氟苯乙氧基)苯基)-6-甲基-1,3,6,2-二氧氮雜硼雜環辛烷(dioxazaborocane)-4,8-二酮：將(4-(4-氟苯乙氧基)苯基)酸(122g,469mmol)及2,2'-(甲基氮烷二基)二乙酸(76g,516mmol)於無水甲苯(500mL)及DMSO(200mL)中之漿液回流4h。隨後，冷卻，用EtOAc(500mL)稀釋，用水(5×200mL)、鹽水(2 x 100mL)洗滌，乾燥(MgSO4)，過濾並濃縮，以產生淺橙色發泡體，藉由急速層析使用5-40%丙酮/CH2Cl2(每2升增加5%)對其進行純化，以得到白色固體狀2-(4-(4-氟苯乙氧基)苯基)-6-甲基-1,3,6,2-二氧氮雜硼雜環辛烷-4,8-二酮(131.38g,354mmol,75%產率)。1H NMR(500MHz,CDCl3)δ 7.43(d,J=8.4Hz,2H),7.28-7.24(m,2H),7.04-6.99(m,2H),6.92(d,J=8.5Hz,2H),4.17(t,J=6.9Hz,2H),4.00(d,J=16.6Hz,2H),3.76(d,J=16.6Hz,2H),3.08(t,J=6.8Hz,2H),2.54(s,3H)。LCMS(M+H)=372.3。
實例1
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸：藉由將N2鼓泡通過反應混合物達10min將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.274g,0.564mmol)、(4-(4-氟苯乙氧基)苯基)酸(0.220g,0.847mmol)及2M Na2CO3(0.706ml,1.411mmol)於DMF(5mL)中之混合物脫氣。隨後，添加Pd(Ph3P)4(0.033g,0.028mmol)，脫氣5min並放置於100℃下之預加熱油浴中。於120℃下3h後，冷卻並藉由prep-HPLC純化，以得到淺紫色固體(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸(0.0791g,0.137mmol,24.22%產率)。1H NMR(500MHz,CDCl3)δ 7.32-7.27(m,2H),7.16(dd,J=8.6,2.1Hz,1H),7.10-7.02(m,3H),7.02-6.97(m,2H),5.91(br.s.,1H),4.98(d,J AB =14.8Hz,1H),4.67(d,J AB =14.8Hz,1H),4.28-4.20(m,2H),3.13(t,J=6.9Hz,2H),2.79-2.50(m,1H),2.25(s,3H),1.38-1.26(m,3H),1.24(s,9H),1.22-1.19(m,1H),0.78(br.s.,6H)。3個六氫吡啶及CO2H質子未拆分。LCMS(M+H)=579.5。亦分離一種下文所示之額外副產物。
(S)-5-(第三丁氧基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-2-甲基-5H-吡喃并[3,4-b]吡啶-6(8H)-酮：白色固體(0.0445
g,0.079mmol,14.06%產率)。1H NMR(500MHz,CDCl3)δ 7.32-7.27(m,2H),7.13-7.09(m,1H),7.08-7.02(m,3H),6.98(d,J=9.0Hz,2H),5.88(d,J AB =13.7Hz,1H),5.34(s,1H),5.16(d,J AB =13.7Hz,1H),4.23(t,J=6.9Hz,2H),3.13(t,J=6.9Hz,2H),2.71(br.s.,2H),2.64-2.57(m,2H),2.23(s,3H),1.37(s,9H),1.32-1.24(m,4H),0.82(br.s.,6H)。LCMS(M+H)=561.15。
替代程序：將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(690mg,1.421mmol)、2-(4-(4-氟苯乙氧基)苯基)-6-甲基-1,3,6,2-二氧氮雜硼雜環辛烷-4,8-二酮(580mg,1.563mmol)、2-二環己基膦基-2’,6’-二甲氧基聯苯(117mg,0.284mmol)及2M K3PO4(5.33mL,10.66mmol)於1,4-二噁烷(12mL)及水(2.400mL)中之混合物脫氣10min。隨後，添加Pd(OAc)2(31.9mg,0.142mmol)，脫氣5min並將混合物於80℃下加熱3h。此時，LCMS顯示主要產物呈酸而非期望酯形式且亦有環化產物。在冷卻至室溫後，添加水並將混合物用乙酸乙酯萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(0-50% CH2Cl2/MeOH)純化殘餘物，以得到灰白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸(300mg,0.518mmol,36.5%產率)。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯：藉由使N2鼓泡通過反應混合物將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-
(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(1.3g,2.68mmol)、(4-(4-氟苯乙氧基)苯基)酸(1.045g,4.02mmol)及2M Na2CO3(3.35ml,6.69mmol)於DMF(10mL)中之混合物脫氣10min。隨後，添加Pd(Ph3P)4(0.155g,0.134mmol)，脫氣5min並放置於100℃下之預加熱油浴中。於110℃下特定小時後，將反應混合物冷卻，用醚(100mL)稀釋，用水(4×10ml)、鹽水(10mL)洗滌，乾燥(MgSO4)，過濾，濃縮並藉由急速層析使用EtOAc/Hex純化，以得到灰白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(1.026g,1.653mmol,61.7%產率)。1H NMR(500MHz,CDCl3)δ 7.33-7.26(m,2H),7.13(d,J=7.9Hz,1H),7.09-7.02(m,3H),7.01-6.93(m,2H),6.05(br.s.,1H),5.08-5.13(m,1H),4.41(d,J AB =15.4Hz,1H),4.29-4.19(m,2H),4.07(d,J AB =15.4Hz,1H),3.24(d,J=8.8Hz,1H),3.14(t,J=6.8Hz,2H),2.89(t,J=11.7Hz,1H),2.64(s,3H),2.30(br.s.,1H),2.13(t,J=11.0Hz,1H),1.57(br.s.,1H),1.37(d,J=10.4Hz,1H),1.24(dd,J=10.9,6.3Hz,7H),1.20(s,9H),1.10(d,J=11.5Hz,1H),0.92(br.s.,3H),0.68(br.s.,3H)。LCMS(M+H)=621.55。
實例2
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(0.045g,0.072mmol)及
KOH(0.092g,1.450mmol)於90% EtOH(2mL)中之混合物回流2.5h。隨後，冷卻並藉由prep-HPLC純化，以得到灰白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸(0.0323g,0.056mmol,77%產率)。1H NMR(500MHz,CDCl3)δ 7.31-7.26(m,2H),7.16-7.12(m,1H),7.08-7.01(m,3H),6.99-6.94(m,2H),5.90(br.s.,1H),4.45(d,J AB =15.3Hz,1H),4.27-4.18(m,2H),4.13(d,J AB =15.3Hz,1H),3.13(t,J=6.9Hz,2H),2.67(s,3H),2.63-2.31(m,1H),1.41-1.26(m,4H),1.22(s,9H),0.79(br.s.,6H)。3個六氫吡啶、OH及CO2H質子未拆分。LCMS(M+H)=579.35。
實例3
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸：於-78℃下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(0.102g,0.164mmol)於無水CH2Cl2(3mL)中之攪拌溶液中一次性添加Deoxofluor(0.033ml,0.181mmol)。4h後，用MeOH(0.5mL)淬滅反應，於rt下攪拌15min，用醚(25mL)稀釋，用飽和Na2CO3(5mL)洗滌，乾燥(MgSO4)，過濾並濃縮，以產生殘餘物，其不經純化即用於下一步驟。LCMS(M+H)=641.3。
將上述殘餘物及KOH(0.092g,1.643mmol)於9：1 MeOH/H2O中之混合物回流24h。隨後，冷卻並藉由prep-HPLC純化，以得到灰白色
固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸(0.0331g,0.056mmol,34.0%產率)。1H NMR(500MHz,CDCl3)δ 7.32-7.25(m,3H),7.14-7.09(m,1H),7.07-7.01(m,2H),6.99-6.95(m,2H),6.06(br.s.,1H),4.29-4.19(m,2H),4.17-4.07(m,2H),3.54(br.s.,1H),3.26(s,3H),3.13(t,J=6.9Hz,2H),2.94(br.s.,1H),2.63(s,3H),2.25(br.s.,1H),2.07(br.s.,1H),1.60-1.48(m,1H),1.41-1.27(m,2H),1.22(s,9H),1.14-1.04(m,1H),0.90(br.s.,3H),0.67(br.s.,3H)。
LCMS(M+H)=593.8
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯：於rt下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(1g,1.611mmol)於CH2Cl2(5mL)中之攪拌溶液中一次性添加戴斯-馬丁過碘烷(Dess-MartinPeriodinane)(0.820g,1.933mmol)。2h後，將反應混合物用乙酸乙酯(50mL)稀釋，用飽和NaHCO3(10ml)、鹽水(10mL)洗滌，乾燥(Na2SO4)，過濾並濃縮，以產生黃色膏糊，藉由Biotage(5-30% EtOAc/己烷)對其進行純化，以得到白色發泡體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(900mg,1.454mmol,90%產率)。1H NMR(500MHz,CDCl3)δ 9.84(s,1H),7.31(br.s.,2H),7.22(t,J=9.1Hz,2H),7.10-6.90(m,4H),6.09(br.s.,1H),5.13(dt,J=12.5,6.2Hz,
1H),4.32-4.18(m,2H),3.24(br.s.,1H),3.14(t,J=6.9Hz,2H),2.98(br.s.,1H),2.72(s,3H),2.31(br.s.,1H),2.13(br.s.,1H),1.59(s,2H),1.38(br.s.,1H),1.25(dd,J=10.8,6.2Hz,6H),1.19(s,9H),1.12(d,J=11.0Hz,1H),0.93(br.s.,3H),0.71(br.s.,3H)。LCMS(M+H)=619.25。
實例4
(S)-2-(第三丁氧基)-2-(6-(二氟甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於rt下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(0.124g,0.2mmol)於無水CH2Cl2(3mL)中之攪拌溶液中添加Deoxofluor(0.063ml,0.340mmol)。添加EtOH(2.336μl,0.040mmol)並將黃色混合物於rt下攪拌24h。隨後，用醚(25mL)稀釋，用飽和Na2CO3(5mL)洗滌，乾燥(MgSO4)，過濾並濃縮，以產生梅紅色膏糊狀(S)-2-(第三丁氧基)-2-(6-(二氟甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯。LCMS(M+H)=641.3。
將(S)-2-(第三丁氧基)-2-(6-(二氟甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯及固體KOH(0.112g,2.000mmol)於90% EtOH(3mL)中之混合物回流4h。隨後，冷卻並藉由prep-HPLC純化，以得到淺褐色固體狀(S)-2-(第三丁氧基)-2-(6-(二氟甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0897g,0.150mmol,74.9%產
率)。1H NMR(500MHz,CDCl3)δ 7.31-7.27(m,2H),7.25-7.21(m,1H),7.18-7.14(m,1H),7.08-7.02(m,2H),7.01-6.96(m,2H),6.41-6.17(m,1H),6.10(br.s.,1H),4.29-4.19(m,2H),3.55(br.s.,1H),3.14(t,J=6.9Hz,2H),2.96(t,J=12.3Hz,1H),2.66(s,3H),2.26(d,J=11.0Hz,1H),2.10-2.02(m,1H),1.58-1.50(m,1H),1.39-1.28(m,2H),1.24(s,9H),1.14-1.08(m,1H),0.91(s,3H),0.68(s,3H)。LCMS(M+H)=599.7。
實例5及6
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(氟甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(6-((4-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於-78℃下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(75mg,0.121mmol)於無水CH2Cl2(3mL)中之攪拌溶液中一次性添加Deoxofluor(0.025mL,0.133mmol)。4h後，添加4-氯苯酚(31.1mg,0.242mmol)並將混合物攪拌16h。此時，LCMS指示主要產物呈氟化合物形式且次要產物呈4-氯苯基衍生物形式。隨後將混合物濃縮並於80℃下用EtOH(2mL)中之10N NaOH(0.121mL,1.208mmol)處理4h。隨後將混合物冷卻並藉由prep-HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(氟甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)
乙酸(11.7mg,0.020mmol,16.68%產率)：1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.24(d,J=8.1Hz,1H),7.18-7.08(m,3H),7.04(t,J=8.3Hz,2H),5.84(br.s.,1H),5.10(d,J=9.5Hz,0.5H),4.99(t,J=11.0Hz,1H),4.89(d,J=9.9Hz,0.5H),4.34-4.15(m,2H),3.70-3.62(m,1H),3.06(t,J=6.6Hz,2H),2.84(t,J=11.9Hz,1H),2.48(s,3H),2.19(br.s.,1H),1.51(br.s.,1H),1.29(br.s.,1H),1.20(d,J=13.6Hz,1H),1.13(s,9H),1.04(d,J=13.6Hz,1H),0.86(br.s.,3H),0.62(br.s.,3H)。LCMS(M+H)=581.2；及(S)-2-(第三丁氧基)-2-(6-((4-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(4.9mg,7.11μmol,5.88%產率)：1H NMR(500MHz,DMSO-d6)δ 7.36-7.29(m,2H),7.29-7.19(m,3H),7.15-7.07(m,3H),6.99(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.85(d,J=8.8Hz,2H),5.81(br.s.,1H),4.72(d,J=9.9Hz,1H),4.55(d,J=9.9Hz,1H),4.25-4.04(m,2H),3.41(br.s.,2H),2.99(t,J=6.6Hz,2H),2.85-2.77(m,1H),2.48(s,3H),2.20(d,J=11.4Hz,1H),1.51(br.s.,1H),1.30(br.s.,1H),1.26-1.18(m,1H),1.14(s,9H),1.03(d,J=13.6Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=689.1。
(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(930mg,1.498mmol)於CH2Cl2(20mL)中之溶液中添加CBr4(546mg,1.648mmol)，
之後添加Ph3P(432mg,1.648mmol)並將所得混合物於室溫下攪拌16h。隨後添加水(10mL)並將混合物用二氯甲烷(10mL)萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-30% EtOAc/己烷)純化殘餘物，以得到白色固體狀(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(850mg,1.243mmol,83%產率)。1H NMR(500MHz,CDCl3)δ 7.38(d,J=8.2Hz,1H),7.31(br.s.,1H),7.13(d,J=7.7Hz,2H),7.05(t,J=8.4Hz,2H),6.99(t,J=7.2Hz,2H),6.07(br.s.,1H),5.11(dt,J=12.5,6.3Hz,1H),4.34(d,J=9.3Hz,1H),4.25(br.s.,2H),4.18(d,J=9.3Hz,1H),3.20(d,J=11.7Hz,1H),3.14(t,J=6.9Hz,2H),2.87(t,J=12.7Hz,1H),2.63(s,3H),2.30(d,J=9.6Hz,1H),2.11-1.96(m,1H),1.51(br.s.,1H),1.37(br.s.,1H),1.24(d,J=6.3Hz,3H),1.26(d,J=6.5Hz,3H),1.20(s,9H),1.09(d,J=14.5Hz,1H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+2H)=685.4。
實例7
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸：於0℃下向氧雜環丁-3-基甲醇(10.31mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫
吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸(20.4mg,0.031mmol,53.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.33(m,2H),7.23(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.09-6.95(m,3H),5.83(br.s.,1H),4.53(t,J=7.0Hz,2H),4.29-4.20(m,2H),4.20-4.12(m,3H),4.01(d,J=9.9Hz,1H),3.40(d,J=6.6Hz,2H),3.31(d,J=12.1Hz,1H),3.05(t,J=6.4Hz,2H),3.02-2.94(m,1H),2.82(t,J=11.4Hz,1H),2.47(s,3H),2.16(br.s.,1H),1.98-1.88(m,1H),1.49(br.s.,1H),1.29(br.s.,1H),1.18(d,J=13.2Hz,1H),1.12(s,9H),1.02(d,J=12.5Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=649.2。
實例8
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水乙醇(27.0mg,0.585mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯
基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(23.7mg,0.039mmol,66.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.26(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.09-6.96(m,3H),5.81(br.s.,1H),4.30-4.16(m,2H),4.10(d,J=9.5Hz,1H),3.95(d,J=9.5Hz,1H),3.35(br.s.,1H),3.20(d,J=7.0Hz,2H),3.05(t,J=6.6Hz,2H),2.86-2.78(m,1H),2.47(s,3H),2.16(br.s.,1H),1.93(br.s.,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.18(d,J=11.7Hz,1H),1.12(s,9H),1.02(d,J=12.8Hz,1H),0.98(t,J=7.0Hz,3H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=607.2。
實例9
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水丙-2-醇(35.2mg,0.585mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059
mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸(21mg,0.034mmol,57.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.27(d,J=8.4Hz,1H),7.14(t,J=9.0Hz,2H),7.09-6.96(m,3H),5.81(br.s.,1H),4.31-4.16(m,2H),4.12(d,J=9.2Hz,1H),3.92(d,J=9.2Hz,1H),3.35(br.s.,1H),3.24(dt,J=12.0,5.9Hz,2H),3.04(d,J=6.6Hz,1H),2.85-2.76(m,1H),2.47(s,3H),2.18(d,J=12.1Hz,1H),1.99-1.92(m,1H),1.49(d,J=9.9Hz,1H),1.37-1.24(m,1H),1.18(d,J=12.5Hz,1H),1.13(s,9H),1.02(d,J=12.8Hz,1H),0.95(d,J=6.2Hz,3H),0.89(d,J=6.2Hz,3H),0.85(s,3H),0.61(s,3H)。LCMS(M+H)=621.2。
實例10
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水2-乙氧基乙醇(10.55mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-
(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(20.5mg,0.031mmol,53.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38(t,J=6.6Hz,2H),7.29(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.09-7.00(m,2H),6.98(d,J=8.4Hz,1H),5.82(br.s.,1H),4.30-4.18(m,2H),4.13(d,J=9.5Hz,1H),3.99(d,J=9.9Hz,1H),3.34-3.26(m,3H),3.06(t,J=6.6Hz,2H),2.82(t,J=11.7Hz,1H),2.47(s,3H),2.17(d,J=10.6Hz,1H),1.99-1.87(m,1H),1.51(br.s.,1H),1.35-1.24(m,1H),1.19(d,J=12.8Hz,1H),1.13(s,9H),1.07-1.02(m,4H),0.85(br.s.,3H),0.62(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=651.2。
實例11
(S)-2-(第三丁氧基)-2-(6-((環戊基氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水環戊醇(10.08mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯
乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((環戊基氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(12.5mg,0.019mmol,33.0%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.34(m,2H),7.25(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.08-6.97(m,3H),5.84(br.s.,1H),4.31-4.16(m,2H),4.08(d,J=9.2Hz,1H),3.90(d,J=8.8Hz,1H),3.61(br.s.,1H),3.30(br.s.,1H),3.05(t,J=6.6Hz,2H),2.85-2.76(m,1H),2.47(s,3H),2.17(br.s.,1H),1.99-1.91(m,1H),1.54-1.41(m,5H),1.35(br.s.,3H),1.25(br.s.,2H),1.18(d,J=12.1Hz,1H),1.13(s,9H),1.02(d,J=11.0Hz,1H),0.85(s,3H),0.61(s,3H)。LCMS(M+H)=647.2。
實例12
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸：於0℃下向無水四氫-2H-吡喃-4-醇(11.95mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁
氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸(24.9mg,0.038mmol,64.2%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.35(m,2H),7.28(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.10-7.05(m,1H),7.05-6.98(m,2H),5.82(br.s.,1H),4.28-4.18(m,3H),4.00(d,J=9.2Hz,1H),3.74-3.58(m,2H),3.33(br.s.,1H),3.25-3.13(m,3H),3.05(t,J=6.6Hz,2H),2.87-2.77(m,1H),2.47(s,3H),2.17(br.s.,1H),1.97(br.s.,1H),1.72-1.56(m,2H),1.50(br.s.,1H),1.38-1.22(m,2H),1.18(dt,J=8.8,4.4Hz,2H),1.13(s,9H),1.03(d,J=12.1Hz,1H),0.85(s,3H),0.61(s,3H)。LCMS(M+H)=663.2。
實例13
(S)-2-(第三丁氧基)-2-(6-((環戊基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水環戊基甲醇(11.72mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-
(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用EtOH(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((環戊基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(17.1mg,0.026mmol,44.2%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.27(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.09-7.00(m,2H),6.98(d,J=8.4Hz,1H),5.84(br.s.,1H),4.30-4.16(m,2H),4.11(d,J=9.9Hz,1H),3.96(d,J=9.9Hz,1H),3.31(br.s.,1H),3.09-2.99(m,4H),2.87-2.77(m,1H),2.47(s,3H),2.18(d,J=11.4Hz,1H),2.02-1.88(m,2H),1.61-1.49(m,3H),1.49-1.36(m,4H),1.30(br.s.,1H),1.19(d,J=12.1Hz,1H),1.13(s,9H),1.10-0.98(m,3H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=661.2。
實例14
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((噁唑-2-基甲氧基)甲基)吡啶-3-基)乙酸：於0℃下向無水噁唑-2-基甲醇(11.59mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後
添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((噁唑-2-基甲氧基)甲基)吡啶-3-基)乙酸(29.3mg,0.044mmol,76%產率)。1H NMR(500MHz,DMSO-d6)δ 8.00(s,1H),7.42-7.35(m,2H),7.21(d,J=8.1Hz,1H),7.18-7.10(m,3H),7.07-6.97(m,2H),6.94(d,J=8.8Hz,1H),5.81(br.s.,1H),4.48-4.29(m,2H),4.29-4.14(m,3H),4.07(d,J=9.5Hz,1H),3.33(br.s.,2H),3.06(t,J=6.4Hz,2H),2.85-2.76(m,1H),2.47(s,3H),2.17(d,J=12.1Hz,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.18(d,J=12.1Hz,1H),1.12(s,9H),1.02(d,J=12.5Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=660.1。
實例15
(S)-2-(第三丁氧基)-2-(6-((3-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將
所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((3-氯苯氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(27.3mg,0.040mmol,67.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.36-7.30(m,2H),7.27(d,J=7.7Hz,1H),7.22(t,J=8.1Hz,1H),7.12(t,J=8.3Hz,3H),7.00(d,J=8.1Hz,1H),6.94-6.88(m,3H),6.80(d,J=8.1Hz,1H),5.84(br.s.,1H),4.76(d,J=9.9Hz,1H),4.59(d,J=9.9Hz,1H),4.23-4.06(m,2H),3.34(br.s.,2H),3.00(t,J=6.4Hz,2H),2.87-2.77(m,1H),2.50(br.s.,3H),2.21(d,J=11.4Hz,1H),1.51(br.s.,1H),1.31(br.s.,1H),1.20(d,J=12.5Hz,1H),1.14(s,9H),1.03(d,J=12.1Hz,1H),0.86(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=689.1。
實例16
(S)-2-(第三丁氧基)-2-(6-(((3-氯苄基)氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向無水(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟
苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(((3-氯苄基)氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(27.5mg,0.039mmol,66.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.34(m,2H),7.30-7.21(m,4H),7.17-7.06(m,4H),7.04-6.99(m,1H),6.97(d,J=7.7Hz,1H),5.82(br.s.,1H),4.31(s,2H),4.28-4.19(m,3H),4.06(d,J=9.5Hz,1H),3.34(br.s.,1H),3.06(t,J=6.4Hz,2H),2.82(t,J=13.0Hz,1H),2.49(s,3H),2.18(d,J=11.7Hz,1H),1.93(br.s.,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.19(d,J=13.2Hz,1H),1.12(s,9H),1.02(d,J=12.1Hz,1H),0.85(br.s.,3H),0.61(s,3H)。LCMS(M+H)=703.1。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸異丙基酯：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(100mg,0.146mmol)於DMF(1.5mL)中之溶液中添加甲硫醇鈉(12.30mg,0.176
mmol)並將所得混合物於室溫下攪拌2h。隨後將混合物用乙酸乙酯稀釋並用飽和NaHCO3及鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮，以得到灰白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸異丙基酯(92mg,0.141mmol,97%產率)，其不經進一步純化即用於下一步驟。1H NMR(500MHz,CDCl3)δ 7.35-7.31(m,3H),7.11(d,J=7.9Hz,1H),7.05(t,J=8.4Hz,2H),6.97(d,J=8.0Hz,2H),6.07(br.s.,1H),5.10(dt,J=12.4,6.2Hz,1H),4.30-4.19(m,2H),3.55(d,J=12.6Hz,1H),3.44(d,J=12.5Hz,1H),3.25-3.17(m,1H),3.13(t,J=6.8Hz,2H),2.87(t,J=12.1Hz,1H),2.61(s,3H),2.29(d,J=11.3Hz,1H),2.10(s,3H),2.04(t,J=11.7Hz,1H),1.55(br.s.,1H),1.37(t,J=11.8Hz,1H),1.24(dd,J=13.0,6.2Hz,7H),1.20(s,9H),1.08(d,J=11.7Hz,1H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=651.5。
實例17
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸異丙基酯(25mg,0.038mmol)於乙醇(1mL)中之溶液中添加10N NaOH(0.038mL,0.384mmol)並將所得混合物於80℃下加熱3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-
(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸(15.3mg,0.025mmol,65.4%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.33(m,2H),7.28(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.10-6.97(m,3H),5.84(br.s.,1H),4.30-4.15(m,2H),3.43(d,J=12.5Hz,2H),3.32-3.24(m,2H),3.05(t,J=6.6Hz,2H),2.84-2.75(m,1H),2.46(s,3H),2.19(d,J=12.1Hz,1H),1.94-1.88(m,2H),1.49(br.s.,1H),1.29(br.s.,1H),1.18(d,J=12.1Hz,1H),1.13(s,9H),1.02(d,J=13.2Hz,1H),0.85(s,3H),0.60(s,3H)。LCMS(M+H)=609.1。
實例18
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基磺醯基)甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲硫基)甲基)吡啶-3-基)乙酸異丙基酯(70mg,0.108mmol)於MeOH(2mL)及水(2mL)中之溶液中添加過硫酸氫鉀複合鹽(198mg,0.323mmol)並於rt下攪拌1h。隨後，用水(10mL)稀釋，用EtOAc(2×20mL)萃取，乾燥(Na2SO4)，過濾，濃縮。隨後於80℃下將殘餘物用乙醇(1.5mL)中之10N NaOH(0.108mL,1.075mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以產生(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基磺醯基)甲基)吡啶-3-基)乙酸(39.6mg,0.062mmol,57.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.27
(d,J=9.5Hz,1H),7.14(t,J=8.6Hz,2H),7.07(br.s.,3H),5.85(br.s.,1H),4.26(q,J=7.1Hz,2H),4.19(d,J=14.3Hz,1H),4.11(d,J=14.3Hz,1H),3.39(br.s.,3H),3.30(d,J=8.8Hz,1H),3.14(s,3H),3.06(t,J=6.8Hz,2H),2.85-2.76(m,1H),2.16(br.s.,1H),1.91-1.82(m,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.19(d,J=12.5Hz,1H),1.13(s,9H),1.03(d,J=11.4Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=641.2。
實例19
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸：於0℃下向(四氫-2H-吡喃-4-基)甲醇(16.99mg,0.146mmol)於THF(1)中之溶液中添加NaH(5.85mg,0.146mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(50mg,0.073mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.073mL,0.731mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸(41mg,0.061mmol,83%產率)。
1H NMR(500MHz,DMSO-d6)δ 7.44-7.31(m,2H),7.25(d,J=7.7Hz,1H),7.14(t,J=8.6Hz,2H),7.10-6.93(m,3H),5.70(br.s.,1H),4.34-4.16(m,2H),4.12(d,J=9.5Hz,1H),3.97-3.84(m,1H),3.76(d,J=10.3Hz,2H),3.22-3.15(m,2H),3.10-2.97(m,4H),2.46(s,3H),2.16(d,J=8.8Hz,1H),1.90(s,3H),1.61(br.s.,1H),1.50(br.s.,1H),1.42(d,J=12.8Hz,2H),1.29(br.s.,1H),1.17(d,J=12.1Hz,1H),1.11(s,9H),1.08-0.96(m,3H),0.85(br.s.,3H),0.62(br.s.,3H)。LCMS(M+H)=677.3。
實例20
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(((4,5-二甲基噻唑-2-基)甲氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向(4,5-二甲基噻唑-2-基)甲醇(20.95mg,0.146mmol)於THF(1)中之溶液中添加NaH(5.85mg,0.146mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(50mg,0.073mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.073mL,0.731mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(((4,5-二甲基噻唑-2-基)甲氧基)甲基)-5-(4-
(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(18.3mg,0.026mmol,35.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.43-7.32(m,2H),7.23(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.09-6.98(m,2H),6.94(d,J=8.1Hz,1H),5.82(br.s.,1H),4.54-4.35(m,2H),4.30-4.15(m,3H),4.12(d,J=9.9Hz,1H),3.05(t,J=6.6Hz,2H),2.85-2.77(m,1H),2.48(s,3H),2.26(s,3H),2.17(s,3H),1.97-1.87(m,1H),1.50(br.s.,1H),1.38-1.23(m,1H),1.19(d,J=12.1Hz,1H),1.12(s,9H),1.02(d,J=11.7Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=704.2。
實例21
(S)-2-(第三丁氧基)-2-(6-(((1-(第三丁氧基羰基)氮雜環丁-3-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向3-(羥基甲基)氮雜環丁烷-1-甲酸第三丁基酯(21.91mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-
(第三丁氧基)-2-(6-(((1-(第三丁氧基羰基)氮雜環丁-3-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(30mg,0.040mmol,68.6%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.25(d,J=8.1Hz,1H),7.14(t,J=8.4Hz,3H),7.03(s,1H),6.97(d,J=9.2Hz,1H),5.58(s,1H),4.28-4.18(m,5H),4.13(d,J=10.3Hz,2H),4.00(d,J=9.9Hz,2H),3.77(br.s.,5H),3.44(br.s.,2H),3.30(d,J=5.5Hz,2H),2.58(br.s.,1H),2.46(s,3H),1.34(s,9H),1.15(d,J=10.3Hz,1H),1.09(s,9H),0.84(s,3H),0.62(s,3H)。LCMS(M+H)=748.2。
實例22
(S)-2-(6-((氮雜環丁-3-基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：隨後將(S)-2-(第三丁氧基)-2-(6-(((1-(第三丁氧基羰基)氮雜環丁-3-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸用CH2Cl2(1mL)中之TFA(0.090mL,1.170mmol)處理1h。隨後將混合物濃縮並藉由製備型HPLC純化，以得到(S)-2-(6-((氮雜環丁-3-基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(16mg,0.025mmol,42.2%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.24(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.09
-7.04(m,1H),7.04-6.96(m,2H),5.68(br.s.,1H),4.29-4.17(m,3H),4.09(d,J=10.3Hz,1H),3.87-3.72(m,2H),3.67-3.53(m,3H),3.36-3.32(m,3H),3.25-3.19(m,1H),3.05(t,J=6.8Hz,2H),2.84(br.s.,1H),2.82-2.69(m,1H),2.45(s.,3H),2.16(br.s.,1H),1.94-1.85(m,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.16(d,J=12.5Hz,1H),1.10(s,9H),1.01(d,J=12.1Hz,1H),0.84(br.s.,3H),0.61(s,3H)。LCMS(M+H)=648.2。
實例23
(S)-2-(第三丁氧基)-2-(6-((2-(二乙基胺基)乙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向2-(二乙基胺基)乙醇(8.57mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((2-(二乙基胺基)乙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(18.5mg,0.027mmol,74.6%產率)。1H
NMR(500MHz,DMSO-d6)δ 7.41-7.33(m,2H),7.28(d,J=8.1Hz,1H),7.14(t,J=8.4Hz,2H),7.03(br.s.,2H),6.98(d,J=8.1Hz,1H),5.71(br.s.,1H),4.22(dd,J=14.3,6.6Hz,2H),4.12(d,J=10.3Hz,1H),3.98(d,J=9.2Hz,1H),3.51(br.s.,2H),3.25-3.18(m,3H),2.79(br.s.,1H),2.46(s,3H),2.39(d,J=7.0Hz,4H),2.42-2.33(m,2H),2.16(d,J=9.5Hz,1H),1.51(br.s.,1H),1.29(br.s.,1H),1.17(d,J=11.0Hz,1H),1.10(s,9H),1.02(d,J=11.4Hz,1H),0.90-0.79(m,9H),0.62(br.s.,3H)。LCMS(M+H)=678.2。
實例24
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-嗎啉基乙氧基)甲基)吡啶-3-基)乙酸：於0℃下向2-嗎啉基乙醇(9.59mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-嗎啉基乙氧基)甲基)吡啶-
3-基)乙酸(16.9mg,0.024mmol,66.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.28(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.09-7.00(m,2H),6.98(d,J=9.9Hz,1H),5.78(br.s.,1H),4.30-4.16(m,2H),4.13(d,J=9.9Hz,1H),3.99(d,J=9.9Hz,1H),3.49(d,J=4.0Hz,1H),3.39(br.s.,2H),3.29(t,J=5.5Hz,3H),3.06(t,J=6.6Hz,2H),2.81(t,J=12.1Hz,1H),2.47(s,3H),2.33-2.23(m,6H),2.16(d,J=9.9Hz,1H),1.96-1.90(m,2H),1.50(br.s.,1H),1.30(br.s.,1H),1.18(d,J=12.1Hz,1H),1.12(s,9H),1.02(d,J=12.8Hz,1H),0.85(br.s.,3H),0.62(br.s.,3H)。LCMS(M+H)=692.4。
實例25
(S)-2-(第三丁氧基)-2-(6-(((3,5-二甲基-1H-吡唑-1-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向(3,5-二甲基-1H-吡唑-1-基)甲醇(14.76mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-
(((3,5-二甲基-1H-吡唑-1-基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(27.1mg,0.039mmol,67.4%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.34(m,2H),7.24-7.07(m,3H),6.98(s,2H),6.87(d,J=8.8Hz,1H),5.73(s,1H),5.68(br.s.,1H),5.19-5.08(m,2H),4.23(dd,J=13.4,6.1Hz,2H),4.10(d,J=10.3Hz,1H),4.01(d,J=9.9Hz,1H),3.51(br.s.,3H),3.06(t,J=6.4Hz,2H),2.75(d,J=13.9Hz,1H),2.46(s,3H),2.13(s,4H),1.98(s,3H),1.49(br.s.,1H),1.27(d,J=9.5Hz,1H),1.16(d,J=13.6Hz,1H),1.10(s,9H),1.00(d,J=12.8Hz,1H),0.84(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=687.2。
實例26
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((2-側氧基吡咯啶-1-基)甲氧基)甲基)吡啶-3-基)乙酸：於0℃下向1-(羥基甲基)吡咯啶-2-酮(13.47mg,0.117mmol)於THF(1)中之溶液中添加NaH(4.68mg,0.117mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.059mmol)並將混合物攪拌16h。此時，LCMS指示反應完成。隨後將混合物濃縮於80℃下用乙醇(1mL)中之10N NaOH(0.059mL,0.585mmol)處理4h。隨後將混合物冷
卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((2-側氧基吡咯啶-1-基)甲氧基)甲基)吡啶-3-基)乙酸(13mg,0.019mmol,32.9%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.23(d,J=7.3Hz,1H),7.15(t,J=8.8Hz,2H),7.10-7.05(m,1H),7.05-6.98(m,2H),5.84(br.s.,1H),4.52(d,J=10.3Hz,1H),4.42(d,J=10.3Hz,1H),4.30-4.17(m,2H),4.09(d,J=9.5Hz,1H),3.96-3.87(m,1H),3.32(d,J=16.1Hz,1H),3.24-3.12(m,1H),3.10-2.99(m,3H),2.86-2.75(m,1H),2.47(s,3H),2.16(br.s.,1H),2.13-2.04(m,2H),1.96-1.89(m,1H),1.80-1.65(m,2H),1.50(br.s.,1H),1.28(d,J=11.0Hz,1H),1.19(d,J=11.0Hz,1H),1.13(s,9H),1.03(d,J=12.5Hz,1H),0.85(s,3H),0.61(s,3H)。LCMS(M+H)=676.2。
實例27
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-(六氫吡啶-1-基)乙氧基)甲基)吡啶-3-基)乙酸：於0℃下向2-(六氫吡啶-1-基)乙醇(9.45mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌4h。此時，
LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理16h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((2-(六氫吡啶-1-基)乙氧基)甲基)吡啶-3-基)乙酸(14.5mg,0.021mmol,57.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.29(d,J=8.8Hz,1H),7.14(t,J=8.8Hz,2H),7.06-6.94(m,3H),5.76(s,1H),4.32-4.16(m,2H),4.12(d,J=9.9Hz,1H),3.98(d,J=9.9Hz,1H),3.42(br.s.,2H),3.05(t,J=6.4Hz,2H),2.84-2.76(m,1H),2.47(s,3H),2.33-2.21(m,6H),2.16(d,J=8.8Hz,1H),1.95(br.s.,1H),1.50(br.s.,1H),1.45-1.38(m,4H),1.32(br.s.,3H),1.18(d,J=14.3Hz,1H),1.12(s,9H),1.02(d,J=11.4Hz,1H),0.85(br.s.,3H),0.62(br.s.,3H)。LCMS(M+H)=690.3。
實例28
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-(1,1-二氧離子基硫嗎啉基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向4-(2-羥基乙基)硫嗎啉1,1-二氧化物(13.11mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基
吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理16h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-(1,1-二氧離子基硫嗎啉基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(19.3mg,0.026mmol,71.3%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.33(m,2H),7.26(d,J=8.1Hz,1H),7.14(t,J=8.6Hz,2H),7.08-6.96(m,3H),5.79(br.s.,1H),4.30-4.18(m,2H),4.15(d,J=10.3Hz,1H),4.01(d,J=9.9Hz,1H),3.30(dd,J=13.0,5.3Hz,2H),3.06(t,J=6.8Hz,2H),3.04-2.97(m,4H),2.85(br.s.,4H),2.83-2.78(m,1H),2.56-2.53(m,3H),2.47(s,3H),2.17(d,J=12.5Hz,1H),1.91(s,1H),1.50(br.s.,1H),1.30(br.s.,1H),1.18(d,J=13.6Hz,1H),1.12(s,9H),1.02(d,J=13.2Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=740.2。
實例29
(S)-2-(第三丁氧基)-2-(6-((環丁基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向環丁基甲醇(6.30mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-
(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌16h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((環丁基甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(19.9mg,0.031mmol,84%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38(dd,J=8.3,5.7Hz,2H),7.26(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.08-6.97(m,3H),5.80(br.s.,1H),4.30-4.17(m,2H),4.10(d,J=9.5Hz,1H),3.95(d,J=9.5Hz,1H),3.36(br.s.,2H),3.14(d,J=6.6Hz,2H),3.05(t,J=6.6Hz,2H),2.85-2.78(m,1H),2.47(s,3H),2.35(dt,J=14.8,7.5Hz,1H),2.17(d,J=11.4Hz,1H),1.97-1.84(m,3H),1.83-1.67(m,2H),1.63-1.46(m,3H),1.34-1.23(m,1H),1.19(d,J=9.9Hz,1H),1.12(s,9H),1.02(d,J=11.4Hz,1H),0.85(s,3H),0.61(s,3H)。LCMS(M+H)=647.2。
實例30
(S)-2-(第三丁氧基)-2-(6-(((3,3-二氟環丁基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向(3,3-二氟環丁基)甲醇(8.93mg,0.073mmol)於THF(1)中之溶液中添加NaH(2.93mg,0.073mmol)並將所得混合物攪拌10
min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)並將混合物攪拌16h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.037mL,0.366mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(((3,3-二氟環丁基)甲氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(21.7mg,0.032mmol,87%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.24(d,J=8.1Hz,1H),7.14(t,J=8.6Hz,2H),7.03(s,2H),6.99(d,J=8.4Hz,1H),5.65(br.s.,1H),4.28-4.18(m,2H),4.15(d,J=9.9Hz,1H),4.00(d,J=9.9Hz,1H),3.60(br.s.,1H),3.60(br.s.,2H),3.23(d,J=5.1Hz,2H),3.05(t,J=6.6Hz,2H),2.82-2.75(m,1H),2.46(s,3H),2.28-2.07(m,4H),1.90(s,1H),1.51(br.s.,1H),1.29(br.s.,1H),1.16(d,J=11.7Hz,1H),1.10(s,9H),1.01(d,J=11.0Hz,1H),0.85(s,3H),0.62(s,3H)。LCMS(M+H)=683.3。
實例31、32及33
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸、(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((3-甲基-4H-1,2,4-三唑-4-基)甲基)吡啶- 3-基)乙酸：於0℃下向3-甲基-1H-1,2,4-三唑(45.6mg,0.548mmol)於THF(2mL)中之溶液中添加NaH(21.94mg,0.548mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(75mg,0.110mmol)並將混合物攪拌16h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.110mL,1.097mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到三種化合物：(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸(8mg,0.012mmol,10.76%產率)。1H NMR(500MHz,DMSO-d6)δ 8.02(s,1H),7.39(dd,J=8.1,5.9Hz,2H),7.32(d,J=8.1Hz,1H),7.15(t,J=8.8Hz,2H),7.12-7.03(m,3H),5.62(br.s.,1H),4.91(d,J=16.1Hz,1H),4.74(d,J=15.8Hz,1H),4.35-4.14(m,2H),3.62(br.s.,1H),3.07(t,J=6.6Hz,2H),2.76(br.s.,1H),2.38(s,3H),2.19(br.s.,1H),2.10(s,3H),1.90(br.s,1H),1.51(br.s.,1H),1.29(br.s.,1H),1.16(d,J=10.6Hz,1H),1.09(s,9H),1.02(d,J=12.5Hz,1H),0.85(br.s.,3H),0.62(s,3H)。LCMS(M+H)=644.2。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)-苯基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸(3.2mg,4.72μmol,4.30%產率)：1H NMR(500MHz，甲醇-d4)δ 7.84(s,1H),7.36(dd,J=8.4,5.5Hz,2H),7.27(d,J=8.2Hz,1H),7.09-7.01(m,3H),7.01-6.91(m,2H),6.02(s,1H),5.21(d,J=14.7Hz,1H),5.06(d,J=14.7Hz,1H),4.27(td,J=6.6,2.9Hz,2H),3.12(t,J=6.6Hz,2H),2.58(s,3H),2.26(s,3H),1.33(d,J=7.4Hz,3H),1.22(s,9H),0.79(br.s.,6H)。4個六氫吡啶氫未拆分。LCMS(M+H)=644.2。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)-苯基)-2-甲基-6-((3-甲基-4H-1,2,4-三唑-4-基)甲基)吡啶-3-基)乙酸(2.1mg,3.10μmol,2.82%產率)：1H NMR(500MHz，甲醇-d4)δ 7.74(s,1H),7.36(dd,J=8.4,5.7Hz,2H),7.20-7.14(m,1H),7.10-6.99(m,5H),6.01(s,1H),5.09(s,2H),4.27(td,J=6.6,3.2Hz,2H),3.15-3.07(m,2H),2.54(s,3H),2.18(s,3H),1.32(t,J=7.2Hz,3H),1.21(s,9H),0.78(br.s.,6H)。4個六氫吡啶氫未拆分。LCMS(M+H)=644.2。
(S)-2-(5-溴-6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(500mg,1.030mmol)於CH2Cl2(10mL)中之溶液中添加CBr4(376mg,1.133mmol)，之後添加Ph3P(297mg,1.133mmol)並將所得混合物於室溫下攪拌16h。隨後添加水(2mL)並將混合物用二氯甲烷(10mL)萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-30% EtOAc/己烷)純化殘餘物，以得到白色固體狀(S)-2-(5-溴-6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(350mg,0.638mmol,62.0%產率)。1H NMR(500MHz,CDCl3)δ 6.25(br.s.,1H),5.14-4.94(m,1H),4.76(d,J=9.6Hz,1H),4.69(d,J=9.6Hz,1H),4.04(br.s.,1H),3.51(t,J=11.9Hz,1H),2.91(d,J=11.5Hz,1H),2.66(d,J=12.1Hz,1H),2.58(s,3H),1.68-1.55(m,2H),1.47(d,J=12.5Hz,1H),1.37(d,J=12.8Hz,1H),1.26-1.23(m,3H),1.22
(s,9H),1.16(d,J=6.1Hz,3H),1.09(s,3H),1.04(s,3H)。LCMS(M+2H)=549.2。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：於0℃下向無水2-乙氧基乙醇(99mg,1.094mmol)於THF(5mL)中之溶液中添加NaH(43.8mg,1.094mmol)並將所得混合物攪拌10min。隨後添加THF(5mL)中之(S)-2-(5-溴-6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(300mg,0.547mmol)並將混合物攪拌16h。此時，LCMS指示反應完成。隨後添加水並將混合物用醚萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-30% EtOAc/己烷)純化殘餘物，以得到黏性油狀(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(200mg,0.359mmol,65.6%產率)。1H NMR(500MHz,CDCl3)δ 5.05(dt,J=12.5,6.2Hz,1H),4.87-4.68(m,2H),4.07(br.s.,1H),3.86-3.76(m,2H),3.73-3.65(m,2H),3.62-3.55(m,2H),3.55-3.43(m,1H),2.95-2.86(m,1H),2.65(d,J=11.5Hz,1H),2.59(s,3H),1.64-1.52(m,2H),1.50-1.41(m,1H),1.36(d,J=12.5Hz,1H),1.26-1.21(m,5H),1.21(s,9H),1.15(d,J=6.1Hz,3H),1.09(s,3H),1.04(s,3H)。LCMS(M+2H)=559.3.
實例34及35
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基-5-苯基吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)乙酸：藉由使N2鼓泡通過反應混合物達10min將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(30mg,0.054mmol)、苯基酸(19.68mg,0.161mmol)及2M Na2CO3(0.081mL,0.161mmol)於DMF(3mL)中之混合物脫氣。隨後，添加Pd(Ph3P)4(6.22mg,5.38μmol)，將其脫氣5min並放置於100℃下之預加熱油浴中。於130℃下3h後，將反應混合物冷卻，用水稀釋，用醚萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用EtOH(1mL)中之10N NaOH(0.054mL,0.538mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以產生兩種化合物。(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基-5-苯基吡啶-3-基)乙酸(7.7mg,0.015mmol,27.9%產率)：1H NMR(500MHz,DMSO-d6)δ 7.52-7.36(m,4H),7.17(d,J=7.0Hz,1H),5.86(br.s.,1H),4.15(d,J=9.9Hz,1H),3.99(d,J=9.9Hz,1H),3.37-3.33(m,6H),3.28(d,J=4.0Hz,2H),2.85-2.76(m,1H),2.49(s,3H),2.17(br.s.,1H),1.85(t,J=11.2Hz,1H),1.49(br.s.,1H),1.34-1.24(m,1H),1.19(d,J=12.1Hz,1H),1.14(s,9H),1.09-1.03(m,3H),0.99(d,J=12.8Hz,1H),0.85(br.s.,3H),0.58(s,3H)。LCMS(M+H)=513.1。及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)乙
酸(1.6mg,3.66μmol,6.81%產率)：1H NMR(500MHz,DMSO-d6)δ 7.06(s,1H),5.58(s,1H),4.46(s,2H),3.62(d,J=4.4Hz,2H),3.58-3.51(m,2H),3.46(q,J=7.3Hz,2H),3.36(br.s.,1H),3.23(br.s.,2H),2.66(br.s.,2H),2.37(s,3H),1.55(d,J=7.3Hz,2H),1.45(br.s.,2H),1.16-1.11(m,2H),1.10(s,9H),1.00(s,6H)。LCMS(M+H)=437.1。
實例36及37
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2,5-二甲基吡啶-3-基)乙酸及(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：藉由使N2鼓泡通過反應混合物達10min將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(60mg,0.108mmol)、甲基酸(32.2mg,0.538mmol)及2M Na2CO3(0.269mL,0.538mmol)於DMF(3mL)中之混合物脫氣。隨後，添加Pd(Ph3P)4(12.44mg,10.76μmol)，將其脫氣5min並放置於100℃下之預加熱油浴中。於100℃下3h後，將反應混合物冷卻，用乙酸乙酯稀釋並用水、鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(2mL)中之10N NaOH(0.108mL,1.076mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到兩種化合物。(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2,5-二甲基吡啶-3-基)乙酸(1.8mg,3.99μmol,3.71%產率)：1H NMR(500MHz,DMSO-d6)δ 5.93(br.s.,1H),4.57-4.41(m,2H),3.63-3.52(m,2H),3.49(t,J=4.6Hz,
3H),3.45-3.28(m,3H),3.16(t,J=11.2Hz,1H),3.04(br.s.,1H),2.64(br.s.,1H),2.41(s,3H),2.30(s,3H),1.68-1.50(m,2H),1.39(d,J=12.1Hz,1H),1.30(d,J=11.4Hz,1H),1.13(s,9H),1.09(t,J=7.0Hz,3H),1.02(br.s.,3H),0.98(br.s.,3H)。LCMS(M+H)=451.1。及(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(1.6mg,3.10μmol,2.88%產率)：1H NMR(500MHz,DMSO-d6)δ 5.89(br.s.,1H),4.67-4.48(m,2H),3.95(t,J=11.2Hz,1H),3.67-3.59(m,2H),3.51(t,J=4.8Hz,2H),3.45-3.38(m,2H),3.38-3.26(m,1H),3.01(d,J=9.5Hz,1H),2.58-2.55(m,1H),2.45(s,3H),1.63-1.46(m,2H),1.41(d,J=12.1Hz,1H),1.30(d,J=12.5Hz,1H),1.14(s,9H),1.11-1.07(m,3H),1.03(s,3H),0.98(s,3H)。LCMS(M+H)=515.0。
(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(900mg,1.454mmol)於DMSO(25mL)中之溶液中添加水(10mL)中之KH2PO4(1386mg,10.18mmol)，之後添加水(10mL)中之亞氯酸鈉(1052mg,11.64mmol)並將混合物攪拌48h。隨後將混合物用鹽水飽和並用乙酸乙酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-100% EtOAc/己烷)純化殘餘物，以得到灰白色固體狀(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-
甲基吡啶甲酸(500mg,0.788mmol,54.2%產率)。1H NMR(500MHz,CDCl3)δ 7.30-7.23(m,3H),7.09-7.02(m,3H),6.96(d,J=8.4Hz,2H),6.05(br.s.,1H),5.13(dt,J=12.4,6.2Hz,1H),4.30-4.18(m,2H),3.16-3.07(m,3H),2.67(s,3H),2.64(s,4H),1.30-1.23(m,9H),1.20(s,9H),0.81(br.s.,6H)。LCMS(M+H)=635.3。
實例38
(S)-5-(第三丁氧基(羧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸：將(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(20mg,0.032mmol)及10N NaOH(0.032mL,0.315mmol)於乙醇(1mL)中之混合物於80℃下加熱3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-5-(第三丁氧基(羧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(12.7mg,0.021mmol,68.0%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.4,5.5Hz,2H),7.19(d,J=8.4Hz,1H),7.16-7.06(m,3H),6.94(d,J=8.4Hz,1H),6.97(d,J=8.1Hz,1H),5.79(s,1H),4.28-4.14(m,2H),3.48(br.s.,1H),3.04(t,J=6.6Hz,2H),2.46(s,3H),1.25(br.s.,3H),1.12(s,9H),0.74(br.s.,6H)。4個六氫吡啶氫未拆分。LCMS(M+H)=593.2。
實例39
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((2-甲氧基乙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(40mg,0.063mmol)及2-甲氧基乙胺(9.47mg,0.126mmol)於DMF(1mL)中之溶液中添加DIEA(0.055mL,0.315mmol)，之後添加HATU(47.9mg,0.126mmol)並將所得混合物於室溫下攪拌2h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.063mL,0.630mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((2-甲氧基乙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸(23.2mg,0.036mmol,56.7%產率)。1H NMR(500MHz,DMSO-d6)δ 8.15(br.s.,1H),7.43-7.29(m,2H),7.21-7.05(m,4H),6.97(d,J=7.7Hz,1H),6.91(d,J=8.4Hz,1H),5.75(br.s.,1H),4.26-4.12(m,2H),3.48(br.s.,2H),3.09-2.96(m,7H),2.85(br.s.,1H),2.48(s,3H),2.13(br.s.,1H),1.96(br.s.,1H),1.52(br.s.,1H),1.29(br.s.,1H),1.27-1.17(m,1H),1.13(s,9H),1.03(d,J=11.7Hz,1H),0.86(br.s.,3H),0.64(br.s.,3H)。LCMS(M+H)=650.1。
實例40
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺甲醯基)吡啶-3-基)乙酸：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(20mg,0.032mmol)及甲胺(0.032mL,0.063mmol)於DMF(1mL)中之溶液中添加DIEA(0.028mL,0.158mmol)，之後添加HATU(23.96mg,0.063mmol)並將所得混合物於室溫下攪拌16h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.032mL,0.315mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺甲醯基)吡啶-3-基)乙酸(7.2mg,0.012mmol,37.7%產率)。1H NMR(500MHz,DMSO-d6)δ 8.04(d,J=4.8Hz,1H),7.37(dd,J=8.6,5.7Hz,2H),7.14(q,J=9.2Hz,3H),7.07(d,J=8.4Hz,1H),6.96(d,J=8.1Hz,1H),6.92-6.86(m,1H),5.74(s,1H),4.28-4.12(m,2H),3.04(t,J=6.8Hz,2H),2.84(br.s.,1H),2.48(s,3H),2.45(d,J=4.8Hz,3H),2.13(br.s.,1H),1.52(br.s.,1H),1.29(br.s.,1H),1.27-1.15(m,3H),1.13(s,9H),1.06-0.96(m,1H),0.86(br.s.,3H),0.63(br.s.,3H)。LCMS(M+H)=606.2。
實例41
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基((四氫-2H-吡喃-4-基)甲基)胺甲醯基)吡啶-3-基)乙酸：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(40mg,0.063mmol)及N-甲基-1-(四氫-2H-吡喃-4-基)甲胺(16.28mg,0.126mmol)於DMF(1mL)中之溶液中添加DIEA(0.055mL,0.315mmol)，之後添加HATU(47.9mg,0.126mmol)並將所得混合物於室溫下攪拌16h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.063mL,0.630mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基((四氫-2H-吡喃-4-基)甲基)胺甲醯基)吡啶-3-基)乙酸(13.2mg,0.019mmol,29.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.36(dd,J=8.4,5.5Hz,2H),7.17(d,J=8.1Hz,1H),7.12(t,J=8.8Hz,2H),6.94(d,J=8.4Hz,1H),6.97(d,J=8.4Hz,2H),5.77(s,1H),4.24-4.07(m,3H),3.58(d,J=10.3Hz,1H),3.06-2.94(m,5H),2.90(s,1H),2.55(s,3H),2.47(s,3H),2.16(br.s.,1H),1.47(br.s.,2H),1.25(br.s.,3H),1.12(s,9H),1.11(s,2H),1.03(br.s.,2H),0.85(br.s.,3H),0.63(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=704.2。
實例42
(S)-2-(第三丁氧基)-2-(6-((環己基甲基)(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(20mg,0.032mmol)及1-環己基-N-甲基甲胺(8.02mg,0.063mmol)於DMF(1mL)中之溶液中添加DIEA(0.028mL,0.158mmol)，之後添加HATU(23.96mg,0.063mmol)並將所得混合物於室溫下攪拌16h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.032mL,0.315mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((環己基甲基)(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(7.4mg,10.54μmol,33.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.35(dd,J=8.4,5.5Hz,2H),7.18-7.06(m,4H),6.98(dd,J=8.4,2.6Hz,1H),6.92(dd,J=8.4,2.6Hz,1H),5.76-5.60(m,1H),4.26-4.05(m,2H),3.03(t,J=6.4Hz,2H),2.85(br.s.,1H),2.53(br.s.,1H),2.47(s,2H),2.15(br.s.,1H),1.54(br.s.,2H),1.42(br.s.,3H),1.23(d,J=11.4Hz,3H),1.12(s,9H),1.06-1.00(m,2H),0.96-0.78(m,7H),0.64(br.s.,4H),0.61-0.46(m,2H)。6個六氫吡啶氫未拆分。LCMS(M+H)=
702.3。
實例43
(S)-2-(第三丁氧基)-2-(6-(丁基(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(20mg,0.032mmol)及N-甲基丁-1-胺(5.49mg,0.063mmol)於DMF(1mL)中之溶液中添加DIEA(0.028mL,0.158mmol)，之後添加HATU(23.96mg,0.063mmol)並將所得混合物於室溫下攪拌16h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.032mL,0.315mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(丁基(甲基)胺甲醯基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(11.9mg,0.018mmol,57.1%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.30(m,2H),7.17-7.03(m,4H),7.01-6.96(m,1H),6.93(dd,J=8.3,2.8Hz,1H),5.69-5.63(m,1H),4.29-4.08(m,2H),3.09-2.98(m,2H),2.86(br.s.,1H),2.48-2.43(m,3H),2.15(br.s.,1H),1.53(br.s.,1H),1.24(br.s.,2H),1.11(s,6H),1.09(s,3H),1.06-0.95(m,3H),0.91-0.77(m,4H),0.73-0.62(m,6H)。8個六氫吡啶氫未拆分。LCMS(M+H)=662.2。
實例44
(S)-2-(第三丁氧基)-2-(6-(6-氯-1H-苯并[d]咪唑-2-基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向((S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(80mg,0.126mmol)及4-氯苯-1,2-二胺(25.2mg,0.176mmol)於DMF(2mL)中之溶液中添加DIEA(0.088mL,0.504mmol)，之後添加HATU(67.1mg,0.176mmol)並將所得混合物於室溫下攪拌2h。隨後添加水並將混合物用乙酸乙基酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後將粗製醯胺溶解於乙酸(3mL)中並於80℃下加熱1h。隨後將混合物濃縮，用乙酸乙酯稀釋並用飽和NaHCO3溶液及鹽水洗滌。分離各層，並乾燥(Na2SO4)有機層，過濾並濃縮。隨後於80℃下將殘餘物用EtOH(2mL)中之10N NaOH(0.126mL,1.260mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(6-氯-1H-苯并[d]咪唑-2-基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(42.1mg,0.060mmol,47.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.43(s,1H),7.40(d,J=8.4Hz,1H),7.35-7.26(m,2H),7.18-7.06(m,5H),6.95(d,J=7.3Hz,1H),6.78(d,J=7.7Hz,1H),5.85(br.s.,1H),4.24-4.03(m,2H),3.47(br.s.,1H),3.37(br.s.,1H),2.99(t,J=6.6Hz,2H),2.90(s,2H),2.59(s,3H),2.20(br.s.,1H),1.99-1.81(m,1H),1.54(br.s.,1H),1.32(br.s.,1H),1.22(d,J=11.4
Hz,1H),1.16(s,9H),1.04(d,J=11.4Hz,1H),0.87(br.s.,3H),0.64(br.s.,3H)。LCMS(M+H)=699.1。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((3-(4-氟苯基)-2-側氧基丙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸異丙基酯：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(100mg,0.158mmol)於CH2Cl2(2mL)中之溶液中添加2M草醯氯(0.095mL,0.189mmol)，之後添加1滴DMF並將所得混合物於室溫下攪拌15min。此時，LCMS(於甲醇中)指示反應完成(甲基酯質量，LCMS(M+H)=649.4)。隨後將此溶液添加至1-胺基-3-(4-氟苯基)丙-2-酮，2 HCl(64.3mg,0.268mmol)及TEA(0.110mL,0.788mmol)於CH2Cl2(2mL)中之預攪拌溶液中並將混合物攪拌1h。隨後添加水並將混合物用DCM萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-40% EtOAc/己烷)純化殘餘物，以得到灰白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((3-(4-氟苯基)-2-側氧基丙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸異丙基酯(110mg,0.140mmol,89%產率)。1H NMR(500MHz,CDCl3)δ 8.31(br.s.,1H),7.26(br.s.,1H),7.22(d,J=7.4Hz,1H),7.15(t,J=6.0Hz,2H),7.08(d,J=7.6Hz,1H),7.02(q,J=8.6Hz,4H),6.91(t,
J=9.1Hz,2H),6.10(br.s.,1H),5.16-5.04(m,1H),4.29-4.09(m,3H),3.68(s,2H),3.18-3.06(m,3H),3.00-2.84(m,1H),2.64(s,3H),2.28(br.s.,1H),2.07(s,1H),2.05-1.93(m,1H),1.41-1.32(m,2H),1.29(t,J=7.2Hz,2H),1.24(dd,J=11.2,6.5Hz,6H),1.20(s,9H),1.09(d,J=12.8Hz,1H),0.91(br.s.,3H),0.67(br.s.,3H)。LCMS(M+H)=784.5。
實例45
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(5-(4-氟苄基)噁唑-2-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向25mL微波小瓶中裝入(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((3-(4-氟苯基)-2-側氧基丙基)胺甲醯基)-2-甲基吡啶-3-基)乙酸異丙基酯(25mg,0.032mmol)、Burgess試劑(15.20mg,0.064mmol)及無水THF(1mL)，密封並放置於115℃下之預加熱油浴中。2.5h後，冷卻，用醚(20mL)稀釋，用水(5mL)、鹽水(5mL)洗滌，乾燥(Na2SO4)，過濾，濃縮並於80℃下將所得殘餘物用EtOH(1mL)中之10N NaOH(0.032mL,0.319mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(5-(4-氟苄基)噁唑-2-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(3.9mg,5.39μmol,16.90%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.30(m,2H),7.13(t,J=8.6Hz,2H),7.08(d,J=7.0Hz,5H),6.93(t,J=9.4Hz,2H),6.79(s,1H),6.74
(d,J=7.3Hz,1H),5.67(br.s.,1H),4.22-4.05(m,2H),3.88(s,2H),3.64(br.s.,1H),3.35(br.s.,2H),3.03(t,J=6.6Hz,2H),2.83(br.s.,1H),2.14(br.s.,1H),1.52(br.s.,1H),1.30(br.s.,1H),1.24(br.s.,1H),1.18(br.s.,1H),1.12(s,9H),1.02(br.s.,1H),0.85(br.s.,3H),0.63(br.s.,3H)。4個丟失六氫吡啶氫。LCMS(M+H)=724.1。
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶甲酸(400mg,0.630mmol)及TEA(0.176mL,1.260mmol)於甲苯(10mL)中之溶液中添加水(0.057mL,3.15mmol)，之後添加二苯基磷醯基疊氮化物(0.272mL,1.260mmol)並將所得混合物於90℃下加熱30min，且隨後再添加一份DPPA(0.07mL)並繼續再加熱1h。隨後將混合物冷卻至室溫，用EtOAc(100mL)稀釋並用飽和NaHCO3溶液、水及鹽水洗滌。隨後乾燥(Na2SO4)有機層，過濾並濃縮。隨後藉由Biotage(5-80% EtOAc/己烷)純化殘餘物，以得到白色固體狀(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(300mg,0.495mmol,79%產率)。1H NMR(500MHz,CDCl3)δ 7.29-7.23(m,3H),7.14(d,J=8.5Hz,1H),7.08-6.95(m,4H),5.92(br.s.,1H),5.08(dt,J=12.4,6.3Hz,1H),4.27-4.19(m,2H),4.16(br.s.,2H),3.27(d,J=12.5Hz,1H),3.13(t,J=6.9Hz,2H),2.84(t,J=12.2Hz,1H),2.48(s,3H),2.30(d,J=10.7Hz,1H),2.07(t,J=11.7Hz,1H),1.71(br.
s.,1H),1.56(t,J=10.7Hz,1H),1.43-1.34(m,1H),1.24(dd,J=8.5,6.6Hz,6H),1.20(s,9H),1.08(d,J=12.1Hz,1H),0.90(s,3H),0.67(s,3H)。LCMS(M+H)=606.4。
實例46
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(13mg,0.021mmol)於乙醇(1mL)中之溶液中添加10N NaOH(0.021mL,0.215mmol)並將所得混合物於80℃下加熱4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(7.6mg,0.013mmol,62.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.35(m,2H),7.22-7.10(m,3H),7.08-6.99(m,3H),5.71(br.s.,1H),4.86(br.s.,1H),4.31-4.13(m,2H),3.35(br.s.,2H),3.25(br.s.,1H),3.05(t,J=6.4Hz,2H),2.77(t,J=11.4Hz,1H),2.28(s,3H),2.17(d,J=13.6Hz,1H),2.00-1.87(m,1H),1.47(br.s.,1H),1.34-1.23(m,1H),1.18(br.s.,1H),1.13(s,9H),1.01(d,J=10.6Hz,1H),0.84(s,3H),0.60(s,3H)。LCMS(M+H)=564.2。
實例47
(S)-2-(6-乙醯胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：於0℃下向(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(20mg,0.035mmol)及DIEA(0.019mL,0.106mmol)於DCM(0.5mL)中之溶液中添加乙醯氯(2.77μl,0.039mmol)。將混合物於rt下攪拌16h。隨後將混合物濃縮並藉由製備型HPLC純化，以得到(S)-2-(6-乙醯胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(3.4mg,5.61μmol,15.82%產率)。1H NMR(500MHz,DMSO-d6)δ 9.08(br.s.,1H),7.37(dd,J=8.6,5.7Hz,2H),7.22-7.09(m,3H),7.03-6.91(m,3H),5.81(s,1H),4.29-4.13(m,2H),3.04(t,J=6.8Hz,2H),2.85(br.s.,1H),2.45(s,3H),2.12(br.s.,1H),1.73(s,3H),1.52(br.s.,1H),1.30(br.s.,1H),1.21(d,J=12.5Hz,1H),1.14(s,9H),1.03(d,J=13.2Hz,1H),0.86(br.s.,3H),0.63(br.s.,3H)。2個六氫吡啶氫未拆分。LCMS(M+H)=606.2。
實例48
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基磺醯胺基)吡啶-3-基)乙酸：於0℃下向
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(15mg,0.025mmol)及TEA(6.90μl,0.050mmol)於CH2Cl2(0.5mL)中之溶液中添加甲磺醯氯(3.83μl,0.050mmol)並將所得混合物於室溫下攪拌16h。隨後將混合物濃縮並於80℃下用EtOH(1mL)中之10N NaOH(0.025mL,0.248mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基磺醯胺基)吡啶-3-基)乙酸(13.8mg,0.022mmol,87%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38(dd,J=8.3,5.7Hz,2H),7.23(d,J=7.7Hz,1H),7.14(t,J=8.8Hz,2H),7.09-6.96(m,3H),5.57(br.s.,1H),4.31-4.18(m,2H)3.41(br.s.,5H),3.06(t,J=6.8Hz,3H),2.76(br.s.,1H),2.43(s,3H),2.12(br.s.,1H),1.51(br.s.,1H),1.24(br.s.,1H),1.20(br.s.,1H),1.12(s,9H),1.01(d,J=12.5Hz,1H),0.85(br.s.,3H),0.63(br.s.,3H)。LCMS(M+H)=642.0。
實例49
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺基)吡啶-3-基)乙酸：於0℃下向(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(23mg,0.041mmol)於THF(2mL)中之溶液中添加NaH(6.53mg,0.163mmol)並將所得混合物於室溫下攪拌30min。隨後添加碘甲烷(0.013mL,0.204mmol)並將混合物於60℃下加熱6h。隨後將混合物濃縮並於70℃下用MeOH(1mL)中之1N
NaOH(0.408mL,0.408mmol)處理2h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(甲基胺基)吡啶-3-基)乙酸；1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.4,5.5Hz,2H),7.19-7.10(m,3H),7.09-6.95(m,3H),5.71(s,1H),4.30-4.12(m,2H),3.25(d,J=11.4Hz,1H),3.05(t,J=6.6Hz,2H),2.77-2.70(m,1H),2.68(d,J=4.8Hz,3H),2.55(s,2H),2.36-2.27(m,3H),2.16(d,J=11.7Hz,1H),1.94-1.84(m,1H),1.52-1.40(m,1H),1.37-1.24(m,1H),1.17-1.09(m,9H),0.99(d,J=11.4Hz,1H),0.83(s,3H),0.58(s,3H)。LCMS(M+H)=578.2。且下文所示化合物分離為副產物。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-亞胺基-1,2-二甲基-1,6-二氫吡啶-3-基)乙酸：(2.2mg,3.81μmol,9.33%產率)。1H NMR(500MHz,DMSO-d6)δ 7.35(dd,J=8.6,5.7Hz,2H),7.26(dd,J=8.4,2.2Hz,1H),7.15-7.07(m,5H),7.04(dd,J=8.3,2.4Hz,1H),5.13(s,1H),4.31-4.17(m,2H),3.75-3.66(m,2H),3.04(t,J=6.4Hz,2H),1.21(br.s.,3H),1.11-1.02(m,11H),0.73(br.s.,6H)。8個六氫吡啶氫未拆分。LCMS(M+H)=578.2。
實例50、51及52
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯 乙氧基)苯基)-6-羥基-2-甲基吡啶-3-基)乙酸、(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲氧基-2-甲基吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(6-氯-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.041mmol)及CuCl2(16.65mg,0.124mmol)組合於37% HCl(0.5mL)及MeOH(0.5mL)中。隨後將混合物冷卻至0℃並添加亞硝酸鈉(8.54mg,0.124mmol)於0.2mL H2O中之溶液。隨後密封燒瓶且隨後將混合物升溫至室溫並攪拌16h。將混合物用乙酸乙酯稀釋並用水、鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.041mL,0.413mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到三種化合物。第一溶析：(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-羥基-2-甲基吡啶-3-基)乙酸(4.3mg,7.61μmol,18.45%產率)：1H NMR(500MHz,DMSO-d6)δ 7.38(dd,J=8.6,5.7Hz,2H),7.14(t,J=9.0Hz,3H),6.94(d,J=8.8Hz,3H),5.28(br.s.,1H),4.28-4.12(m,2H),3.05(t,J=6.8Hz,2H),2.71(br.s.,1H),2.21(s,3H),2.07(br.s.,1H),1.52(br.s.,1H),1.24(br.s.,1H),1.20(br.s.,1H),1.12(s,9H),1.00(d,J=10.3Hz,1H),0.84(br.s.,3H),0.67(br.s.,3H)。2個六氫吡啶氫、酸及酚質子未拆分。LCMS(M+H)=565.2。第二溶析：(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲氧基-2-甲基吡啶-3-基)乙酸(2.1mg,3.63μmol,8.79%產率)：1H NMR(500MHz,DMSO-d6)δ 7.38(dd,J=8.6,5.7Hz,2H),7.22-7.09(m,3H),6.98(t,J=8.3Hz,3H),5.66(s,1H),4.30-4.13(m,2H),3.05(t,J=6.6Hz,2H),2.82(t,J=12.3Hz,1H),2.41(s,3H),2.14(br.s.,1H),
1.51(br.s.,1H),1.30(br.s.,1H),1.19(d,J=14.3Hz,1H),1.12(s,9H),1.03(d,J=13.9Hz,1H),0.85(s,3H),0.64(s,3H)。5個六氫吡啶氫未拆分。LCMS(M+H)=579.2。第三溶析：(S)-2-(第三丁氧基)-2-(6-氯-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(1.8mg,3.09μmol,7.48%產率)：1H NMR(500MHz,DMSO-d6)δ 7.38(dd,J=8.6,5.7Hz,2H),7.29-7.22(m,1H),7.18-7.11(m,2H),7.08-6.99(m,3H),5.69(s,1H),4.29-4.16(m,2H),3.06(t,J=6.8Hz,2H),2.80(br.s.,1H),2.46(s,3H),2.21(br.s.,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.23(d,J=15.8Hz,1H),1.12(s,9H),1.07-0.99(m,1H),0.86(br.s.,3H),0.62(br.s.,3H)。2個六氫吡啶氫未拆分。LCMS(M+H)=584.2。
實例53
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基)吡啶-3-基)乙酸：將(S)-2-(第三丁氧基)-2-(6-氯-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(10mg,0.016mmol)及六氫吡啶(0.158mL,1.599mmol)於NMP(0.25mL)中之混合物於150℃下微波加熱32h。隨後將混合物用乙酸乙酯稀釋並用水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用EtOH(0.5mL)中之10N NaOH(0.016mL,0.160mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基)吡啶-3-基)乙
酸(1.8mg,2.85μmol,17.81%產率)。1H NMR(500MHz,DMSO-d6)δ 7.36(dd,J=8.4,5.9Hz,2H),7.25-7.13(m,4H),7.01(d,J=7.3Hz,2H),5.73(br.s.,1H),4.27-4.17(m,2H),3.94-3.77(m,1H),3.04(t,J=6.6Hz,2H),2.94(q,J=6.6Hz,1H),2.88-2.79(m,3H),2.75-2.65(m,2H),2.40(s,3H),2.07(d,J=11.4Hz,1H),1.52(br.s.,2H),1.32(d,J=11.4Hz,2H),1.24(s,4H),1.13(s,9H),0.97(d,J=11.0Hz,1H),0.89-0.79(m,4H),0.64(s,3H)。LCMS(M+H)=632.3。
(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯及(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯：於0℃下向(2-異丙氧基乙基)三苯基溴化鏻鹽(69.4mg,0.162mmol)於THF(1ml)中之懸浮液中添加NaH(6.63mg,0.166mmol)並將所得混合物於rt下攪拌45min。向溶解於THF(0.5mL)中之(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(50mg,0.081mmol)中逐滴添加THF(1ml)並將混合物於0℃下攪拌1h，隨後升溫至rt並攪拌2h。用水淬滅反應並用EtOAc萃取產物。將有機相用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。藉由急速層析(Biotage；0%-30% EtOAc/己烷)純化殘餘物，以得到兩種產物。(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧
基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(33mg,0.048mmol,59.3%產率)。1H NMR(500MHz,CDCl3)δ 7.31(br.s.,2H),7.15(d,J=7.6Hz,1H),7.11-7.01(m,3H),6.99-6.90(m,2H),6.10(br.s.,1H),6.06(d,J=12.1Hz,1H),5.81-5.74(m,1H),5.10(dt,J=12.4,6.1Hz,1H),4.78-4.70(m,2H),4.28-4.18(m,2H),3.69(dt,J=12.0,6.0Hz,1H),3.21(d,J=10.7Hz,1H),3.13(t,J=6.8Hz,2H),2.89(t,J=12.0Hz,1H),2.62(s,3H),2.27(d,J=11.0Hz,1H),2.11-2.00(m,1H),1.43-1.31(m,1H),1.26-1.16(m,22H),1.13-1.05(m,2H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=689.5。及(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(10mg,0.015mmol,17.96%產率)。1H NMR(500MHz,CDCl3)δ 7.31(br.s.,2H),7.16(d,J=7.1Hz,1H),7.10(d,J=9.0Hz,1H),7.05(t,J=8.4Hz,2H),7.00-6.93(m,2H),6.90(dt,J=15.2,5.5Hz,1H),6.33(d,J=15.3Hz,1H),6.08(br.s.,1H),5.10(dt,J=12.4,6.3Hz,1H),4.29-4.19(m,2H),4.05(d,J=5.0Hz,2H),3.57(dt,J=12.1,6.0Hz,1H),3.21(d,J=11.3Hz,1H),3.13(t,J=6.7Hz,2H),2.88(t,J=12.5Hz,1H),2.28(d,J=13.6Hz,1H),2.11-1.98(m,1H),1.42-1.27(m,3H),1.26-1.16(m,19H),1.08(dd,J=9.1,6.1Hz,6H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=689.5。
實例54
(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟 苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸：向(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(33mg,0.048mmol)於乙醇(1mL)中之溶液中添加10N NaOH(0.048mL,0.479mmol)並將所得混合物於80℃下加熱3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸(5.5mg,8.50μmol,17.75%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.32(m,2H),7.14(t,J=8.6Hz,3H),7.09-6.96(m,3H),5.92(d,J=12.1Hz,1H),5.86(br.s.,1H),5.69-5.59(m,1H),4.58(d,J=2.9Hz,2H),4.29-4.17(m,2H),3.59(dt,J=11.8,6.0Hz,1H),3.26(br.s.,1H),3.06(t,J=6.6Hz,2H),2.81(t,J=12.7Hz,1H),2.50(br.s.,3H),2.19(d,J=12.5Hz,1H),1.99-1.85(m,1H),1.49(br.s.,1H),1.35-1.24(m,1H),1.18(d,J=12.8Hz,1H),1.13(s,9H),1.08(d,J=3.7Hz,3H),1.09(d,J=3.7Hz,3H),1.02(d,J=12.5Hz,1H),0.85(s,3H),0.60(s,3H)。LCMS(M+H)=647.2。
實例55
(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸：向(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯
乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(10mg,0.015mmol)於乙醇(0.5mL)中之溶液中添加10N NaOH(0.015mL,0.145mmol)並將所得混合物於80℃下加熱3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S,Z)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸(1.7mg,2.63μmol,18.11%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(br.s.,2H),7.14(br.s.,3H),7.09-6.95(m,3H),6.70(d,J=15.0Hz,1H),6.19(d,J=15.0Hz,1H),5.86(br.s.,1H),4.23(d,J=6.2Hz,2H),3.94(br.s.,2H),3.24(br.s.,1H),3.05(br.s.,2H),2.82(br.s.,1H),2.48(s,3H),2.18(br.s.,1H),1.93(br.s.,1H),1.49(br.s.,1H),1.27(d,J=18.3Hz,1H),1.19(br.s.,1H),1.13(br.s.,9H),1.08(br.s.,1H),1.02(d,J=13.2Hz,1H),0.96(t,J=7.0Hz,6H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=647.2。
實例56
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙基)-2-甲基吡啶-3-基)乙酸：向(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙-1-烯-1-基)-2-甲基吡啶-3-基)乙酸(25mg,0.039mmol)於乙醇(1mL)中之溶液中添加10% Pd-C(8.23mg,7.73μmol)並將所得混合物在氫氣球氣氛下攪拌2h。隨後將混合物過濾並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶
-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(3-異丙氧基丙基)-2-甲基吡啶-3-基)乙酸(14.3mg,0.022mmol,57.0%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.3,5.7Hz,2H),7.20(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.08-6.94(m,3H),5.89(s,1H),4.31-4.14(m,2H),3.36-3.31(m,1H),3.24-3.14(m,4H),3.05(t,J=6.6Hz,2H),2.79(t,J=12.5Hz,1H),2.45(s,3H),2.35(br.s.,2H),2.19(d,J=10.3Hz,1H),1.72-1.57(m,2H),1.48(br.s.,1H),1.29(br.s.,1H),1.17(d,J=12.1Hz,1H),1.13(s,9H),1.02(d,J=12.8Hz,1H),0.95(t,J=5.5Hz,6H),0.84(s,3H),0.59(s,3H)。LCMS(M+H)=649.2。
(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸異丙基酯：於0℃下向(甲氧基甲基)三苯基氯化鏻鹽(78mg,0.226mmol)於THF(2ml)中之懸浮液中添加NaH(9.28mg,0.232mmol)並將所得混合物於rt下攪拌45min。向溶解於THF(0.5mL)中之(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(70mg,0.113mmol)中逐滴添加THF(2ml)並將混合物於0℃下攪拌1h，隨後升溫至rt並攪拌16h。用水淬滅反應並用EtOAc萃取產物。將有機相用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。藉由急速層析(Biotage；0%-30% EtOAc/己烷)純化殘餘物，以得到(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸異丙基酯(40mg,0.062mmol,54.7%產率)。1H NMR
(500MHz,CDCl3)δ 7.58(d,J=12.3Hz,1H),7.31(br.s.,1H),7.16(d,J=7.7Hz,1H),7.11-7.01(m,3H),6.99-6.92(m,2H),6.07(br.s.,1H),5.50(d,J=12.1Hz,1H),5.09(dt,J=12.5,6.3Hz,1H),4.30-4.16(m,2H),3.52(s,3H),3.21(d,J=12.0Hz,1H),3.13(t,J=6.9Hz,2H),2.87(t,J=11.7Hz,1H),2.59(s,3H),2.27(d,J=11.7Hz,1H),2.09-1.97(m,1H),1.55(br.s.,3H),1.39-1.28(m,1H),1.25-1.16(m,15H),1.07(d,J=9.1Hz,1H),0.90(s,3H),0.66(s,3H)。LCMS(M+H)=647.5。
實例57及58
(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙基)-2-甲基吡啶-3-基)乙酸：向(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸異丙基酯(30mg,0.046mmol)於乙醇(1mL)中之溶液中添加10N NaOH(0.046mL,0.464mmol)並將所得混合物於80℃下加熱5h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S,E)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙烯基)-2-甲基吡啶-3-基)乙酸(20mg,0.033mmol,71.3%產率)。1H NMR(500MHz,DMSO-d6)δ 7.44(d,J=12.1Hz,1H),7.41-7.32(m,2H),7.14(t,J=8.8Hz,3H),7.05-7.02(m,2H),5.81(s,1H),5.34(d,J=12.1Hz,1H),4.24(d,J=10.3Hz,2H),
3.44(s,3H),3.41(br.s.,7H),3.05(t,J=6.6Hz,2H),2.43(s,3H),1.12(s,9H),1.06-0.97(m,2H),0.84(s,3H),0.60(s,3H)。LCMS(M+H)=605.2。隨後將所得酸用乙醇(1mL)稀釋並用10% Pd-C(1.481mg,0.014mmol)處理並在氫氣球氣氛下攪拌3h。隨後將混合物過濾並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(2-甲氧基乙基)-2-甲基吡啶-3-基)乙酸(15.7mg,0.026mmol,55.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.35(m,2H),7.21(d,J=7.7Hz,1H),7.14(t,J=8.6Hz,2H),7.07-6.98(m,3H),5.84(br.s.,1H),4.24(d,J=8.8Hz,2H),3.56-3.44(m,3H),3.08(s,3H),3.05(t,J=6.6Hz,3H),2.85-2.74(m,1H),2.61-2.56(m,2H),2.45(s,3H),2.16(br.s.,1H),1.48(br.s.,1H),1.29(br.s.,1H),1.18(br.s.,1H),1.12(s,9H),1.01(d,J=9.5Hz,1H),0.84(s,3H),0.59(s,3H)。LCMS(M+H)=607.2。
實例59
(S)-2-(第三丁氧基)-2-(6-(3-(二甲基胺基)丙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於0℃下向(2-(二甲基胺基)乙基)三苯基溴化鏻鹽(67.0mg,0.162mmol)於THF(2ml)中之懸浮液中添加NaH(6.63mg,0.166mmol)並將所得混合物於rt下攪拌45min。逐滴添加溶解於THF(0.5mL)中之(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(50mg,0.081mmol)並將混合物於0℃下攪拌1h，隨後升溫至rt並攪拌2h。用水淬滅反應並用
EtOAc萃取產物。將有機相用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(2mL)中之10N NaOH(0.081ml,0.808mmol)處理4h。隨後將混合物冷卻並用乙酸中和。隨後添加10% Pd-C(17.20mg,0.016mmol)並將混合物在氫氣球氣氛下攪拌3h。隨後將混合物過濾並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(3-(二甲基胺基)丙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(11.4mg,0.018mmol,22.26%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.34(m,2H),7.21(d,J=8.1Hz,1H),7.14(t,J=9.0Hz,2H),7.08-6.93(m,3H),5.85(s,1H),4.31-4.17(m,2H),3.91(s,1H),3.18(s,1H),3.05(t,J=6.6Hz,2H),2.45(s,3H),2.37(s,1H),2.33-2.22(m,1H),2.19(br.s.,1H),2.07(d,J=5.5Hz,2H),1.98(s,6H),1.91(s,3H),1.58(s,1H),1.51(br.s.,2H),1.13(s,9H),1.01(d,J=11.7Hz,1H),0.85(s,3H),0.59(s,3H)。LCMS(M+H)=634.3。
實例60
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(4-甲氧基苄基)-2-甲基吡啶-3-基)乙酸：將(4-甲氧基苯基)酸(0.007g,0.046mmol)、(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.01g,0.015mmol)、碳酸鈉(0.06ml,0.120mmol)
於二噁烷(1mL)中之混合物脫氣並回填N2。添加Pd(Ph3P)4(0.004g,3.46μmol)並脫氣，回填N2。將混合物於80℃下在密封小瓶中攪拌18h。在減壓下移除溶劑，將殘餘物溶解於EtOH中並過濾出固體。於80℃下將濾液用氫氧化鈉(0.01g,0.250mmol)處理4h，隨後冷卻並藉由prep-HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(4-甲氧基苄基)-2-甲基吡啶-3-基)乙酸(0.0012g,1.794μmol,12.27%產率)。LCMS(M+H)=669.2。1H NMR(500MHz,DMSO-d6)δ 7.42-7.34(m,2H),7.18-7.08(m,3H),7.00(d,J=8.8Hz,2H),6.91(d,J=8.1Hz,1H),6.82-6.78(m,J=8.4Hz,2H),6.74-6.69(m,J=8.4Hz,2H),5.77(s,1H),4.29-4.20(m,2H),3.74(d,J=13.9Hz,1H),3.66(s,3H),3.56(d,J=13.9Hz,1H),3.06(t,J=6.8Hz,2H),2.75(t,J=11.9Hz,1H),2.45(s,3H),2.18(d,J=11.0Hz,1H),1.95-1.82(m,1H),1.52-1.45(m,1H),1.32-1.21(m,J=11.4Hz,1H),1.19-1.04(m,11H),1.00(d,J=14.3Hz,1H),0.84(s,3H),0.59(s,3H)。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸異丙基酯：於0℃下向甲基三苯基溴化鏻(90mg,0.323mmol)於THF(1ml)中之懸浮液中添加氫化鈉(13mg,0.325mmol)並將所得混合物於rt下攪拌45min。逐滴添加溶解於THF(0.5mL)中之(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(100mg,0.162mmol)並將混合物於0℃下攪拌1h，隨後
升溫至rt並攪拌2h。用水淬滅反應並用EtOAc萃取產物。將有機相用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。藉由矽膠急速層析(EtOAc/己烷：0%-30%)純化殘餘物，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸異丙基酯(0.05g,0.081mmol,50.2%產率)。1H NMR(500MHz,CDCl3)δ 7.33-7.27(m,2H),7.16(dd,J=8.6,2.1Hz,1H),7.11(dd,J=8.5,2.0Hz,1H),7.08-7.02(m,2H),7.00-6.94(m,2H),6.51-6.42(m,1H),6.36-6.29(m,1H),6.11(s,1H),5.23(dd,J=10.6,2.5Hz,1H),5.14-5.03(m,1H),4.24(td,J=6.8,3.5Hz,2H),3.26-3.18(m,1H),3.14(t,J=6.9Hz,2H),2.93-2.85(m,1H),2.65(s,3H),2.34-2.24(m,1H),2.07(s,1H),1.42(s,2H),1.25-1.21(m,7H),1.20(s,9H),1.08(d,J=12.0Hz,1H),0.91(s,3H),0.67(s,3H)。LCMS(M+H)=617.4。
實例61
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸：將(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸異丙基酯(10mg,0.016mmol)溶解於EtOH(1ml)中並添加氫氧化鈉(0.01g,0.250mmol)。將混合物於80℃下加熱18h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-乙烯基吡啶-3-基)乙酸(0.0021g,3.65μmol,22.54%產率)。LCMS
(M+H)=575.2。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲醯基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：於rt下向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(1.0g,2.1mmol)於CH2Cl2(19ml)中之攪拌溶液中一次性添加戴斯-馬丁過碘烷(1.3g,3.1mmol)。16h後，將反應混合物用醚稀釋，用1M NaOH、之後用鹽水洗滌。將有機相經(Na2SO4)乾燥，濃縮並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以得到(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲醯基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(960mg,1.99mmol,96%產率)。1H NMR(500MHz，氯仿-d)δ 10.29(s,1H),6.26(br s,1H),5.12-4.97(m,1H),4.15-4.05(m,1H),3.54(t,J=12.1Hz,1H),2.94(d,J=10.9Hz,1H),2.71(d,J=11.0Hz,1H),2.66-2.62(m,3H),1.59(br s,1H),1.51(br s,1H),1.41-1.35(m,1H),1.30-1.25(m,1H),1.22-1.18(m,12H),1.16-1.13(m,3H),1.11-1.03(m,6H)。LCMS(M+H)=483.0,485.0。
(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶甲酸：向(S)-2-(5-溴-4-(4,4-二甲基六
氫吡啶-1-基)-6-甲醯基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(2.0g,4.1mmol)於DMSO(41ml)中之溶液中添加水(10mL)中之磷酸二氫鉀(1.69g,12.4mmol)，之後添加水(10mL)中之亞氯酸鈉(1.12g,12.4mmol)，並將混合物攪拌過夜。立刻形成沈澱。在攪拌反應物時，沈澱物質黏附至燒瓶之側。在攪拌過夜後，倒掉溶液並將固體吸收於EtOAc中且隨後用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮，以得到預計產物。DMSO溶液亦含有相同產物。將其用EtOAc稀釋並用鹽水洗滌。將有機相經Na2SO4乾燥，並濃縮並與自沈澱分離之物質合併。合併之物質得到定量之(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶甲酸(定量)。LCMS(M+H)=499.04。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶甲酸(1.3g,2.60mmol)於甲苯(30mL)中之溶液中添加水(0.234mL,13.01mmol)，之後添加二苯基磷醯基疊氮化物(1.125mL,5.21mmol)並將所得混合物於90℃下加熱2h。隨後，將混合物冷卻至室溫，用EtOAc(100mL)稀釋並用飽和NaHCO3、水及鹽水洗滌。將有機層乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-50% EtOAc/己烷)純化殘餘物，以得到灰白色固體狀(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(800mg,1.757mmol,67.5%產率)。1H NMR(500MHz,CDC3)δ 8.46(s,1H),6.27(br.s.,1H),5.11-4.98(m,1H),4.03(t,J=10.6Hz,1H),3.45(t,J=11.3Hz,1H),2.92(d,
J=11.3Hz,1H),2.60-2.55(m,3H),1.62-1.55(m,2H),1.47(d,J=12.6Hz,1H),1.37(d,J=13.1Hz,1H),1.25-1.20(m,12H),1.15(d,J=6.1Hz,3H),1.09(s,3H),1.04(s,3H)。LCMS(M+2H)=457.4。
實例62
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.044mmol)及10N NaOH(0.044mL,0.439mmol)於乙醇(1mL)中之混合物於80℃下加熱5h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(11.9mg,0.029mmol,65.6%產率)。1H NMR(500MHz,DMSO-d6)δ 8.42(s,1H),5.94(br.s.,1H),3.91(t,J=11.6Hz,1H),2.97(br.s.,1H),2.47-2.41(m,3H),1.63-1.48(m,2H),1.42(d,J=12.1Hz,1H),1.32(d,J=12.5Hz,1H),1.15(s,9H),1.03(s,3H),0.99(s,3H)。2個六氫吡啶氫未拆分。LCMS(M+H)=413.0。
實例63
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(80mg,
0.176mmol)、2-(4-(4-氟苯乙氧基)苯基)-6-甲基-1,3,6,2-二氧氮雜硼雜環辛烷-4,8-二酮(98mg,0.263mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(14.42mg,0.035mmol)及2M K3PO4(0.659mL,1.317mmol)於1,4-二噁烷(3mL)及水(0.600mL)中之混合物脫氣10min。隨後，添加Pd(OAc)2(3.94mg,0.018mmol)，脫氣5min並將混合物於80℃下加熱3h。在冷卻至室溫後，添加水並將混合物用乙酸乙酯萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用EtOH(3mL)中之10N NaOH(0.176mL,1.757mmol)處理5h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(72mg,0.131mmol,74.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.99(s,1H),7.37(dd,J=8.4,5.5Hz,2H),7.25-7.18(m,J=8.8Hz,2H),7.13(t,J=9.0Hz,2H),7.04-6.97(m,J=8.8Hz,2H),5.82(s,1H),4.29-4.13(m,2H),3.05(t,J=6.6Hz,2H),2.47(s,3H),1.54(br.s.,1H),1.30(br.s.,2H),1.11(s,9H),0.86(br.s.,3H),0.73(br.s.,3H)。6個六氫吡啶氫未拆分。LCMS(M+H)=549.4。
實例64
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸：向甲胺(0.1mL,0.200mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt
下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱4h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(0.0114g,0.019mmol,43.9%產率)。LCMS(M+H)=592.1H NMR(500MHz,DMSO-d6)δ 7.41-7.34(m,2H),7.23(d,J=7.7Hz,1H),7.14(t,J=8.6Hz,2H),7.06-6.97(m,3H),5.59(s,1H),4.28-4.18(m,2H),3.37(s,1H),3.06(t,J=6.6Hz,2H),2.90(s,1H),2.74(s,1H),2.55(s,1H),2.48(s,3H),2.36(s,3H),2.15(br.s.,1H),1.49(br.s.,1H),1.28(br.s.,1H),1.13(d,J=13.6Hz,1H),1.08(s,9H),1.00(d,J=9.9Hz,1H),0.83(br.s.,3H),0.61(br.s.,3H)。
實例65
(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向二甲胺/THF(0.2mL,0.400mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌3h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0231g,87%)。LCMS(M+H)=606.2。1H NMR(500MHz,DMSO-d6)δ 7.42-7.34(m,1H),7.14(t,J=8.6Hz,2H),7.05-6.94(m,3H),5.83(br.s.,1H),4.32-4.16(m,
2H),3.59-3.26(m,7H),3.16(d,J=13.6Hz,1H),3.05(d,J=7.7Hz,1H),2.85-2.76(m,1H),2.47(s,3H),2.17(br.s.,1H),2.07(s,6H),1.50(br.s.,1H),1.30(br.s.,1H),1.18(d,J=12.8Hz,1H),1.12(s,9H),1.02(d,J=12.1Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。
實例66
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((異丙基胺基)甲基)-2-甲基吡啶-3-基)乙酸：向異丙胺(0.05mL,0.770mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((異丙基胺基)甲基)-2-甲基吡啶-3-基)乙酸(0.0221g,0.036mmol,81%產率)。LCMS(M+H)=620.3。
實例67
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸：向(四氫-2H-吡喃-4-基)甲胺(0.1g,0.868mmol)於乙醇(0.5mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.06g,0.088mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸(0.0342g,0.051mmol,57.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.44-7.35(m,2H),7.24(d,J=8.8Hz,1H),7.14(t,J=8.8Hz,2H),7.05(s,2H),7.01(d,J=8.1Hz,1H),5.74(br.s.,1H),4.31-4.17(m,2H),3.82-3.72(m,2H),3.47(d,J=13.9Hz,2H),3.31(d,J=13.9Hz,1H),3.24-3.12(m,3H),3.05(d,J=6.2Hz,1H),2.79(t,J=8.3Hz,1H),2.48(s,3H),2.36(d,J=5.5Hz,2H),2.22-2.13(m,J=8.1Hz,1H),1.97-1.92(m,1H),1.57-1.44(m,4H),1.35-1.23(m,1H),1.16(d,J=10.6Hz,1H),1.11(s,9H),1.08-0.98(m,3H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=676.2。
實例68
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸：
向2-甲氧基乙胺(0.1g,1.331mmol)於乙醇(0.5mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.06g,0.088mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸(0.040g,0.063mmol,71.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.35(m,2H),7.22(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.05(s,2H),7.01(d,J=8.4Hz,1H),5.79(s,1H),4.32-4.14(m,2H),3.46(d,J=13.9Hz,1H),3.43-3.35(m,J=9.2Hz,3H),3.31(d,J=4.8Hz,1H),3.17(s,3H),3.06(t,J=6.2Hz,2H),2.83-2.76(m,J=13.0,13.0Hz,1H),2.62-2.57(m,2H),2.48(s,3H),2.21-2.14(m,1H),1.99-1.92(m,1H),1.55-1.43(m,1H),1.35-1.24(m,1H),1.17(d,J=12.1Hz,1H),1.12(s,9H),1.05-0.98(m,J=11.4Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=636.3。
實例69
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-羥基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸：向2-胺基乙醇(0.02g,0.327mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲
基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱4h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-羥基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸(0.0116g,0.019mmol,42.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.43-7.34(m,2H),7.23(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.07-6.91(m,3H),5.69(br.s.,1H),4.31-4.16(m,2H),3.60(d,J=14.7Hz,1H),3.36(d,J=13.9Hz,1H),3.72-3.24(m,7H),3.06(t,J=6.4Hz,1H),2.83-2.71(m,2H),2.64(br.s.,2H),2.48(s,3H),2.16(br.s.,1H),1.49(br.s.,1H),1.28(br.s.,1H),1.14(br.s.,1H),1.10(s,9H),1.01(d,J=10.6Hz,1H),0.84(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=622.2。
實例70
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(嗎啉基甲基)吡啶-3-基)乙酸：向嗎啉(0.04g,0.459mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(嗎啉基甲基)
吡啶-3-基)乙酸(0.0232g,0.036mmol,82%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.32(m,3H),7.14(t,J=8.6Hz,2H),7.06-6.93(m,3H),5.81(br.s.,1H),4.34-4.14(m,2H),3.63-3.27(m,4H),3.21-2.99(m,5H),2.85-2.77(m,1H),2.46(s,3H),2.18(br.s.,5H),1.98-1.92(m,1H),1.57-1.45(m,1H),1.30(br.s.,1H),1.16(br.s.,1H),1.11(s,9H),1.02(d,J=13.9Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS((M+H)=648.4。
實例71
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((乙基胺基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向乙胺(0.04g,0.621mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱4h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((乙基胺基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0202g,0.033mmol,74.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.34(m,2H),7.25(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.06-6.94(m,3H),5.63(s,1H),4.30-4.18(m,2H),3.65(d,J=14.7Hz,2H),3.36(d,J=14.7Hz,1H),2.90(s,1H),2.74(s,2H),2.63(d,J=7.0Hz,2H),2.49(s,3H),2.23-2.12(m,1H),1.50(br.s.,1H),1.28(br.s.,1H),1.20-1.11(m,1H),1.09(s,9H),
1.01(t,J=7.2Hz,4H),0.84(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=606.2。
實例72
(S)-2-(6-((苄基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向苯基甲胺(0.04g,0.373mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-((苄基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0157g,0.023mmol,52.0%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.35(m,2H),7.28-7.11(m,8H),7.04(q,J=8.4Hz,2H),6.95(d,J=7.7Hz,1H),5.82(br.s.,1H),4.22(dd,J=11.7,6.6Hz,2H),3.69-3.58(m,3H),3.46-3.25(m,5H),3.05(d,J=6.6Hz,1H),2.80(br.s.,1H),2.49(s,3H),2.23-2.11(m,J=12.5Hz,1H),1.98-1.92(m,1H),1.56-1.42(m,1H),1.34-1.23(m,1H),1.18(d,J=12.1Hz,1H),1.13(s,9H),1.02(d,J=12.5Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=668.2。
實例73
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((苯基胺基)甲基)吡啶-3-基)乙酸：向苯胺(0.025g,0.263mmol)於THF(2mL)中之溶液中添加t-BuOK(0.03g,0.267mmol)，將混合物於rt下攪拌5min，隨後添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.06g,0.088mmol)並於rt下攪拌4天。添加氫氧化鈉(0.04g,1.000mmol)並於80℃下加熱4h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((苯基胺基)甲基)吡啶-3-基)乙酸(0.0207g,0.032mmol,36.1%產率。1H NMR(500MHz,DMSO-d6)δ 7.45-7.35(m,J=6.6,6.6Hz,1H),7.33(d,J=8.1Hz,1H),7.19-7.10(m,3H),7.09-6.99(m,4H),6.55-6.48(m,J=7.3,7.3Hz,1H),6.45(d,J=8.1Hz,2H),5.88(br.s.,1H),4.30-4.18(m,2H),3.91(d,J=14.7Hz,1H),3.72(d,J=14.7Hz,1H),3.06(t,J=6.4Hz,2H),2.88-2.79(m,1H),2.54(s,3H),2.25-2.19(m,J=12.1Hz,1H),2.03-1.90(m,1H),1.51(br.s.,1H),1.34-1.17(m,2H),1.15(s,9H),1.04(d,J=12.5Hz,1H),0.86(br.s.,3H),0.62(br.s.,3H)，丟失4個質子)。LCMS(M+H)=654.2。
實例74
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸：向吡啶-4-基甲胺(20mg,0.185mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.025g,0.625mmol)並於80℃下加熱4h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸(0.0189g,0.027mmol,62.5%產率)。1H NMR(500MHz,DMSO-d6)δ 8.39(d,J=5.1Hz,2H),7.40-7.32(m,2H),7.20-7.11(m,5H),7.08-6.98(m,2H),6.93(d,J=6.2Hz,1H),5.81(br.s.,1H),4.30-4.13(m,2H),3.37(d,J=13.6Hz,1H),3.27(d,J=13.6Hz,1H),3.05(t,J=6.6Hz,2H),2.80(br.s.,1H),2.50(br.s.,3H),2.22-2.14(m,J=5.1Hz,1H),2.02-2.00(m,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.19(br.s.,1H),1.13(s,9H),1.02(d,J=12.8Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=669.2。
實例75
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸：向吡咯啶(0.020g,0.281mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.025g,0.625mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸(0.0176g,0.028mmol,63.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(t,J=6.6Hz,2H),7.31(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.02(s,2H),6.99(d,J=8.8Hz,1H),5.80(s,1H),4.31-4.13(m,2H),3.46(d,J=13.2Hz,1H),3.23(d,J=12.5Hz,1H),3.05(t,J=6.6Hz,2H),2.80(br.s.,1H),2.47(s,3H),2.43(br.s.,4H),2.18(br.s.,1H),1.61(br.s.,4H),1.50(br.s.,1H),1.33-1.23(m,J=5.9Hz,1H),1.17(d,J=11.0Hz,1H),1.14-1.09(m,9H),1.02(d,J=12.1Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=632.2。
實例76
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((氧雜環丁-3-基甲基)胺基)甲基)吡啶-3-基)乙酸：向氧雜環丁-3-基甲胺(0.01g,0.115mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.025g,0.625mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((氧雜環丁-3-基甲基)胺基)甲基)吡啶-3-基)乙酸(0.0074g,0.011mmol,25.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.34(m,2H),7.24(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.05(s,2H),7.02(d,J=8.4Hz,1H),5.77(s,1H),4.58-4.47(m,2H),4.29-4.21(m,2H),4.18(t,J=5.9Hz,2H),3.46(d,J=13.9Hz,1H),3.65-3.33(m,5H),3.28(d,J=13.9Hz,1H),3.06(t,J=6.4Hz,2H),2.97-2.90(m,1H),2.83-2.76(m,J=9.5Hz,1H),2.48(s,3H),2.21-2.14(m,J=9.9Hz,1H),1.97-1.92(m,1H),1.49(br.s.,1H),1.34-1.23(m,1H),1.17(d,J=12.1Hz,1H),1.14-1.08(m,9H),1.02(d,J=13.2Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=648.2。
實例77
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基胺基)甲基)吡啶-3-基)乙酸：向氧雜環丁-3-胺(0.03g,0.410mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.045g,0.066mmol)並將混合物於rt下攪拌2h。添加氫氧化鈉(0.050g,1.250mmol)並於80℃下加熱3h，隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((氧雜環丁-3-基胺基)甲基)吡啶-3-基)乙酸(0.0049g,7.31μmol,11.11%產率)。LCMS(M+H)=634.2。
實例78
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((噁唑-4-基甲基)胺基)甲基)吡啶-3-基)乙酸：向噁唑-4-基甲胺，HCl(0.02g,0.149mmol)及TEA(0.05ml,0.359mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌2h。添
加氫氧化鈉(0.025g,0.625mmol)並於80℃下加熱4h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((噁唑-4-基甲基)胺基)甲基)吡啶-3-基)乙酸(0.0042g,6.38μmol,14.53%產率)。1H NMR(500MHz,DMSO-d6)δ 8.23(s,1H),7.76(s,1H),7.43-7.35(m,2H),7.21(d,J=8.1Hz,1H),7.15(t,J=8.6Hz,2H),7.08-7.02(m,2H),6.98(d,J=8.4Hz,1H),5.81(br.s.,1H),4.31-4.15(m,2H),3.44(d,J=13.6Hz,2H),3.38-3.30(m,3H),3.30(d,J=13.9Hz,1H),3.06(t,J=6.4Hz,2H),2.80(br.s.,1H),2.48(s,3H),2.17(br.s.,1H),1.50(br.s.,1H),1.29(br.s.,1H),1.18(d,J=13.6Hz,1H),1.12(s,9H),1.02(d,J=15.4Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=659.1
實例79
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸：向硫嗎啉(0.03g,0.291mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌18h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱2h。隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸(0.0226g,0.034mmol,78%產率)。1H NMR
(500MHz,DMSO-d6)δ 7.41-7.35(m,2H),7.33(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.03(s,2H),6.98(s,1H),5.82(br.s.,1H),4.31-4.15(m,2H),3.20(d,J=12.5Hz,1H),3.06(d,J=7.7Hz,3H),2.80(br.s.,1H),2.48-2.34(m,12H),2.19(d,J=10.3Hz,1H),2.01-1.92(m,1H),1.56-1.43(m,1H),1.35-1.25(m,1H),1.17(d,J=13.6Hz,1H),1.12(s,9H),1.02(d,J=12.5Hz,1H),0.85(s.,3H),0.60(s.,3H)。LCMS(M+H)=664.2。
實例80
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸：向六氫吡啶(0.03g,0.352mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌18h。添加氫氧化鈉(0.03g,0.750mmol)並將混合物於80℃下加熱3h。隨後冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸(0.0238g,0.037mmol,84%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.32(m,3H),7.14(t,J=8.8Hz,2H),7.01(s,2H),6.97(d,J=9.2Hz,1H),5.83(br.s.,1H),4.33-4.18(m,2H),3.34(br.s.,3H),3.12-3.02(m,1H),2.80(br.s.,1H),2.46(s,3H),2.18(br.s.,3H),2.14(br.s.,2H),1.99-1.91(m,
1H),1.50(br.s.,1H),1.34(br.s.,4H),1.30(br.s.,3H),1.17(d,J=12.5Hz,1H),1.12(s,9H),1.02(d,J=12.1Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=646.2。
實例81
(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向氮雜環丁烷(0.03g,0.525mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌18h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0179g,0.027mmol,62.1%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.35(m,2H),7.26(d,J=9.2Hz,1H),7.14(t,J=8.6Hz,2H),7.04-6.97(m,3H),5.75(br.s.,1H),4.27-4.18(m,2H),3.44(d,J=13.6Hz,3H),3.29(br.s.,1H),3.08-2.99(m,2H),2.76(d,J=17.6Hz,1H),2.46(s,3H),2.14(br.s.,1H),1.96(t,J=7.2Hz,2H),1.49(br.s.,1H),1.28(br.s.,1H),1.16(d,J=9.9Hz,1H),1.12-1.07(m,9H),1.03(d,J=9.5Hz,4H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=618.2。
實例82
(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向7-氮雜螺[3.5]壬烷(0.05g,0.399mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.05g,0.073mmol)並將混合物於rt下攪拌18h。添加EtOH(1ml)及氫氧化鈉(0.03g,0.750mmol)並將混合物於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0465g,0.068mmol,93%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.30(m,3H),7.14(t,J=8.8Hz,2H),7.01(s,2H),6.97(d,J=8.8Hz,1H),5.86(s,1H),4.30-4.14(m,2H),3.30-3.20(m,1H),3.09(br.s.,2H),3.04(t,J=6.4Hz,2H),2.84-2.76(m,1H),2.46(s,3H),2.23-2.04(m,5H),1.98-1.92(m,1H),1.82-1.72(m,2H),1.67-1.59(m,4H),1.53-1.46(m,1H),1.40(br.s.,4H),1.34-1.23(m,1H),1.21-1.14(m,1H),1.12(s,9H),1.04-0.93(m,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=686.3。
實例83
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((1,1-二氧離子基硫嗎啉基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向硫嗎啉1,1-二氧化物(0.03g,0.222mmol)於乙醇(2mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.03g,0.044mmol)並將混合物於rt下攪拌18h。添加氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((1,1-二氧離子基硫嗎啉基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0117g,0.017mmol,38.3%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.30(m,3H),7.15(t,J=8.8Hz,2H),7.09-6.97(m,3H),5.84(br.s.,1H),4.33-4.15(m,2H),3.38(br.s.,1H),3.26-3.20(m,1H),3.05(t,J=6.6Hz,2H),3.01-2.93(m,2H),2.90(s,3H),2.84-2.77(m,J=12.5Hz,1H),2.76-2.66(m,4H),2.47(s,3H),2.24-2.14(m,1H),2.02-1.92(m,1H),1.50(br.s.,1H),1.30(br.s.,1H),1.18(d,J=12.1Hz,1H),1.13(s,9H),1.02(br.s.,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=696.1。
實例84
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸：向N-甲基-1-(四氫-2H-吡喃-4-基)甲胺(0.04g,0.310mmol)於乙醇(0.5mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.05g,0.073mmol)。將混合物於rt下攪拌1h並添加氫氧化鈉(0.04g,1.000mmol)。隨後，將反應混合物於80℃下加熱2.5h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸(0.0477g,0.069mmol,95%產率)。LCMS(M+H)=690.3。
實例85
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-甲氧基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙 酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及4-甲氧基六氫吡啶(0.02g,0.174mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-甲氧基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(0.0116g,0.017mmol,78%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.4,5.9Hz,2H),7.32(d,J=8.8Hz,1H),7.13(t,J=8.8Hz,2H),7.01(s,2H),6.97(d,J=9.2Hz,1H),5.83(s,1H),4.28-4.14(m,2H),3.35-3.27(m,1H),3.16(s,3H),3.13-3.00(m,4H),2.85-2.76(m,1H),2.45(s,4H),2.43-2.32(m,2H),2.21-2.12(m,1H),2.02-1.92(m,3H),1.68(d,J=11.0Hz,2H),1.54-1.44(m,1H),1.33-1.15(m,4H),1.12(s,9H),1.05-0.96(m,1H),0.84(br.s.,3H),0.60(br.s.,3H)；LCMS(M+H)=676.2。
實例86
(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,
0.022mmol)、4,4-二氟六氫吡啶，HCl(0.015g,0.095mmol)及TEA(0.02ml,0.143mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0128g,0.019mmol,86%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.30(m,3H),7.14(t,J=9.0Hz,2H),7.06-6.97(m,3H),5.80(s,1H),4.28-4.17(m,2H),3.37(br.s.,1H),3.22(d,J=12.4Hz,1H),3.13(d,J=12.3Hz,1H),3.05(t,J=6.8Hz,2H),2.80(br.s.,1H),2.46(s,3H),2.38-2.26(m,4H),2.22-2.11(m,1H),1.99-1.93(m,1H),1.87-1.70(m,4H),1.58-1.44(m,1H),1.37-1.25(m,1H),1.20-1.14(m,1H),1.12(s,9H),1.03(d,J=6.2Hz,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=682.2。
實例87
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-羥基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：將六氫吡啶-4-醇(0.02g,0.198mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80
℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-羥基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(0.0133g,0.020mmol,91%產率)。1H NMR(500MHz,DMSO-d6)δ 7.39-7.29(m,3H),7.13(t,J=8.6Hz,2H),7.01(s,2H),6.97(d,J=9.2Hz,1H),5.82(s,1H),4.31-4.13(m,2H),3.47(br.s.,5H),3.34(br.s.,2H),3.09(d,J=5.1Hz,2H),3.05(t,J=6.6Hz,2H),2.83-2.76(m,1H),2.46(s,3H),2.41(br.s.,1H),2.22-2.11(m,1H),1.94(d,J=11.0Hz,2H),1.57(d,J=11.0Hz,2H),1.54-1.42(m,1H),1.28(d,J=9.5Hz,2H),1.21-1.16(m,1H),1.12(s,9H),1.03(br.s.,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=662.2。
實例88
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及4,4-二甲基六氫吡啶(0.02g,0.177mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡
啶-1-基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0136g,0.019mmol,88%產率)。1H NMR(500MHz,DMSO-d6)δ 7.36(dt,J=8.3,5.8Hz,3H),7.13(t,J=8.8Hz,2H),7.01(s,2H),6.97(d,J=8.4Hz,1H),5.80(s,1H),4.31-4.16(m,2H),3.37(br.s.,2H),3.14(s,2H),3.04(t,J=6.8Hz,2H),2.86-2.75(m,1H),2.45(s,3H),2.30-2.13(m,5H),1.96-1.91(m,1H),1.55-1.40(m,1H),1.34-1.25(m,1H),1.25-1.14(m,5H),1.11(s,9H),1.05-0.96(m,1H),0.84(br.s.,3H),0.84-0.80(m,6H),0.60(br.s.,3H)。LCMS(M+H)=674.2。
實例89
(S)-2-(第三丁氧基)-2-(6-((3,4-二氫喹啉-1(2H)-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及1,2,3,4-四氫喹啉(0.02g,0.150mmol)於THF(0.5mL)中之溶液中添加第三丁醇鉀(0.008g,0.071mmol)並於rt下攪拌18h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((3,4-二氫喹啉-1(2H)-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0084g,0.012mmol,55.2%產率)。1H NMR(500MHz,DMSO-d6)δ 7.36(dd,J=8.1,5.9Hz,2H),7.30(d,J=8.4Hz,1H),7.13(t,J=8.8Hz,3H),7.10-7.05(m,1H),7.02
(dd,J=8.4,2.2Hz,1H),6.78(d,J=7.3Hz,1H),6.73(t,J=7.7Hz,1H),6.35(t,J=7.3Hz,1H),6.19(d,J=8.4Hz,1H),5.84(s,1H),4.32-4.17(m,2H),4.13(d,J=16.1Hz,1H),4.04(d,J=16.1Hz,1H),3.35-3.23(m,2H),3.14-3.08(m,J=5.5Hz,1H),3.04(t,J=6.6Hz,2H),2.82(t,J=12.5Hz,1H),2.66-2.57(m,J=4.8Hz,2H),2.41(s,3H),2.22(d,J=12.1Hz,1H),1.97(t,J=12.1Hz,1H),1.77(dd,J=11.4,5.5Hz,2H),1.55-1.44(m,1H),1.34-1.26(m,1H),1.17(d,J=12.8Hz,1H),1.12(s,9H),1.03(d,J=11.7Hz,1H),0.85(s,3H),0.60(s,3H)。LCMS(M+H)=694.2。
實例90
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)、4-氟六氫吡啶，HCl(0.015g,0.107mmol)及TEA(0.02ml,0.143mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(0.0115g,0.017mmol,77%產率)。1H NMR(500MHz,
DMSO-d6)δ 7.38(d,J=5.5Hz,1H),7.13(t,J=8.8Hz,2H),7.06-6.94(m,3H),5.85(s,1H),4.66-4.44(m,1H),4.29-4.15(m,2H),3.31-3.24(m,1H),3.18-3.12(m,1H),3.09-3.01(m,3H),2.85-2.75(m,1H),2.46(s,3H),2.41-2.25(m,2H),2.22-2.04(m,3H),1.99-1.92(m,1H),1.80-1.63(m,2H),1.60-1.44(m,3H),1.35-1.23(m,1H),1.20-1.15(m,1H),1.12(s,9H),1.03(br.s.,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=664.2。
實例91
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基苯基)胺基)甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及2-甲氧基苯胺(0.02g,0.162mmol)於THF(0.5mL)中之溶液中添加t-BuOK(0.008g,0.071mmol)並於rt下攪拌4h。隨後，添加NaOH(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(((2-甲氧基苯基)胺基)甲基)-2-甲基吡啶-3-基)乙酸(0.0088g,0.013mmol,58.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.44-7.36(m,2H),7.32(d,J=8.4Hz,1H),7.15(t,J=8.8Hz,2H),7.11-7.04(m,3H),6.80(d,J=7.7Hz,1H),6.70(t,J=7.7Hz,1H),6.53(t,J=7.7Hz,1H),6.17(d,J=7.7Hz,1H),
5.87(br.s.,1H),4.30-4.21(m,2H),3.98(d,J=15.4Hz,1H),3.80(s,3H),3.68(d,J=15.4Hz,1H),3.35(br.s.,1H),3.07(t,J=6.6Hz,2H),2.81-2.81(m,1H),2.88-2.79(m,1H),2.28-2.19(m,J=1.5Hz,1H),2.02-1.92(m,1H),1.56-1.47(m,1H),1.35-1.27(m,1H),1.20(d,J=12.1Hz,1H),1.15(s,9H),1.05(d,J=11.7Hz,1H),0.86(s,3H),0.62(s,3H)。Me質子未拆分。LCMS(M+H)=684.2。
實例92
(2S)-2-(第三丁氧基)-2-(6-((2,6-二甲基嗎啉基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及2,6-二甲基嗎啉(0.02g,0.174mmol)於EtOH(1mL)中之溶液攪拌18h。添加氫氧化鈉(0.015g,0.375mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(2S)-2-(第三丁氧基)-2-(6-((2,6-二甲基嗎啉基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0102g,0.015mmol,68.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.3,5.7Hz,2H),7.32(d,J=8.8Hz,1H),7.14(t,J=8.8Hz,2H),7.02(br.s.,2H),6.98(d,J=8.4Hz,1H),5.82(br.s.,1H),4.29-4.18(m,2H),3.50-3.26(m,4H),3.09-3.01(m,2H),2.80(br.s.,1H),2.46(s,3H),2.39(d,J=10.6Hz,1H),2.33(d,J=11.4Hz,2H),2.20(d,J=12.8Hz,2H),
1.91(s,1H),1.59(t,J=10.6Hz,1H),1.55-1.45(m,1H),1.30(br.s.,1H),1.17(d,J=13.2Hz,1H),1.12(s,9H),0.95(d,J=6.2Hz,3H),0.91(d,J=6.2Hz,3H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=676.2。
實例93
(S)-2-(6-((雙(2-甲氧基乙基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及雙(2-甲氧基乙基)胺(0.02g,0.150mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-((雙(2-甲氧基乙基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0127g,0.018mmol,83%產率)。LCMS(M+H)=694.2。
實例94
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸：將1-甲基六氫吡嗪(0.02g,0.200mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸(0.0146g,0.021mmol,98%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.30(m,3H),7.14(t,J=9.0Hz,2H),7.01(s,2H),6.97(d,J=9.2Hz,1H),5.83(s,1H),4.31-4.15(m,2H),3.57-3.25(m,4H),3.12-3.00(m,4H),2.85-2.75(m,1H),2.55(s,2H),2.45(s,3H),2.20(br.s.,4H),2.09(s,3H),1.98-1.93(m,1H),1.55-1.42(m,1H),1.31-1.23(m,1H),1.20-1.15(m,1H),1.12(s,9H),1.05-0.97(m,1H),0.85(br.s.,3H),0.60(s,3H)。LCMS(M+H)=661.2。
實例95
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-2-基甲基)胺基)甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.015g,0.022mmol)及吡啶-2-基甲胺(0.02g,0.185mmol)於EtOH(1mL)中之溶液於rt下攪拌2h。隨後，添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌5h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((吡啶-2-基甲基)胺基)甲基)吡啶-3-基)乙酸(0.0048g,32%)。LCMS(M+H)=669.2。
實例96
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.04g,0.059mmol)、(1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛烷，HCl(0.04g,0.246mmol)及三乙胺(0.04ml,0.287mmol)
於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸(0.0394g,0.057mmol,98%產率)。LCMS(M+H)=687.3。
實例97
(S)-2-(6-((苄基(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.012g,0.018mmol)及N-甲基-1-苯基甲胺(0.02g,0.165mmol)於EtOH(1mL)中之溶液於rt下攪拌2h。隨後，添加NaOH(0.01g,0.250mmol)並將反應混合物於80℃下攪拌2h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-((苄基(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0082g,0.012mmol,68.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.33(m,3H),7.25-7.19(m,2H),7.16(s,1H),7.15-7.08(m,4H),7.05-7.00(m,2H),6.99-6.94(m,J=8.4Hz,1H),5.85(s,1H),4.28-4.16(m,2H),3.35-3.29(m,1H),3.28-3.16(m,3H),3.04(t,J=6.6Hz,2H),2.86-2.78(m,1H),2.48(s,3H),2.27-2.15(m,1H),1.96-1.91(m,1H),1.90(s,3H),1.56-1.43(m,1H),1.34-1.26(m,1H),1.20-1.15
(m,1H),1.11(s,9H),1.05-0.99(m,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=682.3。
實例98
(2S)-2-(6-((3-苄基-3,6-二氮雜二環[3.1.1]庚-6-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.012g,0.018mmol)、(1R,5S)-3-苄基-3,6-二氮雜二環[3.1.1]庚烷(0.03g,0.159mmol)於EtOH(1mL)中之溶液攪拌2h。添加氫氧化鈉(0.01g,0.250mmol)並將反應混合物於80℃下攪拌2h，冷卻並藉由製備型HPLC純化，以得到(2S)-2-(6-((3-苄基-3,6-二氮雜二環[3.1.1]庚-6-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0059g,7.80μmol,44.4%產率)。LCMS(M+H)=749.3。
實例99
(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向
(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.04g,0.059mmol)於EtOH(1mL)中之攪拌溶液中添加環己基甲胺(0.05g,0.442mmol)。將混合物於rt下攪拌2h。隨後，添加氫氧化鈉(0.03g,0.750mmol)並於80℃下攪拌3h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0121g,0.018mmol,30.1%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37(dd,J=8.3,5.7Hz,2H),7.23(d,J=7.7Hz,1H),7.14(t,J=8.8Hz,2H),7.04(s,2H),7.01(d,J=7.7Hz,1H),5.71(br.s.,1H),4.28-4.17(m,2H),3.53(d,J=13.9Hz,1H),3.33(d,J=13.9Hz,1H),3.05(t,J=6.8Hz,2H),2.83-2.75(m,1H),2.48(s,3H),2.36(d,J=6.2Hz,2H),2.20-2.13(m,1H),1.99-1.91(m,1H),1.67-1.54(m,5H),1.54-1.42(m,1H),1.31(br.s.,2H),1.24-0.96(m,15H),0.84(br.s.,3H),0.80(d,J=11.0Hz,2H),0.61(br.s.,3H)。LCMS(M+H)=674.3。
實例100
(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0096g,0.014mmol)於MeOH(0.2mL)中之溶液中添加甲醛水溶液(5μl,0.067mmol)。將混合物於rt下攪拌2h且隨後添加三乙醯氧基硼氫
化鈉(0.015g,0.071mmol)。3h後，藉由製備型HPLC純化粗製混合物，以得到(S)-2-(第三丁氧基)-2-(6-(((環己基甲基)(甲基)胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0090g,0.013mmol,92%產率)。1H NMR(500MHz,DMSO-d6)δ 7.44-7.34(m,3H),7.13(t,J=8.8Hz,2H),7.03-6.93(m,3H),5.76(s,1H),4.27-4.16(m,2H),3.15-3.09(m,1H),3.07-3.00(m,3H),2.84-2.75(m,1H),2.45(s,3H),2.13(br.s.,2H),1.98(s,3H),1.50(br.s.,6H),1.31-1.23(m,1H),1.17(br.s.,2H),1.09(s,9H),1.03(br.s.,4H),0.84(br.s.,3H),0.61(br.s.,5H)。LCMS(M+H)=688.3。
實例101
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(0.015g,0.025mmol)及TEA(0.02ml,0.143mmol)於DCM(0.5mL)中之溶液中添加乙醯氯(0.005mL,0.070mmol)。將混合物於rt下攪拌0.5h，用水淬滅，濃縮並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸(0.0098g,0.015mmol,61.0%產率)。LCMS(M+H)=534.2。
實例102
(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-N-甲基-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向2-(二甲基胺基)-2-側氧基乙酸(30mg,0.256mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.05ml,0.100mmol)。將混合物於rt下攪拌1h，在真空下濃縮至乾燥。將殘餘物溶解於THF(0.5ml)中並添加至(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(0.015g,0.025mmol)及TEA(0.06ml,0.430mmol)於THF(0.5ml)中之溶液中。將混合物於rt下攪拌2h，移除溶劑並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-N-甲基-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0063g,9.12μmol,36.0%產率)。LCMS(M+H)=691.2。
實例103
(S)-2-(第三丁氧基)-2-(6-((N,5-二甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基 吡啶-3-基)乙酸：向5-甲基-1,3,4-噁二唑-2-甲酸鉀(0.101g,0.608mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.190ml,0.380mmol)。將混合物於rt下攪拌1h，在真空下濃縮至乾燥。將殘餘物溶解於DCM(0.5mL)中並添加至(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(0.09g,0.152mmol)於DCM(0.5mL)中之溶液中。將混合物於rt下攪拌2h，隨後移除溶劑並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((N,5-二甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0151g,0.021mmol,13.86%產率)。LCMS(M+H)=702.2。
實例104
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸：向5-甲基-1,3,4-噁二唑-2-甲酸鉀(30mg,0.181mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.05ml,0.100mmol)。將混合物於rt下攪拌1h，在真空下濃縮至乾燥。將殘餘物溶解於THF(0.5mL)中並添加至(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.018g,0.031mmol)及DIPEA(0.05ml,0.286mmol)於THF(0.5mL)中之溶液中。將混合物於rt下攪拌1h並添加0.1ml水並於rt下攪拌0.5h。隨
後，在真空中移除溶劑並藉由prep-HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸(0.0077g,0.011mmol,35.9%產率)。LCMS(M+H)=688.2。
實例105
(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：向2-(二甲基胺基)-2-側氧基乙酸(30mg,0.256mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.05ml,0.100mmol)。將混合物於rt下攪拌1h，在真空下濃縮至乾燥。將殘餘物溶解於THF(0.5ml)中並添加至(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.015g,0.026mmol)於THF(0.5ml)中之溶液中。於rt下攪拌混合物，隨後移除溶劑並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(0.0119g,0.018mmol,67.7%產率)。LCMS(M+H)=677.3。
實例106
(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.015g,0.026mmol)及DIPEA(0.01ml,0.057mmol)於DCM(0.5mL)中之溶液中添加乙醯氯(0.005mL,0.070mmol)。將混合物於rt下攪拌1h並藉由添加水淬滅，移除溶劑並藉由製備型HPLC純化，以得到(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.0122g,0.020mmol,76%產率)。LCMS(M+H)=620.3。
實例107
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲醯胺基甲基)-2-甲基吡啶-3-基)乙酸：向甲酸(0.15ml,3.98mmol)及乙酸酐(0.3mL,3.18mmol)之溶液中添加(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(0.015g,0.026mmol)。將反應混合物於50℃下攪拌48h。將反應混合物用水淬滅並藉由製備型HPLC純
化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲醯胺基甲基)-2-甲基吡啶-3-基)乙酸(0.0077g,0.013mmol,49.0%產率)。1H NMR(500MHz,DMSO-d6)δ 8.21-8.16(m,1H),7.38(dd,J=8.6,5.7Hz,2H),7.26(d,J=8.4Hz,1H),7.14(t,J=8.8Hz,2H),7.10-7.02(m,3H),5.89(s,1H),4.25(d,J=8.4Hz,2H),4.07-4.01(m,1H),3.90-3.82(m,1H),3.06(t,J=6.6Hz,2H),2.87-2.77(m,1H),2.25-2.16(m,1H),2.01-1.93(m,1H),1.54-1.46(m,1H),1.33-1.25(m,1H),1.23-1.17(m,1H),1.14(s,10H),1.07-0.98(m,1H),0.86(s,3H),0.61(s,3H)。LCMS(M+H)=606.2。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸甲基酯：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸(259mg,0.448mmol)於CH2Cl2(5mL)及甲醇(0.5mL)中之溶液中添加2M TMS-重氮甲烷(0.246mL,0.492mmol)並將所得混合物於室溫下攪拌2h。隨後將混合物濃縮並藉由Biotage(5-40% EtOAc/己烷)純化，以得到黏性油狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸甲基酯(250mg,0.422mmol,94%產率)。1H NMR(500MHz,CDCl3)δ 7.31(br.s.,1H),7.17(d,J=7.1Hz,1H),7.12-7.02(m,3H),6.99(d,J=8.5Hz,2H),6.05(s,1H),4.99(d,J=14.7Hz,1H),4.90(br.s.,1H),4.63(dd,J=15.1,4.7Hz,1H),4.30-4.16(m,2H),3.75(s,2H),3.14(t,J=6.9Hz,2H),3.08(d,
J=12.0Hz,1H),2.85(t,J=12.1Hz,1H),2.30(d,J=11.0Hz,1H),2.24(s,2H),2.12(t,J=11.6Hz,1H),1.82(br.s.,1H),1.72(d,J=5.5Hz,1H),1.62-1.51(m,1H),1.40-1.31(m,2H),1.21(s,9H),1.10(d,J=12.9Hz,1H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=593.4。
(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-(羥基甲基)-6-甲基吡啶-3-基)乙酸甲基酯(250mg,0.422mmol)於CH2Cl2(5mL)中之溶液中添加CBr4(154mg,0.464mmol)，之後添加Ph3P(122mg,0.464mmol)並將所得混合物於室溫下攪拌3h。隨後添加水(2mL)並將混合物用二氯甲烷(10mL)萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-30% EtOAc/己烷)純化殘餘物，以得到黏性油狀(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(140mg,0.214mmol,50.6%產率)。1H NMR(500MHz,CDCl3)δ 7.31(br.s.,1H),7.16(d,J=7.1Hz,1H),7.12-7.01(m,3H),6.99(t,J=5.9Hz,2H),6.13(s,1H),5.02(d,J=9.8Hz,1H),4.74(d,J=9.9Hz,1H),4.29-4.19(m,2H),3.79(s,3H),3.21(d,J=11.2Hz,1H),3.14(t,J=6.9Hz,2H),2.86(t,J=11.7Hz,1H),2.27(br.s.,1H),2.24(s,3H),2.12-2.02(m,2H),1.37(d,J=4.6Hz,1H),1.31-1.25(m,2H),1.23(s,9H),1.09(d,J=12.5Hz,1H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+2H)=
657.3。
實例108
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸：於0℃下向無水2-乙氧基乙醇(5.50mg,0.061mmol)於THF(1)中之溶液中添加NaH(2.440mg,0.061mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(20mg,0.031mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.031mL,0.305mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-乙氧基乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸(11.5mg,0.018mmol,57.9%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.33(m,2H),7.23(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.08-6.98(m,3H),5.82(br.s.,1H),4.68(d,J=11.4Hz,1H),4.54(d,J=11.0Hz,1H),4.29-4.17(m,2H),3.61-3.51(m,2H),3.51-3.47(m,2H),3.43(q,J=6.8Hz,2H),3.06(t,J=6.6Hz,2H),2.78(br.s.,1H),2.17(br.s.,1H),2.10(s,3H),1.50(br.s.,1H),1.30(br.s.,1H),1.12(s,9H),1.11-1.07(m,3H),1.01(d,J=12.1Hz,1H),0.84(br.s.,
3H),0.60(br.s.,3H)。LCMS(M+H)=651.2。
實例109
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基-2-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸：於0℃下向無水氧雜環丁-3-基甲醇(5.38mg,0.061mmol)於THF(1)中之溶液中添加NaH(2.440mg,0.061mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(20mg,0.031mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.031mL,0.305mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基-2-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸(11.5mg,0.018mmol,58.1%產率)。1H NMR(500MHz,DMSO-d6)δ 7.44-7.34(m,2H),7.24(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.08-6.98(m,3H),5.84(br.s.,1H),4.72(d,J=11.0Hz,1H),4.61(t,J=6.8Hz,2H),4.53(d,J=11.4Hz,1H),4.32(dt,J=15.2,6.0Hz,2H),4.28-4.13(m,2H),3.72-3.55(m,3H),3.16(dd,J=13.0,6.8Hz,1H),3.06(t,J=6.4Hz,2H),2.78(d,J=12.5Hz,1H),2.17(br.s.,1H),2.10(s,3H),2.01-1.91(m,2H),1.50(br.s.,1H),1.36
-1.23(m,1H),1.17(br.s.,1H),1.12(s,9H),1.02(d,J=12.1Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=649.1。
實例110
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-(2-乙氧基乙氧基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸：於0℃下向無水2-(2-乙氧基乙氧基)乙醇(8.19mg,0.061mmol)於THF(1)中之溶液中添加NaH(2.440mg,0.061mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(20mg,0.031mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.031mL,0.305mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-2-((2-(2-乙氧基乙氧基)乙氧基)甲基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸(14.6mg,0.021mmol,68.9%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.33(m,2H),7.23(d,J=8.4Hz,1H),7.14(t,J=8.6Hz,2H),7.08-6.95(m,3H),5.87(br.s.,1H),4.71(d,J=11.0Hz,1H),4.52(d,J=10.6Hz,1H),4.32-4.14(m,2H),3.60-3.50(m,6H),3.49-3.33(m,5H),3.28(br.s.,1H),3.06(t,
J=6.8Hz,2H),2.79(br.s.,1H),2.17(br.s.,1H),2.10(s,3H),1.95(br.s.,1H),1.50(br.s.,1H),1.30(br.s.,1H),1.13(s,9H),1.11-1.06(m,3H),1.01(br.s.,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=695.2。
實例111
(S)-2-(2-((3-(苄基氧基)丙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：於0℃下向無水3-(苄基氧基)丙-1-醇(10.14mg,0.061mmol)於THF(1)中之溶液中添加NaH(2.440mg,0.061mmol)並將所得混合物攪拌10min。隨後添加THF(0.5mL)中之(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(20mg,0.031mmol)並將混合物攪拌4h。此時，LCMS指示反應完成。隨後將混合物濃縮並於80℃下用乙醇(1mL)中之10N NaOH(0.031mL,0.305mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(2-((3-(苄基氧基)丙氧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(8.2mg,0.011mmol,37.0%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.35(m,2H),7.34-7.24(m,5H),7.20(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.07-6.96(m,3H),5.76(br.s.,
1H),4.64-4.52(m,2H),4.44(s,2H),4.30-4.14(m,2H),3.57-3.47(m,5H),3.05(t,J=6.4Hz,2H),2.16(br.s.,1H),2.08(s,3H),1.84-1.66(m,2H),1.50(br.s.,1H),1.28(d,J=8.8Hz,1H),1.11(s,9H),1.02(br.s.,1H),0.84(br.s.,3H),0.59(br.s.,3H)。LCMS(M+H)=727.2。
實例112
(S)-2-(第三丁氧基)-2-(2-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸：向二甲胺(0.153mL,0.305mmol)於乙醇(1.405mg,0.031mmol)中之溶液中添加(S)-2-(2-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸甲基酯(20mg,0.031mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用乙醇(2mL)中之10N NaOH(0.031mL,0.305mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(2-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸(16.3mg,0.027mmol,88%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.31(m,2H),7.21(d,J=8.1Hz,1H),7.14(t,J=8.8Hz,2H),7.10-6.94(m,3H),5.76(s,1H),5.07(br.s.,1H),4.29-4.18(m,2H),3.71(d,J=11.7Hz,1H),3.09(br.s.,1H),3.05(t,J=6.4Hz,2H),2.66(d,J=11.4Hz,1H),2.59(s,6H),2.21(br.s.,1H),2.11(s,3H),2.00(d,J=13.2Hz,1H),1.84(br.s.,1H),1.29(br.s.,1H),1.16(s,9H),1.05(br.s.,2H),0.86(br.s.,3H),0.59(br.s.,3H)。LCMS(M+H)=606.2。
(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯：將(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(4g,8.24mmol)、6-(6-甲基-4,8-二氧離子基-1,3,6,2-二氧氮雜硼雜環辛烷-2-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(3.83g,9.06mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(0.677g,1.648mmol)及2M K3PO4(30.9mL,61.8mmol)於1,4-二噁烷(70mL)及水(14.00mL)中之混合物脫氣10min。隨後，添加Pd(OAc)2(0.185g,0.824mmol)，脫氣5min並將混合物於80℃下加熱3h。在冷卻至室溫後，添加水並將混合物用乙酸乙酯萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-40% EtOAc/己烷)純化殘餘物，以得到白色發泡體狀(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(3.5g,5.21mmol,63.2%產率)。1H NMR(500MHz,CDCl3)δ 7.46-7.33(m,5H),7.19(br.s.,1H),7.11-6.88(m,2H),6.02(br.s.,1H),5.24(s,2H),5.16-5.07(m,1H),4.98(br.s.,1H),4.78(d,J=19.1Hz,1H),4.74-4.64(m,1H),4.44(t,J=15.2Hz,1H),4.12-3.99(m,1H),3.89(br.s.,1H),3.77(br.s.,2H),3.36-3.16(m,1H),2.65(s,3H),2.40-2.24(m,1H),2.16-2.05(m,1H),2.01(t,J=11.8Hz,1H),1.70-1.50(m,2H),1.44-1.32(m,1H),1.28-1.22(m,6H),1.21-1.18(m,9H),1.14-1.02(m,1H),0.92(br.s.,3H),0.72-0.57(m,3H)。LCMS
(M+H)=672.5。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl：向(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(1.3g,1.935mmol)於EtOH(25mL)中之溶液中添加1N HCl(3.87mL,3.87mmol)溶液，之後添加10% Pd-C(0.412g,0.387mmol)並將所得混合物在氫氣球氣氛下攪拌5h。隨後將混合物經由小的矽藻土墊過濾，濃縮並在高真空下乾燥過夜，以得到白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl(1.1g,1.801mmol,93%產率)。1H NMR(500MHz,CDCl3)δ 10.41(br.s.,1H),7.33(d,J=6.0Hz,1H),7.25-7.10(m,1H),7.05-6.88(m,1H),5.58(br.s.,1H),5.15(dt,J=12.2,6.0Hz,1H),4.66(d,J=13.2Hz,1H),4.50(d,J=13.9Hz,3H),3.79-3.69(m,1H),3.59(br.s.,1H),3.52(br.s.,1H),3.29(br.s.,2H),2.97(s,3H),2.72(br.s.,3H),1.44(br.s.,1H),1.40(br.s.,1H),1.31(t,J=6.5Hz,6H),1.26(t,J=6.9Hz,1H),1.20(s,9H),0.95-0.80(m,6H)。LCMS(M+H)=538.4。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2- 甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl(520mg,0.852mmol)於MeOH(10mL)中之溶液中添加TEA(0.237mL,1.703mmol)並將所得混合物攪拌10min。隨後，添加MeOH(1mL)中之4-氟-2-甲基苯甲醛(235mg,1.703mmol)並將混合物再攪拌2h。隨後添加NaCNBH3(161mg,2.55mmol)並將混合物於室溫下攪拌16h。用水(10mL)稀釋並將混合物用乙酸乙酯(50mL)萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(0-10% CH2Cl2/MeOH)純化殘餘物，以得到白色固體狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(480mg,0.727mmol,85%產率)。1H NMR(500MHz,CDCl3)δ 7.37-7.30(m,1H),7.11-7.02(m,1H),7.02-6.95(m,1H),6.94-6.84(m,3H),6.03(br.s.,1H),5.15-5.03(m,2H),4.51-4.40(m,1H),4.17-3.99(m,1H),3.77-3.67(m,2H),3.66(s,2H),3.25(br.s.,1H),2.90(d,J=5.2Hz,3H),2.86-2.74(m,2H),2.64(s,3H),2.48-2.35(m,3H),2.28-2.11(m,1H),1.56(br.s.,2H),1.34(d,J=15.3Hz,1H),1.28-1.22(m,7H),1.20(s,9H),0.92(br.s.,3H),0.67(br.s.,3H)。LCMS(M+H)=660.5。
實例113
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2- 甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(40mg,0.061mmol)及10M NaOH(0.061mL,0.606mmol)於EtOH(1mL)中之混合物於80℃下加熱4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸(23.9mg,0.039mmol,63.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37-7.27(m,1H),7.09(s,2H),7.04(d,J=9.5Hz,1H),6.98(t,J=7.7Hz,1H),6.88(br.s.,1H),5.74(d,J=8.4Hz,1H),4.27-4.16(m,1H),4.03(d,J=13.6Hz,1H),3.47(br.s.,5H),2.83(br.s.,3H),2.72(br.s.,2H),2.36(br.s.,3H),2.09(br.s.,1H),1.91(br.s,5H),1.49(br.s.,1H),1.32-1.16(m,2H),1.11(s,9H),0.99(br.s.,1H),0.85(br.s.,3H),0.62(br.s.,3H)。LCMS(M+H)=618.2。
(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(480mg,0.727mmol)於CH2Cl2(10mL)中之溶液中添加CBr4(265mg,0.800mmol)，之後添加Ph3P(210mg,0.800mmol)並將所得混合物於室溫下攪拌2h。隨後將混合物濃縮並藉由
Biotage(5-40% EtOAc/己烷)純化，以得到白色固體狀(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(370mg,0.512mmol,70.4%產率)。1H NMR(500MHz,CDCl3)δ 7.39-7.30(m,1H),7.24(br.s.,1H),7.08(d,J=7.7Hz,1H),6.97(br.s.,1H),6.95-6.80(m,2H),6.06(br.s.,1H),5.18-5.02(m,1H),4.36(dd,J=13.0,9.5Hz,1H),4.23(d,J=9.3Hz,1H),3.78-3.69(m,2H),3.66(s,2H),3.26-3.14(m,1H),2.94(dd,J=12.5,5.7Hz,2H),2.90-2.79(m,2H),2.78-2.71(m,1H),2.63(s,3H),2.43(d,J=7.3Hz,3H),2.24(d,J=11.7Hz,1H),1.93(t,J=10.5Hz,1H),1.54(br.s.,2H),1.41-1.30(m,1H),1.25(dt,J=10.6,5.1Hz,6H),1.20(s,9H),1.07(d,J=9.5Hz,1H),0.92(br.s.,3H),0.66(br.s.,3H)。LCMS(M+2H)=724.4。
實例114
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸：於rt下將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.1g,0.138mmol)之溶液逐滴添加至甲胺/THF溶液(2mL,4.00mmol)中。將混合物於rt下攪拌2h，且在減壓下移除溶劑。於80℃下將殘餘物用NaOH(0.1g,2.500mmol)處理3h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到稠膏糊狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-
1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(40mg,0.063mmol,45.8%產率)。1H NMR(500MHz,CDCl3)δ 7.38-7.30(m,2H),7.04(d,J=7.7Hz,1H),6.97-6.85(m,3H),5.84(br.s.,1H),3.82-3.62(m,2H),3.58-3.43(m,2H),2.96-2.85(m,4H),2.85-2.74(m,4H),2.58(s,2H),2.57-2.54(m,5H),2.43(d,J=8.4Hz,3H),2.06(s,3H),1.56(br.s.,1H),1.32(br.s.,1H),1.20(s,9H),1.09(d,J=11.3Hz,2H),0.89(br.s.,3H),0.66(br.s.,3H)。LCMS(ESI)m/z(M+H)+=631.2。
實例115
(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向二甲胺(0.138mL,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((二甲基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(3.1mg,4.81μmol,17.37%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.29(m,1H),7.29-7.16(m,1H),7.13-6.93(m,3H),6.84(s,1H),5.78(d,J=7.7Hz,1H),3.67-3.59(m,4H),3.57(br.s.,1H),3.43(br.
s.,4H),3.27(d,J=12.1Hz,1H),3.19-3.13(m,1H),3.09-2.97(m,1H),2.81(br.s.,2H),2.72-2.60(m,2H),2.47(s,3H),2.36(br.s.,3H),2.11(s,4H),1.48(br.s.,1H),1.24(br.s.,1H),1.19(d,J=8.8Hz,1H),1.10(s,9H),0.98(br.s.,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=645.2。
實例116
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸：向2-甲氧基乙胺(20.78mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((2-甲氧基乙基)胺基)甲基)-2-甲基吡啶-3-基)乙酸(17.7mg,0.026mmol,95%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.23(m,1H),7.16-6.93(m,4H),6.87(br.s.,1H),5.74(d,J=11.4Hz,1H),3.55-3.24(m,12H),2.83(br.s.,3H),2.75-2.66(m,3H),2.65-2.58(m,2H),2.48(s,3H),2.36(br.s.,
3H),2.08(br.s.,1H),1.78(d,J=12.5Hz,1H),1.49(br.s,1H),1.25(br.s.,1H),1.18(d,J=13.9Hz,1H),1.11(s,9H),0.99(br.s.,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=675.2。
實例117
(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向氮雜環丁烷(15.80mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-(氮雜環丁-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(13.9mg,0.021mmol,76%產率)。1H NMR(500MHz,DMSO-d6)δ 7.39-7.24(m,1H),7.17-7.02(m,3H),6.98(t,J=7.9Hz,1H),6.89-6.76(m,1H),5.70(d,J=11.7Hz,1H),3.62(br.s.,3H),3.49(br.s.,2H),3.33-3.20(m,5H),2.82(br.s.,1H),2.78(br.s.,1H),2.74(s,2H),2.69(br.s.,1H),2.45(s,2H),2.38-2.29(m,3H),2.05(br.s.,1H),2.00-1.93(m,2H),1.75(d,J=13.9Hz,1H),1.48(br.s.,1H),1.24(br.s.,1H),1.15(br.s.,1H),1.10(s,9H),1.07-1.00(m,2H),0.97(br.
s.,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=657.2。
實例118
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸：向吡咯啶(19.68mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸(15.6mg,0.023mmol,84%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.27(m,1H),7.19(d,J=8.1Hz,1H),7.11-6.92(m,3H),6.85(s,1H),5.75(d,J=8.4Hz,1H),3.52(d,J=13.2Hz,2H),3.43(br.s.,2H),3.24-3.09(m,2H),2.82(br.s.,2H),2.64(s,2H),2.47-2.39(m,7H),2.38-2.33(m,3H),2.20(br.s.,1H),2.08(br.s.,1H),1.76(br.s.,1H),1.62(br.s.,4H),1.49(br.s.,1H),1.26(br.s.,1H),1.17(br.s.,1H),1.11(s,9H),0.98(br.s.,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=671.2。
實例119
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸：向六氫吡啶(23.56mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸(16.7mg,0.024mmol,88%產率)。1H NMR(500MHz,DMSO-d6)δ 7.39-7.25(m,1H),7.21(d,J=7.7Hz,1H),7.12-7.02(m,2H),7.01-6.93(m,1H),6.84(s,1H),5.79(br.s.,1H),3.37(br.s.,6H),3.02(br.s.,1H),2.82(br.s.,2H),2.73-2.67(m,2H),2.45(s,3H),2.36(br.s.,3H),2.27(br.s.,1H),2.20(d,J=17.6Hz,2H),2.12(br.s.,2H),1.49(br.s.,1H),1.37(br.s.,3H),1.30(br.s.,3H),1.24(br.s.,1H),1.17(br.s.,1H),1.11(s,9H),1.03(br.s.,1H),0.99(br.s.,1H),0.85(br.s.,3H),0.66-0.52(m,3H)。LCMS(M+H)=685.2。
實例120
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向4,4-二甲基六氫吡啶(31.3mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(19.5mg,0.027mmol,99%產率)。1H NMR(500MHz,DMSO-d6)δ 7.39-7.25(m,2H),7.11-7.01(m,2H),6.98(t,J=7.5Hz,1H),6.87-6.75(m,1H),5.80(br.s.,1H),3.42(br.s.,7H),3.22(br.s.,1H),3.20-3.06(m,2H),2.82(br.s.,3H),2.72(br.s.,1H),2.46(s,3H),2.36(br.s.,3H),2.25(br.s.,3H),2.10(br.s.,1H),1.48(br.s.,1H),1.20(br.s.,6H),1.11(s,9H),0.97(d,J=16.1Hz,1H),0.84(d,J=4.0Hz,9H),0.60(br.s.,3H)。LCMS(M+H)=713.2。
實例121
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(嗎啉基甲基)吡啶-3-基)乙酸：向嗎啉(24.11mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(嗎啉基甲基)吡啶-3-基)乙酸(12.1mg,0.018mmol,63.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.25(m,1H),7.22(d,J=7.7Hz,1H),7.11-7.02(m,2H),6.99(t,J=7.9Hz,1H),6.90-6.80(m,1H),5.83(br.s.,1H),3.62(br.s.,4H),3.44(d,J=13.9Hz,3H),3.37(br.s.,3H),3.18-3.09(m,1H),2.82(br.s.,2H),2.46(s,3H),2.36(br.s.,3H),2.21(br.s.,3H),2.11(br.s.,1H),1.48(br.s.,1H),1.25(d,J=12.5Hz,1H),1.18(br.s.,1H),1.12(s,9H),0.99(d,J=12.1Hz,1H),0.85(br.s.,3H),0.66-0.52(m,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=687.2。
實例122
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸：向硫嗎啉(28.6mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(硫嗎啉基甲基)吡啶-3-基)乙酸(14.9mg,0.021mmol,77%產率)。1H NMR(500MHz,DMSO-d6)δ 7.39-7.26(m,1H),7.26-7.14(m,1H),7.12-7.02(m,2H),6.99(t,J=8.8Hz,1H),6.85(br.s.,1H),5.83(br.s.,1H),3.61(d,J=4.4Hz,4H),3.25-3.01(m,2H),2.82(br.s.,3H),2.72(br.s.,2H),2.46(br.s,7H),2.41(br.s.,2H),2.36(br.s.,3H),2.21(br.s.,1H),2.17-2.04(m,1H),1.84(br.s.,1H),1.49(br.s.,1H),1.25(d,J=10.6Hz,1H),1.18(br.s.,1H),1.12(s,9H),1.04(d,J=10.3Hz,1H),0.98(d,J=10.3Hz,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=703.2。
實例123
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-6-((1,1-二氧離子基硫嗎啉基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向硫嗎啉1,1-二氧化物(37.4mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((1,1-二氧離子基硫嗎啉基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(15.8mg,0.021mmol,78%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.27(m,1H),7.25-7.15(m,1H),7.14-6.96(m,3H),6.90(br.s.,1H),5.79(br.s.,1H),3.61(br.s.,4H),3.47-3.34(m,3H),3.34-3.18(m,2H),2.94(br.s.,2H),2.84(d,J=9.9Hz,3H),2.77-2.68(m,6H),2.47(s,3H),2.36(br.s.,3H),2.12(br.s.,1H),1.89-1.79(m,1H),1.49(br.s.,1H),1.35-1.14(m,2H),1.12(s,9H),1.06-0.91(m,1H),0.85(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=735.1。
實例124
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸：向吡啶-4-基甲胺(29.9mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-4-基甲基)胺基)甲基)吡啶-3-基)乙酸(8.6mg,0.012mmol,43.9%產率)。1H NMR(500MHz,DMSO-d6)δ 8.40(d,J=4.8Hz,2H),7.33(br.s.,1H),7.18-7.11(m,2H),7.08-6.94(m,4H),6.88(br.s.,1H),5.76(br.s.,1H),3.66(br.s.,2H),3.61(d,J=13.9Hz,4H),3.38-3.35(m,5H),3.32-3.27(m,2H),2.82(br.s.,2H),2.70(d,J=12.5Hz,2H),2.39-2.32(m,3H),2.08(br.s.,1H),1.77(d,J=12.1Hz,1H),1.49(br.s.,1H),1.24(br.s.,1H),1.17(br.s.,1H),1.12(s,9H),1.04(br.s.,1H),0.99(br.s.,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=708.2。
實例125
(S)-N-((5-(第三丁氧基(羧基)甲基)4-(4,4-二甲基六氫吡啶1-基)-3-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-甲基吡啶-2-基)甲基)-N,N-二乙基乙銨：向吡嗪-2-基甲胺(15.10mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.039mL,0.277mmol)，之後添加吡嗪-2-基甲胺(15.10mg,0.138mmol)並將所得混合物於室溫下攪拌16h。此時，LCMS指示TEA加成物而非期望產物。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-N-((5-(第三丁氧基(羧基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-甲基吡啶-2-基)甲基)-N,N-二乙基乙銨(13.1mg,0.017mmol,62.2%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.29(m,1H),7.25-7.11(m,2H),7.06(d,J=9.9Hz,1H),7.00(t,J=8.4Hz,1H),6.91(s,1H),5.40(s,1H),4.30(d,J=15.0Hz,1H),4.23(d,J=14.7Hz,1H),4.03(d,J=14.7Hz,2H),3.43(dd,J=13.9,7.0Hz,3H),3.27(td,J=13.2,6.2Hz,3H),2.86(br.s.,2H),2.71(br.s.,3H),2.53(s,2H),2.38-2.34(m,3H),2.04(br.s.,1H),1.63(br.s.,1H),1.51(br.s.,1H),1.24(br.s.,1H),1.14(br.s.,1H),1.07(s,9H),1.05-0.98(m,9H),0.93(d,J=13.9Hz,1H),0.85(br.s.,3H),0.73(br.s.,1H),0.62(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=702.3。
實例126
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-3-基甲基)胺基)甲基)吡啶-3-基)乙酸：向吡啶-3-基甲胺(29.9mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((吡啶-3-基甲基)胺基)甲基)吡啶-3-基)乙酸(8.8mg,0.012mmol,44.9%產率)。1H NMR(500MHz,DMSO-d6)δ 8.59(br.s.,2H),7.85(d,J=7.7Hz,1H),7.59(br.s.,1H),7.48-7.42(m,1H),7.41-7.31(m,1H),7.22(s,1H),7.26(s,1H),7.16(s,1H),7.05(d,J=6.6Hz,1H),5.83(br.s.,1H),4.39(br.s.,3H),4.20(br.s.,3H),3.54(br.s.,1H),3.43(br.s.,2H),3.30(br.s.,1H),3.13(br.s.,1H),2.57(s,2H),2.55(s,3H),2.45(br.s.,3H),2.22(br.s.,1H),1.53(br.s.,1H),1.26(br.s.,2H),1.14(s,9H),1.01(br.s.,1H),0.88(br.s.,3H),0.65(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=708.3。
實例127
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((((四7氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸：向(四氫-2H-吡喃-4-基)甲胺(31.9mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸(5.0mg,6.99μmol,25.3%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.26(m,1H),7.15-7.02(m,3H),6.98(t,J=7.9Hz,1H),6.87(br.s.,1H),5.71(d,J=8.8Hz,1H),3.78(d,J=9.9Hz,2H),3.51(d,J=14.3Hz,2H),3.39(d,J=13.2Hz,3H),3.24-3.13(m,3H),2.82(br.s.,2H),2.71(br.s.,2H),2.47(s,3H),2.38-2.30(m,5H),2.08(br.s.,1H),1.79(d,J=11.0Hz,1H),1.50(br.s.,2H),1.48-1.41(m,1H),1.26(br.s.,1H),1.17(d,J=13.2Hz,1H),1.10(s,9H),1.04(d,J=7.0Hz,2H),0.97(d,J=11.4Hz,1H),0.85(br.s.,3H),0.61(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=715.2。
實例128
(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及4,4-二氟六氫吡啶，HCl(21.80mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((4,4-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(17.4mg,0.024mmol,87%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37-7.27(m,1H),7.25-7.16(m,1H),7.13-7.02(m,2H),6.99(t,J=8.4Hz,1H),6.91-6.79(m,1H),5.80(br.s.,1H),3.61(d,J=4.0Hz,4H),3.23-3.10(m,2H),2.87-2.79(m,3H),2.68(br.s.,1H),2.46(s,3H),2.42-2.26(m,8H),2.11(br.s.,1H),1.87-1.67(m,5H),1.49(br.s.,1H),1.25(d,J=11.0Hz,1H),1.19(d,J=12.1Hz,1H),1.11(s,9H),1.04(d,J=6.6Hz,1H),0.98(d,J=9.5Hz,1H),0.85(br.s.,3H),0.64-0.55(m,3H)。LCMS(M+H)=721.4。
實例129
(S)-2-(第三丁氧基)-2-(6-((3,3-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及3,3-二氟六氫吡啶，HCl(21.80mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((3,3-二氟六氫吡啶-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(12.9mg,0.018mmol,64.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.29(m,1H),7.28-7.19(m,1H),7.12-7.03(m,2H),7.02-6.93(m,1H),6.87-6.79(m,1H),5.72(br.s.,1H),3.40(br.s.,4H),3.23(s,1H),3.18-3.05(m,1H),2.81(br.s.,3H),2.68(br.s.,2H),2.46(s,3H),2.36(d,J=3.7Hz,4H),2.26(br.s.,1H),2.20(br.s.,1H),2.09(br.s.,1H),1.80(d,J=7.3Hz,3H),1.50(br.s.,3H),1.24(br.s.,2H),1.17(br.s.,1H),1.10(s,9H),0.98(d,J=12.1Hz,1H),0.85(br.s.,3H),0.67-0.50(m,3H)。LCMS(M+H)=721.2。
實例130
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及4-氟六氫吡啶，HCl(19.31mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(11.2mg,0.016mmol,57.6%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.29(m,1H),7.20(d,J=7.7Hz,1H),7.12-7.03(m,2H),6.99(t,J=8.4Hz,1H),6.88-6.80(m,1H),5.76(br.s.,1H),4.62(br.s.,1H),4.52(br.s.,1H),3.40(br.s.,4H),3.20-3.05(m,3H),2.87-2.78(m,3H),2.73-2.65(m,2H),2.45(s,3H),2.36(d,J=3.3Hz,4H),2.21(br.s.,1H),2.18-2.05(m,3H),1.82(t,J=12.8Hz,1H),1.71(br.s.,2H),1.56(br.s.,2H),1.49(br.s.,2H),1.25(d,J=16.1Hz,1H),1.18(d,J=10.3Hz,1H),1.11(s,9H),1.04(d,J=12.5Hz,1H),0.85(br.s.,3H),0.65-0.57(m,3H)。LCMS(M+H)=703.3。
實例131
(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((3-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及3-氟六氫吡啶，HCl(19.31mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((3-氟六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(15.5mg,0.022mmol,80%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37-7.29(m,1H),7.22(d,J=8.1Hz,1H),7.11-7.01(m,2H),6.99(t,J=8.6Hz,1H),6.87-6.79(m,1H),5.74(br.s.,1H),4.45(br.s.,1H),3.61(br.s.,2H),3.46(br.s.,2H),3.19-3.11(m,2H),3.11-3.00(m,2H),2.82(br.s.,3H),2.69(d,J=6.6Hz,2H),2.46(s,3H),2.39-2.33(m,3H),2.25(d,J=19.4Hz,1H),2.18(br.s.,1H),2.13(br.s.,1H),2.09-1.96(m,1H),1.77(d,J=6.6Hz,2H),1.58(br.s.,1H),1.49(br.s.,1H),1.42(br.s.,1H),1.26(br.s.,2H),1.17(br.s.,1H),1.10(s,9H),1.06-0.94(m,1H),0.85(br.s.,3H),0.65-0.49(m,3H)。LCMS(M+H)=703.2。
實例132
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((S)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及(S)-3-氟吡咯啶，HCl(17.37mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((S)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(11mg,0.016mmol,57.7%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.30(m,1H),7.20(d,J=7.7Hz,1H),7.13-7.02(m,2H),7.01-6.94(m,1H),6.89-6.71(m,1H),5.75(d,J=5.1Hz,1H),5.04(br.s.,1H),3.67-3.56(m,3H),3.37(d,J=11.4Hz,3H),3.20-3.13(m,1H),3.13-3.04(m,1H),2.87-2.77(m,3H),2.72(br.s.,2H),2.70-2.58(m,3H),2.46(s,3H),2.36(d,J=3.7Hz,3H),2.31-2.21(m,1H),2.08(br.s.,1H),2.06-1.93(m,1H),1.78(dt,J=15.3,7.9Hz,1H),1.50(br.s.,1H),1.25(d,J=9.5Hz,1H),1.18(d,J=8.8Hz,1H),1.11(s,9H),1.04(d,J=12.5Hz,1H)0.85(br.s.,3H),0.66-0.54(m,3H)。LCMS(M+H)=689.4。
實例133
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((R)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及(R)-3-氟吡咯啶，HCl(17.37mg,0.138mmol)於乙醇(1mL)中之溶液中添加TEA(0.023mL,0.166mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(((R)-3-氟吡咯啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(11.8mg,0.017mmol,61.9%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.28(m,1H),7.24-7.15(m,1H),7.12-7.02(m,2H),6.99(t,J=8.4Hz,1H),6.89-6.74(m,1H),5.76(d,J=5.9Hz,1H),5.17(br.s.,1H),5.05(br.s.,1H),3.43(d,J=12.5Hz,2H),3.35(d,J=12.5Hz,2H),3.19-3.08(m,1H),2.86-2.77(m,3H),2.72-2.58(m,4H),2.46(s,3H),2.39-2.32(m,3H),2.28-2.15(m,2H),2.14-1.94(m,2H),1.85-1.68(m,2H),1.49(br.s.,1H),1.25(d,J=11.0Hz,1H),1.18(d,J=11.7Hz,1H),1.11(s,9H),1.04(d,J=8.4Hz,1H),0.85(br.s.,3H),0.64-0.57(m,3H)。LCMS(M+H)=689.2。
實例134
(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及7-氮雜螺[3.5]壬烷(17.32mg,0.138mmol)於乙醇(1mL)中之溶液於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(14mg,0.019mmol,69.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.32(br.s.,1H),7.21(d,J=8.1Hz,1H),7.04(d,J=8.4Hz,2H),6.98(br.s.,1H),6.82(br.s.,1H),5.78(br.s.,1H),3.39(br.s.,5H),3.09(br.s.,1H),3.05-2.94(m,1H),2.90(s,2H),2.80(br.s.,3H),2.74(br.s.,3H),2.45(br.s.,3H),2.36(br.s.,3H),2.19(br.s.,2H),2.11(br.s.,4H),1.78(br.s.,2H),1.63(br.s.,3H),1.48(br.s.,1H),1.40(br.s.,3H),1.23(br.s.,1H),1.11(br.s.,9H),0.99(br.s.,1H),0.85(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=725.3。
實例135
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-羥基六氫吡啶1-基)甲基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及六氫吡啶-4-醇(13.99mg,0.138mmol)於乙醇(1mL)中之溶液於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-((4-羥基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(11.7mg,0.017mmol,60.3%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.29(m,1H),7.20(d,J=7.7Hz,1H),7.12-7.01(m,2H),6.99(t,J=7.5Hz,1H),6.87-6.76(m,1H),5.80(br.s.,1H),3.35(br.s.,6H),3.12(s,1H),3.08-2.97(m,1H),2.82(br.s.,3H),2.69(d,J=6.2Hz,2H),2.45(s,3H),2.36(d,J=2.9Hz,4H),2.20(br.s.,1H),2.11(d,J=10.6Hz,1H),1.99(d,J=10.6Hz,1H),1.59(br.s.,2H),1.49(br.s.,1H),1.35-1.23(m,2H),1.19(d,J=9.2Hz,2H),1.12(s,9H),1.05(br.s.,1H),0.85(br.s.,3H),0.67-0.55(m,3H)。LCMS(M+H)=701.3。
實例136
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)及1-甲基六氫吡嗪(13.86mg,0.138mmol)於乙醇(1mL)中之溶液於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((4-甲基六氫吡嗪-1-基)甲基)吡啶-3-基)乙酸(17.4mg,0.025mmol,90%產率)。1H NMR(500MHz,DMSO-d6)δ 7.37-7.29(m,1H),7.20(d,J=7.7Hz,1H),7.11-7.01(m,2H),6.98(t,J=8.6Hz,1H),6.88-6.79(m,1H),5.79(br.s.,1H),3.45(br.s.,6H),3.17-3.10(m,1H),3.08-2.99(m,1H),2.86-2.77(m,3H),2.73-2.66(m,2H),2.45(s,3H),2.36(s,3H),2.22(br.s.,7H),2.09(d,J=4.0Hz,4H),1.88-1.75(m,1H),1.49(br.s.,1H),1.25(d,J=13.2Hz,1H),1.17(br.s.,1H),1.11(s,9H),0.98(d,J=6.2Hz,1H),0.85(br.s.,3H),0.65-0.51(m,3H)。LCMS(M+H)=700.3。
實例137
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸：向N-甲基-1-(四氫-2H-吡喃-4-基)甲胺(35.8mg,0.277mmol)於乙醇(1mL)中之溶液中添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)並將所得混合物於室溫下攪拌16h。隨後於80℃下將混合物用10N NaOH(0.028mL,0.277mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基((四氫-2H-吡喃-4-基)甲基)胺基)甲基)吡啶-3-基)乙酸(15mg,0.021mmol,74.4%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.26(m,1H),7.24-7.14(m,1H),7.11-7.01(m,2H),7.01-6.90(m,1H),6.87-6.76(m,1H),5.78(d,J=9.5Hz,1H),3.74-3.64(m,2H),3.61(br.s.,3H),3.57(br.s.,1H),3.31(d,J=11.7Hz,1H),3.24-3.05(m,4H),2.80(br.s.,3H),2.69(dd,J=16.1,5.9Hz,2H),2.45(s,3H),2.38-2.32(m,3H),2.23-2.15(m,1H),2.15-2.07(m,1H),2.05-1.94(m,5H),1.48(br.s.,1H),1.35(d,J=7.7Hz,3H),1.30-1.14(m,2H),1.09(s,9H),0.98(br.s.,1H),0.89(br.s.,1H),0.84(br.s.,3H),0.81-0.71(m,1H),0.60(br.s.,3H)。LCMS(M+H)=
729.3。
實例138
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.028mmol)、(1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛烷，HCl(22.51mg,0.138mmol)及三乙胺(0.027mL,0.194mmol)於EtOH(1mL)中之溶液攪拌2h。隨後，添加10N NaOH(0.100mL,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後將反應混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((1R,5S)-3-甲基-3,8-二氮雜二環[3.2.1]辛-8-基)甲基)吡啶-3-基)乙酸(17.8mg,0.025mmol,89%產率)。1H NMR(500MHz,DMSO-d6)δ 7.38-7.26(m,2H),7.13-7.02(m,2H),7.01-6.95(m,1H),6.90-6.83(m,1H),5.83(br.s.,1H),3.36(br.s.,1H),3.24(d,J=12.1Hz,1H),3.07(d,J=12.1Hz,1H),2.98(d,J=12.5Hz,1H),2.91(br.s.,1H),2.89-2.79(m,4H),2.73-2.66(m,2H),2.47-2.43(m,3H),2.42-2.30(m,5H),2.21-2.09(m,1H),2.08-2.04(m,3H),1.87(d,J=9.9Hz,1H),1.76(br.s.,1H),1.68(br.s.,1H),1.65-1.56(m,2H),1.50(br.s.,1H),1.34-1.15(m,2H),1.12(s,9H),0.99(d,J=8.4Hz,1H),0.86(br.s.,3H),0.67-0.57(m,
3H)。6個六氫吡啶氫未拆分。LCMS(M+H)=726.3。
(S)-2-(6-(疊氮基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(200mg,0.277mmol)於DMF(4mL)中之溶液中添加NaN3(27.0mg,0.415mmol)並將所得混合物於室溫下攪拌3h。隨後添加水(10mL)並將混合物用乙酸乙酯(25mL)萃取，用鹽水(20mL)洗滌，乾燥(Na2SO4)，過濾並濃縮，以得到(S)-2-(6-(疊氮基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(180mg,0.263mmol,95%產率)。1H NMR(500MHz,CDCl3)δ 7.38-7.31(m,1H),7.12-6.99(m,2H),6.97-6.84(m,3H),6.06(br.s.,1H),5.11(dq,J=9.6,6.3Hz,1H),4.23-4.02(m,2H),3.75-3.68(m,2H),3.66(s,2H),3.25(d,J=12.3Hz,1H),2.93(br.s.,2H),83-2.72(m,2H),2.65(s,3H),2.43(d,J=6.1Hz,3H),2.24(d,J=12.1Hz,1H),1.96(t,J=11.8Hz,1H),1.55(br.s.,1H),1.42-1.30(m,1H),1.24(dt,J=10.9,5.6Hz,7H),1.20(d,J=2.8Hz,9H),1.08(d,J=9.6Hz,1H),0.92(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=685.5。不經進一步純化即原樣用於下一步驟。
(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：將(S)-2-(6-(疊氮基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(180mg,0.263mmol)及Ph3P(103mg,0.394mmol)於9：1 THF/H2O(10mL)中之混合物回流2h。隨後，冷卻，用乙酸乙酯(50mL)稀釋並用水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(10-100% CH2Cl2/MeOH)純化殘餘物，以得到稠膏糊狀(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(120mg,0.182mmol,69.3%產率)。1H NMR(500MHz,CDCl3)δ 7.38-7.29(m,1H),7.09-6.97(m,2H),6.95-6.83(m,3H),6.07(br.s.,1H),5.16-5.04(m,1H),3.74-3.67(m,2H),3.65(s,2H),3.63-3.43(m,1H),3.23(d,J=11.3Hz,1H),2.96-2.84(m,3H),2.84-2.72(m,2H),2.66-2.59(m,3H),2.46-2.39(m,3H),2.29(br.s.,1H),2.22(d,J=6.6Hz,1H),2.16-2.06(m,1H),1.99-1.75(m,2H),1.54(br.s.,1H),1.43-1.30(m,1H),1.24(ddd,J=9.9,6.2,3.9Hz,7H),1.20(s,9H),1.10-1.00(m,1H),0.91(br.s.,3H),0.66(br.s.,3H)。LCMS(M+H)=659.7。
實例139
(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(15mg,0.023mmol)於乙醇(1mL)及10N NaOH(0.028mL,0.277mmol)中之混合物於80℃下加熱4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(7.7mg,0.012mmol,54.8%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.27(m,1H),7.18-7.07(m,2H),7.07-6.94(m,2H),6.90-6.83(m,1H),5.59-5.54(m,1H),3.85-3.68(m,1H),3.62(s,2H),2.84(br.s.,1H),2.77(br.s.,1H),2.72(br.s.,2H),2.44(br.s.,1H),2.38-2.32(m,3H),1.90(s,3H),1.50(br.s.,1H),1.24(br.s.,1H),1.15(br.s.,1H),1.12-1.04(m,9H),0.97(d,J=7.0Hz,1H),0.85(br.s.,3H),0.62(br.s.,3H)。8個六氫吡啶氫未拆分。LCMS(M+H)=617.3。
實例140
(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟 -2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(15mg,0.024mmol)於DCM(0.5mL)中之溶液中添加TEA(0.06ml,0.430mmol)，之後添加乙醯氯(1.902μl,0.027mmol)並將所得混合物於室溫下攪拌2h。隨後將混合物濃縮並藉由製備型HPLC純化，以得到(S)-2-(6-(乙醯胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(10.4mg,0.016mmol,64.9%產率)。1H NMR(500MHz,DMSO-d6)δ 7.86(br.s.,1H),7.38-7.29(m,1H),7.17-7.02(m,3H),6.98(td,J=8.5,2.8Hz,1H),6.93-6.87(m,1H),5.84(d,J=11.0Hz,1H),4.10-3.95(m,1H),3.92-3.75(m,1H),2.83(br.s.,3H),2.76-2.66(m,2H),2.39-2.34(m,3H),2.12(d,J=10.3Hz,1H),1.83-1.78(m,3H),1.49(br.s.,1H),1.32-1.18(m,2H),1.14(d,J=1.8Hz,9H),1.07-0.95(m,1H),0.86(s,3H),0.61(s,3H)。8個六氫吡啶氫未拆分。LCMS(M+H)=659.3。
實例141
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸：向5-甲基-1,3,4-噁二唑-2-甲酸鉀
(4.45mg,0.027mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.013mL,0.027mmol)。1h後，將混合物添加至(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(15mg,0.024mmol)及TEA(10.17μl,0.073mmol)於DCM(0.5mL)中之預攪拌溶液中。將所得混合物於室溫下攪拌2h且隨後濃縮並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1,3,4-噁二唑-2-甲醯胺基)甲基)吡啶-3-基)乙酸(1.5mg,2.064μmol,8.49%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.31(m,2H),7.18-7.07(m,2H),7.04(d,J=9.9Hz,1H),7.02-6.96(m,1H),6.91-6.73(m,1H),5.46-5.39(m,1H),4.34(d,J=13.2Hz,1H),4.09-3.94(m,2H),3.63(br.s.,3H),3.05(br.s.,1H),2.88-2.79(m,3H),2.77-2.68(m,4H),2.58(s,3H),2.39-2.30(m,3H),2.10(br.s.,1H),1.52(br.s.,1H),1.24(br.s.,2H),1.14(br.s.,1H),1.09(s,9H),0.96(br.s.,1H),0.85(br.s.,3H),0.63(br.s.,3H)。LCMS(M+H)=727.2。
實例142
(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向2-(二甲基胺基)-2-側氧基乙酸
(3.13mg,0.027mmol)於DCM(0.5mL)中之溶液中添加草醯氯(0.013ml,0.027mmol)。1h後，將混合物添加至(S)-2-(6-(胺基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(15mg,0.024mmol)及TEA(0.06ml,0.430mmol)於DCM(0.5mL)中之預攪拌溶液中。將所得混合物於室溫下攪拌2h且隨後濃縮並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((2-(二甲基胺基)-2-側氧基乙醯胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(5.1mg,7.12μmol,29.3%產率)。1H NMR(500MHz,DMSO-d6)δ 8.70(br.s.,1H),7.43-7.32(m,1H),7.19-7.10(m,2H),7.04(d,J=10.3Hz,1H),6.98(td,J=8.4,2.6Hz,1H),6.92(s,1H),5.82(d,J=11.0Hz,1H),4.27-4.08(m,1H),3.98-3.77(m,1H),3.62-3.49(m,1H),3.12-3.00(m,3H),2.85(s,6H),2.76-2.67(m,3H),2.47(s,3H),2.38-2.30(m,4H),2.13(d,J=11.0Hz,1H),1.49(br.s.,1H),1.35-1.17(m,2H),1.13(d,J=2.2Hz,9H),1.08-0.94(m,1H),0.86(s,3H),0.61(s,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=716.3。
實例143
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-
1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((甲基胺基)甲基)吡啶-3-基)乙酸(12mg,0.019mmol)於DCM(0.5mL)中之溶液中添加TEA(7.95μl,0.057mmol)，之後添加乙醯氯(1.488μl,0.021mmol)並將所得混合物於室溫下攪拌1h。隨後將混合物濃縮並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((N-甲基乙醯胺基)甲基)吡啶-3-基)乙酸(6.2mg,9.21μmol,48.4%產率)。1H NMR(500MHz,DMSO-d6)δ 7.41-7.27(m,1H),7.19-7.02(m,3H),6.98(t,J=8.6Hz,1H),6.92(d,J=17.2Hz,1H),5.86(d,J=7.3Hz,1H),4.44-4.27(m,1H),4.13-3.99(m,1H),3.67-3.54(m,3H),2.84(br.s.,3H),2.73(d,J=11.4Hz,2H),2.66-2.60(m,2H),2.46(d,J=3.7Hz,3H),2.37(d,J=3.7Hz,3H),1.99-1.87(m,2H),1.83(s,1H),1.81-1.73(m,1H),1.49(br.s.,1H),1.35-1.16(m,2H),1.14(s,9H),1.08-0.95(m,1H),0.86(s,3H),0.60(br.s.,3H)。4個六氫吡啶氫未拆分。LCMS(M+H)=673.3。
實例144、145及146
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸、(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四 氫異喹啉-6-基)-2-甲基-6-((3-甲基-4H-1,2,4-三唑-4-基)甲基)吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.030g,0.042mmol)及3-甲基-1H-1,2,4-三唑(0.02g,0.241mmol)於THF(0.5mL)中之溶液中添加t-BuOK(0.008g,0.071mmol)並於rt下攪拌4h。添加氫氧化鈉(0.04g,1.000mmol)並將反應混合物於80℃下攪拌2h。隨後，冷卻並藉由製備型HPLC純化，以得到三種產物。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((3-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸(0.0037g,5.31μmol,12.79%產率)。LCMS(M+H)=683.2。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸(0.0086g,0.012mmol,29.1%產率)。(M+H)=683.2。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((5-甲基-1H-1,2,4-三唑-1-基)甲基)吡啶-3-基)乙酸(0.0112g,0.016mmol,38.3%產率)。(M+H)=683.2。
(S)-6-(2-胺基-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)- 甲酸苄基酯：將(S)-2-(6-胺基-5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(90mg,0.191mmol)、6-(6-甲基-4,8-二氧離子基-1,3,6,2-二氧氮雜硼雜環辛烷-2-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(97mg,0.230mmol)、2-二環己基膦基-2',6'-二甲氧基苯(15.71mg,0.038mmol)及2M K3PO4(0.717mL,1.435mmol)於1,4-二噁烷(2mL)及水(0.400mL)中之混合物脫氣10min。隨後，添加Pd(OAc)2(4.30mg,0.019mmol)，脫氣5min並將混合物於80℃下加熱3h。在冷卻至室溫後，添加水並將混合物用乙酸乙酯萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-40% EtOAc/己烷)純化殘餘物，以得到白色發泡體狀(S)-6-(2-胺基-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(90mg,0.137mmol,71.6%產率)。1H NMR(500MHz,CDCl3)δ 7.49-7.34(m,5H),7.26-7.13(m,2H),7.10-6.96(m,1H),5.89(br.s.,1H),5.24(s,2H),5.14-5.02(m,1H),4.76(br.s.,1H),4.72-4.63(m,1H),4.25-4.15(m,1H),3.87(d,J=12.1Hz,1H),3.77(br.s.,1H),3.32(d,J=12.6Hz,1H),2.91(br.s.,1H),2.84(t,J=12.5Hz,1H),2.48(s,3H),2.32-2.21(m,1H),2.01-1.90(m,1H),1.57-1.50(m,1H),1.28-1.22(m,7H),1.20(s,9H),1.18(br.s.,1H),1.14(s,1H),1.12-1.01(m,2H),0.90(s,3H),0.68-0.58(m,3H)。LCMS(M+H)=657.6。
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯，2 HCl：向
(S)-6-(2-胺基-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(90mg,0.137mmol)於EtOH(2)中之溶液中添加1N HCl(0.274mL,0.274mmol)溶液，之後添加10% Pd-C(29.2mg,0.027mmol)並將所得混合物在氫氣球氣氛下攪拌5h。隨後將混合物經由小的矽藻土墊過濾，濃縮並在高真空下乾燥過夜，以得到白色固體狀(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯，2 HCl(80mg,0.134mmol,98%產率)。1H NMR(500MHz,CDCl3)δ 7.37(br.s.,1H),7.27-7.18(m,1H),7.00(br.s.,1H),6.68(br.s.,1H),6.55(br.s.,1H),5.49(d,J=6.3Hz,1H),5.11(dt,J=12.4,6.1Hz,1H),4.48(br.s.,2H),3.64(br.s.,1H),3.50(br.s.,1H),3.33(br.s.,1H),3.21(d,J=18.0Hz,2H),2.66(d,J=8.5Hz,3H),1.91(br.s.,1H),1.80(br.s.,2H),1.35-1.26(m,9H),1.19(s,9H),0.84(br.s.,6H)。LCMS(M+H)=523.5。
實例147
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯，2 HCl(20mg,0.034mmol)於MeOH(1)中之溶液中添加TEA(0.00936mL,0.067mmol)並將所得混合物攪拌10min。隨後，添加MeOH(1mL)中之4-氟-2-甲基苯甲醛(9.28mg,0.067mmol)並將混合物再攪拌2h。隨後添
加NaCNBH3(6.33mg,0.101mmol)並將混合物於室溫下攪拌16h。用水(10mL)稀釋並將混合物用乙酸乙酯(50mL)萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.034mL,0.336mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(8.4mg,0.014mmol,41.5%產率)。1H NMR(500MHz,DMSO-d6)δ 7.40-7.29(m,1H),7.18-7.09(m,1H),7.07-7.02(m,2H),7.01-6.94(m,1H),6.92-6.83(m,1H),5.69(d,J=6.6Hz,1H),4.93(br.s.,1H),3.62(br.s.,3H),2.91-2.77(m,3H),2.72(br.s.,2H),2.36(d,J=4.0Hz,3H),2.29(s,3H),2.20(br.s.,1H),2.08(br.s.,1H),1.46(br.s.,1H),1.24(br.s.,2H),1.18(d,J=11.7Hz,1H),1.13(s,9H),0.98(d,J=16.9Hz,1H),0.84(br.s.,3H),0.60(br.s.,3H)。LCMS(M+H)=603.3。
實例148
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(6-甲基嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯，2 HCl(20mg,0.034mmol)、4-氯-6-甲基嘧啶(21.58mg,0.168mmol)、K2CO3(27.8mg,0.201mmol)及NaI(10.07mg,0.067mmol)於二噁烷(2mL)中之混合物於85℃下加熱48hr。將混合物用EtOAc稀釋，用水洗滌，乾
燥(Na2SO4)，過濾並濃縮。隨後於80℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.034mL,0.336mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(6-甲基嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸(9.1mg,0.016mmol,47.3%產率)。1H NMR(500MHz,DMSO-d6)δ 8.42(s,1H),7.37(dd,J=11.4,7.7Hz,1H),7.16(br.s.,1H),7.05-6.95(m,1H),6.77(s,1H),5.69(d,J=6.2Hz,1H),4.94(br.s.,1H),4.90-4.83(m,1H),4.80(br.s.,1H),4.77-4.66(m,1H),3.92-3.83(m,1H),3.80(br.s.,1H),2.99-2.86(m,2H),2.80(br.s.,1H),2.31-2.25(m,6H),1.46(br.s.,1H),1.24(br.s.,1H),1.18(br.s.,1H),1.13(s,9H),0.96(br.s.,1H),0.81(br.s.,3H),0.59(br.s.,1.3H),0.49(br.s.,1.7H)。4個六氫吡啶氫未拆分。LCMS(M+H)=573.2。
實例149
(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯，2 HCl(20mg,0.034mmol)、4-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶(28.3mg,0.168mmol)、K2CO3(32.5mg,0.235mmol)及NaI(10.07mg,0.067mmol)於二噁烷(2mL)中之混合物於85℃下加熱48hr。將混合物用EtOAc稀釋，用水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後於80
℃下將殘餘物用乙醇(1mL)中之10N NaOH(0.034mL,0.336mmol)處理4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到(S)-2-(6-胺基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-5-(2-(1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)-2-(第三丁氧基)乙酸(9.3mg,0.015mmol,45.2%產率)。1H NMR(500MHz,DMSO-d6)δ 8.43(br.s.,1H),8.34(s,1H),7.54(br.s.,1H),7.33-7.16(m,1H),7.09(s,1H),5.65(br.s.,1H),5.24-5.11(m,1H),5.11-4.97(m,1H),4.17(br.s.,1H),4.09(d,J=19.8Hz,1H),3.94(s,3H),3.06(br.s.,1H),2.33(s,3H),1.45(br.s.,1H),1.24(br.s.,3H),1.14(d,J=2.6Hz,9H),0.80(br.s.,6H)。6個六氫吡啶氫未拆分。LCMS(M+H)=613.2。
(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶1-基)-2-甲醯基-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯：於rt下向(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(羥基甲基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(1g,1.488mmol)於CH2Cl2(5mL)中之攪拌溶液中一次性添加戴斯-馬丁過碘烷(0.758g,1.786mmol)。2h後，將反應混合物用乙酸乙酯(50mL)稀釋，用飽和NaHCO3(10ml)、鹽水(10mL)洗滌，乾燥(Na2SO4)，過濾並濃縮，以產生黃色膏糊，藉由Biotage(5-30% EtOAc/己烷)對其進行純化，以得到白色發泡體狀(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲醯基-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(750mg,1.120mmol,75%產率)。1H NMR
(500MHz,CDCl3)δ 9.88(s,1H),7.54-7.31(m,4H),7.26-7.05(m,3H),6.07(br.s.,1H),5.30-5.20(m,2H),5.17-5.07(m,1H),4.83(br.s.,1H),4.80-4.61(m,1H),3.91(br.s.,1H),3.83(br.s.,1H),3.77(br.s.,1H),3.26(br.s.,1H),2.92(br.s.,2H),2.73(s,3H),2.39-2.19(m,1H),1.64(br.s.,1H),1.56(br.s.,1H),1.34(d,J=18.0Hz,1H),1.25(ddd,J=11.0,6.4,4.1Hz,6H),1.19(d,J=2.4Hz,9H),1.15-1.09(m,1H),1.06(d,J=8.2Hz,1H),0.93(br.s.,3H),0.88(br.s.,1H),0.70(br.s.,1H),0.66(br.s.,2H)。LCMS(M+H2O)=688.7。
6-(5-((S)-1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(1-羥基乙基)-6-甲基吡啶-3-基)-3，4-二氫異喹啉-2(1H)-甲酸苄基酯：於-78℃下向(S)-6-(5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲醯基-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(650mg,0.970mmol)於THF(10mL)中之溶液中添加3M甲基溴化鎂(0.356mL,1.067mmol)並將所得混合物攪拌1h。隨後，添加飽和NH4Cl並將混合物用乙酸乙酯萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-100% EtOAc/己烷)純化殘餘物，以得到呈非鏡像異構物之混合物形式之6-(5-((S)-1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(1-羥基乙基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(600mg,0.875mmol,90%產率)。LCMS(M+H)=686.6。
(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(1-羥基乙基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl：向6-(5-((S)-1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-2-(1-羥基乙基)-6-甲基吡啶-3-基)-3,4-二氫異喹啉-2(1H)-甲酸苄基酯(650mg,0.948mmol)於EtOH(10mL)中之溶液中添加1N HCl(1.895mL,1.895mmol)溶液，之後添加10% Pd-C(202mg,0.190mmol)並將所得混合物在氫氣球氣氛下攪拌5h。隨後將混合物經由小的矽藻土墊過濾，濃縮並在高真空下乾燥過夜，以得到呈非鏡像異構物之混合物形式之(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(1-羥基乙基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl(590mg,0.944mmol,100%產率)。LCMS(M+H)=552.5。
(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸異丙基酯：向(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(1-羥基乙基)-2-甲基-5-(1,2,3,4-四氫異喹啉-6-基)吡啶-3-基)乙酸異丙基酯，2 HCl(300mg,0.480mmol)於MeOH(5mL)中之溶液中添加TEA(0.134mL,0.960mmol)並將所得混合物攪拌10min。隨後添
加MeOH(0.5mL)中之4-氟-2-甲基苯甲醛(133mg,0.960mmol)並將混合物再攪拌2h。添加氰基硼氫化鈉(91mg,1.441mmol)並將混合物於室溫下攪拌16h。隨後添加水(10mL)並將混合物用乙酸乙酯(50mL)萃取，用鹽水洗滌，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(0-10% CH2Cl2/MeOH)純化殘餘物，以得到呈非鏡像異構物之不可分離混合物形式之(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸異丙基酯(200mg,0.297mmol,61.8%產率)。LCMS(M+H)=674.7。
(2S)-2-(6-(1-溴乙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：向(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸異丙基酯(200mg,0.297mmol)於CH2Cl2(5mL)中之溶液中添加CBr4(128mg,0.386mmol)，之後添加Ph3P(101mg,0.386mmol)並將所得混合物於室溫下攪拌2h。添加水(2mL)並將混合物用二氯甲烷(10mL)萃取，乾燥(Na2SO4)，過濾並濃縮。隨後藉由Biotage(5-30% EtOAc/己烷)純化殘餘物，以得到呈非鏡像異構物之混合物形式之(2S)-2-(6-(1-溴乙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(160mg,0.217mmol,73.2%產率)。LCMS(M+2H)=738.6。
實例150及151
(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(1-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)吡啶-3-基)乙酸：向N-甲基-1-(四氫-2H-吡喃-4-基)甲胺(35.1mg,0.271mmol)於乙醇(1mL)中之溶液中添加(2S)-2-(6-(1-溴乙基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(40mg,0.054mmol)並將所得混合物於室溫下攪拌16h。隨後，添加10N NaOH(0.054mL,0.543mmol)並將混合物於80℃下加熱4h。將混合物冷卻並藉由製備型HPLC純化，以得到兩種非鏡像異構物。非鏡像異構物1：1H NMR(500MHz,DMSO-d6)δ 7.39-7.24(m,2H),7.09(d,J=7.7Hz,1H),7.04(d,J=10.3Hz,1H),7.01-6.93(m,1H),6.84-6.76(m,1H),5.76(d,J=12.5Hz,1H),3.72(d,J=9.2Hz,1H),3.68-3.52(m,2H),3.23-3.04(m,2H),2.89-2.71(m,5H),2.71-2.59(m,2H),2.47(s,3H),2.36(d,J=2.6Hz,3H),2.14(d,J=3.3Hz,3H),2.09-2.02(m,1H),1.98-1.93(m,1H),1.47(d,J=10.6Hz,3H),1.34(d,J=12.1Hz,1H),1.26(d,J=13.9Hz,1H),1.17(d,J=12.5Hz,1H),1.12-1.03(m,12H),0.97(d,J=10.6Hz,2H),0.85(s,3H),0.60(br.s.,3H)。6個六氫吡啶氫未拆分。LCMS(M+H)=743.3及非鏡像異構物2：1H NMR(500MHz,DMSO-d6)δ 7.34-7.27(m,1H),7.15-7.06(m,
1H),7.03(d,J=8.1Hz,1H),6.99-6.94(m,2H),6.92-6.85(m,1H),5.86(br.s.,1H),3.85(d,J=6.6Hz,1H),3.71-3.56(m,3H),3.51(br.s.,1H),3.05(q,J=11.0Hz,2H),2.83(br.s.,3H),2.74-2.67(m,2H),2.48(s,3H),2.38-2.30(m,3H),2.06(s,2H),2.08(s,3H),1.91(s,2H),1.48(br.s.,1H),1.34(d,J=9.9Hz,1H),1.27-1.18(m,6H),1.15-1.10(m,9H),0.84(br.s.,3H),0.80-0.67(m,2H),0.58(br.s.,3H)。6個六氫吡啶氫未拆分。LCMS(M+H)=743.3。
實例152及153
(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸：將(2S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(1-羥基乙基)-2-甲基吡啶-3-基)乙酸異丙基酯(40mg,0.059mmol)及10N NaOH(0.059mL,0.594mmol)於乙醇(1mL)中之混合物於80℃下加熱4h。隨後將混合物冷卻並藉由製備型HPLC純化，以得到兩種非鏡像異構物。
非鏡像異構物1：第一溶析，1H NMR(500MHz,DMSO-d6)δ 7.38-7.27(m,1H),7.17-7.09(m,2H),7.05(d,J=10.3Hz,1H),6.98(td,J=8.4,2.6Hz,1H),6.88(s,1H),5.76(d,J=9.9Hz,1H),3.70-3.64(m,4H),2.88-2.78(m,3H),2.77-2.66(m,2H),2.38-2.34(m,3H),2.09(d,J=12.1Hz,1H),1.48(d,J=9.9Hz,1H),1.33-1.22(m,1H),1.18(d,J=13.2Hz,1H),1.12(s,9H),1.04-0.98(m,3H),0.85(s,3H),0.61(s,3H)。8個六氫吡啶氫未拆分。LCMS(M+H)=632.3。非鏡像異構物
2：第二溶析，1H NMR(500MHz,DMSO-d6)δ 7.38-7.27(m,1H),7.16-7.02(m,2H),7.02-6.95(m,2H),6.94-6.89(m,1H),5.80-5.72(m,1H),2.84(br.s.,2H),2.79(br.s.,1H),2.77-2.65(m,3H),2.39-2.33(m,3H),2.14(d,J=9.9Hz,1H),1.47(br.s.,1H),1.26(dd,J=14.1,6.1Hz,4H),1.18(br.s.,1H),1.14-1.10(m,9H),1.05-0.90(m,2H),0.85(s,3H),0.59(s,3H)。8個六氫吡啶氫未拆分。LCMS(M+H)=632.3。
實例154
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸：向氧雜環丁-3-基甲醇(0.03g,0.341mmol)於THF(0.6mL)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.018g,0.025mmol)於THF(0.6mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)並將混合物於rt下攪拌1h。隨後，添加EtOH(0.5ml)及氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-((氧雜環丁-3-基甲氧基)甲基)吡啶-3-基)乙酸(0.0146g,0.021mmol,83%產率)。LCMS(M+H)=688.4。
實例155
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸：向四氫-2H-吡喃-4-醇(0.02g,0.196mmol)於二噁烷(0.5mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)，隨後添加(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.018g,0.025mmol)。將混合物於rt下攪拌1h，隨後添加EtOH(0.5ml)及氫氧化鈉(0.02g,0.500mmol)並於80℃下加熱3h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)氧基)甲基)吡啶-3-基)乙酸(0.0090g,0.013mmol,50.5%產率)。LCMS(M+H)=702.3。
實例156
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向乙醇(0.05ml,0.856mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.018g,0.025
mmol)於二噁烷(0.5mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)。將混合物於rt下攪拌2h。隨後，添加EtOH(0.5ml)及氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱2h。隨後，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(乙氧基甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(0.0132g,0.020mmol,80%產率)。LCMS(M+H)=646.3。
實例157
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸：向(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.018g,0.025mmol)及甲醇(0.05ml,1.236mmol)於二噁烷(0.5mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)並將混合物於rt下攪拌2h。隨後，添加EtOH(0.5ml)及氫氧化鈉(0.03g,0.750mmol)並將混合物於80℃下加熱2h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(甲氧基甲基)-2-甲基吡啶-3-基)乙酸(0.0146g,0.022mmol,87%產率)。LCMS(M+H)=632.2。
實例158
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸：向2-丙醇(0.05ml,0.649mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.018g,0.025mmol)於THF(0.6mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)。將混合物於rt下攪拌2h，隨後添加EtOH(0.5ml)及氫氧化鈉(0.03g,0.750mmol)並於80℃下加熱2h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-(異丙氧基甲基)-2-甲基吡啶-3-基)乙酸(0.0066g,9.50μmol,38.2%產率)。LCMS(M+H)=660.2。
實例159
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸：向(四氫-2H-吡喃-4-基)甲醇(0.02g,0.172mmol)於二噁烷(0.5mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-
甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.02g,0.028mmol)。將混合物於rt下攪拌2h，隨後添加EtOH(0.5ml)及氫氧化鈉(0.2g,5.00mmol)。將混合物於80℃下加熱3h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基-6-(((四氫-2H-吡喃-4-基)甲氧基)甲基)吡啶-3-基)乙酸(0.0131g,0.018mmol,66.1%產率)。LCMS(M+H)=716.4。
實例160
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-6-((2-乙氧基乙氧基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸：向2-乙氧基乙醇(0.1g,1.110mmol)於二噁烷(0.5mL)中之溶液中添加t-BuOK(0.015g,0.134mmol)及(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.02g,0.028mmol)。將混合物於rt下攪拌2h。添加乙醇(0.5ml)及氫氧化鈉(0.2g,5.00mmol)並於80℃下加熱3h，冷卻並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-((2-乙氧基乙氧基)甲基)-5-(2-(4-氟-2-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-2-甲基吡啶-3-基)乙酸(0.0164g,0.024mmol,86%產率)。LCMS(M+H)=690.3。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯：於rt下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲醯基-2-甲基吡啶-3-基)乙酸異丙基酯(310mg,0.501mmol)及K2CO3(312mg,2.254mmol)於MeOH(5ml)中之攪拌溶液中添加(1-重氮基-2-側氧基丙基)膦酸二甲基酯(109mg,0.57mmol)。將反應物攪拌1hr。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度0-100%，在10CV內)上純化。(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(275mg,0.447mmol,89%產率)。1H NMR(500MHz,CDCl3)δ 7.33-7.28(m,3H),7.12-7.07(m,1H),7.07-6.99(m,2H),6.96(d,J=8.8Hz,2H),6.00(br.s.,1H),5.10(dt,J=12.6,6.2Hz,1H),4.22(qd,J=6.9,2.3Hz,2H),3.24(br.s.,1H),3.12(t,J=6.9Hz,2H),2.94(s,2H),2.63-2.58(m,3H),2.27-2.15(m,1H),2.09(d,J=19.7Hz,1H),1.41-1.31(m,1H),1.29-1.25(m,2H),1.24-1.20(m,6H),1.19-1.16(m,9H),1.09(d,J=10.1Hz,1H),0.90(br.s.,3H),0.69(br.s.,3H)。LCMS(M+H)：615.30。
實例161
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於80℃下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(12mg,0.020mmol)於EtOH(0.2ml)中之攪拌溶液中添加NaOH(5M,aq)(27μl,0.14mmol)。將反應物攪拌5hr且隨後經由製備型LC/MS純化粗物質，以產生期望產物(7.0mg)。1H NMR(500MHz,DMSO-d6)δ 7.36(dd,J=8.1,5.9Hz,2H),7.26(d,J=7.0Hz,1H),7.14-7.04(m,3H),7.01(d,J=6.2Hz,2H),5.82(s,1H),4.29-4.19(m,2H),3.80(s,1H),3.05(t,J=6.6Hz,2H),2.54(s,6H),2.47(s,3H),1.25(br.s.,2H),1.13(s,9H),0.74(br.s.,6H)。LCMS(M+H)=573.16。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：於rt下向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲醯基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(960mg,1.99mmol)及K2CO3(1.2g,8.9mmol)於MeOH(10ml)中之攪拌溶液中添加(1-重氮基-2-側氧基丙基)膦酸二甲基酯(358μl,2.38mmol)。將反應物攪拌1hr。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%梯度)上純化，以產生預計產物(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(830mg,1.731mmol,87%產率)。1H NMR(500MHz,CDCl3)δ 6.24(br.s.,1H),5.11-4.99(m,1H),4.03(br.s.,1H),3.56-3.42(m,1H),3.41(s,1H),2.99-
2.84(m,1H),2.64(d,J=7.9Hz,2H),2.57(br.s.,3H),1.23-1.22(m,3H),1.21-1.18(m,12H),1.14(d,J=6.3Hz,3H),1.09-1.02(m,6H)。LCMS(M+H)：479.10,481.05。
(S)-2-(5-溴-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：在N2下，於rt下在N2下向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(830mg,1.73mmol)及2-甲基吡啶1-氧化物(378mg,3.46mmol)於THF(12ml)中之攪拌溶液中添加亞硝酸第三丁基酯(412μl,3.46mmol)。使反應物升溫至70℃並攪拌過夜。LCMS顯示起始材料與產物之混合物。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以產生預計產物(S)-2-(5-溴-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(306mg,0.637mmol,36.8%產率)。1H NMR(500MHz,CDCl3)δ 6.20(br.s.,1H),5.06(quin,J=6.3Hz,1H),4.07-3.91(m,1H),3.50-3.33(m,1H),3.00-2.83(m,1H),2.71-2.62(m,1H),2.58(s,3H),1.59(br.s.,1H),1.52(br.s.,2H),1.39(d,J=11.8Hz,1H),1.21(d,J=6.3Hz,3H),1.20(s,9H),1.16(d,J=6.1Hz,3H),1.06(d,J=18.1Hz,6H)。LCMS(M+H)：480.10,482.05。
(S)-2-(第三丁氧基)-2-(6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯：在N2下合併(S)-2-(5-溴-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(18mg,0.037mmol)、2-(4-(4-氟苯乙氧基)苯基)-6-甲基-1,3,6,2-二氧氮雜硼雜環辛烷-4,8-二酮(21mg,0.056mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(3.1mg,7.5μmol)、Pd(OAc)2(0.841mg,3.75μmol)、磷酸鉀(60mg,0.28mmol)。添加1,4-二噁烷(0.6ml)、水(0.1ml)並將反應物於80℃下攪拌。3h後，將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以產生預計產物(S)-2-(第三丁氧基)-2-(6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(10mg,0.016mmol,43%產率)。LCMS(M+H)：616.25。
實例162
(S)-2-(第三丁氧基)-2-(6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：於80℃下向(S)-2-(第三丁氧基)-2-(6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(14mg,0.023mmol)於DCE(909μl)中之攪拌溶液中添加三甲基錫醇(21mg,0.11mmol)。將反應物攪拌5hr。LCMS顯示無反應物。過濾反應物並濃縮。將殘餘物吸收於10：1 EtOH/H2O中並於室溫下添加氫氧化鋰水合物(1M)(23μl,0.023mmol)並將反應物攪拌過夜。LCMS顯示無反應物。使反應物升溫至
40℃並攪拌過夜。LCMS顯示無反應物。將反應物升溫至50℃並攪拌6hr。LCMS顯示無反應物。使反應物升溫至70℃並攪拌過夜。LCMS顯示形成預計產物。將粗物質經由製備型LC/MS純化成期望產物(4.5mg)。1H NMR(500MHz,DMSO-d6)d 7.38(d,J=8.4Hz,3H),7.21-7.04(m,5H),5.64-5.48(m,1H),4.28(d,J=5.1Hz,2H),3.12-3.00(m,1H),2.57-2.46(m,8H),1.91(s,1H),1.25(br.s.,2H),1.10(s,9H),0.77(br.s.,6H),0.33(s,1H)。LCMS(M+H)=574.16。
實例163
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(丙-1-炔-1-基)吡啶-3-基)乙酸：於-20℃下向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(50mg,0.081mmol)於THF(1ml)中之攪拌溶液中逐滴添加雙(三甲基矽基)胺化鈉(1M/THF,98μl,0.098mmol)。將反應物攪拌15min。逐滴添加碘甲烷(15μl,0.24mmol)。將反應物攪拌15min，隨後升溫至室溫並攪拌1hr。LCMS顯示預計產物質量。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以得到
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(丙-1-炔-1-基)吡啶-3-基)乙酸異丙基酯(50mg,0.080mmol)，將其吸收於1mL EtOH中並用0.1ml 5N NaOH水溶液處理。將混合物於80℃下攪拌過夜。經由製備型LC/MS純化粗物質，以
產生期望產物(5.8mg)。1H NMR(500MHz,DMSO-d6)δ 7.36(dd,J=8.4,5.9Hz,2H),7.25(br.s.,1H),7.11(t,J=9.0Hz,2H),7.06-6.96(m,3H),5.80(s,1H),4.29-4.19(m,2H),3.05(t,J=6.6Hz,2H),2.54(s，6H),2.45(s,3H),1.76(s,3H),1.25(br.s.,2H),1.12(s,9H),0.71(br.s.,6H)。LCMS(M+H)=587.16。
6-溴-2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉：向6-溴-1,2,3,4-四氫異喹啉(1.25g,5.88mmol)於DCM(25mL)中之溶液中添加DCM(25mL)中之2-氯-6-甲基苯甲醛(1.0g,6.5mmol)及乙酸(0.337mL,5.88mmol)。隨後添加三乙醯氧基硼氫化鈉(1.62g,7.64mmol)。將混合物於r.t下攪拌16hr。將混合物用水淬滅並用EtOAc萃取。將有機層用鹽水洗滌，經Na2SO4乾燥並濃縮。藉由與EtOAc重結晶純化殘餘物，以產生6-溴-2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉(1.44g,4.11mmol,69.8%產率)。LCMS(M+H)：350.00,352.00。
2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉：在密封瓶中將6-溴-2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉(1.00g,2.85mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧雜硼烷)(1.09g,4.28mmol)、Pd(dppf)Cl2(0.209g,0.285mmol)及乙酸鉀(0.840g,8.55mmol)合併於二噁烷(10mL)中。將混合物脫氣並於85℃下加熱8hr。將混合物用EtOAc稀釋，用水、鹽水洗滌，經Na2SO4乾燥並濃縮。藉由矽膠管柱(EtOAc/己烷梯度，在10個CV內0-100%)純化殘餘物，以產生2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四
甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉(1.05g,2.64mmol,93%產率)。1H NMR(400MHz,CDCl3)δ 7.57-7.51(m,2H),7.23(d,J=7.6Hz,1H),7.14-7.06(m,2H),7.02(d,J=7.6Hz,1H),3.83(s,2H),3.71(s,2H),2.88-2.76(m,4H),2.46(s,3H),1.34(s,12H)。LCMS(M+H)：398.05。
(S)-2-(6-胺基-5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：於rt下向(S)-3-溴-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶甲酸(100mg,0.200mmol)及TEA(56μl,0.40mmol)於甲苯(2ml)中之攪拌溶液中添加水(18μl,1.0mmol)、之後添加二苯基磷醯基疊氮化物(87μl,0.40mmol)。將反應物於90℃下攪拌2hr。隨後將混合物冷卻至室溫，用EtOAc稀釋並用飽和NaHCO3溶液、水及鹽水洗滌。隨後乾燥(Na2SO4)有機層，過濾並濃縮。隨後藉由Biotage(EtOAc/己烷梯度，在10個CV內0-100%)純化殘餘物，以得到白色固體狀(S)-2-(6-胺基-5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(80mg,0.170mmol,85%產率)。1H NMR(500MHz,CDCl3)δ 6.11(br.s.,1H),5.02(spt,J=6.3Hz,1H),4.86(s,2H),3.99(t,J=12.0Hz,1H),3.50-3.40(m,1H),2.91(d,J=11.5Hz,1H),2.62(d,J=11.8Hz,1H),2.46-2.39(m,3H),1.45-1.39(m,1H),1.33(dd,J=12.7,2.3Hz,1H),1.28-1.24(m,1H),1.21-1.16(m,13H),1.13(d,J=6.1Hz,3H),1.09-0.99(m,6H)。LCMS(M+H)：472.05,470.10。
實例164
(S)-2-(6-胺基-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：(S)-2-(6-胺基-5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.053mmol)、2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉(32mg,0.080mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(4.4mg,11μmol)、Pd(OAc)2(1.2mg,5.3μmol)及磷酸鉀(85mg,0.40mmol)於1,4-二噁烷(1ml)及水(0.2ml)中在N2下。將反應物於80℃下加熱1h。將反應物濃縮並將殘餘物吸收於EtOH(1mL)中且隨後用NaOH(5N aq)(106μl,0.531mmol)處理並於80℃下攪拌過夜。隨後將混合物冷卻並經由製備型LC/MS純化粗物質，以提供產物(3.0mg)。1H NMR(500MHz,DMSO-d6)δ 7.28(d,J=7.3Hz,1H),7.24-7.16(m,2H),7.16-7.08(m,1H),7.05-6.99(m,1H),6.87(br.s.,1H),5.71(d,J=8.1Hz,1H),4.82-4.73(m,0.6 H),3.83(br.s.,2H),3.68(br.s.,2H),2.86-2.73(m,5H),2.47-2.41(m,3H),2.36-2.05(m,5H),1.47(br.s.,1H),1.25(br.s.,2H),1.19-1.08(m,13H),1.05-0.92(m,1H),0.84(br.s.,3H),0.59(br.s.,3H)。LCMS(M+H)=619.16。
實例165
(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸：在N2下合併(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(34mg,0.070mmol)、2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉(42mg,0.11mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(5.8mg,0.014mmol)、Pd(OAc)2(1.6mg,7.0μmol)及磷酸鉀(111mg,0.525mmol)。在N2下添加1,4-二噁烷(1.2ml)及水(0.2ml)。將反應物於80℃下加熱2h。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以得到(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(36mg,0.053mmol)，將其吸收於EtOH(1mL)中且隨後用NaOH(5N aq)(140μl,0.700mmol)處理並於80℃下攪拌過夜。隨後將混合物冷卻至rt並經由製備型LC/MS純化粗物質，以產生產物(16.8mg)。1H NMR(500MHz,DMSO-d6)δ 7.28(d,J=7.7Hz,1H),7.24-7.15(m,2H),7.14-7.04(m,2H),6.93-6.84(m,1H),5.86(d,J=9.2Hz,1H),4.26-4.15(m,1H),4.07-3.94(m,1H),3.87-3.78(m,2H),3.76-3.62(m,2H),2.84-2.73(m,4H),2.55-2.51(m,6H),2.47-2.42(m,3H),1.49(br.s.,1H),1.23(d,J=10.6Hz,2H),1.16-1.10(m,10H),1.01(br.s.,1H),0.84(br.s.,3H),0.61(br.s.,3H)。LCMS(M+H)=634.16。
實例166
(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)乙酸：在N2下合併(S)-2-(5-溴-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(34mg,0.071mmol)、2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉(42mg,0.11mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(5.8mg,0.014mmol)、Pd(OAc)2(1.6mg,7.1μmol)及磷酸鉀(113mg,0.531mmol)。在N2下添加1,4-二噁烷(1.2ml)及水(0.2ml)。將反應物於80℃下加熱2h。將反應物濃縮，吸附至矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以得到(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(40mg,0.060mmol,84%產率)。LCMS(M+H)：671.35
於70℃下向上述(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-氰基-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)乙酸異丙基酯(115mg,0.171mmol)於乙醇(3mL)中之攪拌溶液中添加3mL水中之氫氧化鋰水合物(7.9mg,0.19mmol)。將反應物攪拌過夜。隨後向反應物中再添加4mg氫氧化鋰水合物及1mL水並將其攪拌5hr。藉由製備型反相HPLC在C18管柱上使用適宜緩衝之H2O/CH3CN梯度純化反應物，並濃縮，以產生預計產物(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-6-氰基-4-
(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)乙酸(15mg,0.023mmol,14%產率)。1H NMR(400MHz，甲醇-d4)δ 7.36-7.17(m,5H),7.13-7.05(m,1H),5.90(d,J=4.4Hz,1H),4.96-4.86(m,5H),4.18-3.90(m,3H),3.17-2.94(m,4H),2.60(s,3H),2.51(d,J=4.9Hz,3H),1.43-1.27(m,4H),1.18(s,9H),0.94-0.69(m,6H)。LCMS(M+H)：629.35。
4-(6-溴-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶：將4-氯-苯并[4,5]呋喃并[3,2-d]嘧啶(1.06g,5.19mmol)、6-溴-1,2,3,4-四氫異喹啉(1.0g,4.7mmol)、碳酸鉀(1.95g,14.1mmol)及碘化鈉(0.71g,4.7mmol)於二噁烷(50mL)中之混合物於90℃下加熱6hr。將混合物用EtOAc稀釋並用水、鹽水洗滌，經Na2SO4乾燥並濃縮。藉由與EtOAc重結晶純化殘餘物，以產生4-(6-溴-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶(1.2g,3.16mmol,66.9%產率)。LCMS(M+H)：379.90,381.90。
4-(6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶：在密封微波小瓶中將4-(6-溴-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶(1.4g,3.7mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧雜硼烷)(1.4g,5.5mmol)、Pd(dppf)Cl2(0.269g,0.368mmol)及乙酸鉀(1.08g,11.1mmol)合併於二噁烷(15mL)中。將混合物脫氣並於85℃下加熱8hr。將混合物用
EtOAc稀釋，用水、鹽水洗滌，經Na2SO4乾燥並濃縮。藉由矽膠管柱(EtOAc/己烷梯度，在10個CV內0-100%)純化殘餘物，以產生4-(6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶(1.2g,2.8mmol,76%產率)。1H NMR(500MHz,CDCl3)δ 8.65(s,1H),8.18(d,J=7.7Hz,1H),7.73-7.59(m,5H),7.45(ddd,J=7.8,6.8,1.3Hz,1H),7.30(d,J=7.6Hz,1H),5.25(s,2H),4.39(t,J=5.9Hz,2H),3.10(t,J=5.8Hz,2H),1.36(s,12H)。LCMS(M+H)：428.10。
實例167
(S)-2-(6-胺基-5-(2-(苯并呋喃并[3，2-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：在N2下無水合併(S)-2-(6-胺基-5-溴-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.043mmol)、4-(6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶(27mg,0.064mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(4.2mg,10μmol)、Pd(OAc)2(1.1mg,5.1μmol)及磷酸鉀(68mg,0.32mmol)並在N2下將其吸收於1,4-二噁烷(1ml)及水(0.14ml)中。將反應物於80℃下加熱1h。將反應物濃縮，吸收於EtOH(1mL)中並用NaOH(0.1ml,0.4mmol)處理。將混合物於80℃下攪拌過夜。經由製備型LC/MS純化粗物質，以產生產物(12.6mg)。1H NMR(500MHz,DMSO-d6)δ 8.58(d,J=2.2Hz,1H),8.12(d,J=7.7Hz,1H),7.88(d,J=7.7Hz,1H),7.73(t,J=7.5Hz,1H),7.51(t,J=7.5Hz,
1H),7.48-7.40(m,1H),7.22-7.14(m,1H),7.02(s,1H),5.68(d,J=5.5Hz,1H),5.30-5.13(m,1H),4.96(br.s.,1H),4.33(br.s.,1H),2.28(s,4H),1.50(br.s.,1H),1.23(s,9H),1.11(s,10H),0.94-0.68(m,6H)。LCMS(M+H)=649.15。
實例168
(S)-2-(5-(2-(苯并呋喃并[3,2-d]嘧啶-4-基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：向配備有磁力攪拌棒之壓力小瓶中添加二噁烷(1mL)及水(0.200mL)中之(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(30mg,0.062mmol)、4-(6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-3,4-二氫異喹啉-2(1H)-基)苯并呋喃并[3,2-d]嘧啶(39.6mg,0.093mmol)、乙酸鈀(II)(1.734mg,7.72μmol)、S-Phos(7.92mg,0.015mmol)及磷酸鉀(98mg,0.463mmol)。在超音波處理的同時使氬鼓泡通過混合物達5分鐘。將燒瓶加蓋並在預加熱鋁塊內加熱至80℃並將其攪拌2小時。LC/MS顯示呈主要峰形式之期望產物。將反應混合物在真空下濃縮並吸收於乙醇(1mL)中，隨後添加NaOH(10N,0.062mL,0.618mmol)。將小瓶密封並將混合物於80℃下在預加熱鋁塊內加熱16小時。LC/MS顯示反應完全，且消耗起始材料。將反應物冷卻至室溫並過濾。經由製備型LC/MS純化粗物質，以產生產物(12.0mg,28%)。1H NMR(500MHz,DMSO-d 6)δ 8.63-8.50(m,1H),8.12(d,J=7.7Hz,1H),7.86(d,J=8.4Hz,1H),7.72(t,J=7.7Hz,1H),7.51(t,J=7.5Hz,1H),7.47-
7.38(m,1H),7.28-7.19(m,1H),7.06-7.00(m,1H),5.82(d,J=13.2Hz,1H),5.39-5.23(m,1H),5.14(d,J=16.9Hz,1H),4.35(br.s.,1H),4.30(d,J=8.1Hz,1H),4.26-4.16(m,1H),4.10-3.96(m,1H),3.31(d,J=11.7Hz,1H),3.08(br.s.,2H),2.82(br.s.,1H),2.55(s,5H),2.10(br.s.,1H),1.77(br.s.,1H),1.44(br.s.,1H),1.21(s,4H),1.17(br.s.,1H),1.12(d,J=2.9Hz,11H),0.99(br.s.,1H),0.94-0.84(m,1H),0.84-0.71(m,3H),0.53(br.s.,1H),0.39(br.s.,2H)。LCMS(M+H)=706.45。
實例169
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)乙酸：於rt下向碘甲烷(6.1μl,0.098mmol)及碘化銅(I)(9.3mg,0.049mmol)及(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-乙炔基-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(30mg,0.049mmol)於乙腈(1ml)中之攪拌溶液中添加疊氮化鈉(7.9mg,0.12mmol)。將反應物升溫至80℃並攪拌1hr。將反應物濃縮並吸收於1.5mL EtOH中，並添加0.1mL 5N NaOH水溶液。將混合物於80℃下攪拌過夜。經由製備型LC/MS純化粗物質，以產生產物(15.1mg)。1H NMR(500MHz,DMSO-d6)δ 7.44(s,1H),7.34(dd,J=8.3,5.7Hz,2H),7.16-7.07(m,3H),6.99(ddd,J=18.1,8.5,2.4Hz,2H),6.83(dd,J=8.4,2.6Hz,1H),5.88(br.s.,1H),4.25-4.11(m,2H),3.90-3.83(m,3H),
3.05-2.97(m,2H),2.89-2.79(m,1H),2.54(s,3H),2.19(d,J=11.4Hz,1H),1.96-1.83(m,1H),1.54-1.41(m,1H),1.27(d,J=16.1Hz,1H),1.18(d,J=12.1Hz,1H),1.15-1.08(m,10H),1.01(d,J=12.8Hz,1H),0.84(s,3H),0.59(s,3H)。LCMS(M+H)=630.16。
實例170
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(4-氟苄基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(23mg,0.034mmol)、DPPF(3.73mg,6.73μmol)、(4-氟苯基)酸(14.1mg,0.101mmol)及Cs2CO3(22mg,0.067mmol)於DMF(1mL)中之混合物脫氣並裝入N2(3×)。將混合物放置於90℃預加熱油浴中並於此溫度下攪拌1h。將反應混合物冷卻至室溫，吸附至矽藻土上並在矽膠管柱(EtOAc/Hex：在12個CV內0至100%)上純化，以得到無色油狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(4-氟苄基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(10mg,0.014mmol,43%產率)。隨後將此油狀物吸收於EtOH(1mL)中並添加NaOH(5M,0.067mL)。在攪拌下將所得溶液加熱至80℃並持續2h。LCMS顯示轉化成期望產物。將溶液冷卻至室溫並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-6-(4-氟苄基)-5-(4-(4-氟苯乙氧基)苯
基)-2-甲基吡啶-3-基)乙酸(8.0mg,0.012mmol,36%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.31(m,2H),7.19-7.07(m,3H),7.04-6.84(m,7H),5.80(s,1H),3.79(d,J=13.9Hz,1H),3.64(d,J=14.3Hz,1H),3.35(br s,1H),3.05(t,J=6.8Hz,2H),2.76(br s,1H),2.47(s,3H),2.23(br s,1H),1.50(br s,1H),1.13(s,9H),1.00(br s,1H),0.85(d,J=11.7Hz,3H),0.59(br s,3H)。LCMS(M+H)=657.3。
實例171
(S)-2-(第三丁氧基)-2-(6-(環己-1-烯-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(25mg,0.037mmol)、環己-1-烯-1-基酸(18.4mg,0.146mmol)、DPPF(4.05mg,7.31μmol)及Cs2CO3(24mg,0.073mmol)於DMF(1mL)中之混合物脫氣並裝入N2(3×)。將混合物放置於90℃預加熱油浴中並於此溫度下攪拌2h。將反應混合物冷卻至室溫，用EtOAc稀釋，用水、鹽水洗滌，乾燥(Na2SO4)，過濾，濃縮，吸附至矽藻土上並在二氧化矽管柱(EtOAc/Hex：0至50%)上純化，以得到無色油狀期望偶合產物。隨後將此油狀物吸收於EtOH(1mL)中，添加NaOH(5M,0.067mL)並在攪拌下將溶液加熱至80℃並持續2h。LCMS顯示轉化成期望產物。將溶液冷卻至室溫並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(環己-1-烯-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙
氧基)苯基)-2-甲基吡啶-3-基)乙酸(7.3mg,0.011mmol,31%產率)。1H NMR(500MHz,DMSO-d6)δ 7.35(dd,J=8.3,5.7Hz,2H),7.20-7.07(m,3H),7.03-6.93(m,3H),5.86(s,1H),4.82(br s,1H),4.30-4.18(m,2H),3.12-3.01(m,2H),2.92(d,J=15.0Hz,1H),2.79(br s,1H),2.46(s,3H),2.29-2.18(m,1H),1.81(br s,2H),1.66(br s,2H),1.47-1.36(m,4H),1.25(s,2H),1.13(s,9H),1.01(br s,1H),0.85(br s,3H),0.59(br s,3H)。LCMS(M+H)=643.3。
實例172
(S)-2-(第三丁氧基)-2-(6-(環已基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(22mg,0.031mmol)、環己-1-烯-1-基酸(15.8mg,0.126mmol)、DPPF(3.49mg,6.29μmol)及Cs2CO3(21mg,0.063mmol)於DMF(1mL)中之混合物脫氣並裝入N2(3×)。將混合物放置於90℃預加熱油浴中並於此溫度下攪拌2h。將反應混合物冷卻至室溫，用EtOAc稀釋，用水、鹽水洗滌，乾燥(Na2SO4)，過濾，濃縮，吸附至矽藻土上並在二氧化矽管柱(EtOAc/Hex：0至50%)上純化，以得到無色油狀(S)-2-(第三丁氧基)-2-(6-(環己-1-烯-1-基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(7mg,10μmol,33%產率)。將(S)-2-(第三丁氧基)-2-(6-(環己-1-烯-1-基甲基)-4-(4,4-二甲基
六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(7mg,10.22μmol)吸收於乙醇(1mL)中並添加Pd-C(1.09mg,10.2μmol)。將混合物排空並裝入H2(3×)。隨後將混合物在H2氣球下攪拌2h。LCMS顯示轉化成還原產物。過濾混合物並向含有(S)-2-(第三丁氧基)-2-(6-(環己基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯之溶液中添加NaOH(5M)(0.020mL,102μmol)。隨後將溶液加熱至80℃並攪拌過夜。LCMS顯示轉化成期望產物。將溶液冷卻至室溫並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-(環己基甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(2.7mg,4.19μmol,41%產率(對於最後兩個步驟))。1H NMR(500MHz,DMSO-d6)δ 7.34(dd,J=8.4,5.9Hz,2H),7.20-7.06(m,3H),7.06-6.93(m,3H),5.83(s,1H),4.31-4.16(m,2H),3.03(t,J=6.8Hz,2H),2.45(s,3H),2.27(dd,J=13.6,7.3Hz,1H),2.18(dd,J=13.6,6.6Hz,1H),1.64(br s,1H),1.56(br s,1H),1.49(br s,4H),1.36(d,J=12.1Hz,1H),1.11(s,9H),1.07-0.98(m,3H),0.88-0.72(m,4H),0.67-0.52(m,4H)。LCMS(M+H)=645.3。
實例173
(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環已基)甲基)-4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸：將
(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(37mg,0.055mmol)、2-(4,4-二甲基環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(51.7mg,0.219mmol)、DPPF(6.07mg,10.9μmol)及Cs2CO3(35.6mg,0.109mmol)於DMF(1mL)中之混合物脫氣並裝入N2(3×)。將混合物放置於90℃預加熱油浴中並於此溫度下攪拌2h。將反應混合物冷卻至室溫，用EtOAc稀釋，用水、鹽水洗滌，乾燥(Na2SO4)，過濾，濃縮，吸附至矽藻土上並在二氧化矽管柱(EtOAc/Hex：0至50%)上純化，以得到無色油狀(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環己-1-烯-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯(9mg,0.013mmol,23%產率)。將(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環己-1-烯-1-基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯吸收於乙醇(1mL)中並添加Pd-C(1.34mg,12.6μmol)。將混合物排空並裝入H2(3×)。隨後將混合物在H2氣球下攪拌2h。LCMS顯示轉化成還原產物(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環己基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸異丙基酯。過濾溶液並向濾液中添加NaOH(5M)(0.02mL,100μmol)。隨後將溶液加熱至80℃並攪拌過夜。LCMS顯示轉化成期望酸。將溶液冷卻至室溫並藉由製備型HPLC純化，以得到(S)-2-(第三丁氧基)-2-(6-((4,4-二甲基環己基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)乙酸(4.4mg,6.5μmol,52%產率)。1H NMR(500MHz,DMSO-d6)δ 7.34(dd,J=8.3,5.7Hz,2H),7.18-7.07(m,3H),7.05-6.94(m,3H),5.80(s,1H),4.24(q,J=6.6Hz,2H),3.04(t,J=6.4Hz,2H),2.45(s,3H),2.30(dd,J=13.6,7.0Hz,1H),2.21(dd,J=13.4,6.4Hz,2H),1.90(s,2H),1.56(br s,1H),
1.34(d,J=11.7Hz,1H),1.28-1.14(m,5H),1.12(s,9H),1.08-0.92(m,4H),0.88-0.82(m,2H),0.81(s,4H),0.75(s,4H),0.58(br s,2H)。LCMS(M+H)=673.3。
實例174
(S)-2-(6-((二環[1.1.1]戊-1-基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(11mg,0.016mmol)、二環[1.1.1]戊-1-胺(6.7mg,0.080mmol)及N-乙基-N-異丙基丙-2-胺(16.6mg,0.129mmol)於EtOH(1mL)中之溶液攪拌48h。接下來，添加NaOH(5M)(0.032mL,0.161mmol)。將反應混合物加熱至80℃且隨後於此溫度下攪拌過夜。LCMS顯示轉化成期望酸。將溶液冷卻至室溫並藉由製備型HPLC純化成(S)-2-(6-((二環[1.1.1]戊-1-基胺基)甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(2.7mg,4.2μmol,26%產率)。1H NMR(500MHz,DMSO-d6)δ 7.42-7.33(m,2H),7.24(d,J=7.7Hz,1H),7.13(t,J=8.8Hz,2H),7.09-6.95(m,3H),5.81(br s,1H),4.23(dt,J=13.5,6.6Hz,2H),3.11-2.99(m,2H),2.47-2.42(m,3H),1.90(s,2H),1.56-1.45(m,4H),1.23(s,5H),1.18(br s,1H),1.16-1.06(m,9H),0.84(br s,3H),0.60(br s,3H)。LCMS(M+H)=644.3。
(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：在N2下合併(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(0.50g,1.0mmol)、2-(2-氯-6-甲基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,2,3,4-四氫異喹啉(0.41g,1.0mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(0.085g,0.21mmol)、Pd(OAc)2(0.023g,0.10mmol)及磷酸鉀(1.64g,7.72mmol)。在N2下添加1,4-二噁烷(17.1ml)及水(3.43ml)。在攪拌下將反應物於80℃下加熱2h，將反應混合物濃縮，吸附於矽藻土上並在矽膠(Biotage，EtOAc/己烷梯度，在10個CV內0-100%)上純化，以得到(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(0.420g,0.621mmol,60%產率)。向(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-(羥基甲基)-2-甲基吡啶-3-基)乙酸異丙基酯(400mg,0.591mmol)於CH2Cl2(5mL)中之溶液中添加CBr4(255mg,0.769mmol)，之後添加Ph3P(202mg,0.769mmol)。將所得混合物於室溫下攪拌2h。隨後添加水(20mL)並將混合物用二氯甲烷(2×20mL)萃取，乾燥(Na2SO4)，過濾並濃縮。隨後將殘餘物吸附至矽藻土上且隨後藉由Biotage(5-30% EtOAc/己烷)純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡
啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(135mg,0.183mmol,31%產率)。1H NMR(500MHz,DMSO-d6)δ 7.26-7.04(m,5H),6.96-6.87(m,1H),6.04(br s,1H),5.17-5.01(m,1H),4.41-4.27(m,1H),4.21(d,J=9.3Hz,1H),3.91-3.69(m,3H),3.23-3.11(m,1H),2.93-2.76(m,4H),2.63-2.57(m,3H),2.53-2.45(m,3H),2.21(d,J=11.0Hz,1H),1.89(t,J=11.8Hz,1H),1.59(br s,3H),1.52(br s,1H),1.28-1.20(m,7H),1.18(d,J=2.7Hz,9H),0.89(br s,3H),0.69-0.58(m,3H)。LCMS(M+H)=738.1,740.1。
實例175
(S)-2-(6-(氮雜環丁-1-基甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、氮雜環丁烷(15.5mg,0.271mmol)及N-乙基-N-異丙基丙-2-胺(28mg,0.22mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。添加NaOH(5M)(0.054mL,0.27mmol)。隨後將反應混合物加熱至80℃並於此溫度下攪拌2h。隨後將混合物冷卻至室溫並藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(6-(氮雜環丁-1-基甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(12.5mg,0.0190mmol,69%產率)。1H
NMR(500MHz,DMSO-d6)δ 7.29(d,J=7.3Hz,1H),7.25-7.16(m,2H),7.14-7.07(m,2H),6.86-6.80(m,1H),5.63(d,J=12.1Hz,1H),3.85-3.77(m,1H),3.71-3.61(m,1H),3.50(br s,1H),2.79(br s,3H),2.73(d,J=7.0Hz,2H),2.47-2.40(m,8H),2.08-199(m,3H),1.89(s,7H),1.48(br s,2H),1.22(s,8H),1.07(s,11H),0.86-0.79(m,3H),0.58(br s,3H)。LCMS(M+H)=673.3。
實例176
(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、吡咯啶(19.2mg,0.271mmol)及N-乙基-N-異丙基丙-2-胺(28.0mg,0.216mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。接下來，添加NaOH(5M)(0.054mL,0.27mmol)。將反應混合物加熱至80℃並於此溫度下攪拌2h。隨後將反應混合物冷卻至室溫並藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-6-(吡咯啶-1-基甲基)吡啶-3-基)乙酸(12mg,0.017mmol,63%產率)。1H NMR(500MHz,DMSO-d6)δ 7.29(d,J=7.7Hz,1H),7.26-7.14(m,4H),7.13-7.04(m,1H),6.88-6.75(m,1H),5.71(d,J=12.1Hz,1H),
3.85-3.75(m,2H),3.73-3.62(m,1H),2.84-2.70(m,5H),2.59(br.s.,2H),2.48-2.45(m,3H),2.45-2.40(m,4H),2.06(br.s.,1H),1.90(s,2H),1.65(d,J=4.8Hz,5H),1.47(br.s.,1H),1.22(s,3H),1.16(d,J=9.9Hz,1H),1.08(s,10H),0.96(br s,1H),0.88-0.80(m,3H),0.64-0.55(m,3H)。LCMS(M+H)=687.3。
實例177
(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶1-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、六氫吡啶(23.0mg,0.271mmol)及N-乙基-N-異丙基丙-2-胺(28.0mg,0.216mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。接下來，添加NaOH(5M)(0.054mL,0.27mmol)。將反應混合物加熱至80℃並於此溫度下攪拌2h。隨後將反應混合物冷卻至室溫並藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基-6-(六氫吡啶-1-基甲基)吡啶-3-基)乙酸(12mg,0.018mmol,65%產率)。1H NMR(500MHz,DMSO-d6)δ 7.29(d,J=7.7Hz,1H),7.25-7.13(m,3H),7.13-7.01(m,1H),6.85-6.77(m,1H),5.78(d,J=4.8Hz,1H),3.83-3.71(m,1H),3.70-3.58(m,1H),3.32(d,J=7.3Hz,1H),3.22-
3.14(m,1H),3.14-2.99(m,1H),2.84-2.70(m,4H),2.46-2.36(m,7H),2.34-2.22(m,3H),2.18(br s,1H),2.05(br s,1H),1.90(s,1H),1.47(br s,1H),1.38(br s,4H),1.29(br s,2H),1.22(s,3H),1.17(br s,1H),1.09(s,10H),0.96(d,J=10.3Hz,1H),0.82(br s,3H),0.57(br s,3H)。LCMS(M+H)=701.3。
實例178
(S)-2-(6-((6-氮雜螺[2.5]辛-6-基)甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、6-氮雜螺[2.5]辛烷(30mg,0.27mmol)及N-乙基-N-異丙基丙-2-胺(28mg,0.22mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。接下來，添加NaOH(0.054mL,0.27mmol)。將反應混合物加熱至80℃並於此溫度下攪拌2h。將混合物冷卻至室溫且隨後藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(6-(6-氮雜螺[2.5]辛-6-基甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸(12mg,0.016mmol,61%產率)。1H NMR(500MHz,DMSO-d6)δ 7.33-7.25(m,1H),7.25-7.15(m,3H),7.12-7.01(m,1H),6.85-6.78(m,1H),5.80
(br s,1H),3.83-3.76(m,1H),3.71-3.62(m,1H),3.37-3.25(m,1H),3.21(br s,1H),3.10(d,J=7.7Hz,1H),2.86-2.68(m,4H),2.46-2.39(m,6H),2.36(br s,1H),2.34-2.24(m,2H),2.20(br s,1H),2.08(br s,1H),1.90(s,3H),1.47(br s,1H),1.22(s,5H),1.18(br s,3H),1.09(s,9H),0.96(d,J=10.6Hz,1H),0.83(br.s.,3H),0.64-0.55(m,3H),0.17(s,4H)。LCMS(M+H)=727.3。
實例179
(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、4,4-二甲基六氫吡啶(30mg,0.27mmol)及N-乙基-N-異丙基丙-2-胺(28mg,0.22mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。接下來，添加NaOH(5M)(0.054mL,0.27mmol)。將反應混合物加熱至80℃並於此溫度下攪拌2h。最後，將混合物冷卻至室溫且隨後藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(第三丁氧基)-2-(5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-6-((4,4-二甲基六氫吡啶-1-基)甲基)-2-甲基吡啶-3-基)乙酸(8.2mg,0.011mmol,42%產率)。1H NMR(500MHz,DMSO-d6)δ 7.31
-7.14(m,4H),7.11-6.99(m,1H),6.86-6.76(m,1H),5.75(d,J=4.8Hz,1H),3.85-3.74(m,1H),3.71-3.58(m,1H),3.41-3.29(m,1H),3.29-3.19(m,1H),2.86-2.68(m,5H),2.46-2.40(m,5H),2.40-2.16(m,5H),2.06(br s,1H),1.46(br s,2H),1.32-1.13(m,9H),1.08(s,11H),0.95(d,J=11.0Hz,1H),0.82(s,11H),0.64-0.54(m,3H)。LCMS(M+H)=729.3。
實例180
(S)-2-(6-((7-氮雜螺[3.5]壬-7-基)甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸：將(S)-2-(6-(溴甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(20mg,0.027mmol)、7-氮雜螺[3.5]壬烷(33.9mg,0.271mmol)及N-乙基-N-異丙基丙-2-胺(28mg,0.22mmol)於EtOH(1mL)中之溶液於室溫下攪拌過夜。接下來，添加NaOH(5M)(0.054mL,0.27mmol)。將反應混合物加熱至80℃並於此溫度下攪拌2h。隨後將反應混合物冷卻至室溫並藉由製備型HPLC純化，以得到呈非鏡像異構物之混合物形式之(S)-2-(6-(7-氮雜螺[3.5]壬-7-基甲基)-5-(2-(2-氯-6-甲基苄基)-1,2,3,4-四氫異喹啉-6-基)-4-(4,4-二甲基六氫吡啶-1-基)-2-甲基吡啶-3-基)-2-(第三丁氧基)乙酸。1H NMR(500MHz,DMSO-d6)δ 7.29(d,J=7.3Hz,1H),7.26-7.13(m,3H),7.09
-6.99(m,1H),6.85-6.75(m,1H),5.77(br s,1H),3.83-3.75(m,1H),3.70-3.61(m,1H),3.40-3.27(m,1H),3.21-3.09(m,1H),2.83-2.70(m,5H),2.45-2.39(m,7H),2.26(d,J=7.3Hz,1H),2.16(br s,2H),2.09(br s,1H),1.79-1.72(m,3H),1.64-1.56(m,4H),1.41(br s,5H),1.22(s,3H),1.17(br s,1H),1.09(s,10H),0.95(d,J=11.0Hz,1H),0.85-0.80(m,3H),0.63-0.54(m,3H)。LCMS(M+H)=741.3。
3,5-二溴-2-甲基吡啶-4-醇：向2-甲基吡啶-4-醇(5g,45.8mmol)於DCM(56.4ml)及MeOH(6.80ml)中之攪拌溶液中添加第三丁基胺(9.81ml,93mmol)並冷卻至0℃。經60分鐘逐滴添加溴(4.72ml,92mmol)。在室溫下將反應混合物攪拌3小時。將反應混合物經由微細釉料過濾器過濾並將固體白色物質在真空下乾燥18hr。1H NMR(500MHz,DMSO-d6)δ 12.32(br.s.,1H),8.21(s,1H),2.40(s,3H)。LCMS(M+H)=267.7。
3,5-二溴-4-氯-2-甲基吡啶：於0℃下經80min向3,5-二溴-2-甲基吡啶-4-醇(13.12g,49.2mmol)於POCl3(13.74ml,147mmol)中之溶液中緩慢添加三乙胺(6.85ml,49.2mmol)。在添加後，移除冰浴，並將反應物加熱至80℃並攪拌3h。隨後將反應混合物冷卻並藉由將其添加至碎冰中緩慢淬滅。將所得懸浮液用DCM(250ml)萃取。將有機層用飽和NaHCO3溶液(250mL)、之後水(250mL)及鹽水(250mL)洗滌。將有機層乾燥(MgSO4)，過濾並濃縮，以得到米色固體狀3,5-二溴-4-氯-2-甲基吡啶(14.7g,51.5mmol,105%產率)。1H NMR(500MHz,CDCl3)δ 8.55(s,1H),2.72(s,3H)。LCMS(M+H)=285.7。
2-(5-溴-4-氯-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯：經20min向3,5-二溴-4-氯-2-甲基吡啶(9.42g,33.0mmol)及溴化銅(I)-二甲硫錯合物(0.339g,1.651mmol)於THF(75mL)中之-78℃溶液中逐滴添加異丙基氯化鎂(17.33mL,34.7mmol)。使反應物升溫至-10℃並持續60min。隨後於-60℃下將反應混合物經由套管轉移至含有2-氯-2-乙醛酸異丙基酯(4.97g,33.0mmol)於THF(75ml)中之溶液之另一燒瓶並使其升溫至-10℃並保持2.5hr。隨後用10%氯化銨溶液及二乙醚淬滅反應。將有機層用鹽水洗滌，收集，乾燥(MgSO4)，過濾並蒸發揮發物，以產生粗物質。經由矽膠(330g管柱，10-40% EtOAc：Hex)純化粗物質，以產生黃色油狀產物2-(5-溴-4-氯-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯(3.45g,9.15mmol,27.7%產率)，其稍後固化。1H NMR(500MHz，甲醇-d4)δ 8.79(s,1H),5.09(dt,J=12.6,6.2Hz,1H),2.76(s,3H),1.24-1.22(m,3H),1.20(d,J=6.3Hz,3H)。LCMS(M+H)=321.8。
2-(5-溴-4-(4,4-二甲基六氫吡啶1-基)-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯：向配備有攪拌棒之40mL小瓶中添加2-(5-溴-4-氯-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯(5g,15.60mmol)、DIPEA(3.00ml,17.16mmol)及乙腈(10.40ml)，隨後添加4,4-二甲基六氫吡啶(1.942g,17.16mmol)。將小瓶加蓋且隨後放置於85℃下之加熱塊中，同時攪拌。18hr後LCMS分析發現完全轉化。將反應混合物溶解於Et2O(100mL)及
水(100mL)中並轉移至500mL分液漏斗。攪動混合物；分離各相。用Et2O(100mL)反萃取水相。用鹽水(50mL)洗滌合併之有機物。將溶液經MgSO4乾燥；過濾；隨後在真空中濃縮。經由矽膠純化(120g管柱，0-30% EtOAc：Hex)來純化粗產物，以產生黃色油狀產物2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯(4.56g,11.48mmol,73.6%產率)，其部分固化。1H NMR(500MHz,CDCl3)δ 8.45(s,1H),5.26(dt,J=12.5,6.3Hz,1H),3.20-3.14(m,4H),2.76(s,3H),1.52-1.48(m,4H),1.42(d,J=6.3Hz,6H),1.04(s,6H)。LCMS(M+H)=399.0。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-羥基乙酸異丙基酯：向配備有攪拌棒之100mL圓底燒瓶中添加2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-乙醛酸異丙基酯(2.5g,6.29mmol)。向燒瓶裝備橡膠隔片且隨後放置在N2氣氛(真空/填充×3)下。向燒瓶中添加甲苯(17.98ml)。將燒瓶放置於-35℃浴(二氯乙烷/乾冰)中。使用溫度計以監測內部溫度。在內部溫度係-30℃時，向燒瓶中添加(R)-1-甲基-3,3-二苯基六氫吡咯并[1,2-c][1,3,2]氧氮硼雜環戊烯(0.944ml,0.944mmol)。未注意到放熱。經2分鐘向攪拌溶液中添加兒茶酚硼烷(1.886ml,8.81mmol)。在添加期間，溫度升高2℃。在添加後5分鐘內，溫度升至-25℃，之後下降至-30℃。將溶液於-30℃下攪拌3h。將燒瓶轉移至-15℃至-12℃冷浴(冷凍器/循環器)。將黃色溶液於-15℃至-12℃下攪拌1天。1天後，觀察到溶液之顏色為黃色；LCMS分析指示完全轉化，其中主要峰對應於期望產物。不充分
離子化之兩個額外顯著峰之存在與CBS觸媒及兒茶酚之存在一致。用5mL 2M碳酸鈉水溶液淬滅反應。隨後將反應物用100mL EtOAc及100mL 2M碳酸鈉水溶液稀釋並劇烈攪拌2hr。分離各層並收集有機層並再劇烈攪拌1hr。將有機層用鹽水洗滌，經MgSO4乾燥，過濾並蒸發，以產生粗產物。在矽膠層析(80g管柱，10-40% EtOAc：Hex)上純化粗產物，以得到黃色油狀產物(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-羥基乙酸異丙基酯(2g,5.01mmol,80%產率)，其於RT下固化。1H NMR(500MHz,CDCl3)δ 8.33(s,1H),5.31(d,J=6.9Hz,1H),5.13-5.03(m,2H),3.80(br.s.,2H),2.87-2.75(m,1H),2.71(s,3H),2.69-2.60(m,1H),1.71-1.59(m,2H),1.43(d,J=14.8Hz,2H),1.28(d,J=6.1Hz,3H),1.16(d,J=6.3Hz,3H),1.04(s,3H),1.08(s,3H)。LCMS(M+H)=399.0。
(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯：在裝備有具有橡膠隔片(附接空的氣球)之shlenk接頭的250ml圓底燒瓶中，使異丁烯氣體劇烈鼓泡30分鐘至(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-羥基乙酸異丙基酯(2g,5.01mmol)及高氯酸(0.861mL,10.02mmol)於DCM(100mL)中之0℃溶液中，直至體積加倍且氣球填充至堅硬。2hr後，斷開異丁烯管線且將針拉至溶液管線正上方，隨後連接至起泡器以監測異丁烯氣體出口。移除冰浴並在監測用於轉化的同時升溫至RT。2hr後，根據LCMS，反應似乎完全轉化。將反應混合物倒入1L Erlenmeyer燒瓶中並用2M碳酸鈉呈鹼性，同時劇烈攪拌。分離有機層
並用水、之後鹽水洗滌，收集，乾燥(MgSO4)，過濾並蒸發揮發物，以得到粗產物。在矽膠(40g管柱，5-40% EtOAc：Hex)上純化粗產物，以得到澄清油狀產物(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(1.95g,4.28mmol,85%產率)，其稍後結晶成白色固體。1H NMR(500MHz,CDCl3)δ 8.61(s,1H),5.61(s,1H),5.01(dt,J=12.5,6.3Hz,1H),3.81(t,J=10.9Hz,1H),3.60(t,J=11.0Hz,1H),2.76(d,J=11.5Hz,1H),2.69(s,3H),2.64(d,J=12.1Hz,1H),1.63-1.51(m,2H),1.46(d,J=11.2Hz,1H),1.38(d,J=14.2Hz,1H),1.26-1.22(m,12H),1.20(d,J=6.1Hz,3H),1.09-1.03(m,6H)。LCMS(M+H)=457.1。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸異丙基酯：在N2下向(S)-2-(5-溴-4-(4,4-二甲基六氫吡啶-1-基)-6-甲基吡啶-3-基)-2-(第三丁氧基)乙酸異丙基酯(1g,2.196mmol)、(4-(4-氟苯乙氧基)苯基)酸(0.857g,3.29mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(0.180g,0.439mmol)及磷酸鉀(3.50g,16.47mmol)於1,4-二噁烷(36.6ml)及水(7.32ml)中之溶液中添加Pd(OAc)2(0.049g,0.220mmol)。將反應物於80℃下加熱2h。將反應物冷卻，用水稀釋並用EtOAc萃取。將有機層用鹽水洗滌，收集，經MgSO4乾燥，過濾並蒸發揮發物，以得到粗產物。在矽膠(40g管柱，5-50% EtOAc：Hex)上純化粗產物，以產生褐色油狀產物(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸異丙基酯(1.15g,1.947mmol,89%產率)。
1H NMR(400MHz,CDCl3)δ 8.68(s,1H),7.30(d,J=5.4Hz,1H),7.27(br.s.,1H),7.18-7.11(m,1H),7.09-7.01(m,3H),6.98(d,J=8.8Hz,2H),5.52(s,1H),5.04(dt,J=12.6,6.2Hz,1H),4.24(t,J=7.0Hz,2H),3.13(t,J=7.0Hz,2H),2.93(br.s.,1H),2.65(br.s.,1H),2.51(d,J=7.1Hz,1H),2.39(br.s.,1H),2.23(s,3H),1.41-1.31(m,1H),1.27(d,J=6.1Hz,4H),1.25(s,9H),1.23(d,J=6.1Hz,4H),1.16-1.02(m,1H),0.86(br.s.,3H),0.72(br.s.,3H)。LCMS(M+H)=591.4。
(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶1-氧化物：於rt下經5min向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸異丙基酯(1.15g,1.947mmol)於DCM(10ml)中之攪拌溶液中添加77% mCPBA(0.654g,2.92mmol)。4h後，將反應混合物用飽和Na2CO3水溶液(3×25mL)洗滌，乾燥(MgSO4)，過濾並濃縮，以產生(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶1-氧化物(1.1g,1.813mmol,93%產率)，其不經純化即用於下一步驟。1H NMR(500MHz,CDCl3)δ 8.55(s,1H),7.31-7.29(m,1H),7.28-7.27(m,1H),7.13-6.97(m,6H),5.40(s,1H),5.06-4.98(m,1H),4.24(t,J=6.9Hz,2H),3.13(t,J=6.9Hz,2H),2.70(br.s.,1H),2.58-2.44(m,2H),2.39-2.29(m,1H),2.22(s,3H),1.53-1.35(m,2H),1.27(s,3H),1.25(s,9H),1.24(s,3H),1.19-1.05(m,2H),0.91(br.s.,3H),0.64(br.s.,3H)。LCMS(M+H)=607.4。
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸異丙基酯：於室溫下向(S)-5-(1-(第三丁氧基)-2-異丙氧基-2-側氧基乙基)-4-(4,4-二甲基六氫吡啶-1-基)-3-(4-(4-氟苯乙氧基)苯基)-2-甲基吡啶1-氧化物(75mg,0.124mmol)於無水DMF(2ml)中之攪拌溶液中添加三氟乙酸酐(0.070ml,0.494mmol)。3h後，添加飽和NaHCO3(5mL)並用EtOAc萃取。將有機層用水(2×)、之後鹽水洗滌，收集，經MgSO4乾燥，過濾並蒸發揮發物，以產生粗產物，在矽膠(12g管柱，5-60% EtOAc：Hex)上對其進行純化，以得到橙色油狀產物(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸異丙基酯(39mg,0.064mmol,52.0%產率)。LCMS(M+H)=607.4。
實例181
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸異丙基酯(39mg,0.064mmol)於EtOH(1mL)及水(0.111mL)中之溶液中添加氫氧化鋰單水合物(l0.79mg,0.257mmol)並於75℃下加熱60分鐘。將反應物冷卻至RT，經由耐綸0.45μ釉料過濾器過
濾，經由製備型HPLC純化，以得到淺色油狀(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸(18mg,0.032mmol,49.6%產率)。1H NMR(400MHz，甲醇-d4)δ 8.60(s,1H),7.36(dd,J=8.6,5.4Hz,2H),7.31-7.25(m,1H),7.17-7.01(m,5H),5.33(s,1H),4.50(d,J=15.4Hz,1H),4.30(d,J=5.1Hz,1H),4.29-4.24(m,2H),3.12(t,J=6.6Hz,2H),3.05(br.s.,2H),2.85(br.s.,2H),1.44-1.27(m,4H),1.26(s,9H),0.85(s,6H)。LCMS(M+H)=565.3。
實例182
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸異丙基酯(26mg,0.044mmol)於EtOH(1mL)及水(0.1ml)中之溶液中添加氫氧化鋰單水合物(3.69mg,0.088mmol)並於75℃下加熱30min。30分鐘後，LCMS指示反應完全。將反應物冷卻至室溫並經由製備型HPLC純化，以得到產物(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-甲基吡啶-3-基)乙酸(15.7mg,0.029mmol,65%產率)。1H NMR(500MHz,DMSO-d6)δ 8.44(s,1H),7.37(dd,J=8.4,5.9Hz,2H),7.22-7.18(m,1H),7.14-7.08(m,3H),7.04(d,J=9.5Hz,2H),5.35(s,1H),4.26(t,J=6.1Hz,2H),3.06(t,J=7.0Hz,2H),2.12(s,3H),1.32(br.s.,3H),1.20(s,9H),0.73(br.s.,6H)1H NMR(500MHz,DMSO-d6)δ 8.44(s,1H),7.37(dd,J=8.4,
5.9Hz,2H),7.22-7.18(m,1H),7.14-7.08(m,3H),7.04(d,J=9.5Hz,2H),5.35(s,1H),4.26(t,J=6.1Hz,2H),3.06(t,J=7.0Hz,2H),2.12(s,3H),1.32(br.s.,3H),1.20(s,9H),0.73(br.s.,6H)；經由1HNMR，由於實驗中之水抑制，六氫吡啶環上之1個質子及4-氟苯乙氧基上之亞甲基之4個質子未拆分。LCMS(M+H)=549.3。
實例183
(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)吡啶-3-基)乙酸：向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸異丙基酯(29mg,0.048mmol)及碘甲烷(0.026mL,0.053mmol)於DMF(1mL)中之溶液中添加氫化鈉(2.103mg,0.053mmol)並於RT下攪拌2hr。2hr後，LCMS指示起始材料完全轉化成產物。將反應物用水稀釋並用EtOAc萃取。將有機層用鹽水洗滌，收集，經MgSO4乾燥，過濾並蒸發揮發物，以得到粗產物(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(甲氧基甲基)吡啶-3-基)乙酸異丙基酯(30mg,0.048mmol,100%產率)。LCMS(M+H)=621.4。
將上述材料吸收於EtOH(1ml)及水(0.100ml)中並添加氫氧化鋰單水合物(3.46mg,0.082mmol)。將反應物攪拌並於75℃下加熱60分鐘。1hr後，LCMS指示反應完全。將反應物冷卻至RT且隨後經由0.45μ耐綸過濾器過濾，隨後在製備型HPLC上純化，以產生(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-
6-(甲氧基甲基)吡啶-3-基)乙酸(7.4mg,0.013mmol，經2個步驟31%產率)。1H NMR(500MHz,DMSO-d6)δ 8.55(s,1H),7.37(dd,J=8.4,5.5Hz,2H),7.26-7.20(m,1H),7.16-7.08(m,3H),7.06-6.99(m,2H),5.37(s,1H),4.30-4.23(m,2H),4.13-4.02(m,2H),3.10(s,3H),3.06(t,J=6.8Hz,2H),1.32(br.s.,3H),1.20(s,9H),0.74(br.s.,6H)；經由1HNMR，由於實驗中之水抑制，六氫吡啶環上之3個質子及4-氟苯乙氧基上之亞甲基之4個質子未拆分。LCMS(M+H)=579.3。
實例184
(S)-2-(第三丁氧基)-2-(6-(氯甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)吡啶-3-基)乙酸：在1打蘭(dram)小瓶中向(S)-2-(第三丁氧基)-2-(4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)-6-(羥基甲基)吡啶-3-基)乙酸異丙基酯(25mg,0.041mmol)於DCM(.5mL)中之溶液中添加POCl3(0.012mL,0.124mmol)並於50℃下攪拌24hr。將反應物質轉移至分液漏斗並用冰冷2M碳酸鈉水溶液洗滌。將有機層用鹽水洗滌，收集，經MgSO4乾燥，過濾並蒸發揮發物，以產生粗產物(S)-2-(第三丁氧基)-2-(6-(氯甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)吡啶-3-基)乙酸異丙基酯(25mg,0.040mmol,97%產率)。LCMS(M+H)=625.3。
將上述物質吸收於EtOH(1ml)中並向水(0.1ml)中添加氫氧化鋰單水合物(3.36mg,0.080mmol)並於75℃下加熱60分鐘。1hr後，LCMS指示反應不完全。再次向反應物中添加氫氧化鋰單水合物(3.36mg,0.080mmol)並再加熱1hr。此時段後，LCMS指示反應完全。觀
察到Cl之一些EtOH置換。將反應物冷卻至RT且隨後經由0.45μ耐綸過濾器過濾並經由製備型HPLC純化，以產生(S)-2-(第三丁氧基)-2-(6-(氯甲基)-4-(4,4-二甲基六氫吡啶-1-基)-5-(4-(4-氟苯乙氧基)苯基)吡啶-3-基)乙酸(0.8mg，0.0014mmol，經2個步驟3.4%產率)。1H NMR(500MHz,DMSO-d6)δ 8.63-8.55(m,1H),7.40-7.35(m,2H),7.31-7.27(m,1H),7.20-7.16(m,1H),7.12(t,J=8.8Hz,2H),7.07(d,J=8.4Hz,2H),5.38(s,1H),4.41(d,J=10.6Hz,1H),4.34(d,J=10.6Hz,1H),4.30-4.24(m,2H),3.09-3.02(m,2H),1.33-1.23(m,3H),1.22-1.19(m,9H),0.74(br.s.,6H)；經由1HNMR，由於實驗中之水抑制，六氫吡啶環上之3個質子及4-氟苯乙氧基上之亞甲基之4個質子未拆分。LCMS(M+H)=583.3。
生物學方法
HIV複製之抑制：構築重組NL-RLuc原病毒純系，其中NL4-3之nef基因之切片經海腎螢光素酶(Renilla Luciferase)基因置換。此病毒完全傳染且可在細胞培養中經歷多個複製週期。另外，發光報導基因提供定量病毒生長之程度且因此測試化合物之抗病毒活性的簡單且容易之方法。質體pNLRLuc含有在PvuII位點處選殖至pUC18中之原病毒NL-Rluc DNA。藉由用質體pNLRLuc轉染293T細胞製備NL-RLuc病毒。使用來自Invitrogen(Carlsbad,CA)之LipofectAMINE PLUS套組根據製造商實施轉染且在MT-2細胞中滴定所生成病毒。對於易感性分析，在化合物之存在下使用經滴定病毒以感染MT-2細胞，且培育5天後，將細胞處理並藉由表現螢光素酶之量定量病毒生長。分析培養基係補充有10%熱不活化之胎牛血清(FBS)、100個單位/ml青黴素G/100個單位/ml鏈黴素、10mM HEPES緩衝液(pH 7.55)及2mM L-麩醯胺酸之RPMI 1640。使用至少2個實驗之結果以計算EC50值。使用來自Promega(Madison,WI)之雙重螢光素酶套組定量螢光素酶。藉由在化
合物之連續稀釋物存在下培育測定病毒對化合物之易感性。藉由使用中值效應方程之指數形式計算50%有效濃度(EC50)，其中(Fa)=1/[1+(ED50/藥物濃度)m](Johnson VA,Byington RT.Infectivity Assay.In Techniques in HIV Research.編輯Aldovini A,Walker BD.71-76.New York：Stockton Press.1990)。結果示於表1中。活性等於A係指化合物之EC50 100nM，而B及C表示化合物之EC50介於100nM與1uM(B)或>1uM(C)之間。
熟習此項技術者應明瞭，本發明並不受限於上述說明性實例，且其可以其他具體形式來實施而不背離其基本屬性。因此，期望該等實例在所有方面皆應視為說明性的而非限制性的，參照隨附申請專利範圍而非上述實例，且因此本發明意欲涵蓋屬申請專利範圍之等效內容之含義及範圍內的所有變化。
Claims (30)
- 一種式I化合物
- 如請求項1之化合物，其中R1係氫且R5係氫、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基。
- 如請求項1之化合物，其中R1係烷基且R5係氫、鹵代烷基、羥基烷基、烷氧基烷基、(烷氧基)烷氧基烷基、(((烷氧基)烷氧基)烷氧基)烷基、((苄基氧基)烷氧基)烷基、((R10)(R11)N)烷基或(R6)烷基。
- 如請求項1之化合物，其中R2係經1個R7取代基及0至3個選自以下之取代基取代之苯基：鹵基、烷基、鹵代烷基、烷氧基及鹵代烷氧基。
- 如請求項1之化合物，其中R2係四氫異喹啉基且經1個R7取代基取代。
- 如請求項1之化合物，其中R3係經0至3個鹵基或烷基取代基取代之六氫吡啶基。
- 如請求項1之化合物，其中R1或R5中之一者係烷基。
- 如請求項1之化合物，其中R2係鹵基。
- 如請求項8之化合物，其中R1或R5中之一者係烷基。
- 如請求項1之化合物，其中R4選自烷基或鹵代烷基。
- 如請求項10之化合物，其中R1或R5中之一者係烷基。
- 如請求項1之化合物，其中R7選自(Ar1)烷基、(Ar1)烷氧基、N-烷氧基羰基或((Ar1)烷基)HNCO。
- 如請求項1之化合物，其中R7選自經0至1個烷基取代基取代之嘧啶基、苯并呋喃并嘧啶基或吡唑并嘧啶基。
- 如請求項1之化合物，其中R9選自氫或烷基。
- 如請求項1之化合物，其中(R8)(R9)N一起選自氮雜環丁基、吡咯啶基、六氫吡啶基、(螺環丁基)六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基或二氧離子基硫嗎啉基，且經0至3個烷基或烷氧基羰基取代基取代。
- 如請求項1之化合物，其中R11選自氫、烷基、(環烷基)烷基、羥基烷基、烷氧基烷基、(氧雜環丁基)烷基、(四氫吡喃基)烷基、(Ar1)烷基、(Ar2)烷基、(((Ar1)烷基)羰基)烷基、氧雜環丁基、Ar1、甲醯基、烷基羰基、(Ar2)羰基、(二烷基胺基)側氧基乙醯基或烷基磺醯基。
- 如請求項1之化合物，其中(R10)(R11)N一起選自氮雜環丁基、二環[1.1.1]戊烷基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、二氧離子基硫嗎啉基、[3.1.1]二氮雜二環庚基、[3.2.1]二氮雜二環辛烷基或四氫喹啉基，且經0至3個鹵基、烷基、鹵代烷基、苄基、羥基、烷氧基或鹵代烷氧基取代基及0至1個(C3-7)螺伸烷基取代基取代。
- 一種式I化合物
- 一種式I化合物
- 一種式I化合物
- 一種式I化合物
- 一種式I化合物
- 一種式I化合物
- 一種可用於治療HIV感染之組合物，其包含治療有效量之如請求項1至23中任一項之化合物及醫藥上可接受之載劑。
- 如請求項24之組合物，其進一步包含治療有效量之至少一種選自以下之用於治療AIDS或HIV感染之其他藥劑：核苷HIV反轉錄酶抑制劑、非核苷HIV反轉錄酶抑制劑、HIV蛋白酶抑制劑、HIV融合抑制劑、HIV附接抑制劑、CCR5抑制劑、CXCR4抑制劑、HIV出芽或成熟抑制劑與HIV整合酶抑制劑；及醫藥上可接受之載劑。
- 如請求項25之組合物，其中該其他藥劑係德羅格韋(dolutegravir)。
- 一種如請求項1至23中任一項之化合物或其醫藥上可接受之鹽之用途，其用於製造用以治療HIV感染之藥劑。
- 如請求項27之用途，其中該藥劑係與至少一種選自以下之用於治療AIDS或HIV感染之其他藥劑一起投與：核苷HIV反轉錄酶抑制劑、非核苷HIV反轉錄酶抑制劑、HIV蛋白酶抑制劑、HIV融合抑制劑、HIV附接抑制劑、CCR5抑制劑、CXCR4抑制劑、HIV出芽或成熟抑制劑及HIV整合酶抑制劑。
- 如請求項28之用途，其中該其他藥劑係德羅格韋。
- 如請求項28之用途，其中該其他藥劑係在該藥劑投與之前、同時或之後投與。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562204239P | 2015-08-12 | 2015-08-12 |
Publications (1)
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| TW201718537A true TW201718537A (zh) | 2017-06-01 |
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| US (1) | US10351546B2 (zh) |
| EP (1) | EP3334724A1 (zh) |
| JP (1) | JP2018522926A (zh) |
| KR (1) | KR20180035914A (zh) |
| CN (1) | CN108349939A (zh) |
| AR (1) | AR105665A1 (zh) |
| AU (1) | AU2016306087A1 (zh) |
| BR (1) | BR112018002689A2 (zh) |
| CA (1) | CA2995099A1 (zh) |
| IL (1) | IL257247A (zh) |
| RU (1) | RU2018106504A (zh) |
| TW (1) | TW201718537A (zh) |
| WO (1) | WO2017025915A1 (zh) |
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| TWI657086B (zh) * | 2015-08-11 | 2019-04-21 | 英商Viiv醫療保健英國(No.5)有限公司 | 做為人類免疫缺陷病毒複製抑制劑之５－（ｎ－苯甲基四氫異喹啉－６－基）吡啶－３－基乙酸衍生物 |
| KR20180032650A (ko) * | 2015-08-12 | 2018-03-30 | 비브 헬스케어 유케이 (넘버5) 리미티드 | 인간 면역결핍 바이러스 복제의 억제제로서 5-(n-[6,5]-융합된 바이사이클릭 아릴 테트라하이드로이소퀴놀린-6-일) 피리딘-3-일 아세트산 유도체 |
| EP3455217A1 (en) * | 2016-05-11 | 2019-03-20 | ViiV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| US20190152957A1 (en) * | 2016-05-11 | 2019-05-23 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| WO2018127801A1 (en) * | 2017-01-03 | 2018-07-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| TW201835068A (zh) | 2017-01-03 | 2018-10-01 | 英商Viiv醫療保健英國(No.5)有限公司 | 作為人類免疫缺乏病毒複製之抑制劑之吡啶-3-基乙酸衍生物 |
| WO2019244066A2 (en) | 2018-06-19 | 2019-12-26 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| WO2020003093A1 (en) | 2018-06-25 | 2020-01-02 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| PL3999493T3 (pl) * | 2019-07-19 | 2024-04-22 | Abivax | Pochodne arylo-N-arylowe do leczenia zakażenia wirusem RNA |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7939545B2 (en) | 2006-05-16 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
| HRP20120328T2 (hr) | 2007-11-15 | 2012-09-30 | Gilead Sciences | Inhibitori replikacije virusa humane imunodeficijencije |
| EP2574610A1 (en) | 2007-11-15 | 2013-04-03 | Gilead Sciences, Inc. | Inhibitors of human immonodeficiency virus replication |
| WO2009062285A1 (en) | 2007-11-16 | 2009-05-22 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
| CA2705338A1 (en) | 2007-11-16 | 2009-05-22 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
| GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
| US8338441B2 (en) * | 2009-05-15 | 2012-12-25 | Gilead Sciences, Inc. | Inhibitors of human immunodeficiency virus replication |
| GB0913636D0 (en) * | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
| KR101483834B1 (ko) | 2009-12-23 | 2015-01-16 | 카트호리이케 유니버시타이트 로이펜 | 항바이러스 화합물 |
| US8633200B2 (en) | 2010-09-08 | 2014-01-21 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
| US8629276B2 (en) | 2012-02-15 | 2014-01-14 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
| US9034882B2 (en) | 2012-03-05 | 2015-05-19 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
| US9580431B2 (en) * | 2013-03-13 | 2017-02-28 | VIIV Healthcare UK (No.5) Limited | Inhibitors of human immunodeficiency virus replication |
| EP2970274B1 (en) | 2013-03-14 | 2017-03-01 | VIIV Healthcare UK (No.5) Limited | Inhibitors of human immunodeficiency virus replication |
| US9193720B2 (en) * | 2014-02-20 | 2015-11-24 | Bristol-Myers Squibb Company | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| WO2017006281A1 (en) * | 2015-07-09 | 2017-01-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| BR112018000253A2 (pt) * | 2015-07-09 | 2018-09-04 | Viiv Healthcare Uk No 5 Ltd | composto, composição, e, método para tratar a infecção pelo hiv. |
| TWI657086B (zh) * | 2015-08-11 | 2019-04-21 | 英商Viiv醫療保健英國(No.5)有限公司 | 做為人類免疫缺陷病毒複製抑制劑之５－（ｎ－苯甲基四氫異喹啉－６－基）吡啶－３－基乙酸衍生物 |
| CA2995087A1 (en) * | 2015-08-12 | 2017-02-16 | John F. Kadow | 5-(n-fused tricyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
| KR20180032650A (ko) * | 2015-08-12 | 2018-03-30 | 비브 헬스케어 유케이 (넘버5) 리미티드 | 인간 면역결핍 바이러스 복제의 억제제로서 5-(n-[6,5]-융합된 바이사이클릭 아릴 테트라하이드로이소퀴놀린-6-일) 피리딘-3-일 아세트산 유도체 |
-
2016
- 2016-08-09 TW TW105125347A patent/TW201718537A/zh unknown
- 2016-08-10 US US15/749,584 patent/US10351546B2/en not_active Expired - Fee Related
- 2016-08-10 CN CN201680059752.2A patent/CN108349939A/zh active Pending
- 2016-08-10 AR ARP160102454A patent/AR105665A1/es unknown
- 2016-08-10 KR KR1020187006929A patent/KR20180035914A/ko not_active Withdrawn
- 2016-08-10 RU RU2018106504A patent/RU2018106504A/ru not_active Application Discontinuation
- 2016-08-10 WO PCT/IB2016/054830 patent/WO2017025915A1/en not_active Ceased
- 2016-08-10 CA CA2995099A patent/CA2995099A1/en not_active Abandoned
- 2016-08-10 BR BR112018002689A patent/BR112018002689A2/pt not_active Application Discontinuation
- 2016-08-10 EP EP16762868.4A patent/EP3334724A1/en not_active Withdrawn
- 2016-08-10 JP JP2018507001A patent/JP2018522926A/ja not_active Ceased
- 2016-08-10 AU AU2016306087A patent/AU2016306087A1/en not_active Abandoned
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2018
- 2018-01-30 IL IL257247A patent/IL257247A/en unknown
Also Published As
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|---|---|
| JP2018522926A (ja) | 2018-08-16 |
| KR20180035914A (ko) | 2018-04-06 |
| WO2017025915A1 (en) | 2017-02-16 |
| CN108349939A (zh) | 2018-07-31 |
| CA2995099A1 (en) | 2017-02-16 |
| US10351546B2 (en) | 2019-07-16 |
| BR112018002689A2 (pt) | 2018-11-27 |
| EP3334724A1 (en) | 2018-06-20 |
| US20180230124A1 (en) | 2018-08-16 |
| RU2018106504A (ru) | 2019-09-13 |
| IL257247A (en) | 2018-03-29 |
| AR105665A1 (es) | 2017-10-25 |
| AU2016306087A1 (en) | 2018-03-08 |
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