WO2024027706A1 - Bcl-xl degrading compounds - Google Patents
Bcl-xl degrading compounds Download PDFInfo
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- WO2024027706A1 WO2024027706A1 PCT/CN2023/110543 CN2023110543W WO2024027706A1 WO 2024027706 A1 WO2024027706 A1 WO 2024027706A1 CN 2023110543 W CN2023110543 W CN 2023110543W WO 2024027706 A1 WO2024027706 A1 WO 2024027706A1
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- WIPO (PCT)
- Prior art keywords
- compound
- solvate
- pharmaceutically acceptable
- tautomer
- stereoisomer
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- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- SDMCZCALYDCRBH-UHFFFAOYSA-N methoxymethyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SDMCZCALYDCRBH-UHFFFAOYSA-N 0.000 description 1
- NOCGROPYCGRERZ-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 NOCGROPYCGRERZ-UHFFFAOYSA-M 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- VTJVVTQMBGMYAO-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;potassium Chemical compound [K].[K+].CC(C)(C)[O-] VTJVVTQMBGMYAO-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 description 1
- FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 description 1
- HEMCGZPSGYRIOL-UHFFFAOYSA-N spiro[2.4]heptane Chemical compound C1CC11CCCC1 HEMCGZPSGYRIOL-UHFFFAOYSA-N 0.000 description 1
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- DVDJICIUXXAIKJ-UHFFFAOYSA-N spiro[2.6]nonane Chemical compound C1CC11CCCCCC1 DVDJICIUXXAIKJ-UHFFFAOYSA-N 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- IWDANOJGJIFBEL-UHFFFAOYSA-N spiro[3.4]octane Chemical compound C1CCC21CCCC2 IWDANOJGJIFBEL-UHFFFAOYSA-N 0.000 description 1
- VMWOETMUNAQFAX-UHFFFAOYSA-N spiro[3.5]nonane Chemical compound C1CCC21CCCCC2 VMWOETMUNAQFAX-UHFFFAOYSA-N 0.000 description 1
- PLDXRPSSERMPSV-UHFFFAOYSA-N spiro[3.6]decane Chemical compound C1CCC21CCCCCC2 PLDXRPSSERMPSV-UHFFFAOYSA-N 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- NWTSRIZEBKLUFM-UHFFFAOYSA-N spiro[4.6]undecane Chemical compound C1CCCC21CCCCCC2 NWTSRIZEBKLUFM-UHFFFAOYSA-N 0.000 description 1
- NECLQTPQJZSWOE-UHFFFAOYSA-N spiro[5.5]undecane Chemical compound C1CCCCC21CCCCC2 NECLQTPQJZSWOE-UHFFFAOYSA-N 0.000 description 1
- ZDNANLAHKKNCTC-UHFFFAOYSA-N spiro[5.6]dodecane Chemical compound C1CCCCC21CCCCCC2 ZDNANLAHKKNCTC-UHFFFAOYSA-N 0.000 description 1
- NGGUAMSYAYRZGK-UHFFFAOYSA-N spiro[6.6]tridecane Chemical compound C1CCCCCC21CCCCCC2 NGGUAMSYAYRZGK-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- XAWUEOGMYSBNKQ-UHFFFAOYSA-N tert-butyl 2-(4-oxocyclohexyl)acetate Chemical compound CC(C)(C)OC(=O)CC1CCC(=O)CC1 XAWUEOGMYSBNKQ-UHFFFAOYSA-N 0.000 description 1
- RMWVUWLBLWBQDS-UHFFFAOYSA-N tert-butyl 3-bromopropanoate Chemical compound CC(C)(C)OC(=O)CCBr RMWVUWLBLWBQDS-UHFFFAOYSA-N 0.000 description 1
- YBNJZIDYXCGAPX-UHFFFAOYSA-N tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCO)CC1 YBNJZIDYXCGAPX-UHFFFAOYSA-N 0.000 description 1
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- HYNBSBAWGATECV-UHFFFAOYSA-N tert-butyl 4-oxocyclohexane-1-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCC(=O)CC1 HYNBSBAWGATECV-UHFFFAOYSA-N 0.000 description 1
- FUYBPBOHNIHCHM-UHFFFAOYSA-N tert-butyl piperidine-4-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCNCC1 FUYBPBOHNIHCHM-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the BCL-2 (B-cell lymphoma-2) family of proteins serve as key regulators of the mitochondrial pathway of cellular apoptosis, and consists of both anti-apoptotic proteins such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1, and pro-apoptotic proteins such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma [1-2] .
- Pro-apoptotic and anti-apoptotic BCL-2 proteins normally function in opposition to each other.
- BCL-XL belongs to the anti-apoptotic BCL-2 protein family and plays an important role in promoting tumor initiation, progression, and development of drug resistance by protecting tumor cells from apoptosis [5] . Inhibition of these BCL-2 family proteins with small molecule inhibitors has been extensively investigated as a therapeutic strategy for cancers [6-11] .
- Retinal vasculopathies account for the primary causes of loss of sight in the industrialized world and current standards do not fully address these diseases.
- Senescent cells affect the tissue microenvironment to drive disease progression in senescence-associated models of retinopathy, such as age-related macular degeneration (AMD) and diabetic macular edema (DME) .
- AMD age-related macular degeneration
- DME diabetic macular edema
- UNITY provide evidence that as pathological pre-retinal neovascularization forms, cells of the vascular unit rapidly engage pathways leading to p16INK4A activation and upregulation of pro-survival protein BCL-XL, ultimately culminating in cellular senescence.
- UNITY is developing senolytic medicines (UBX1325) to eliminate senescent cells to restore tissue health [12] .
- BCL-XL inhibitor or PROTAC targets a node upstream of anti-VEGF therapies.
- Targeting senescence effector/anti-apoptotic protein BCL-XL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization.
- One embodiment provides a compound, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-A) :
- o 0, 1, 2 or 3;
- each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N (R 2 ) 2 , -SR 2 , -S (O) R 2 , -S (O) 2 R 2 , -S (O) 2 N (R 2 ) 2 , -NR 2 S (O) 2 R 2 , -NR 2 S (O) 2 N (R 2 ) 2 , -C (O) R 2 , -C (O) OR 2 , -OC (O) R 2 , -OC (O) OR 2 , -OC (O) N (R 2 ) 2 , -NR 2 C (O) R 2 , -NR 2 C (O) OR 2 , -NR 2 C (O) N (R 2 ) 2 , -P (O) (OR 2 ) 2 , -P (O) (R 2 ) 2 , optionally substituted C 1-6
- each R 2 is each independently hydrogen or optionally substituted C 1-6 alkyl
- V is a bond, -C ⁇ C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl, or an optionally substituted heterocyclyl; or
- L is selected from a) C 2 -C 15 alkylene, b) C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent, or c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is selected from 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or
- R 3 and R 4 together form an oxo group
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z 1 and Z 2 is heterocyclene or cycloalkylene; and
- U is a recruitment motif selected from a VHL ligand.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable excipient.
- One embodiment provides a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof for use in a method of treatment of a human or animal.
- One embodiment provides a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treatment of cancer or neoplastic disease.
- One embodiment provides the use of a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
- One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
- One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
- FIG. 1 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
- FIG. 2 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
- FIG. 3 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
- Amino refers to the —NH 2 radical.
- Niro refers to the -NO 2 radical.
- Oxa refers to the -O-radical.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl) .
- an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl) .
- an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl) .
- an alkyl comprises one to six carbon atoms (e.g., C 1 -C 6 alkyl) .
- an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl) . In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl) . In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl) . In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl) . In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl) .
- an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl) . In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl) . In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl) . In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl) .
- the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl) , 1-methylethyl (iso-propyl) , 1-butyl (n-butyl) , 1-methylpropyl (sec-butyl) , 2-methylpropyl (iso-butyl) , 1, 1-dimethylethyl (tert-butyl) , 1-pentyl (n-pentyl) .
- the alkyl is attached to the rest of the molecule by a single bond.
- an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where t
- Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain radical as defined above.
- Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.
- ethenyl i.e., vinyl
- prop-1-enyl i.e., allyl
- pent-1-enyl penta-1, 4-dienyl, and the like.
- an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
- an alkynyl comprises two to eight carbon atoms.
- an alkynyl comprises two to six carbon atoms.
- an alkynyl comprises two to four carbon atoms.
- the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
- an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
- Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
- the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
- the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
- an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene) .
- an alkyl comprises one to six carbon atoms (e.g., C 1 -C 6 alkylene) .
- an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene) .
- an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene) .
- an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene) .
- an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene) . In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene) . In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene) . In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene) . In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene) .
- an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where t
- Alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
- the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
- an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene) .
- an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene) .
- an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene) . In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene) . In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene) . In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene) . In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene) .
- an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
- Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
- the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
- an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene) .
- an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene) .
- an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene) . In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene) . In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene) . In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene) . In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkynylene) .
- an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
- Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring atom.
- the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
- the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
- aryl or the prefix “ar-” (such as in “aralkyl” ) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
- Alkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- alkenyl refers to a radical of the formula –R d -aryl where R d is an alkenylene chain as defined above.
- the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
- the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
- Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
- the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
- the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
- Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spirocyclic ring systems, having from three to fifteen carbon atoms.
- a carbocyclyl comprises three to ten carbon atoms.
- a carbocyclyl comprises five to seven carbon atoms.
- the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds) .
- a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.
- monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- An unsaturated carbocyclyl is also referred to as “cycloalkenyl.
- Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like.
- Spirocyclic carbocyclyl or cycloalkyl radicals include, for example, spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane, spiro [2.6] nonane, spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] nonane, spiro [3.6] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [4.6] undecane, spiro [5.5] undecane, spiro [5.6] dodecane, spiro [6.6] tridecane, and the like.
- carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O) -OR a , -R b -OC
- Cycloalkylene refers to a divalent carbocyclyl or cycloalkyl linking the rest of the molecule to a radical group.
- Carbocyclylalkyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Carbocyclylalkynyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -carbocyclyl where R c is an alkylene chain as defined above.
- R c is an alkylene chain as defined above.
- the alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
- Examples of carboxylic acid bioisosteres include, but are not limited to, and the like.
- Halo or halogen refers to bromo, chloro, fluoro or iodo substituents.
- Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
- the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
- Heterocyclyl refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic, ring system, which optionally includes fused, bridged, or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated.
- heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) .
- heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
- heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
- Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, or combinations thereof.
- a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
- heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- heteroalkyl are, for example, –CH 2 -O-CH 2 -, –CH 2 -N (alkyl) -CH 2 -, –CH 2 -N (aryl) -CH 2 -, -OCH 2 CH 2 O-, –OCH 2 CH 2 OCH 2 CH 2 O-, or –OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.
- a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
- Heterocyclene refers to a divalent heterocyclyl linking the rest of the molecule to a radical group.
- N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
- An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
- C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
- a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.
- Heterocyclylalkyl refers to a radical of the formula –R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
- the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
- Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
- Heteroaryl refers to a radical derived from a 3-to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
- the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
- Heteroaryl includes fused or bridged ring systems.
- the heteroatom (s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is attached to the rest of the molecule through any atom of the ring (s) .
- heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzo
- heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -
- N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
- An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
- a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- Heteroarylalkyl refers to a radical of the formula –R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
- Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
- the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) -or (S) -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. ) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
- geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
- positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
- the chemical bond notation in form only means that the two chemical bonds connected to the set of para-substituted substituents are in trans or cis structure relative to the cyclohexyl or cyclobutyl group. Therefore, the compounds represented by exchanging these two chemical bonds with each other, or the compounds represented by switching combo to combo (or vice versa) , also fall within the scope of the present disclosure.
- a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
- the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
- the compound is deuterated in at least one position.
- deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
- structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C-or 14 C-enriched carbon are within the scope of the present disclosure.
- the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
- the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
- isotopes such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
- Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated.
- isotopic substitution with 18 F is contemplated. All isotopic variations
- the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
- the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
- Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
- Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
- Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
- CD 3 I iodomethane-d 3
- LiAlD 4 lithium aluminum deuteride
- Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
- the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- a pharmaceutically acceptable salt of any one of the heteroaromatic Bcl-xL inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
- Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
- acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
- salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts, " Journal of Pharmaceutical Science, 66: 1-19 (1997) ) .
- Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al
- solvates refers to a composition of matter that is the solvent addition form.
- solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
- subject or “patient” encompasses mammals.
- mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
- the mammal is a human.
- Prodrug refers to a compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized protective groups used in a transient manner to alter pharmacological properties in the parent molecule.
- treatment or “treating, ” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
- therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
- compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
- the BCL-2 (B-cell lymphoma-2) family of proteins serve as key regulators of the mitochondrial pathway of cellular apoptosis, and consists of both anti-apoptotic proteins such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1, and pro-apoptotic proteins such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma.
- pro-apoptotic and anti-apoptotic BCL-2 proteins normally function in opposition to each other.
- BCL-XL belong to the anti-apoptotic BCL-2 protein family and play an important role in promoting tumor initiation, progression, and development of drug resistance by protecting tumor cells from apoptosis. Inhibition of these BCL-2 family proteins with small molecule inhibitors has been extensively investigated as a therapeutic strategy for cancers.
- Retinal vasculopathies account for the primary causes of loss of sight in the industrialized world and current standards do not fully address these diseases.
- Senescent cells affect the tissue microenvironment to drive disease progression in senescence-associated models of retinopathy, such as age-related macular degeneration (AMD) and diabetic macular edema (DME) .
- AMD age-related macular degeneration
- DME diabetic macular edema
- UNITY provide evidence that as pathological pre-retinal neovascularization forms, cells of the vascular unit rapidly engage pathways leading to p16INK4A activation and upregulation of pro-survival protein BCL-XL, ultimately culminating in cellular senescence.
- UNITY is developing senolytic medicines (UBX1325) to eliminate senescent cells to restore tissue health. Focused on novel treatment paradigms, elimination of vascular senescent cells by BCL-XL inhibitor or PROTAC should re-establish barrier function and reverse disease progression in DME and AMD patients.
- BCL-XL inhibitor or PROTAC targets a node upstream of anti-VEGF therapies. Targeting senescence effector/anti-apoptotic protein BCL-XL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization.
- the levels of proteins within a cell are determined by both the rate of protein synthesis and the rate of protein degradation.
- two pathways exist for selective protein degradation the ubiquitin-proteasome pathway and the lysosomal proteolysis pathway.
- selective protein degradation is mediated by the presence of a recruitment motif which promotes binding of degradation proteins, such as proteasomal degradation proteins, or proteins associated with ubiquitin-proteasome pathway.
- Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents. Conjugation of recruitment motifs with high affinity ligands for Bcl-xL provides compounds capable of selectively directing pathways for protein degradation to the Bcl-xL protein itself. Such an outcome will reduce levels of Bcl-xL activity.
- heteroaromatic Bcl-xL degradation compound having the general formula provided below:
- the Bcl-xL affinity motif is a molecular construct having high affinity for the Bcl-xL protein independent of the linking motif and/or the recruitment motif
- the linking motif is a molecular construct providing a covalent bond to both the Bcl-xL affinity motif and the recruitment motif
- the recruitment motif is a molecular construct having the ability to selectively target and recruit protein degradation.
- the heteroaromatic Bcl-xL degradation compound has the structure of Formula (I-A) :
- L is the linking motif
- U is the recruitment motif
- Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents.
- the recruitment motif is derived from, VHL ligand, nutlin, bestatin, HIF-1 ⁇ –VHL binding peptide, hydroxy proline-HIF-1 ⁇ -VHL binding peptide, SCFb-TRCP targeting peptide or an inhibitor of apoptosis protein ligand.
- the recruitment motif (for example, U in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) ) is selected from a molecular construct related to a VHL ligand.
- the recruitment motif or the VHL ligand has a structure selected from:
- the recruitment motif is selected from:
- the recruitment motif is In some embodiments, the recruitment motif is In some embodiments, the recruitment motif is
- VHL ligand VHL binder
- VHL E3 ubiquitin ligase binder VHL E3 ubiquitin ligase binder
- the linking motif is a molecular construct providing a covalent bond to both the Bcl-xL affinity motif and the recruitment motif.
- the linking motif comprises a cyclic moiety.
- the linking motif comprises an acyclic moiety.
- the linking motif comprises an unsaturated moiety.
- the linking motif comprises between 4 and 50 non-hydrogen atoms in a linear sequence.
- the linking motif comprises between 4 and 20 non-hydrogen atoms in a linear sequence.
- the linking motif comprises between 4 and 25 non-hydrogen atoms in a linear sequence.
- the linking motif comprises between 4 and 30 non-hydrogen atoms in a linear sequence.
- the linking motif comprises between 6 and 18 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 5 and 10 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 non-hydrogen atoms in a linear sequence. As an example, the following molecular fragment contains 8 non-hydrogen atoms in a linear sequence:
- the linking motif for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is selected from a) C 2 -C 15 alkylene, b) C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent, or c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is selected from 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or
- R 3 and R 4 together form an oxo group
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene;
- Z 1 and Z 2 are heterocyclene or cycloalkylene.
- the linking motif for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is selected from C 2 -C 15 alkylene.
- the linking motif is C 4-15 alkylene.
- the linking motif is C 4-9 alkylene.
- the linking motif is C 5-8 alkylene.
- the linking motif for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is C 2- 15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent.
- the linking motif has the structure – (CR 3 R 4 ) x -O– (CR 3 R 4 ) y -*, wherein: each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or R 3 and R 4 together form an oxo group; and x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14.
- the linking motif has the structure – (CH 2 ) x -O– (CH 2 ) y -*, wherein: x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14.
- x is 0 to 7 and y is 1 to 7.
- x is 0 to 6 and y is 1 to 6.
- the linking motif is C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent having a structure selected from
- the linking motif for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is C 2- 15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent.
- the linking motif has the structure – (CR 3 R 4 ) j -O– (CR 3 R 4 ) p -O– (CH 2 ) v -*, wherein: each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or R 3 and R 4 together form an oxo group; j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of j, p, and v is not more than 13.
- the linking motif has the structure – (CH 2 ) j -O– (CH 2 ) p -O– (CH 2 ) v -*, wherein: j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of j, p, and v is not more than 13.
- j is 0 to 4; p is 1 to 5; and v is 1 to 4. In some embodiments, j is 0 to 2; p is 2 to 4; and v is 1 to 3.
- the linking motif is C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent having a structure selected from
- the linking motif for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I- E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is represented by the following formula:
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is selected from 0 to 6;
- R 3 and R 4 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or R 3 and R 4 are taken together to form an oxo group;
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene, wherein at least one of Z 1 and Z 2 is heterocyclene or cycloalkylene;
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- X, X1 and X2 at each instance are independently CH or N;
- k 0 to 6;
- n 0 to 6;
- n 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl In some embodiments, each R 3 and R 4 is independently selected from hydrogen, halogen, and C 1-3 alkyl. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, fluoro, and -CH 3 . In some embodiments, R 3 and R 4 are both hydrogen.
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- X, X1 and X2 at each instance are independently CH or N;
- k 0 to 6;
- n 0 to 6;
- n 0 to 6;
- m is 0 to 3.
- n is 0 to 2.
- k is 0 to 3
- m is 0 to 3
- n is 0 to 2.
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- X, X1 and X2 at each instance are independently CH or N;
- k 0 to 6;
- n 0 to 6;
- n 0 to 6;
- m is 0 to 3.
- n is 0 to 2.
- k is 0 to 3
- m is 0 to 3
- n is 0 to 2.
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- X1, X2, X3, and X4 at each instance are independently CH or N;
- k 0 to 6;
- n 0 to 6;
- n 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, halogen, and C 1-3 alkyl. In some embodiments, each R 3 and R 4 is independently selected from hydrogen, fluoro, and -CH 3 . In some embodiments, R 3 and R 4 are both hydrogen.
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- X1, X2, X3, and X4 at each instance are independently CH or N;
- k 0 to 6;
- n 0 to 6;
- n 0 to 6;
- k is 0 or 1.
- m is 0 or 1.
- n is 0 to 2.
- k is 0 or 1
- m is 0 or 1
- n is 0 to 2.
- L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*selected from a molecular fragment illustrated below:
- A-1155463 is a potent Bcl-xL binder with a K i of ⁇ 0.01 nM in a TR-FRET assay as described in Tao et al., “Discovery of a Potent and Selective BCL-XL Inhibitor with In Vivo Activity” ACS Med. Chem. Lett. 2014. DOI: 10.1021/ml5001867 [16] which is incorporated herein by reference.
- o 0, 1, 2 or 3;
- each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N (R 2 ) 2 , -SR 2 , -S (O) R 2 , -S (O) 2 R 2 , -S (O) 2 N (R 2 ) 2 , -NR 2 S (O) 2 R 2 , -NR 2 S (O) 2 N (R 2 ) 2 , -C (O) R 2 , -C (O) OR 2 , -OC (O) R 2 , -OC (O) OR 2 , -OC (O) N (R 2 ) 2 , -NR 2 C (O) R 2 , -NR 2 C (O) OR 2 , -NR 2 C (O) N (R 2 ) 2 , -P (O) (OR 2 ) 2 , -P (O) (R 2 ) 2 , optionally substituted C 1-6
- each R 2 is each independently hydrogen or optionally substituted C 1-6 alkyl
- V is a bond, -C ⁇ C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C 3-7 cycloalkyl, or an optionally substituted heterocyclyl; or
- L is selected from a) C 2 -C 15 alkylene, b) C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent, and c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or
- R 3 and R 4 together form an oxo group
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z 1 and Z 2 is heterocyclene or cycloalkylene; and
- U is a VHL ligand.
- o 0, 1, 2 or 3;
- each R 1 is independently selected from halogen, nitro, cyano, -OR 2 , -N (R 2 ) 2 , -SR 2 , -S (O) R 2 , -S (O) 2 R 2 , -S (O) 2 N (R 2 ) 2 , -NR 2 S (O) 2 R 2 , -NR 2 S (O) 2 N (R 2 ) 2 , -C (O) R 2 , -C (O) OR 2 , -OC (O) R 2 , -OC (O) OR 2 , -OC (O) N (R 2 ) 2 , -NR 2 C (O) R 2 , -NR 2 C (O) OR 2 , -NR 2 C (O) N (R 2 ) 2 , -P (O) (OR 2 ) 2 , -P (O) (R 2 ) 2 , optionally substituted C 1-6
- each R 2 is independently hydrogen or optionally substituted C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more R e ; or
- R 2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R e ;
- V is a bond. -C ⁇ C-, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C 3-7 cycloalkyl, or optionally substituted heterocyclyl, wherein the heteroaryl, aryl, cycloalkyl, or heterocyclyl are optionally substituted with one or more R V ; or
- L is selected from a) C 2 -C 15 alkylene, b) C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent, and c) -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is selected from 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or
- R 3 and R 4 together form an oxo group
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z 1 and Z 2 is heterocyclene or cycloalkylene; and
- U is a VHL ligand.
- provided herein is a compound of Formula (I-A) , or a pharmaceutically acceptable salt or solvate thereof.
- each R 1 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-3 alkoxy, halogen, -N (R 2 ) 2 , -OR 2 , and cyano, wherein the alkyl, haloalkyl, and alkoxy are each independently optionally substituted.
- each R 1 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-3 alkoxy, -N (R 2 ) 2 , -OR 2 , and cyano, wherein the alkyl, haloalkyl, and alkoxy are each independently optionally substituted. In some embodiments, the alkyl, haloalkyl, and alkoxy are each independently optionally substituted with one or more R e . In some embodiments, each R 1 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
- each R 1 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , and -CF 3 . In some embodiments, each R 1 is independently selected from -Cl, -CH 3 , and -CF 3 .
- V is a bond.
- provided herein is a compound of Formula (I-B) , or a pharmaceutically acceptable salt or solvate thereof.
- V is an optionally substituted heteroaryl. In some embodiments, V is an optionally substituted N-containing heteroaryl. In some embodiments, V is an optionally substituted N-containing 5-or 6-membered heteroaryl. In some embodiments, V is an optionally substituted N-containing 6-membered heteroaryl selected from pyridinyl, pyrimidnyl, and pyridazinyl. In some embodiments, V is an optionally substituted N-containing 5-membered heteroaryl selected from pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, and oxadiazolyl.
- V is a an optionally substituted N-containing heteroaryl selected from pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, and pyrimidinyl.
- each R V is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF 3 . In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is wherein the asterisk indicates the point of attachment to L.
- V is an optionally substituted aryl. In some embodiments, V is an optionally substituted phenyl or naphthyl. In some embodiments, V is an optionally substituted phenyl. In some embodiments, V is an optionally substituted naphthyl.
- each R V is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF 3 . In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-C) :
- V is an optionally substituted cycloalkyl. In some embodiments, V is an optionally substituted C 3-7 cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted.
- each R V is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF 3 . In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-D1) :
- V is an optionally substituted heterocyclyl. In some embodiments, V is an optionally substituted N-containing heterocyclyl. In some embodiments, V is pyrrolidinyl, piperazinyl, piperidinyl, or morpholino, each of which is optionally substituted.
- each R V is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl. In some embodiments, each R V is independently hydrogen, -Cl, -F, or -CF 3 . In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V is wherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-E1a) or Formula (I-E1b) :
- a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof having the structure of Formula (I-E2a) or Formula (I-E2b) :
- V is -C ⁇ C-.
- the fused bicyclic aryl ring is a naphthyl substituted with o instances of R 1 .
- the fused bicyclic heteroaryl ring is taken together to form a fused bicyclic heteroaryl ring substituted with o instances of R 1 .
- the fused bicyclic heteroaryl ring is an N-containing bicyclic heteroaryl ring substituted with o instances of R 1 .
- the fused bicyclic heteroaryl ring is a quinolinyl, an isoquinolinyl, a cinnolinyl, a quinazolinyl, a quinoxalinyl, or an indolyl, each of which is substituted with o instances of R 1 .
- the fused bicyclic heteroaryl ring is a quinolinyl or an isoquinolinyl, each of which is substituted with o instances of R 1 .
- wherein the asterisk indicates the point of attachment to L.
- L is C 2 -C 15 alkylene. In some embodiments, L is C 2 -C 15 alkylene. In some embodiments, L is C 2 -C 15 alkylene. In some embodiments, L is C 3-15 alkylene. In some embodiments, L is C 4-15 alkylene. In some embodiments, L is C 5-15 alkylene.
- L is C 6-15 alkylene. In some embodiments, L is C 7-15 alkylene. In some embodiments, L is C 8-15 alkylene. In some embodiments, L is C 9-15 alkylene. In some embodiments, L is C 10-15 alkylene. In some embodiments, L is C 11-15 alkylene. In some embodiments, L is C 12-15 alkylene. In some embodiments, L is C 13-15 alkylene. In some embodiments, L is C 14-15 alkylene. In some embodiments, L is C 2-14 alkylene. In some embodiments, L is C 2-13 alkylene. In some embodiments, L is C 2-13 alkylene. In some embodiments, L is C 2-12 alkylene.
- L is C 2-11 alkylene. In some embodiments, L is C 2-10 alkylene. In some embodiments, L is C 2-9 alkylene. In some embodiments, L is C 2-8 alkylene. In some embodiments, L is C 2-7 alkylene. In some embodiments, L is C 2-8 alkylene. In some embodiments, L is C 2-7 alkylene. In some embodiments, L is C 2-8 alkylene. In some embodiments, L is C 2-7 alkylene. In some embodiments, L is C 2-6 alkylene. In some embodiments, L is C 2-5 alkylene. In some embodiments, L is C 2-4 alkylene. In some embodiments, L is C 2-3 alkylene. In some embodiments, L is C 3-8 alkylene. In some embodiments, L is C 4-9 alkylene.
- L is C 5-10 alkylene. In some embodiments, L is C 6-11 alkylene. In some embodiments, L is C 7-12 alkylene. In some embodiments, L is C 8-13 alkylene. In some embodiments, L is C 9-14 alkylene. In some embodiments, L is C 5-8 alkylene. In some embodiments, L is C 2-4 alkylene. In some embodiments, L is C 2 alkylene. In some embodiments, L is C 3 alkylene. In some embodiments, L is C 4 alkylene. In some embodiments, L is C 5 alkylene. In some embodiments, L is C 6 alkylene. In some embodiments, L is C 7 alkylene. In some embodiments, L is C 8 alkylene.
- L is C 9 alkylene. In some embodiments, L is C 10 alkylene. In some embodiments, L is C 11 alkylene. In some embodiments, L is C 12 alkylene. In some embodiments, L is C 13 alkylene. In some embodiments, L is C 14 alkylene. In some embodiments, L is C 15 alkylene.
- each carbon atom of the alkylene is independently optionally substituted with R 3 and R 4 (e.g., (CR 3 R 4 ) 2-15 ) , and each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl, or R 3 and R 4 together on the same carbon atom form an oxo group.
- R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl, or R 3 and R 4 together on the same carbon atom form an oxo group.
- the alkylene is unsubstituted.
- L is C 2-15 alkylene wherein one or more -CH 2 -units are replaced with O, provided that two O atoms are not adjacent. In some embodiments, L is C 3-8 alkylene wherein one or more -CH 2 -units are replaced with O.
- L is C 4-9 alkylene wherein one or more -CH 2 -units are replaced with O. In some embodiments, L is C 5-8 alkylene wherein one or more -CH 2 -units are replaced with O.
- each carbon atom of the alkylene is independently optionally substituted with R 3 and R 4 (e.g., (CR 3 R 4 ) 2-15 ) , and each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl, or R 3 and R 4 together on the same carbon atom form an oxo group.
- the alkylene is unsubstituted.
- L is C 2-15 alkylene wherein one -CH 2 -unit is replaced with O. In some embodiments, L is C 2-15 alkylene wherein one -CH 2 -unit is replaced with O having the structure – (CR 3 R 4 ) x -O– (CR 3 R 4 ) y -*wherein: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14.
- L is C 2-15 alkylene wherein one -CH 2 -unit is replaced with O having the structure – (CH 2 ) x -O– (CH 2 ) y -*wherein: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14.
- x is 0 to 9 and y is 1 to 10.
- x is 0 to 8 and y is 1 to 10.
- x is 0 to 7 and y is 1 to 10.
- x is 0 to 6 and y is 1 to 10. In some embodiments, x is 0 to 10 and y is 1 to 9. In some embodiments, x is 0 to 10 and y is 1 to 8. In some embodiments, x is 0 to 10 and y is 1 to 7. In some embodiments, x is 0 to 10 and y is 1 to 6. In some embodiments, x is 0 to 7 and y is 1 to 7. In some embodiments, x is 0 to 6 and y is 1 to 7. In some embodiments, x is 0 to 7 and y is 1 to 6. In some embodiments, x is 0 to 6 and y is 1 to 6. In some embodiments, x is 0 to 6 and y is 1 to 6.
- L has a structure selected from In some embodiments, L is C 4 - 15 alkylene wherein two -CH 2 -units are replaced with O. In some embodiments, L is C 4 - 15 alkylene wherein two -CH 2 -units are replaced with O having the structure – (CR 3 R 4 ) j -O– (CR 3 R 4 ) p -O– (CR 3 R 4 ) v -*wherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of p, j, and v is not more than 13.
- L is C 4 - 15 alkylene wherein two -CH 2 -units are replaced with O having the structure – (CH 2 ) j -O– (CH 2 ) p -O– (CH 2 ) v -*wherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of p, j, and v is not more than 13. In some embodiments, j is 0 to 10, p is 1 to 10, and v is 1 to 10.
- j is 0 to 10, p is 1 to 5, and v is 1 to 10. In some embodiments, j is 0 to 10, p is 1 to 10, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 10, and v is 1 to 10. In some embodiments, j is 0 to 4, p is 1 to 10, and v is 1 to 10. In some embodiments, j is 0 to 4, p is 1 to 10, and v is 1 to 4. In some embodiments, j is 0 to 10, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 4.
- j is 0 to 4, p is 2 to 4, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 3. In some embodiments, j is 0 to 4, p is 2 to 4, and v is 1 to 3. In some embodiments, j is 0 to 2, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 2, p is 2 to 4, and v is 1 to 4. In some embodiments, j is 0 to 2, p is 1 to 5, and v is 1 to 3. In some embodiments, j is 0 to 2, p is 2 to 4, and v is 1 to 3. In some embodiments, L has a structure selected from
- Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , L has the structure
- Ak 1 is selected from - (CR 3 R 4 ) k -;
- Ak 2 is selected from - (CR 3 R 4 ) m -;
- Ak 3 is selected from - (CR 3 R 4 ) n -;
- each of k, m, and n is 0 to 6;
- each R 3 and R 4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl; or R 3 and R 4 together form an oxo group;
- Z 1 and Z 2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z 1 and Z 2 is heterocyclene or cycloalkylene; and
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from:
- R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C 3 cycloalkyl.
- R 3 and R 4 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 3 and R 4 are both hydrogen.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6.
- k is 0, 1, 2, or 3.
- m is 0, 1, 2, or 3.
- n is 0, 1, or 2.
- k is 0, 1, 2, or 3, m is 0, 1, 2, or 3, and n is 0, 1, or 2.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: and wherein the point of bonding to the VHL ligand is indicated by the asterisk.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak
- -Ak1-Z1-Ak2-Z2-Ak3-* has a structure selected from:
- X1, X2, X3, and X4 at each instance are independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and wherein the point of bonding to U is indicated by the asterisk.
- k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.
- R 3 and R 4 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl.
- R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 3 and R 4 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 3 and R 4 are both hydrogen.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: X1, X2, X3, and X4 at each instance are independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and wherein the point of bonding to U is indicated by the asterisk.
- k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.
- k is 0 or 1.
- m is 0 or 1.
- n is 0, 1, or 2.
- k is 0 or 1
- m is 0 or 1
- n is 0 to 2.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* has a structure selected from: wherein the point of bonding to U is indicated by the asterisk.
- -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiment
- the compounds as described herein have a structure provided in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. In some embodiments, the compounds as described herein have a structure provided in Table 1.
- compounds as described herein has a structure provided in Table 2.
- compounds as described herein has a structure provided in Table 3.
- compounds as described herein has a structure provided in Table 4.
- compounds as described herein has a structure provided in Table 5.
- compounds as described herein has a structure provided in Table 6.
- compounds as described herein has a structure provided in Table 7.
- the heteroaromatic Bcl-xL degradation compound described herein is administered as a pure chemical.
- the heteroaromatic Bcl-xL degradation compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
- a pharmaceutical composition comprising at least one heteroaromatic Bcl-xL degradation compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
- the carrier (s) or excipient (s) ) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
- One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof.
- One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
- Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
- suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
- the injection formulation is an aqueous formulation.
- the injection formulation is a non-aqueous formulation.
- the injection formulation is an oil-based formulation, such as sesame oil, or the like.
- the dose of the composition comprising at least one heteroaromatic Bcl-xL degradation compound as described herein differs depending upon the subject or patient's (e.g., human) condition.
- such factors include general health status, age, and other factors.
- compositions are administered in a manner appropriate to the disease to be treated (or prevented) .
- An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
- an appropriate dose and treatment regimen provides the composition (s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
- Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
- One embodiment provides a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
- One embodiment provides a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
- One embodiment provides a use of a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
- described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof.
- described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
- a pharmaceutical composition comprising a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E
- Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.
- the compounds disclosed herein are synthesized according to the following examples.
- the following abbreviations unless otherwise indicated, shall be understood to have the following meanings: °C degrees Celsius ⁇ H chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH 2 Cl 2 ) DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl g gram (s) h hour (s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry ⁇ micro m multiplet (spectral) ; meter (s) ; milli M molar M + parent molecular ion Me methyl MHz megahertz min minute (s) mol mole (s) ; molecular (as in mol wt
- Step B methyl dec-9-ynoate
- Step D 10- ⁇ 4- [3- (2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl ⁇ dec-9-ynoic acid
- Step E ethyl 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- ⁇ 3- [4- (9- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5- yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ non-1-yn-1-yl) phenoxy] propyl ⁇ -1, 3-thiazole-4-carboxylate
- Step F 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- ⁇ 3- [4- (9- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ non-1-yn-1-yl) phenoxy] propyl ⁇ -1, 3-thiazole-4-carboxylic acid
- Step B tert-butyl 2- (3- (prop-2-yn-1-yloxy) propoxy) acetate
- Step C 2- (3- (prop-2-yn-1-yloxy) propoxy) acetic acid
- Step D 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- [3- (4- ⁇ 3- [3- ( ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ methoxy) propoxy] prop-1-yn-1-yl ⁇ phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
- Step B ethyl 4- (2-hydroxyethoxy) butanoate
- Step D ethyl 4- (prop-2-yn-1-yloxy) butanoate
- Step F 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- (3- ⁇ 4- [3- (3- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ propoxy) prop-1-yn-1-yl] phenoxy ⁇ propyl) -1, 3-thiazole-4-carboxylic acid
- Step A tert-butyl 2- (4- (benzyloxy) butoxy) acetate
- Step B tert-butyl 2- (4-hydroxybutoxy) acetate
- Step C tert-butyl 2- (4- (prop-2-yn-1-yloxy) butoxy) acetate
- Step D 2- (4- (prop-2-yn-1-yloxy) butoxy) acetic acid
- Step E 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- [3- (4- ⁇ 3- [4- ( ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ methoxy) butoxy] prop-1-yn-1-yl ⁇ phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
- Step A tert-butyl 2- (hept-6-yn-1-yloxy) acetate
- Step B (hept-6-yn-1-yloxy) acetic acid
- Step C 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- (3- ⁇ 4- [7- ( ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ methoxy) hept-1-yn-1-yl] phenoxy ⁇ propyl) -1, 3-thiazole-4-carboxylic acid
- tert-butyl 2- (triphenyl-lambda5-phosphanylidene) acetate (4.60 g, 12.229 mmol) was added to the mixture, the mixture was stirred at rt for 2 h. After completion, the reaction was quenched with water (50 mL) . The mixture was extracted with EA (3x50 mL) and the organic layer was dried over Na 2 SO 4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column (0-50%PE : EtOAc) . The organic layers were concentrated under reduced pressure to afford tert-butyl (2E) -4- [2- (benzyloxy) ethoxy] but-2-enoate. LC/MS: MS (ESI) M/Z 265 [M+H] + .
- Step B ethyl 4- (2-hydroxyethoxy) butanoate
- Step C ethyl 4- (2- (prop-2-yn-1-yloxy) ethoxy) butanoate
- Step D 4- (2- (prop-2-yn-1-yloxy) ethoxy) butanoic acid
- Step E 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- [3- (4- ⁇ 3- [2- (3- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ propoxy) ethoxy] prop-1-yn-1-yl ⁇ phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
- Step A ethyl 6- (prop-2-yn-1-yloxy) hexanoate
- Step B 6- (prop-2-yn-1-yloxy) hexanoic acid
- Step C 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- [3- (4- ⁇ 3- [ (5- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ pentyl) oxy] prop-1-yn-1-yl ⁇ phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid.
- Step A methyl 5- (but-3-yn-1-yloxy) pentanoate
- Step C 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- (3- ⁇ 4- [4- (4- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ butoxy) but-1-yn-1-yl] phenoxy ⁇ propyl) -1, 3-thiazole-4-carboxylic acid
- Step A tert-butyl 2- (hex-5-yn-1-yloxy) acetate
- Step B 2- (hex-5-yn-1-yloxy) acetic acid
- Step C 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- (3- ⁇ 4- [6- ( ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ methoxy) hex-1-yn-1-yl] phenoxy ⁇ propyl) -1, 3-thiazole-4-carboxylic acid.
- Step A methyl 10-oxodecanoate
- Step B methyl undec-10-ynoate
- Step D 2- ⁇ 8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl ⁇ -5- ⁇ 3- [4- (10- ⁇ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( ⁇ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl ⁇ carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl ⁇ dec-1-yn-1-yl) phenoxy] propyl ⁇ -1, 3-thiazole-4-carboxylic acid.
- Step A tert-butyl 2- (2- (benzyloxy) ethoxy) acetate
- Step B tert-butyl 2- (2-hydroxyethoxy) acetate
- Step C tert-butyl 2- (2-iodoethoxy) acetate
- Step D tert-butyl 2- (2- (but-3-yn-1-yloxy) ethoxy) acetate
- Step E 2- (2- (but-3-yn-1-yloxy) ethoxy) acetic acid
- Step F 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (4- (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethoxy) but-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid.
- Step B methyl 8-oxooctanoate
- Step C methyl non-8-ynoate
- Step E 9- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (ethoxycarbonyl) thiazol-5-yl) propoxy) phenyl) non-8-ynoic acid
- Step F ethyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step G 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step B benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate
- Step C benzyl 9- (2- (tert-butoxy) -2-oxoethylidene) -3-azaspiro [5.5] undecane-3-carboxylate
- Step D tert-butyl 2- (3-azaspiro [5.5] undecan-9-yl) acetate
- Step E tert-butyl 2- (3- (prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetate
- Step F methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- (tert-butoxy) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- the tube was degassed and backfilled with N 2 for 5 times.
- the resulting mixture was stirred at 60°C for 4 hrs under N 2 .
- the reaction mixture was cooled to RT, quenched with water (100mL) and extracted with EA (3*30mL) .
- the organic layer combined was washed with brine (3*100 mL) , dried over Na 2 SO 4 and concentrated in vacuo.
- Step G 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetic acid
- Step H methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step I 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- the resulting mixture was stirred at 25 °C for 2 hrs.
- the resulting mixture was stirred at 25°C for 2 hrs.
- the organic layer combined was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
- the residue obtained was purified by Prep-HPLC (10 mmol/L NH 4 HCO 3 -ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) .
- Step A methyl 1- (4- (2- (tert-butoxy) -2-oxoethyl) cyclohexyl) azetidine-3-carboxylate
- Step B tert-butyl 2- (4- (3-formylazetidin-1-yl) cyclohexyl) acetate
- Step C tert-butyl 2- (4- (3-ethynylazetidin-1-yl) cyclohexyl) acetate
- Step D 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [4- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] cyclohexyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
- Step A tert-butyl 1- (1- ( (benzyloxy) carbonyl) azetidin-3-yl) piperidine-4-carboxylate
- Step B tert-butyl 1- (azetidin-3-yl) piperidine-4-carboxylate
- Step C tert-butyl 1- (1- (prop-2-yn-1-yl) azetidin-3-yl) piperidine-4-carboxylate
- Step D 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
- Step A tert-butyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate
- Step B tert-butyl 7-formyl-2-azaspiro [3.5] nonane-2-carboxylate
- Step C tert-butyl 7-ethynyl-2-azaspiro [3.5] nonane-2-carboxylate
- Step D methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (tert-butoxycarbonyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step E methyl 5- (3- (4- (2-azaspiro [3.5] nonan-7-ylethynyl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
- Step F 2- (7- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) -2-azaspiro [3.5] nonan-2-yl) acetic acid
- Step G methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step H 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step A tert-butyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate
- Step B tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate
- Step C tert-butyl 2-ethynyl-7-azaspiro [3.5] nonane-7-carboxylate
- Step E tert-butyl 3- (2-ethynyl-7-azaspiro [3.5] nonan-7-yl) propanoate
- Step F 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (7- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropyl) -7-azaspiro [3.5] nonan-2-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid.
- Step A tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate
- Step B tert-butyl 3-formylcyclobutanecarboxylate
- Step C tert-butyl 4-ethynylpiperidine-1-carboxylate
- Step E tert-butyl 3- [ (4-ethynyl-1-piperidyl) methyl] cyclobutanecarboxylate
- Step F 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl- propyl] carbamoyl] cyclobutyl] methyl] -4-piperidyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step A benzyl 4-vinylpiperidine-1-carboxylate
- Step B benzyl 4- (2, 2-dichloro-3-oxocyclobutyl) piperidine-1-carboxylate
- Step C benzyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate
- Step D tert-butyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate
- Step E tert-butyl 4- (3- (methoxymethylene) cyclobutyl) piperidine-1-carboxylate
- Step F tert-butyl 4- (3-formylcyclobutyl) piperidine-1-carboxylate
- Step G tert-butyl 4- (3-ethynylcyclobutyl) piperidine-1-carboxylate
- Step H methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step I methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step J 2- (4- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclobutyl) piperidin-1-yl) acetic acid
- Step K methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step L 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step A tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate
- Step B tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate
- Step D tert-butyl 3- (4-prop-2-ynyl-1-piperidyl) cyclobutanecarboxylate
- Step E methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- (3-tert-butoxycarbonylcyclobutyl) -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step F 3- [4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -1-piperidyl] cyclobutanecarboxylic acid
- Step G methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step H 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5 - [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step B benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate
- Step C benzyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate
- Step D benzyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate
- Step E 3- ( (benzyloxy) carbonyl) -3-azaspiro [5.5] undecane-9-carboxylic acid
- Step F 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate
- Step G 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate
- Step H tert-butyl 3- (prop-2-yn-1-yl) -3-azaspiro [5.5] undecane-9-carboxylate
- Step I methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (tert-butoxycarbonyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- reaction mixture was stirred at 25 °C for 16 hrs under N 2 . After completion, the reaction mixture was poured by addition H 2 O (50.0 mL) , and filtered. The combined organic solid were washed with water (5.0 mL) and concentrated under reduced pressure.
- Step J 3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecane-9-carboxylic acid
- Step K methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step L 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) - 3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- the resulting mixture was stirred at 25 °C for 2 hrs.
- the reaction mixture was concentrated under reduced pressure to give a residue.
- the residue was diluted with H 2 O (3 mL) and the pH value of the solution was adjusted to 6 with aqueous HCl (1M) and extracted with DCM. The organic layers were combined, dried and concentrated under vacuum at 25 °C.
- Step A tert-butyl 2- (2-ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
- Step B tert-butyl 2- (2-ethoxy-2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
- Step C tert-butyl 2- (2- (methoxy (methyl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
- Step D tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
- Step E tert-butyl 2- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate
- Step F methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (tert-butoxycarbonyl) -7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step G methyl 5- (3- (4- (3- (7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
- Step H 2- (2- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -7-azaspiro [3.5] nonan-7-yl) acetic acid
- Step I methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step J 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step B benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate
- Step C benzyl 2- (2-tert-butoxy-2-oxo-ethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
- Step D tert-butyl 2- (7-azaspiro [3.5] nonan-2-yl) acetate
- Step E tert-butyl 2- (7- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonan-2-yl) acetate
- Step F 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
- Step A tert-butyl 3-ethynylazetidine-1-carboxylate
- Step C tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate
- Step D tert-butyl 3-formylcyclobutanecarboxylate
- Step E tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) cyclobutanecarboxylate
- Step F methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- (tert-butoxycarbonyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step G 3- ( (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) methyl) cyclobutanecarboxylic acid
- Step H methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step I 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step A tert-butyl 3- ( (3- (methoxycarbonyl) azetidin-1-yl) methyl) azetidine-1-carboxylate
- Step B tert-butyl 3- ( (3- (methoxycarbonyl) azetidin-1-yl) methyl) azetidine-1-carboxylate
- Step C tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) azetidine-1-carboxylate
- Step D 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [ [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] methyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
- Step A tert-butyl 2- (3- (benzyloxy) cyclobutylidene) acetate
- Step B tert-butyl 2- (3-hydroxycyclobutyl) acetate
- Step C tert-butyl 2- (3-oxocyclobutyl) acetate
- Step D tert-butyl 2- (3- (3-ethynylazetidin-1-yl) cyclobutyl) acetate
- Step E methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- (3- (2- (tert-butoxy) -2-oxoethyl) cyclobutyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step F 2- (3- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) cyclobutyl) acetic acid
- Step G methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) cyclobutyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step A ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate
- Step B diethyl 1, 4-dioxaspiro [4.5] decane-8, 8-dicarboxylate
- Step C 1, 4-dioxaspiro [4.5] decane-8, 8-diyldimethanol
- Step D 2- [ (2, 4-dimethoxyphenyl) methyl] -8, 11-dioxa-2-azadispiro [3.2.4 7 .2 4 ] tridecane
- Step E tert-butyl 8, 11-dioxa-2-azadispiro [3.2.4 7 .2 4 ] tridecane-2-carboxylate
- Step F tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate
- Step G tert-butyl 7- (2-ethoxy-2-oxoethylidene) -2-azaspiro [3.5] nonane-2-carboxylate
- Step H tert-butyl 7- (2-ethoxy-2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate
- Step I tert-butyl 7- (2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate
- Step J tert-butyl7- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonane-2-carboxylate
- Step K 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step A tert-butyl 3- (2- ( ( (3S, 7aR) -3- ( ( (tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- the mixture was stirred at r. t. for 1 h.
- the reaction was quenched with water (5 mL) .
- the mixture was extracted with EA (3 x 20 mL) and the resulting mixture was washed with 3 x 20 mL of water, The organic layer was dried over Na 2 SO 4 and filtered. The organic layers were concentrated.
- the crude product was purified with silica gel column.
- Step B tert-butyl 3- (2- ( ( (3S, 7aR) -3- ( ( (tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step A tert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate
- Step B benzyl 4- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate
- Step C tert-butyl 4- (piperidin-4-yl) cyclohexanecarboxylate
- Step D methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- (tert-butoxycarbonyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step E 4- (1- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) piperidin-4-yl) cyclohexanecarboxylic acid
- Step F methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5- yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step G 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step A Tert-butyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate
- Step B tert-butyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate
- Step C tert-butyl 9-ethynyl-3-azaspiro [5.5] undecane-3-carboxylate
- Step D methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (tert-butoxycarbonyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step E methyl 5- (3- (4- (3-azaspiro [5.5] undecan-9-ylethynyl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
- Step F 2- (9- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) -3-azaspiro [5.5] undecan-3-yl) acetic acid
- Step G methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
- Step H 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
- Example 31 Compound 31 (Compound 31-A and 31-B)
- Step B tert-butyl 4-prop-2-ynoxycyclohexanecarboxylate
- Step C methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (4-tert-butoxycarbonylcyclohexoxy) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step D 4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynoxy] cyclohexanecarboxylic acid
- Step F 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1R) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step G 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step B benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate
- Step C benzyl 7- (2- (tert-butoxy) -2-oxoethylidene) -2-azaspiro [3.5] nonane-2-carboxylate
- Step D tert-butyl 2- (2-azaspiro [3.5] nonan-7-yl) acetate
- Step E tert-butyl 2- (2- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonan-7-yl) acetate
- Step F methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- (tert-butoxy) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- Step G 2- (2- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -2-azaspiro [3.5] nonan-7-yl) acetic acid
- Step H methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
- the resulting mixture was stirred at room temperature for 5 hr under N 2 atmosphere.
- the mixture was diluted with EA (50 mL) , washed with brine (30 mL) and H 2 O (30 mL) , the organic layers was dried over Na 2 SO 4 and concentrated.
- Step I 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
- Step A benzyl 4- (3-tert-butoxy-3-oxo-propoxy) piperidine-1-carboxylate
- Step B tert-butyl 3- (4-piperidyloxy) propanoate
- Step C tert-butyl 3- [ (1-prop-2-ynyl-4-piperidyl) oxy] propanoate
- Step D methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (3-tert-butoxy-3-oxo-propoxy) -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step E 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] oxy] propanoic acid
- Step F 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step G 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [3- [ [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -3-oxo-propoxy] -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
- Step A methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step B 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid
- Step C methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
- Step D 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
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Abstract
Provided herein are heteroaromatic compounds which target Bcl-xL proteins for ubiquitination and proteasomal degradation. Also provided herein are methods for using said compounds for the treatment of diseases.
Description
The BCL-2 (B-cell lymphoma-2) family of proteins serve as key regulators of the mitochondrial pathway of cellular apoptosis, and consists of both anti-apoptotic proteins such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1, and pro-apoptotic proteins such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma [1-2] . Pro-apoptotic and anti-apoptotic BCL-2 proteins normally function in opposition to each other. Blocking the interactions between them, either by treatment with a small molecule or by RNA interference, leads to mitochondria outer membrane permeabilization (MOMP) and the release of cytochrome c, second mitochondria-derived activator of caspases (SMAC) , and other pro-apoptotic factors [3] . These events then trigger the caspase activation cascade and subsequent cellular apoptosis [4] .
BCL-XL belongs to the anti-apoptotic BCL-2 protein family and plays an important role in promoting tumor initiation, progression, and development of drug resistance by protecting tumor cells from apoptosis [5] . Inhibition of these BCL-2 family proteins with small molecule inhibitors has been extensively investigated as a therapeutic strategy for cancers [6-11] .
Retinal vasculopathies account for the primary causes of loss of sight in the industrialized world and current standards do not fully address these diseases. Senescent cells affect the tissue microenvironment to drive disease progression in senescence-associated models of retinopathy, such as age-related macular degeneration (AMD) and diabetic macular edema (DME) . UNITY provide evidence that as pathological pre-retinal neovascularization forms, cells of the vascular unit rapidly engage pathways leading to p16INK4A activation and upregulation of pro-survival protein BCL-XL, ultimately culminating in cellular senescence. UNITY is developing senolytic medicines (UBX1325) to eliminate senescent cells to restore tissue health [12] . Focused on novel treatment paradigms, elimination of vascular senescent cells by BCL-XL inhibitor or PROTAC should re-establish barrier function and reverse disease progression in DME and AMD patients. BCL-XL inhibitor or PROTAC targets a node upstream of anti-VEGF therapies. Targeting senescence effector/anti-apoptotic protein BCL-XL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization.
BRIEF SUMMARY OF THE INVENTION
Provided herein are compounds which target Bcl-xL proteins for ubiquitination and proteasomal degradation. Also provided herein are methods for using said compounds for the treatment of diseases.
One embodiment provides a compound, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-A) :
wherein,
o is 0, 1, 2 or 3;
Y is S or CH=CH;
each R1 is independently selected from halogen, nitro, cyano, -OR2, -N (R2) 2, -SR2, -S (O) R2, -S (O) 2R2, -S (O) 2N (R2) 2, -NR2S (O) 2R2, -NR2S (O) 2N (R2) 2, -C (O) R2, -C (O) OR2, -OC (O) R2, -OC (O) OR2, -OC (O) N (R2) 2, -NR2C (O) R2, -NR2C (O) OR2, -NR2C (O) N (R2) 2, -C (O) N (R2) 2, -P (O) (OR2) 2, -P (O) (R2) 2, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkyl wherein 1 to 2 -CH2-units are replaced with N, O, or S provided that two adjacent-CH2-units are not both replaced, optionally substituted C3-12 carbocyclyl, and optionally substituted 3-to 12-membered heterocyclyl;
each R2 is each independently hydrogen or optionally substituted C1-6 alkyl; or
two R2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring;
V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C3-7 cycloalkyl, or an optionally substituted heterocyclyl; or
is taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1;
L is selected from a) C2-C15 alkylene, b) C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent, or c) -Ak1-Z1-Ak2-Z2-Ak3-*;
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is selected from 0 to 6;
each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or
R3 and R4 together form an oxo group;
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene; and
U is a recruitment motif selected from a VHL ligand.
One embodiment provides a pharmaceutical composition comprising a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable excipient.
One embodiment provides a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof for use in a method of treatment of a human or animal.
One embodiment provides a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treatment of cancer or neoplastic disease.
One embodiment provides the use of a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-A) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
FIG. 1 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
FIG. 2 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
FIG. 3 displays the tumor volume over time in a mouse xenograft model of upon treatment with a compound disclosed herein.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
As used herein and in the appended claims, the singular forms "a, " "an, " and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error) , and thus the number or numerical range, in some instances, will vary between 1%and 15%of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including" ) are inclusive or open-ended and do not exclude additional, unrecited elements.
Definitions
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
"Amino" refers to the –NH2 radical.
"Cyano" refers to the -CN radical.
"Nitro" refers to the -NO2 radical.
"Oxa" refers to the -O-radical.
"Oxo" refers to the =O radical.
"Thioxo" refers to the =S radical.
"Imino" refers to the =N-H radical.
"Oximo" refers to the =N-OH radical.
"Hydrazino" refers to the =N-NH2 radical.
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl) . In certain embodiments, an alkyl comprises one to thirteen carbon
atoms (e.g., C1-C13 alkyl) . In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl) . In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkyl) . In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl) . In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl) . In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl) . In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl) . In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl) . In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl) . In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl) . In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl) . In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl) . In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl) , 1-methylethyl (iso-propyl) , 1-butyl (n-butyl) , 1-methylpropyl (sec-butyl) , 2-methylpropyl (iso-butyl) , 1, 1-dimethylethyl (tert-butyl) , 1-pentyl (n-pentyl) . The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain radical as defined above.
"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The
alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene) . In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkylene) . In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene) . In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene) . In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene) . In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene) . In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene) . In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene) . In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene) . In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene) . Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene) . In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene) . In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene) . In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene) . In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene) . In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene) . In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene) . Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene) . In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene) . In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene) . In other embodiments,
an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene) . In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene) . In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene) . In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene) . Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC (O) -Ra, -N (Ra) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, -N (Ra) C (O) ORa, -OC (O) -N (Ra) 2, -N (Ra) C (O) Ra, -N (Ra) S (O) tRa (where t is 1 or 2) , -S (O) tORa (where t is 1 or 2) , -S (O) tRa (where t is 1 or 2) and -S (O) tN (Ra) 2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) .
"Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl" ) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC (O) -Ra, -Rb-OC (O) -ORa, -Rb-OC (O) -N (Ra) 2, -Rb-N (Ra) 2, -Rb-C (O) Ra, -Rb-C (O) ORa, -Rb-C (O) N (Ra) 2, -Rb-O-Rc-C (O) N (Ra) 2, -Rb-N (Ra) C (O) ORa, -Rb-N (Ra) C (O) Ra, -Rb-N (Ra) S (O) tRa (where t is 1 or 2) , -
Rb-S (O) tRa (where t is 1 or 2) , -Rb-S (O) tORa (where t is 1 or 2) and -Rb-S (O) tN (Ra) 2 (where t is 1 or 2) , where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
"Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
"Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
"Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
"Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
"Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spirocyclic ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single
bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds) . A fully saturated carbocyclyl radical is also referred to as "cycloalkyl. " Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl. " Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Spirocyclic carbocyclyl or cycloalkyl radicals include, for example, spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane, spiro [2.6] nonane, spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] nonane, spiro [3.6] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [4.6] undecane, spiro [5.5] undecane, spiro [5.6] dodecane, spiro [6.6] tridecane, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC (O) -Ra, -Rb-OC (O) -ORa, -Rb-OC (O) -N (Ra) 2, -Rb-N (Ra) 2, -Rb-C (O) Ra, -Rb-C (O) ORa, -Rb-C (O) N (Ra) 2, -Rb-O-Rc-C (O) N (Ra) 2, -Rb-N (Ra) C (O) ORa, -Rb-N (Ra) C (O) Ra, -Rb-N (Ra) S (O) tRa (where t is 1 or 2) , -Rb-S (O) tRa (where t is 1 or 2) , -Rb-S (O) tORa (where t is 1 or 2) and -Rb-S (O) tN (Ra) 2 (where t is 1 or 2) , where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Cycloalkylene” refers to a divalent carbocyclyl or cycloalkyl linking the rest of the molecule to a radical group.
"Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
"Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
"Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,
and the like.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
"Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
"Heterocyclyl" refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic, ring system, which optionally includes fused, bridged, or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) . Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl, 1-azaspiro [2.2] pentane, 1-azaspiro [2.3] hexane, 1-azaspiro [2.4] heptane, 1-azaspiro [2.5] octane, 1-azaspiro [2.6] nonane, 2-azaspiro [3.3] heptane, 2-azaspiro [3.4] octane, 2-azaspiro [3.5] nonane, 2-azaspiro [3.6] decane, 2-azaspiro [4.4] nonane, 2-azaspiro [4.5] decane, 2-azaspiro [4.6] undecane, 3-azaspiro [5.5] undecane, 3-azaspiro [5.6] dodecane, 3-azaspiro [6.6] tridecane, 5-azaspiro [2.3] hexane, 5-azaspiro [2.4] heptane, 6-azaspiro [2.5] octane, 6-azaspiro [2.6] nonane, 6-azaspiro [3.4] octane, 7-azaspiro [3.5] nonane, 7-azaspiro [3.6] decane, 8-azaspiro [4.5] decane, 8-azaspiro [4.6] undecane, 9-azaspiro [5.6] dodecane, 1, 4-diazaspiro [2.2] pentane, 1, 5-diazaspiro [2.3] hexane, 1, 5-diazaspiro [2.4] heptane, 1, 6-diazaspiro [2.5] octane, 1, 6-diazaspiro [2.6] nonane, 2, 6-diazaspiro [3.3] heptane, 2, 6-diazaspiro [3.4] octane, 2, 7-diazaspiro [3.5] nonane, 2, 7-diazaspiro [3.6] decane, 2, 7-diazaspiro [4.4] nonane, 2, 8-diazaspiro [4.5] decane, 2, 8-diazaspiro [4.6] undecane, 3, 9-diazaspiro [5.5] undecane, 3, 9-diazaspiro [5.6] dodecane, and 3, 10-diazaspiro [6.6] tridecane. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC (O) -Ra, -Rb-OC (O) -ORa, -Rb-OC (O) -N (Ra) 2, -Rb-N (Ra) 2, -Rb-C (O) Ra, -Rb-C (O) ORa, -Rb-C (O) N (Ra) 2, -Rb-O-Rc-C (O) N (Ra) 2, -Rb-N (Ra) C (O) ORa, -Rb-N (Ra) C (O) Ra, -Rb-N (Ra) S (O) tRa (where t is 1 or 2) , -Rb-S (O) tRa (where t is 1 or 2) , -Rb-S (O) tORa (where t is 1 or 2) and -Rb-S (O) tN (Ra) 2 (where t is 1 or 2) , where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, –CH2-O-CH2-, –CH2-N (alkyl) -CH2-, –CH2-N (aryl) -CH2-, -OCH2CH2O-, –OCH2CH2OCH2CH2O-, or –OCH2CH2OCH2CH2OCH2CH2O-. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocyclene” refers to a divalent heterocyclyl linking the rest of the molecule to a radical group.
"N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
"C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.
"Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
"Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
"Heteroaryl" refers to a radical derived from a 3-to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom (s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring (s) . Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzothieno [3, 2-d] pyrimidinyl, benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6, 7-dihydro-5H-cyclopenta [4, 5] thieno [2, 3-d] pyrimidinyl, 5, 6-dihydrobenzo [h] quinazolinyl, 5, 6-dihydrobenzo [h] cinnolinyl, 6, 7-dihydro-5H-benzo [6, 7] cyclohepta [1, 2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo [3, 2-c] pyridinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyrimidinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyridazinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5, 8-methano-5, 6, 7, 8-tetrahydroquinazolinyl, naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5, 6, 6a, 7, 8, 9, 10, 10a-octahydrobenzo [h] quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo [3, 4-d] pyrimidinyl, pyridinyl, pyrido [3, 2-d] pyrimidinyl, pyrido [3, 4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroquinazolinyl, 5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d] pyrimidinyl, 6, 7, 8, 9-tetrahydro-5H-cyclohepta [4, 5] thieno [2, 3-d] pyrimidinyl, 5, 6, 7, 8-tetrahydropyrido [4, 5-c] pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno [2, 3-d] pyrimidinyl, thieno [3, 2-d] pyrimidinyl, thieno [2, 3-c] pridinyl, and thiophenyl (i.e. thienyl) . Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC (O) -Ra, -Rb-OC (O) -ORa, -Rb-OC (O) -N (Ra) 2, -Rb-N (Ra) 2, -Rb-C (O) Ra, -Rb-C (O) ORa, -Rb-C (O) N (Ra) 2, -Rb-O-Rc-C (O) N (Ra) 2, -Rb-N (Ra) C (O) ORa, -Rb-N (Ra) C (O) Ra, -Rb-N (Ra) S (O) tRa (where t is 1 or 2) , -Rb-S (O) tRa (where t is 1 or 2) , -Rb-S (O) tORa (where t is 1 or 2) and -Rb-S (O) tN (Ra) 2 (where t is 1 or 2) , where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
"N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
"C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
"Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
"Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) -or (S) -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. ) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
In the embodiments of the present disclosure, in the case when a cyclohexyl or cyclobutyl has a set of para-substituted substituents, and the two carbon atoms on the cyclohexyl or cyclobutyl are connected to the set of para-substituted substituents are not chiral centers, the chemical bond notation in formonly means that the two chemical bonds connected to the set of para-substituted substituents are in trans or cis structure relative to the cyclohexyl or cyclobutyl group. Therefore, the compounds represented by exchanging these two chemical bondswith each other, or the compounds represented by switching combo
to combo (or vice versa) , also fall within the scope of the present disclosure.
A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C-or 14C-enriched carbon are within the scope of the present disclosure.
The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H) , tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N,
15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 125I are all contemplated. In some embodiments, isotopic substitution with 18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I) , are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4) , are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.
Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
"Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heteroaromatic Bcl-xL inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,
and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts, " Journal of Pharmaceutical Science, 66: 1-19 (1997) ) . Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
"Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
"Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
"Prodrug" refers to a compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized protective groups used in a transient manner to alter pharmacological properties in the parent molecule.
As used herein, “treatment” or “treating, ” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. Bcl-xL
The BCL-2 (B-cell lymphoma-2) family of proteins serve as key regulators of the mitochondrial pathway of cellular apoptosis, and consists of both anti-apoptotic proteins such as BCL-2, BCL-XL, BCL-W, A1, and MCL-1, and pro-apoptotic proteins such as Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, and Puma. Pro-apoptotic and anti-apoptotic BCL-2 proteins normally function in opposition to each other. Blocking the interactions between them, either by treatment with a small molecule or by RNA interference, leads to mitochondria outer membrane permeabilization (MOMP) and the release of cytochrome c, second mitochondria-derived activator of caspases (SMAC) , and other pro-apoptotic factors. These events then trigger the caspase activation cascade and subsequent cellular apoptosis.
BCL-XL belong to the anti-apoptotic BCL-2 protein family and play an important role in promoting tumor initiation, progression, and development of drug resistance by protecting tumor cells from apoptosis. Inhibition of these BCL-2 family proteins with small molecule inhibitors has been extensively investigated as a therapeutic strategy for cancers. Retinal vasculopathies account for the primary causes of loss of sight in the industrialized world and current standards do not fully address these diseases. Senescent cells affect the tissue microenvironment to drive disease progression in senescence-associated models of retinopathy, such as age-related macular
degeneration (AMD) and diabetic macular edema (DME) . UNITY provide evidence that as pathological pre-retinal neovascularization forms, cells of the vascular unit rapidly engage pathways leading to p16INK4A activation and upregulation of pro-survival protein BCL-XL, ultimately culminating in cellular senescence. UNITY is developing senolytic medicines (UBX1325) to eliminate senescent cells to restore tissue health. Focused on novel treatment paradigms, elimination of vascular senescent cells by BCL-XL inhibitor or PROTAC should re-establish barrier function and reverse disease progression in DME and AMD patients. BCL-XL inhibitor or PROTAC targets a node upstream of anti-VEGF therapies. Targeting senescence effector/anti-apoptotic protein BCL-XL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization.
Additional information may be found in a) J Kale, EJ Osterlund, and DW Andrews. BCL-2 family proteins: changing partners in the dance towards death. Cell Death &Differentiation. 2018; 25: 65-80 [13] , b) M Stevens and S Oltean. Modulation of the Apoptosis Gene Bcl-x Function Through Alternative Splicing. Front. Genet. 2019 Sept 6; 10 (804) [14] and c) LP Billen, CL Kokoski, JF Lovell, B Leber, and DW Andrews. Bcl-XL Inhibits Membrane Permeabilization by Competing with Bax. PLoS Biology. 2008 June 10; 6 (6) : e147 [15] , each of which is incorporated herein by reference.
Selective Protein Degradation
The levels of proteins within a cell are determined by both the rate of protein synthesis and the rate of protein degradation. In eukaryotic cells two pathways exist for selective protein degradation, the ubiquitin-proteasome pathway and the lysosomal proteolysis pathway. In general, selective protein degradation is mediated by the presence of a recruitment motif which promotes binding of degradation proteins, such as proteasomal degradation proteins, or proteins associated with ubiquitin-proteasome pathway. Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents. Conjugation of recruitment motifs with high affinity ligands for Bcl-xL provides compounds capable of selectively directing pathways for protein degradation to the Bcl-xL protein itself. Such an outcome will reduce levels of Bcl-xL activity.
Heteroaromatic Bcl-xL degradation compounds
In one aspect, provided herein is a heteroaromatic Bcl-xL degradation compound having the general formula provided below:
wherein the Bcl-xL affinity motif is a molecular construct having high affinity for the Bcl-xL protein independent of the linking motif and/or the recruitment motif, the linking motif is a molecular construct providing a covalent bond to both the Bcl-xL affinity motif and the recruitment motif, and the recruitment motif is a molecular construct having the ability to selectively target and recruit protein degradation. In some embodiments, the heteroaromatic Bcl-xL degradation compound has the structure of Formula (I-A) :
wherein Y is S or CH=CH, L is the linking motif and U is the recruitment motif.
Recruitment motif
Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents. In some embodiments the recruitment motif is derived from, VHL ligand, nutlin, bestatin, HIF-1α –VHL binding peptide, hydroxy proline-HIF-1α-VHL binding peptide, SCFb-TRCP targeting peptide or an inhibitor of apoptosis protein ligand.
In some embodiments, the recruitment motif (for example, U in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) ) is selected from a molecular construct related to a VHL ligand. In some embodiments, the recruitment motif or the VHL ligand has a structure selected from:
with the point of bonding to the linking motif as indicated by the wavy bond. In some embodiments, the recruitment motif is selected from:
In some embodiments, the recruitment motif is
In some embodiments, the recruitment motif is In some embodiments, the recruitment motif is
The terms “VHL ligand” , “VHL binder” , and “VHL E3 ubiquitin ligase binder” are used herein interchangeably to refer to a compound or motif that binds Von Hippel–Lindau tumor suppressor (VHL) .
Linking Motif
The linking motif is a molecular construct providing a covalent bond to both the Bcl-xL affinity motif and the recruitment motif. In some embodiments, the linking motif comprises a cyclic moiety. In some embodiments, the linking motif comprises an acyclic moiety. In some embodiments, the linking motif comprises an unsaturated moiety. In some embodiments, the linking motif comprises between 4 and 50 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 4 and 20 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 4 and 25 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 4 and 30 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 6 and 18 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises between 5 and 10 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
or 20 non-hydrogen atoms in a linear sequence. As an example, the following molecular fragment contains 8 non-hydrogen atoms in a linear sequence:
In some embodiments, the linking motif, for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is selected from a) C2-C15 alkylene, b) C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent, or c) -Ak1-Z1-Ak2-Z2-Ak3-*;
wherein,
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is selected from 0 to 6;
each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or
R3 and R4 together form an oxo group; and
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene;
wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene.
In some embodiments, the linking motif, for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is selected from C2-C15 alkylene. In some embodiments, the linking motif is C4-15 alkylene. In some embodiments, the linking motif is C4-9 alkylene. In some embodiments, the linking motif is C5-8 alkylene.
In some embodiments, the linking motif, for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is C2-
15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent. In some embodiments, the linking motif has the structure – (CR3R4) x-O– (CR3R4) y-*, wherein: each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or R3 and R4 together form an oxo group; and x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14. In some embodiments, the linking motif has the structure – (CH2) x-O– (CH2) y-*, wherein: x is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; y is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14. In some embodiments, x is 0 to 7 and y is 1 to 7. In some embodiments, x is 0 to 6 and y is 1 to 6. In some embodiments, the linking motif is C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent having a structure selected from
In some embodiments, the linking motif, for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is C2-
15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent. In some embodiments, the linking motif has the structure – (CR3R4) j-O– (CR3R4) p-O– (CH2) v-*, wherein: each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or R3 and R4 together form an oxo group; j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of j, p, and v is not more than 13. In some embodiments, the linking motif has the structure – (CH2) j-O– (CH2) p-O– (CH2) v-*, wherein: j is selected from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; p is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; v is selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of j, p, and v is not more than 13. In some embodiments, j is 0 to 4; p is 1 to 5; and v is 1 to 4. In some embodiments, j is 0 to 2; p is 2 to 4; and v is 1 to 3. In some embodiments, the linking motif is C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent having a structure selected from
In some embodiments, the linking motif, for example L in Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-
E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , is represented by the following formula:
-Ak1-Z1-Ak2-Z2-Ak3-*
wherein,
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is selected from 0 to 6;
R3 and R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or R3 and R4 are taken together to form an oxo group;
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene, wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene; and
the point of bonding to the VHL ligand is indicated by the asterisk.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
X, X1 and X2 at each instance are independently CH or N;
k is 0 to 6;
m is 0 to 6;
n is 0 to 6; and
wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, k is 0 to 3. In some embodiments, m is 0 to 3. In some embodiments, n is 0 to 2. In some embodiments, k is 0 to 3, m is 0 to 3, and n is 0 to 2. In some embodimens, each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl In some embodiments, each R3 and R4 is independently selected from hydrogen, halogen, and C1-3 alkyl. In some embodiments, each R3 and R4 is independently selected from hydrogen, fluoro, and -CH3. In some embodiments, R3 and R4 are both hydrogen.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
X, X1 and X2 at each instance are independently CH or N;
k is 0 to 6;
m is 0 to 6;
n is 0 to 6; and
wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, m is 0 to 3. In some embodiments, n is 0 to 2. In some embodiments, k is 0 to 3, m is 0 to 3, and n is 0 to 2.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
X, X1 and X2 at each instance are independently CH or N;
k is 0 to 6;
m is 0 to 6;
n is 0 to 6; and
wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, m is 0 to 3. In some embodiments, n is 0 to 2. In some embodiments, k is 0 to 3, m is 0 to 3, and n is 0 to 2.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
wherein the point of bonding to the VHL ligand is indicated by the asterisk.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
X1, X2, X3, and X4 at each instance are independently CH or N;
k is 0 to 6;
m is 0 to 6;
n is 0 to 6; and
wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is 0 to 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is 0 to 2. In some embodiments, each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, each R3 and R4 is independently selected from
hydrogen, halogen, and C1-3 alkyl. In some embodiments, each R3 and R4 is independently selected from hydrogen, fluoro, and -CH3. In some embodiments, R3 and R4 are both hydrogen.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
X1, X2, X3, and X4 at each instance are independently CH or N;
k is 0 to 6;
m is 0 to 6;
n is 0 to 6; and
wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is 0 to 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is 0 to 2.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , or Formula (I-H) , L is -Ak1-Z1-Ak2-Z2-Ak3-*selected from a molecular fragment illustrated below:
wherein the point of bonding to the VHL ligand is indicated by the asterisk.
Bcl-xL Affinity Motif
A-1155463 is a potent Bcl-xL binder with a Ki of <0.01 nM in a TR-FRET assay as described in Tao et al., “Discovery of a Potent and Selective BCL-XL Inhibitor with In Vivo Activity” ACS Med. Chem. Lett. 2014. DOI: 10.1021/ml5001867 [16] which is incorporated herein by reference.
Heteroaromatic Bcl-xL degradation compounds
In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-A) :
wherein,
o is 0, 1, 2 or 3;
Y is S or CH=CH;
each R1 is independently selected from halogen, nitro, cyano, -OR2, -N (R2) 2, -SR2, -S (O) R2, -S (O) 2R2, -S (O) 2N (R2) 2, -NR2S (O) 2R2, -NR2S (O) 2N (R2) 2, -C (O) R2, -C (O) OR2, -OC (O) R2, -OC (O) OR2, -OC (O) N (R2) 2, -NR2C (O) R2, -NR2C (O) OR2, -NR2C (O) N (R2) 2, -C (O) N (R2) 2, -P (O) (OR2) 2, -P (O) (R2) 2, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkyl wherein 1 to 2 -CH2-units are replaced with N, O, or S provided that two adjacent-CH2-units are not both replaced, optionally substituted C3-12 carbocyclyl, and optionally substituted 3-to 12-membered heterocyclyl;
each R2 is each independently hydrogen or optionally substituted C1-6 alkyl; or
two R2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring;
V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C3-7 cycloalkyl, or an optionally substituted heterocyclyl; or
is taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1;
L is selected from a) C2-C15 alkylene, b) C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent, and c) -Ak1-Z1-Ak2-Z2-Ak3-*;
wherein,
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is 0 to 6;
each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or
R3 and R4 together form an oxo group;
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene; and
U is a VHL ligand.
In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-A) :
wherein,
o is 0, 1, 2 or 3;
Y is S or CH=CH;
each R1 is independently selected from halogen, nitro, cyano, -OR2, -N (R2) 2, -SR2, -S (O) R2, -S (O) 2R2, -S (O) 2N (R2) 2, -NR2S (O) 2R2, -NR2S (O) 2N (R2) 2, -C (O) R2, -C (O) OR2, -OC (O) R2, -OC (O) OR2, -OC (O) N (R2) 2, -NR2C (O) R2, -NR2C (O) OR2, -NR2C (O) N (R2) 2, -C (O) N (R2) 2, -P (O) (OR2) 2, -P (O) (R2) 2, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkyl wherein 1 to 2 -CH2-units are replaced with N, O, or S provided that two adjacent-CH2-units are not both replaced, optionally substituted C3-12 carbocyclyl, and optionally substituted 3-to 12-membered heterocyclyl, wherein the alkyl, alkoxy, carbocyclyl, and heterocyclyl are independently optionally substituted with one or more Re;
each R2 is independently hydrogen or optionally substituted C1-6 alkyl, wherein the alkyl is optionally substituted with one or more Re; or
two R2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more Re;
each Re is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or
two Re attached to the same atom are taken together to form an oxo.
V is a bond. -C≡C-, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C3-7 cycloalkyl, or optionally substituted heterocyclyl,
wherein the heteroaryl, aryl, cycloalkyl, or heterocyclyl are optionally substituted with one or more RV; or
is taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1; and
each RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or
two RV attached to the same atom of a cycloalkyl or heterocyclyl are taken together to form an oxo;
L is selected from a) C2-C15 alkylene, b) C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent, and c) -Ak1-Z1-Ak2-Z2-Ak3-*;
wherein,
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is selected from 0 to 6;
each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or
R3 and R4 together form an oxo group;
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene; and
U is a VHL ligand.
In some embodiments, provided herein is a compound of Formula (I-A) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, Y is S. In some other embodiments, Y is CH=CH.
In some embodiments, each R1 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-3 alkoxy, halogen, -N (R2) 2, -OR2, and cyano, wherein the alkyl, haloalkyl, and alkoxy are each independently optionally substituted. In some embodiments, each R1 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-3 alkoxy, -N (R2) 2, -OR2,
and cyano, wherein the alkyl, haloalkyl, and alkoxy are each independently optionally substituted. In some embodiments, the alkyl, haloalkyl, and alkoxy are each independently optionally substituted with one or more Re. In some embodiments, each R1 is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R1 is independently selected from -F, -Cl, -CH3, -CH2CH3, and -CF3. In some embodiments, each R1 is independently selected from -Cl, -CH3, and -CF3. In some embodiments, each Re is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two Re attached to the same atom are taken together to form an oxo.
In some embodiments, V is a bond. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-B) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH.
In some embodiments, provided herein is a compound of Formula (I-B) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, V is an optionally substituted heteroaryl. In some embodiments, V is an optionally substituted N-containing heteroaryl. In some embodiments, V is an optionally substituted N-containing 5-or 6-membered heteroaryl. In some embodiments, V is an optionally substituted N-containing 6-membered heteroaryl selected from pyridinyl, pyrimidnyl, and pyridazinyl. In some embodiments, V is an optionally substituted N-containing 5-membered heteroaryl selected from pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, and oxadiazolyl. In some embodiments, V is a an optionally substituted N-containing heteroaryl selected from pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, and pyrimidinyl. In some embodiments, the heteroaryl is optionally substituted with one or more RV, and each RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6
aminoalkyl, and C1-C6 heteroalkyl. In some embodiments, each RV is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each RV is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V is
wherein the asterisk indicates the point of attachment to L. In some embodiments, V isIn some embodiments, V is
In some embodiments, V is
In some embodiments, V is
wherein the asterisk indicates the point of attachment to L. In some embodiments, V is
wherein the asterisk indicates the point of attachment to L.
In some embodiments, V is an optionally substituted aryl. In some embodiments, V is an optionally substituted phenyl or naphthyl. In some embodiments, V is an optionally substituted phenyl. In some embodiments, V is an optionally substituted naphthyl. In some embodiments, V is phenyl optionally substituted with one or more RV, and each RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl. In some embodiments, each RV is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each RV is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V iswherein the asterisk indicates the point of attachment to L. In some embodiments, V isIn
some embodiments, V iswherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-C) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-C1) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-C2) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-C2) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, V is an optionally substituted cycloalkyl. In some embodiments, V is an optionally substituted C3-7 cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted. In some embodiments, V is optionally substituted with one or more RV, and each RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl,
and C1-C6 heteroalkyl; or two RV attached to the same atom are taken together to form an oxo. In some embodiments, each RV is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each RV is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V is
wherein the asterisk indicates the point of attachment to L. In some embodiments, V is In some embodiments, V isIn some embodiments, V iswherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-D1) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-D1) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-D2) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-D2) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, V is an optionally substituted heterocyclyl. In some embodiments, V is an optionally substituted N-containing heterocyclyl. In some embodiments, V is pyrrolidinyl, piperazinyl, piperidinyl, or morpholino, each of which is optionally substituted. In some embodiments, V is optionally substituted with one or more RV, and each RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two RV attached to the same atom are taken together to form an oxo. In some embodiments, each RV is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl. In some embodiments, each RV is independently hydrogen, -Cl, -F, or -CF3. In some embodiments, V is
wherein the asterisk indicates the point of attachment to L. In some embodiments, V isIn some embodiments, V iswherein the asterisk indicates the point of attachment to L. In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-E1a) or Formula (I-E1b) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-E1a) or Formula (I-E1b) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-E2a) or Formula (I-E2b) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-E1a) or Formula (I-E1b) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, V is -C≡C-. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-F) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-F) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, is taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring each of which is substituted with o instances of R1. In some embodiments, is taken together to form a fused bicyclic aryl ring substituted with o instances of R1. In some embodiments, the fused bicyclic aryl ring is a naphthyl substituted with o instances of R1. In some embodiments, is
wherein the asterisk indicates the point of attachment to L. In some embodiments, isIn some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-G) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-G) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, is taken together to form a fused bicyclic heteroaryl ring substituted with o instances of R1. In some embodiments, the fused bicyclic heteroaryl ring is an N-containing bicyclic heteroaryl ring substituted with o instances of R1. In some embodiments, the fused bicyclic heteroaryl ring is a quinolinyl, an isoquinolinyl, a cinnolinyl, a quinazolinyl, a quinoxalinyl, or an indolyl, each of which is substituted with o instances of R1. In some embodiments, the fused bicyclic heteroaryl ring is a quinolinyl or an isoquinolinyl, each of which is substituted with o instances of R1. In some embodiments,
wherein the asterisk indicates the point of attachment to L. In some embodiments, is
In some embodiments, isIn some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-H) :
wherein Y is S or CH=CH. In some embodiments, Y is S. In some embodiments, Y is CH=CH. In some embodiments, provided herein is a compound of Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , L is C2-C15 alkylene. In some embodiments, L is C2-C15 alkylene. In some embodiments, L is C3-15 alkylene. In some embodiments, L is C4-15 alkylene. In some embodiments, L is C5-15 alkylene. In some embodiments, L is C6-15 alkylene. In some embodiments, L is C7-15 alkylene. In some embodiments, L is C8-15 alkylene. In some embodiments, L is C9-15 alkylene. In some embodiments, L is C10-15 alkylene. In some embodiments, L is C11-15 alkylene. In some embodiments, L is C12-15 alkylene. In some embodiments, L is C13-15 alkylene. In some embodiments, L is C14-15 alkylene. In some embodiments, L is C2-14 alkylene. In some embodiments, L is C2-13 alkylene. In some embodiments, L is C2-13 alkylene. In some embodiments, L is C2-12 alkylene. In some embodiments, L is C2-11 alkylene. In some embodiments, L is C2-10 alkylene. In some embodiments, L is C2-9 alkylene. In some embodiments, L is C2-8 alkylene. In some embodiments, L is C2-7 alkylene. In some embodiments, L is C2-8 alkylene. In some embodiments, L is C2-7 alkylene. In some embodiments, L is C2-6 alkylene. In some embodiments, L is C2-5 alkylene. In some embodiments, L is C2-4 alkylene. In some embodiments, L is C2-3 alkylene. In some embodiments, L is C3-8 alkylene. In some embodiments, L is C4-9 alkylene. In some embodiments, L is C5-10 alkylene. In some embodiments, L is C6-11 alkylene. In some
embodiments, L is C7-12 alkylene. In some embodiments, L is C8-13 alkylene. In some embodiments, L is C9-14 alkylene. In some embodiments, L is C5-8 alkylene. In some embodiments, L is C2-4 alkylene. In some embodiments, L is C2 alkylene. In some embodiments, L is C3 alkylene. In some embodiments, L is C4 alkylene. In some embodiments, L is C5 alkylene. In some embodiments, L is C6 alkylene. In some embodiments, L is C7 alkylene. In some embodiments, L is C8 alkylene. In some embodiments, L is C9 alkylene. In some embodiments, L is C10 alkylene. In some embodiments, L is C11 alkylene. In some embodiments, L is C12 alkylene. In some embodiments, L is C13 alkylene. In some embodiments, L is C14 alkylene. In some embodiments, L is C15 alkylene. In some embodiments, each carbon atom of the alkylene is independently optionally substituted with R3 and R4 (e.g., (CR3R4) 2-15) , and each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl, or R3 and R4 together on the same carbon atom form an oxo group. In some embodiments, the alkylene is unsubstituted.
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , L is C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent. In some embodiments, L is C3-8 alkylene wherein one or more -CH2-units are replaced with O. In some embodiments, L is C4-9 alkylene wherein one or more -CH2-units are replaced with O. In some embodiments, L is C5-8 alkylene wherein one or more -CH2-units are replaced with O. In some embodiments, each carbon atom of the alkylene is independently optionally substituted with R3 and R4 (e.g., (CR3R4) 2-15) , and each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl, or R3 and R4 together on the same carbon atom form an oxo group. In some embodiments, the alkylene is unsubstituted. In some embodiments, L is C2-15 alkylene wherein one -CH2-unit is replaced with O. In some embodiments, L is C2-15 alkylene wherein one -CH2-unit is replaced with O having the structure – (CR3R4) x-O– (CR3R4) y-*wherein: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14. In some embodiments, L is C2-15 alkylene wherein one -CH2-unit is replaced with O having the structure – (CH2) x-O– (CH2) y-*wherein: x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of x and y is not more than 14. In some embodiments, x is 0 to 9 and y is 1 to 10. In some embodiments, x is 0 to 8 and y is 1 to 10. In some embodiments, x is 0 to 7 and y is 1 to 10. In some embodiments, x is 0 to 6 and y is 1 to 10. In some embodiments, x is 0 to 10 and y is 1 to 9. In some embodiments, x is 0
to 10 and y is 1 to 8. In some embodiments, x is 0 to 10 and y is 1 to 7. In some embodiments, x is 0 to 10 and y is 1 to 6. In some embodiments, x is 0 to 7 and y is 1 to 7. In some embodiments, x is 0 to 6 and y is 1 to 7. In some embodiments, x is 0 to 7 and y is 1 to 6. In some embodiments, x is 0 to 6 and y is 1 to 6. In some embodiments, L has a structure selected from
In some embodiments, L is C4-15 alkylene wherein two -CH2-units are replaced with O. In some embodiments, L is C4-15 alkylene wherein two -CH2-units are replaced with O having the structure – (CR3R4) j-O– (CR3R4) p-O– (CR3R4) v-*wherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of p, j, and v is not more than 13. In some embodiments, L is C4-15 alkylene wherein two -CH2-units are replaced with O having the structure – (CH2) j-O– (CH2) p-O– (CH2) v-*wherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; v is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the point of bonding to the recruitment motif indicated by the asterisk; and wherein the sum of p, j, and v is not more than 13. In some embodiments, j is 0 to 10, p is 1 to 10, and v is 1 to 10. In some embodiments, j is 0 to 10, p is 1 to 5, and v is 1 to 10. In some embodiments, j is 0 to 10, p is 1 to 10, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 10, and v is 1 to 10. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 10. In some embodiments, j is 0 to 4, p is 1 to 10, and v is 1 to 4. In some embodiments, j is 0 to 10, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 2 to 4, and v is 1 to 4. In some embodiments, j is 0 to 4, p is 1 to 5, and v is 1 to 3. In some embodiments, j is 0 to 4, p is 2 to 4, and v is 1 to 3. In some embodiments, j is 0 to 2, p is 1 to 5, and v is 1 to 4. In some embodiments, j is 0 to 2, p is 2 to 4, and v is 1 to 4. In some embodiments, j is 0 to 2, p is 1 to 5, and v is 1 to 3. In some embodiments, j is 0 to 2, p is 2 to 4, and v is 1 to 3. In some embodiments, L has a structure selected from
In some embodiments of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , L has the structure
-Ak1-Z1-Ak2-Z2-Ak3-*;
wherein,
Ak1 is selected from - (CR3R4) k-;
Ak2 is selected from - (CR3R4) m-;
Ak3 is selected from - (CR3R4) n-;
each of k, m, and n is 0 to 6;
each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; or R3 and R4 together form an oxo group;
Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene; and
wherein the point of bonding to U is indicated by the asterisk.
In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, hydroxyl, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R3 and R4 are both hydrogen. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from: wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, k is 0, 1, 2, or 3. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, k is 0, 1, 2, or 3, m is 0, 1, 2, or 3, and n is 0, 1, or 2. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
and wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, - Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1- Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is selected from In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is,
wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from: wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1, 2, 3, 4, 5, or 6, each m is independently 0, 1, 2, 3, 4, 5, or 6, and each n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, k is 0, 1, 2, or 3. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, k is 0, 1, 2, or 3, m is 0, 1, 2, or 3, and n is 0, 1, or 2. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
and wherein the point of bonding to the VHL ligand is indicated by the asterisk. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, - Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1- Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is selected from In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is,
In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
X1, X2, X3, and X4 at each instance are independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and wherein the point of bonding to U is indicated by the asterisk. In some embodiments, k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, hydroxyl, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, halogen, C1-3 alkyl, and C3 cycloalkyl. In some embodiments, R3 and R4 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R3 and R4 are both hydrogen. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
X1, X2, X3, and X4 at each instance are independently CH or N; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and wherein the point of bonding to U is indicated by the asterisk. In some embodiments, k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. In some embodiments, k is 0 or 1. In some embodiments, m is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, k is 0 or 1, m is 0 or 1, and n is 0 to 2. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*has a structure selected from:
wherein the point of bonding to U is indicated by the asterisk. In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn
some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is andIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*isIn some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is,
In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is,
In some embodiments, -Ak1-Z1-Ak2-Z2-Ak3-*is,
In some embodiments, the compounds as described herein have a structure provided in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. In some embodiments, the compounds as described herein have a structure provided in Table 1.
Table 1
In some embodiments, compounds as described herein has a structure provided in Table 2.
Table 2
In some embodiments, compounds as described herein has a structure provided in Table 3.
Table 3
In some embodiments, compounds as described herein has a structure provided in Table 4.
Table 4
In some embodiments, compounds as described herein has a structure provided in Table 5.
Table 5
In some embodiments, compounds as described herein has a structure provided in Table 6.
Table 6
In some embodiments, compounds as described herein has a structure provided in Table 7.
Table 7
Preparation of Compounds
The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA) , Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka) , Apin Chemicals Ltd. (Milton Park, UK) , Avocado Research (Lancashire, U.K. ) , BDH Inc. (Toronto, Canada) , Bionet (Cornwall, U.K. ) , Chemservice Inc. (West Chester, PA) , Crescent Chemical Co. (Hauppauge, NY) , Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY) , Fisher Scientific Co. (Pittsburgh, PA) , Fisons Chemicals (Leicestershire, UK) , Frontier Scientific (Logan, UT) , ICN Biomedicals, Inc. (Costa Mesa, CA) , Key Organics (Cornwall, U.K. ) , Lancaster Synthesis (Windham, NH) , Maybridge Chemical Co. Ltd. (Cornwall, U.K. ) , Parish Chemical Co. (Orem, UT) , Pfaltz & Bauer, Inc. (Waterbury, CN) , Polyorganix (Houston, TX) , Pierce Chemical Co. (Rockford, IL) , Riedel de Haen AG (Hanover, Germany) , Spectrum Quality Product, Inc.
(New Brunswick, NJ) , TCI America (Portland, OR) , Trans World Chemicals, Inc. (Rockville, MD) , and Wako Chemicals USA, Inc. (Richmond, VA) .
Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry" , John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations, " 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions" , 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry" , 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure" , 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials" , Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D. C. for more details) . Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of
pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts" , Verlag Helvetica Chimica Acta, Zurich, 2002.
Pharmaceutical Compositions
In certain embodiments, the heteroaromatic Bcl-xL degradation compound described herein is administered as a pure chemical. In other embodiments, the heteroaromatic Bcl-xL degradation compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005) ) .
Provided herein is a pharmaceutical composition comprising at least one heteroaromatic Bcl-xL degradation compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier (s) (or excipient (s) ) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof.
One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
In certain embodiments, the heteroaromatic Bcl-xL degradation compound as described by Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005) ) .
In some embodiments, the heteroaromatic Bcl-xL degradation compound as described by Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.
The dose of the composition comprising at least one heteroaromatic Bcl-xL degradation compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) . An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition (s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
Methods of Treatment
One embodiment provides a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
One embodiment provides a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
One embodiment provides a use of a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.
Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
In some embodiments, the compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
℃ degrees Celsius
δH chemical shift in parts per million downfield from tetramethylsilane
DCM dichloromethane (CH2Cl2)
DMF dimethylformamide
DMSO dimethylsulfoxide
EA ethyl acetate
ESI electrospray ionization
Et ethyl
g gram (s)
h hour (s)
HPLC high performance liquid chromatography
Hz hertz
J coupling constant (in NMR spectrometry)
LCMS liquid chromatography mass spectrometry
μ micro
m multiplet (spectral) ; meter (s) ; milli
M molar
M+ parent molecular ion
Me methyl
MHz megahertz
min minute (s)
mol mole (s) ; molecular (as in mol wt)
mL milliliter
MS mass spectrometry
nm nanometer (s)
NMR nuclear magnetic resonance
pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution
PE petroleum ether
RT room temperature
s singlet (spectral)
t triplet (spectral)
T temperature
TFA trifluoroacetic acid
THF tetrahydrofuran
DIEA diisopropylethyl amine
HATU O- (7-Azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate
℃ degrees Celsius
δH chemical shift in parts per million downfield from tetramethylsilane
DCM dichloromethane (CH2Cl2)
DMF dimethylformamide
DMSO dimethylsulfoxide
EA ethyl acetate
ESI electrospray ionization
Et ethyl
g gram (s)
h hour (s)
HPLC high performance liquid chromatography
Hz hertz
J coupling constant (in NMR spectrometry)
LCMS liquid chromatography mass spectrometry
μ micro
m multiplet (spectral) ; meter (s) ; milli
M molar
M+ parent molecular ion
Me methyl
MHz megahertz
min minute (s)
mol mole (s) ; molecular (as in mol wt)
mL milliliter
MS mass spectrometry
nm nanometer (s)
NMR nuclear magnetic resonance
pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution
PE petroleum ether
RT room temperature
s singlet (spectral)
t triplet (spectral)
T temperature
TFA trifluoroacetic acid
THF tetrahydrofuran
DIEA diisopropylethyl amine
HATU O- (7-Azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate
Example 1: Compound 1
Step A: methyl 9-oxononanoate
To a solution of 9-hydroxy pelargonic acid (2.00 g, 11.478 mmol) in MeOH (20 mL) was added AcCl (1 mL, 14.013 mmol) , the mixture was stirred at 25 ℃ for 1 hour. The resulting mixture was combined, then added DCM (40 mL) , molecular sieves (4A) (3 g) , PCC (3.5 g, 16.237 mmol) , the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was quenched with water (100 mL) . The resulting mixture was extracted with ethyl acetate (3*100 mL) . The organic layers were combined, watched with brine (4*100 mL) . The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford the methyl 9-oxononanoate.
Step B: methyl dec-9-ynoate
To a solution of methyl 9-oxononanoate (1.1 g, 5.91 mmol) in MeOH (20 mL) was added K2CO3 (1.63 g, 11.82 mmol) , dimethyl 1-diazo-2-oxopropylphosphonate (1.70 g, 8.859 mmol) . The resulting mixture was stirred at 25 ℃ overnight. The reaction was concentrated, then quenched with water (50 mL) . The resulting mixture was extracted with ethyl acetate (3 *50 mL) . The organic layers were combined and concentrated. The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford the methyl dec-9-ynoate.
Step C: 9-decynoic acid
To a solution of methyl dec-9-ynoate (800 mg, 4.39 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (1231.31 mg, 21.94 mmol) . The resulting mixture was stirred at 45 ℃ 1.5 h. After cooling down rt. The pH value of the resulting mixture was adjusted to 5 using 2M HCl solution. Then extracted with EA (3*15 mL) , washed with brine (4 *15 mL) . The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford the 9-decynoic acid.
Step D: 10- {4- [3- (2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl} dec-9-ynoic acid
To a solution of ethyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- [3- (4-iodophenoxy) propyl] -1, 3-thiazole-4-carboxylate (170.00 mg, 0.235 mmol) in DMF (3 mL) was added 9-decynoic acid (118.41 mg, 0.705 mmol) , DIEA (151.60 mg, 1.175 mmol) , Pd (PPh3) 2Cl2 (82.33 mg, 0.12 mmol, ) and CuI (13.40 mg, 0.070 mmol) . The resulting mixture was stirred at 25 ℃ under nitrogen for 1 h. The reaction was purified by reverse phase column to afford the 10- {4- [3- (2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl} dec-9-ynoic acid. LC/MS: MS (ESI) M/Z 765.5 [M+H] +.
Step E: ethyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-
yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylate
To a solution of 10- {4- [3- (2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl} dec-9-ynoic acid (170.00 mg, 0.222 mmol) in DMF (5 mL) was added DIEA (143.61 mg, 1.110 mmol) , HATU (101.40 mg, 0.266 mmol) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethylbutanoyl] -4-hydroxy-N- { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} pyrrolidine-2-carboxamide (114.82 mg, 0.266 mmol) . The resulting mixture was stirred at 25 ℃ for 1 h. The reaction was quenched with H2O (10 mL) , then extracted with EA (3*10 mL) , washed with brine (4*10 mL) . The organic layers were combined and concentrated. The residue obtained was purified by TLC (1/14 MeOH/DCM) to afford the ethyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 1177.4 [M+H] +.
Step F: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylic acid
To a solution of ethyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylate (160.00 mg, 0.136 mmol) in MeOH (4 mL) was added 2M NaOH (5 mL) . The mixture was stirred at 50 ℃ for 3 h. After cooling down to rt. The reaction was quenched with H2O (5 mL) . The pH value of the aqueous phase was adjusted to 5 with HCl solution (2 M) and filtered. Then purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water with 10 mmol/L NH4HCO3+0.1%NH3. H2O, Mobile Phase B: CH3CN (37 %to 50%in 13 min, 50 %to 100 %in 0.1 min, 100 %to 100 %in 2 min, 100%to 37%in 0.1 min, 37 %to 37%in 1 min; Detector, UV 254 nm to afford the 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylic acid. 1HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H) , 8.58 (t, J = 6.4 Hz, 1H) , 7.81 -8.08 (m, 2H) , 7.65 -7.80 (m, 2H) , 7.12 -7.50 (m, 11H) , 6.65 -6.95 (m, 2H) , 4.80 -4.92 (m, 1H) , 4.51 -4.60 (m, 1H) , 4.40 -4.50 (m, 2H) , 4.30 -4.39 (m, 1H) , 4.19 -4.29 (m, 1H) , 3.90 -4.00 (m, 1H) , 3.61 -3.88 (m, 5H) ,
3.11 -3.21 (m, 2H) , 3.00 -3.10 (m, 3H) , 2.44 (s, 3 H) , 2.21 -2.40 (m, 4 H) , 1.89 -2.18 (m, 5H) , 1.45 -1.52 (m, 3H) , 1.21 -1.40 (m, 7H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1149.4 [M+H] +.
Example 2: Compound 2
Step A: 3- (prop-2-yn-1-yloxy) propan-1-ol
To a solution of 1, 3-propandiol (3 g, 39.42 mmol) in DMF (90 mL) was added NaH (1.14 g, 60%w/w) at 0℃. The mixture was stirred at rt for 0.5 h. Then propargyl bromide (3.75 g, 31.54 mmol) was added. The mixture was stirred at rt for 3 h. After completion, the reaction was quenched with water (100 mL) . The mixture was extracted with EA (3 x 200 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column (0-50%PE: EtOAc) . The organic layers were concentrated under reduced pressure to afford 3- (prop-2-yn-1-yloxy) propan-1-ol. LCMS: MS (ESI) M/Z: 115 [M+H] +.
Step B: tert-butyl 2- (3- (prop-2-yn-1-yloxy) propoxy) acetate
To a solution of 3- (prop-2-yn-1-yloxy) propan-1-ol (2.09 g, 18.31 mmol) in DCM (30 mL) was added tert-butyl 2-bromoacetate (5.36 g, 27.46 mmol) , 35%NaOH (aq. 30 mL) and Bu4NCl (5.07 g, 18.310 mmol) . The mixture was stirred overnight at rt. After completion, the reaction was quenched with water (50 mL) . The mixture was extracted with DCM (3x100 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column (0-50%PE: EtOAc) . The organic layers were concentrated under reduced pressure to afford tert-butyl 2- [3- (prop-2-yn-1-yloxy) propoxy] acetate. LC/MS: MS (ESI) M/Z 229 [M+H] +.
Step C: 2- (3- (prop-2-yn-1-yloxy) propoxy) acetic acid
To a solution of tert-butyl 2- [3- (prop-2-yn-1-yloxy) propoxy] acetate (2 g, 8.761 mmol) in THF (10 mL) , MeOH (10 mL) and H2O (10 mL) was added LiOH (2.10 g, 87.610 mmol) . The mixture was stirred at 30℃ for 3 h. After completion, the reaction was quenched with water (30 mL) . The pH value of the solution was adjusted to 4~5 with HCl. The mixture was extracted with EA (3 x 50 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated under reduced pressure to afford [3- (prop-2-yn-1-yloxy) propoxy] acetic acid. LC/MS: MS (ESI) M/Z 173 [M+H] +.
Step D: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- [3- (4- {3- [3- ( { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} methoxy) propoxy] prop-1-yn-1-yl} phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
The compound 2 was prepared following the similar procedure as described in Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H) , 8.64 (t, J = 6.1 Hz, 1H) , 8.00 (d, J = 7.8 Hz, 1H) , 7.69 -7.76 (m, 2H) , 7.26 -7.40 (m, 12H) , 6.89 (d, J = 8.3 Hz, 2H) , 4.85 (s, 2H) , 4.56 (d, J = 9.6 Hz, 1H) , 4.44 -4.19 (m, 5H) , 4.03 -3.86 (m, 4H) , 3.50 -3.71 (m, 5H) , 3.22 -3.11 (m, 2H) , 3.02 (t, J = 6.0 Hz, 2H) , 2.32 -2.60 (m, 5H) , 1.70 -2.16 (m, 6H) , 0.94 (s, 9H) . LC/MS: MS (ESI) M/Z 1153.4 [M+H] +.
Example 3: Compound 3
Step A: ethyl (E) -4- (2- (benzyloxy) ethoxy) but-2-enoate
To a solution of DMSO (1.6 g) in DCM (20 mL) was added (COCl) 2 (1.95 g) , the mixture was stirred at -78 ℃ under nitrogen atmosphere. After 30 min, the solution of 2- (2- (benzyloxy) ethoxy) ethan-1-ol (2 g, 1.00 equiv) in DCM was added, after 1h, the TEA (5.0 g, 5 equiv) was added. The resulting mixture was stirred at 25 ℃ for 1 h. Then methyl 2- (triphenyl-lambda5-phosphanylidene) acetate (4.20 g, 1.2 equiv) was added. The resulting mixture was stirred at 25 ℃ for 2 h. The reaction was concentrated. The residue obtained was purified by silica gel chromatography (0-50%ethyl acetate/petroleum ether) to afford ethyl (E) -4- (2- (benzyloxy) ethoxy) but-2-enoate. LC/MS: MS (ESI) M/Z 265.1 [M+H] +.
Step B: ethyl 4- (2-hydroxyethoxy) butanoate
To a solution of ethyl (E) -4- (2- (benzyloxy) ethoxy) but-2-enoate (1.9 g) in MeOH (20 mL) was added Pd/C (1.9 g, 10%w/w) . The mixture was stirred at 50 ℃ under hydrogen atmosphere for 16 h. The reaction was filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-30%ethyl acetate/petroleum ether) to afford ethyl 4- (2-hydroxyethoxy) butanoate. LC/MS: MS (ESI) M/Z 177.1 [M+H] +.
Step C: ethyl 4- (2-oxoethoxy) butanoate
To a solution of DMSO (0.89 g) in DCM (15 mL) was added (COCl) 2 (1.08 g, 8.512 mmol) , the mixture was stirred at -78 ℃ under nitrogen atmosphere. After 30 min, the solution of ethyl 4- (2-hydroxyethoxy) butanoate (1 g) in DCM was added, after 1h, TEA (2.88 g) was added. The resulting mixture was stirred at 25 ℃ 1 h. The reaction was concentrated. The residue obtained was purified by silica gel chromatography (0-50%ethyl acetate/petroleum ether) to afford ethyl 4- (2-oxoethoxy) butanoate. LC/MS: MS (ESI) M/Z 175.1 [M+H] +.
Step D: ethyl 4- (prop-2-yn-1-yloxy) butanoate
To a solution of ethyl 4- (2-oxoethoxy) butanoate (600 mg) in MeOH (10 mL) was added K2CO3 (950 mg) , dimethyl 1-diazo-2-oxopropylphosphonate (990 mg) . The resulting mixture was stirred at 25 ℃ overnight. The reaction was concentrated, then quenched with water (20 mL) . The resulting mixture was extracted with ethyl acetate (3 *20 mL) . The organic layers were combined and concentrated. The residue obtained was purified by silica gel chromatography (0-30%ethyl acetate/petroleum ether) to afford the ethyl 4- (prop-2-yn-1-yloxy) butanoate. LC/MS: MS (ESI) M/Z 171.1 [M+H] +.
Step E: 4- (prop-2-yn-1-yloxy) butanoic acid
To a solution of methyl 4- (but-3-yn-1-yloxy) butanoate (220 mg) in THF (3 mL) , MeOH (3 mL) was added LiOH. H2O (271.20 mg) and H2O (3 mL) . The resulting mixture was stirred at 25 ℃ for 16 h. The pH value of the resulting mixture was adjusted to 6 used 2 N HCl solution. The resulting mixture was extracted with EA (3*10 mL) . The organic layers were combined,
dried over Na2SO4, filtered and concentrated to afford the 4- (prop-2-yn-1-yloxy) butanoic acid. LC/MS: MS (ESI) M/Z 141.1 [M-H] -.
Step F: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- (3- {4- [3- (3- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} propoxy) prop-1-yn-1-yl] phenoxy} propyl) -1, 3-thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.57 (t, J = 6.1 Hz, 1H) , 8.01 (d, J = 7.9 Hz, 1H) , 7.91 (d, J = 9.3 Hz, 1H) , 7.77 (d, J = 7.9 Hz, 1H) , 7.72 -7.51 (m, 2H) , 7.28 -7.49 (m, 10H) , 6.93 -6.84 (m, 2H) , 4.85 (s, 2H) , 4.54 (d, J = 9.3 Hz, 1H) , 4.49 -4.39 (m, 2H) , 4.33 (d, J = 16.4 Hz, 3H) , 4.22 -4.30 (m, 1H) , 3.99 (t, J = 6.2 Hz, 2H) , 3.75 -3.61 (m, 4H) , 3.31 -3.54 (m, 3H) , 3.17 (t, J = 7.6 Hz, 2H) , 3.02 (t, J = 6.0 Hz, 2H) , 2.44 (s, 3H) , 2.34 -2.15 (m, 2H) , 2.09 -1.96 (m, 3H) , 1.90 -1.95 (m, 1H) , 1.75 -1.85 (m, 2H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1123.4 [M+H] +.
Example 4: Compound 4
Step A: tert-butyl 2- (4- (benzyloxy) butoxy) acetate
To a stirred mixture of 4- (benzyloxy) butan-1-ol (2 g, 11.10 mmol) and tert-butyl 2-bromoacetate (3.25 g, 16.64 mmol) in DCM (10 mL) were added 35%NaOH (aq. 10 mL) and
tetrabutylammonium chloride (3.08 g, 11.096 mmol) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL) . The combined organic layers were washed with brine (1 x 50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (5: 1) to afford tert-butyl 2- [4- (benzyloxy) butoxy] acetate. LC/MS: MS (ESI) M/Z 295.2 [M+H] +.
Step B: tert-butyl 2- (4-hydroxybutoxy) acetate
To a stirred solution of tert-butyl 2- [4- (benzyloxy) butoxy] acetate (1.74 g, 5.91 mmol) in MeOH (20 mL) were added Pd/C (1 g, 9.40 mmol, 10%w/w) in portions at 50 ℃ under hydrogen atmosphere. The resulting mixture was stirred for overnight at 50 ℃ under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x20 mL) . The filtrate was concentrated under reduced pressure to afford tert-butyl 2- (4-hydroxybutoxy) acetate. The crude product was used in the next step directly without further purification. LC/MS: MS (ESI) M/Z 227.0 [M+Na] +.
Step C: tert-butyl 2- (4- (prop-2-yn-1-yloxy) butoxy) acetate
To a stirred mixture of tert-butyl 2- (4-hydroxybutoxy) acetate (1.0178 g, 4.983 mmol) and propargyl bromide (0.89 g, 7.481 mmol) in DCM (10.18 mL) were added 35%aqueous NaOH (10 mL) and tetrabutylammonium chloride (1.38 g, 4.966 mmol) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL) . The combined organic layers were washed with brine (1x50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (1: 1) to afford tert-butyl 2- [4- (prop-2-yn-1-yloxy) butoxy] acetate. LC/MS: MS (ESI) M/Z 242.2 [M+H] +.
Step D: 2- (4- (prop-2-yn-1-yloxy) butoxy) acetic acid
A solution of tert-butyl 2- [ (6-hydroxyhex-3-yn-1-yl) oxy] acetate (669 mg, 2.931 mmol) in MeOH (3 mL) , THF (3 mL) and H2O (3 mL) was added LiOH. H2O (1229.76 mg, 29.310 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 5 with 2M HCl. The resulting mixture was extracted with EA (3 x 20 mL) . The combined organic layers were washed with brine (1 x 50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford [ (6-hydroxyhex-3-yn-1-yl) oxy] acetic acid. The crude product was used in the next step directly without further purification. LC/MS: MS (ESI) M/Z 185.0 [M+H] +.
Step E: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- [3- (4- {3- [4- ( { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} methoxy) butoxy] prop-1-yn-1-yl} phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.63 (t, J = 6.1 Hz, 1H) , 8.00 (d, J = 7.9 Hz, 1H) , 7.69 -7.76 (m, 2H) , 7.27 -7.48 (m, 11H) , 6.89 (d, J = 8.4 Hz, 2H) , 4.86 (s, 2H) , 4.56 (d, J = 9.6 Hz, 1H) , 4.22 -4.49 (m, 6H) , 3.90 -4.04 (m, 4H) , 3.57 -3.75 (m, 4H) , 3.50 (d, J = 5.5 Hz, 5H) , 3.16 (t, J = 7.5 Hz, 2H) , 3.00 -3.05 (m, 2H) , 2.44 (s, 3H) , 1.86 -2.11 (m, 4H) , 1.59 -1.65 (m, 4H) , 0.94 (s, 9H) . LC/MS: MS (ESI) M/Z 1167.4 [M+H] +.
Example 5: Compound 5
Step A: tert-butyl 2- (hept-6-yn-1-yloxy) acetate
To a solution of hept-6-yn-1-ol (2.0 g, 17.83 mmol) in DCM (20 mL) was added tert-butyl 2-bromoacetate (5.22 g, 26.74 mmol) , 35%NaOH (aq. 20 mL) and tetrabutylammonium chloride (4.96 g, 17.830 mmol) . The mixture was stirred at 25℃ overnight. The reaction was quenched with H2O (50 mL) . The resulting mixture was extracted with DCM (3*50 mL) . The organic layers were combined concentrated. The residue obtained was purified by silica gel column chromatography (0-30%ethyl acetate/petroleum ether) to afford the tert-butyl 2- (hept-6-yn-1-yloxy) acetate.
Step B: (hept-6-yn-1-yloxy) acetic acid
To a solution of tert-butyl 2- (hept-6-yn-1-yloxy) acetate (1.4 g, 6.186 mmol) in THF (8 mL) was added LiOH. H2O (2.60 g, 61.958 mmol) , H2O (8 mL) , MeOH (8 mL) . The resulting mixture was stirred at 30 ℃ for 1h. The reaction was concentrated to remove MeOH, then the pH value of the resulting mixture was adjusted to 7 with 2N HCl solution. Then extracted with EtOAc (3*50mL) . The organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the (hept-6-yn-1-yloxy) acetic acid.
Step C: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- (3- {4- [7- ( { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} methoxy) hept-1-yn-1-yl] phenoxy} propyl) -1, 3-thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H) , 8.62 (t, J = 6.0 Hz, 1H) , 7.99 (d, J = 7.9 Hz, 1H) , 7.66 -7.78 (m, 2H) , 7.20 -7.50 (m, 12H) , 6.80 -6.90 (m, 2H) , 4.84 -4.88 (m, 2H) , 4.56 (d, J = 9.6 Hz, 1H) , 4.41 -4.49 (m, 1H) , 4.34 -4.38 (m, 2H) , 4.21 -4.30 (m, 1H) , 3.85 -3.99 (m, 4H) , 3.60 -3.75 (m, 4H) , 3.48 -3.55 (m, 3H) , 3.14 -3.18 (m, 2H) , 3.00 -3.04 (m, 2H) , 2.44 (s, 3H) , 2.35 -2.40 (m, 2H) , 1.89 -2.10 (m, 4H) , 1.51 -1.61 (m, 3H) , 1.46 -1.50 (m, 3H) , 1.24 (s, 1H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1151.5 [M+H] +
Example 6: Compound 6
Step A: ethyl (E) -4- (2- (benzyloxy) ethoxy) but-2-enoate
To a solution of DMSO (1.59 g) in DCM (20 mL) was added (COCl) 2 (1.94 g, 15.29 mmol) N2 atmosphere. The mixture was stirred at -78℃ for 30 min. 2- [2- (benzyloxy) ethoxy] ethanol (2 g, 10.19 mmol) was added to the mixture. The mixture was stirred at -78℃ for 1 h. TEA (5.16 g, 50.96 mmol) was added to the mixture, the mixture was stirred at rt for 1 h. tert-butyl 2- (triphenyl-lambda5-phosphanylidene) acetate (4.60 g, 12.229 mmol) was added to the mixture, the mixture was stirred at rt for 2 h. After completion, the reaction was quenched with water (50 mL) . The mixture was extracted with EA (3x50 mL) and the organic
layer was dried over Na2SO4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column (0-50%PE : EtOAc) . The organic layers were concentrated under reduced pressure to afford tert-butyl (2E) -4- [2- (benzyloxy) ethoxy] but-2-enoate. LC/MS: MS (ESI) M/Z 265 [M+H] +.
Step B: ethyl 4- (2-hydroxyethoxy) butanoate
The solution of ethyl (2E) -4- [2- (benzyloxy) ethoxy] but-2-enoate (2.7 g, 10.22 mmol) and Pd/C (1.5 g, 10%w/w) in MeOH (30 mL) was stirred for overnight at 50 ℃ under a H2 (g) (10 atm) atmosphere. The mixture was filtered through a celite pad. The organic layers were concentrated. The organic layers were concentrated under reduced pressure to afford ethyl 4- (2-hydroxyethoxy) butanoate as white oil. LC/MS: MS (ESI) M/Z 177 [M+H] +.
Step C: ethyl 4- (2- (prop-2-yn-1-yloxy) ethoxy) butanoate
To a solution of ethyl 4- (2-hydroxyethoxy) butanoate (1.5 g, 8.51 mmol) in DCM (22.5 mL) was added propargyl bromide (1.52 g, 12.77 mmol) , 35%NaOH (aq. 22.5 mL) and Bu4NCl (2.36 g, 8.51 mmol) . The mixture was stirred overnight at rt. After completion, the reaction was quenched with water (50 mL) . The mixture was extracted with DCM (3x100 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column (0-50%PE: EtOAc) . The organic layers were concentrated under reduced pressure to afford ethyl 4- [2- (prop-2-yn-1-yloxy) ethoxy] butanoate. LC/MS: MS (ESI) M/Z 215 [M+H] +.
Step D: 4- (2- (prop-2-yn-1-yloxy) ethoxy) butanoic acid
To a solution of ethyl 4- [2- (prop-2-yn-1-yloxy) ethoxy] butanoate (1.18 g, 5.51 mmol) in MeOH (6 mL) and H2O (6 mL) was added KOH (3.09 g, 55.07 mmol) . The mixture was stirred at rt for 3 h. After completion, the reaction was quenched with water (20 mL) . The pH value of the solution was adjusted to 4~5 with HCl. The mixture was extracted with EA (3x30 mL) and the organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated under reduced pressure to afford 4- [2- (prop-2-yn-1-yloxy) ethoxy] butanoic acid. LC/MS: MS (ESI) M/Z 187 [M+H] +.
Step E: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- [3- (4- {3- [2- (3- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} propoxy) ethoxy] prop-1-yn-1-yl} phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H) , 8.58 (t, J = 6.1 Hz, 1H) , 8.02 (d, J = 7.9 Hz, 1H) , 7.90 (d, J = 9.2 Hz, 1H) , 7.78 (d, J = 8.1 Hz, 1H) , 7.69 (d, J = 7.3 Hz, 1H) , 7.52 -7.29 (m, 10H) , 6.90 (d, J = 8.3 Hz, 2H) , 4.84 (s, 2H) , 4.55 (d, J = 9.3 Hz, 1H) , 4.31 -4.60 (m, 5H) , 4.22
(dd, J = 15.8, 5.4 Hz, 1H) , 3.99 (s, 2H) , 3.69 -3.79 (m, 2H) , 3.64 -3.69 (m, 2H) , 3.61 (d, J = 4.8 Hz, 2H) , 3.52 (dd, J = 5.8, 3.3 Hz, 2H) , 3.32 -3.43 (m, 3H) , 3.17 (s, 2H) , 3.04 (s, 2H) , 2.45 (s, 3H) , 2.13 -2.40 (m, 2H) , 1.83 -2.11 (m, 4H) , 1.72 (s, 2H) , 0.94 (s, 9H) . LC/MS: MS (ESI) M/Z 1167.4 [M+H] +.
Example 7: Compound 7
Step A: ethyl 6- (prop-2-yn-1-yloxy) hexanoate
To a solution of ethyl 6-hydroxyhexanoate (1.0 g, 6.84 mmol) in DMF (5 mL) was added NaH (0.3 g, 60%purity) at 0 ℃, 3-bromoprop-1-yne (0.82 g, 6.893 mmol) was added an hour later. The resulting mixture was stirred at 25℃ for 2 h. The reaction was quenched with H2O (10 mL) and extracted with EA (3 x 20 mL) , washed with brine (3 x 20 mL) , the organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA/PE to afford the ethyl 6- (prop-2-yn-1-yloxy) hexanoate.
Step B: 6- (prop-2-yn-1-yloxy) hexanoic acid
To a solution of ethyl 6- (prop-2-yn-1-yloxy) hexanoate (660 mg, 3.58 mmol) in MeOH (4 mL) and H2O (4 mL) was added KOH (660 mg, 11.76 mmol) . The resulting mixture was stirred at 45 ℃ for 1 h. The reaction was added 2 M HCl to pH~6 and extracted with EA (3 x 20 mL) , washed with brine (3 x 20 mL) , the organic layers were combined and concentrated under vacuum to afford the 6- (prop-2-yn-1-yloxy) hexanoic acid. LCMS: MS (ESI) M/Z: 155.1 [M-H] -.
Step C: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- [3- (4- {3- [ (5- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} pentyl) oxy] prop-1-yn-1-yl} phenoxy) propyl] -1, 3-thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1HNMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H) , 8.57 (t, J = 6.0 Hz, 1H) , 8.00 (d, J = 7.6 Hz, 1H) , 7.81 -7.91 (m, 1H) , 7.72 -7.80 (m, 1H) , 7.62 -7.71 (m, 1H) , 7.22 -7.58 (m, 11H) , 6.82 -6.98 (m, 2H) , 4.85 (s, 2H) , 4.49 -4.60 (m, 1H) , 4.39 -4.48 (m, 2H) , 4.18 -4.38 (m, 4H) , 3.92 -4.01 (m, 2H) , 3.61 -3.71 (m, 4H) , 3.40 -3.51 (m, 3H) , 3.12 -3.21 (m, 2H) , 3.00 -3.10 (m, 2H) , 2.50 (s, 3H) , 2.20 -2.31 (m, 1H) , 2.09 -2.19 (m, 1H) , 1.95 -2.08 (m, 3H) , 1.88 -1.94 (m, 1H) , 1.45 -1.61 (m, 4H) , 1.18 -1.38 (m, 2H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1151.4 [M+H] +.
Example 8: Compound 8
Step A: methyl 5- (but-3-yn-1-yloxy) pentanoate
To a solution of but-3-yn-1-ol (2.0 g, 28.57 mmol) in DCM (20 mL) was added methyl 5-bromopentanoate (8.31 g, 42.86 mmol) , 35%NaOH (aq. 40 mL) and tetrabutylammonium chloride (7.91 g, 28.57 mmol) . The mixture was stirred at 25 ℃ overnight. The reaction was quenched with H2O (50 mL) . The resulting mixture was extracted with DCM (3*50 mL) . The organic layers were combined concentrated. The residue obtained was purified by silica gel column chromatography (0-30%ethyl acetate/petroleum ether) to afford the methyl 5- (but-3-yn-1-yloxy) pentanoate.
Step B: 5- (but-3-yn-1-yloxy) pentanoic acid
To a solution of methyl 5- (but-3-yn-1-yloxy) pentanoate (1.5 g, 8.16 mmol) in THF (8 mL) was added LiOH. H2O (3.26 g, 81.57 mmol) , H2O (8 mL) , MeOH (8 mL) . The resulting mixture was stirred at 30 ℃ for 1h. The reaction was concentrated to remove MeOH, then the pH value of the resulting mixture was adjusted to 7 used 2N HCl solution. Then extracted with
EtOAc (3*50 mL) , dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the 5- (but-3-yn-1-yloxy) pentanoic acid.
Step C: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- (3- {4- [4- (4- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} butoxy) but-1-yn-1-yl] phenoxy} propyl) -1, 3-thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H) , 8.59 (t, J = 6.0 Hz, 1H) , 7.99 (d, J = 7.9 Hz, 1H) , 7.91 -7.84 (m, 1H) , 7.70 -7.80 (m, 1H) , 7.60 -7.69 (m, 1H) , 7.20 -7.45 (m, 11H) , 6.86 (d, J = 8.4 Hz, 2H) , 4.88 -4.84 (m, 2H) , 4.58 -4.52 (m, 1H) , 4.49 -4.39 (m, 2H) , 4.38 -4.33 (m, 1H) , 4.27 -4.17 (m, 1H) , 4.01 -3.93 (m, 2H) , 3.65 -3.72 (m, 4H) , 3.50 -3.52 (m, 2H) , 3.40 -3.42 (m, 2H) , 3.20 -3.12 (m, 2H) , 3.04 -3.00 (m, 2H) , 2.65 -2.57 (m, 2H) , 2.43 (s, 3H) , 2.21 -2.30 (m, 1H) , 2.18 -2.10 (m, 1H) , 2.07 (s, 1H) , 1.82 -2.05 (m, 4H) , 1.20 -1.75 (m, 5H) , 0.91 (s, 9H) . LC/MS: MS (ESI) M/Z 1151.4 [M+H] +.
Example 9: Compound 9
Step A: tert-butyl 2- (hex-5-yn-1-yloxy) acetate
To a solution of hex-5-yn-1-ol (1.0 g, 10.19 mmol) in DCM (10 mL) was added NaOH (10M) (aq. 10 mL) , tert-butyl 2-bromoacetate (2.38 g, 12.23 mmol) and TBAC (2.8 g, 10.20 mmol) . The resulting mixture was stirred at 25 ℃ for 16 h. The reaction was extracted with DCM (3 x 30 mL) , washed with brine (3 x 40 mL) , the organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA/PE to afford the tert-butyl 2- (hex-5-yn-1-yloxy) acetate.
Step B: 2- (hex-5-yn-1-yloxy) acetic acid
To a solution of tert-butyl 2- (hex-5-yn-1-yloxy) acetate (1.8 g, 8.48 mmol) in THF (5 mL) , MeOH (5 mL) and H2O (5 mL) was added LiOH. H2O (3.56 g, 84.79 mmol) . The resulting mixture was stirred at 25 ℃ for 1 h. pH value was adjusted to 6 using 2 M HCl, extracted with EA (3 x 40 mL) , washed with brine (3 x 50 mL) , the organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA/PE to afford the (hex-5-yn-1-yloxy) acetic acid. LC/MS: MS (ESI) M/Z 155.1 [M-H] -.
Step C: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- (3- {4- [6- ( { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} methoxy) hex-1-yn-1-yl] phenoxy} propyl) -1, 3-thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1HNMR (400 MHz, DMSO-d6) δ 9.00 (s, 1 H) , 8.62 (t, J = 6.0 Hz, 1 H) , 7.91 -8.05 (m, 1 H) , 7.61 -7.81 (m, 2 H) , 7.20 -7.52 (m, 12 H) , 6.75 -6.95 (m, 2 H) , 4.85 (s, 2 H) , 4.51 -4.67 (m, 1 H) , 4.31 -4.50 (m, 3 H) , 4.21 -4.30 (m, 1 H) , 3.89 -4.00 (m, 4 H) , 3.60 -3.75 (m, 4 H) , 3.50 -3.55 (m, 2 H) , 3.10 -3.20 (m, 2 H) , 3.00 -3.09 (m, 2 H) , 2.41 -2.45 (m, 6 H) , 1.89 -2.11 (m, 4 H) , 1.58 -1.71 (m, 4 H) , 0.94 (s, 9 H) . LC/MS: MS (ESI) M/Z 1137.4 [M+H] +.
Example 10: Compound 10
Step A: methyl 10-oxodecanoate
To a solution of 10-hydroxydecanoic acid (2 g, 10.62 mmol) in MeOH (20 mL) was added AcCl (1.3 mL, 18.22 mmol) , the mixture was stirred at 25 ℃ for 1 hour. The resulting mixture was combined, then added DCM (40 mL) , molecular sieves (4A) (3 g) , PCC (3.5 g, 16.24 mmol) , the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was quenched with water (100 mL) . The resulting mixture was extracted with ethyl acetate (3*100 mL) . The organic layers were combined, watched with brine (4*100 mL) . The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford the methyl 10-oxodecanoate.
Step B: methyl undec-10-ynoate
To a solution of methyl 10-oxodecanoate (1.37 g, 6.84 mmol) in MeOH (15 mL) was added K2CO3 (1.89 g, 13.68 mmol) , dimethyl 1-diazo-2-oxopropylphosphonate (1.97 g, 10.26 mmol) . The resulting mixture was stirred at 25 ℃ overnight. The reaction was concentrated, then quenched with water (50 mL) . The resulting mixture was extracted with ethyl acetate (3*50 mL) . The organic layers were combined and concentrated. The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford the methyl undec-10-ynoate.
Step C: 10-undecynoic acid
To a solution of methyl undec-10-ynoate (1.0 g, 5.10 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (1.43 g, 25.48 mmol) . The resulting mixture was stirred at 45 ℃ 1.5 h. After cooling down to rt. The pH value of the resulting mixture was adjusted to 5 used 2M HCl solution. Then extracted with EA (3*15 mL) , washed with brine (4*15mL) . The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford the 10-undecynoic acid.
Step D: 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (10- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( { [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl} carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} dec-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H) , 8.59 (t, J = 8.0 Hz, 1H) , 7.81 -8.01 (m, 2H) , 7.62 -7.70 (m, 2H) , 7.00 -7.60 (m, 10H) , 6.65 -6.92 (m, 2H) , 4.82 -4.91 (m, 1H) , 4.51 -4.61 (m, 1H) , 4.40 -4.50 (m, 2H) , 4.30 -4.39 (m, 1H) , 4.19 -4.29 (m, 1H) , 3.90 -4.09 (m, 2H) , 3.60 -3.89 (m, 5H) , 3.11 -3.21 (m, 2H) , 3.00 -3.10 (m, 2H) , 2.44 -2.50 (m, 4H) , 2.20 -2.40 (m, 3H) , 1.79 -2.15 (m, 5H) , 1.42 -1.61 (m, 4H) , 1.32 -1.41 (m, 2H) , 1.20 -1.30 (m, 6H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1163.6 [M+H] +.
Example 11: Compound 11
Step A: tert-butyl 2- (2- (benzyloxy) ethoxy) acetate
To a stirred mixture of tert-butyl 2-bromoacetate (3.84 g, 19.71 mmol) and benzyl glycol (2.00 g, 13.14 mmol) in DCM (20.00 mL) and 35%NaOH (aq. 20 mL) were added tetrabutylammonium chloride (3.65 g, 13.14 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL) . The combined organic layers were washed with brine (1x50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (5: 1) to afford tert-butyl 2- [2- (benzyloxy) ethoxy] acetate. LC/MS: MS (ESI) M/Z 289.0 [M+Na] +.
Step B: tert-butyl 2- (2-hydroxyethoxy) acetate
To a stirred solution of tert-butyl 2- [2- (benzyloxy) ethoxy] acetate (2.67 g) in MeOH (20 mL) were added Pd/C (1 g, 10%w/w) in portions at room temperature under hydrogen atmosphere and stirred overnight. The resulting mixture was filtered, the filter cake was washed with MeOH (4x20 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (1: 1) to afford tert-butyl 2- (2-hydroxyethoxy) acetate) . LC/MS: MS (ESI) M/Z 177.2 [M+H] +.
Step C: tert-butyl 2- (2-iodoethoxy) acetate
To a stirred mixture of tert-butyl 2- (2-hydroxyethoxy) acetate (1.1345 g, 6.44 mmol) and PPh3 (1.86 g, 7.082 mmol) in DCM (10 mL) were added imidazole (0.53 g, 7.726 mmol) and I2 (1.80 g, 7.092 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. sodium hyposulfite (aq. ) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL) . The combined organic layers were washed with brine (1x50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (5: 1) to afford tert-butyl 2- (2-iodoethoxy) acetate. LC/MS: MS (ESI) M/Z 309.0 [M+Na] +.
Step D: tert-butyl 2- (2- (but-3-yn-1-yloxy) ethoxy) acetate
To a stirred mixture of tert-butyl 2- (2-iodoethoxy) acetate (1.38 g, 4.81 mmol) and 3-butyn-1-ol (0.281 g, 4.01 mmol) in 35%NaOH (aq. 10 mL) and DCM (10 mL) were added tetrabutylammonium chloride (1.11 g, 3.99 mmol) in portions at room temperature and stirred at rt overnight. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL) . The combined organic layers were washed with brine (1x50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EA (1: 1) to afford tert-butyl 2- [ (6-hydroxyhex-3-yn-1-yl) oxy] acetate. LC/MS: MS (ESI) M/Z 246.2 [M+H2O] +.
Step E: 2- (2- (but-3-yn-1-yloxy) ethoxy) acetic acid
A solution of tert-butyl 2- (2- (but-3-yn-1-yloxy) ethoxy) acetate (450 mg, 1.97 mmol) in MeOH (3 mL) , THF (3 mL) and H2O (3 mL) was added LiOH. H2O (809 mg, 19.73 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 5 with 2M HCl. The resulting mixture was extracted with EA (3 x 20mL) . The combined organic layers were washed with brine (1x50 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2- (2- (but-3-yn-1-yloxy) ethoxy) acetic acid. The crude product was used in the next step directly without further purification. LC/MS: MS (ESI) M/Z 171.2 [M-H] -.
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (4- (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethoxy) but-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H) , 8.61 (s, 1H) , 7.99 (s, 1H) , 7.63 -7.81 (m, 2H) , 7.13 -7.52 (m, 12H) , 6.84 (s, 2H) , 4.86 (s, 2H) , 4.58 (d, J = 9.6 Hz, 1H) , 4.30 -4.54 (m, 3H) , 4.17 -4.31 (s, 1H) , 3.90 -4.10 (m, 3H) , 3.52 -3.79 (m, 8H) , 3.16 (s, 2H) , 3.03 (s, 2H) , 2.62 -2.71 (m, 2H) , 2.37 -2.46 (m, 5H) , 1.78 -2.16 (m, 6H) , 0.95 (s, 9H) . LC/MS: MS (ESI) M/Z 1153.4 [M+H] +.
Example 12: Compound 12
Step A: methyl 8-hydroxyoctanoate
To a solution of 8-hydroxy caprylic acid (1.0 g, 6.24 mmol) in MeOH (20 mL) was added AcCl (449.09 mg, 1.54 mmol) . The resulting mixture was stirred at rt for 1 h. Subsequently, the resulting mixture was concentrated to afford the methyl 8-hydroxyoctanoate.
Step B: methyl 8-oxooctanoate
To a solution of methyl 8-hydroxyoctanoate (600 mg, 3.44 mmol) in DCM (20 mL) was added PCC (1.75 g, 8.13 mmol) , 4A MS (1.5 g) . The resulting mixture was stirred at rt for 1 h. Subsequently, the reaction was filtered and extracted with DCM (3 x 50 mL) . The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford the methyl 8-oxooctanoate.
Step C: methyl non-8-ynoate
To a solution of methyl 8-oxooctanoate (770 mg, 4.47 mmol) in MeOH (15 mL) was added K2CO3 (1.1 g, 7.96 mmol) , dimethyl (1-diazo-2-oxopropyl) phosphonate (1.0 g, 5.19 mmol) . The resulting mixture was stirred at rt for 16 h. Subsequently, the reaction was filtered and concentrated. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20%ethyl acetate/petroleum ether) to afford methyl non-8-ynoate.
Step D: non-8-ynoic acid
To a solution of methyl non-8-ynoate (469 mg, 2.79 mmol) in MeOH (5 mL) and H2O (5 mL) was added KOH (469 mg, 8.36 mmol) . The resulting mixture was stirred at 45 ℃ for 1 h. After cooling down to rt, the reaction was quenched with water (10 mL) . The resulting mixture was added 2 N HCl to pH ~ 6 and extracted with ethyl acetate (3 x 50 mL) . The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to afford the 8-nonynoic acid.
LC/MS: MS (ESI) M/Z 153.2 [M-H] -.
Step E: 9- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (ethoxycarbonyl) thiazol-5-yl) propoxy) phenyl) non-8-ynoic acid
To a solution of ethyl 2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] -1, 3-thiazole-4-carboxylate (50 mg, 0.069 mmol) in DMF (2mL) was added 8-nonynoic acid (30 mg, 0.20 mmol) , DIPEA (0.05 mL, 0.39 mmol) , CuI (4 mg, 0.02 mmol) , Pd (PPh3) 2Cl2 (15 mg, 0.021 mmol) . The resulting mixture was maintained under nitrogen and stirred at rt for 16 h. Subsequently, the reaction was quenched with water (10 mL) . The resulting mixture was purified by reverse phase column (0-90%) to afford the 9- [4- [3- (2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl] non-8-ynoic acid. LC/MS: MS (ESI) M/Z 751.3 [M+H] +.
Step F: ethyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 9- [4- [3- (2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -4- (ethoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl] non-8-ynoic acid (100 mg, 0.13 mmol) in DMF (5 mL) was added (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethylbutanoyl] -4-hydroxy-N- [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (65 mg, 0.15 mmol) and HATU (62 mg, 0.16 mmol) , DIEA (0.07 mL) . The resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (10 mL) , extracted with ethyl acetate (3 x 20 mL) . The organic layers were combined, washed with brine (3 x 50 mL) and concentrated. The residue obtained was purified by silica gel chromatography (0-10%MeOH/DCM) to afford the crude of ethyl 2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- (8- [ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl] carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl] oct-1-yn-1-yl) phenoxy] propyl] -1, 3-thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 1163.4 [M+H] +.
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of ethyl 2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- (8- [ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl] carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl] oct-1-yn-1-yl) phenoxy] propyl] -1, 3-thiazole-4-carboxylate (100 mg, 0.086 mmol) in MeOH (4 mL) was added 2 M NaOH (aq. 2 mL) . The resulting mixture was stirred at 50 ℃ for 3 h. Then the reaction was cooled down to r. t, the resulting mixture was adjusted pH to 5 with 2 N HCl. The mixture was filtered and dried under vacuum. The residue obtained was purified by Prep-HPLC with the following conditions (1#waters2767-5) : Column, Xselect CSH OBD column 30*150mm 5 um, n; Mobile phase, Phase A: water with 10 mmol/L NH4HCO3 + 0.1%NH3. H2O, Phase B: CH3CN (40%CH3CN up to 70%in 10 min, then 70%to 100%in 1 min, hold 100%in 1 min, down to 40%in 1 min, hold 40%in 1 min) ; Detector, UV220&254nm to afford the 2- [8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- (8- [ [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ( [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] methyl] carbamoyl) pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl] oct-1-yn-1-yl) phenoxy] propyl] -1, 3-thiazole-4-carboxylic acid. 1HNMR (300 MHz, DMSO-d6) δ: 9.00 (s, 1H) , 8.50 -8.65 (m, 1H) , 7.88 -8.00 (brs, 1H) , 7.85 (d, J = 8.7 Hz, 1H) , 7.60 -7.75 (m, 2H) , 7.10 -7.50 (m, 11H) , 6.65 -6.92 (m, 2H) , 4.87 (brs, 2H) , 4.52 -4.64 (m, 1H) , 4.30 -4.50 (m, 3H) , 4.15 -4.28 (m, 1H) , 3.60 -4.02 (m, 8H) , 2.98 -3.24 (m, 5H) , 2.45 (s, 3H) , 2.20 -2.40 (m, 2H) , 1.85 -2.17 (m, 4H) , 1.20 -1.70 (m, 8H) , 0.95 (s, 9H) . LC/MS: MS (ESI) M/Z 1135.6 [M+H] +.
Example 13: Compound 13
Step A: 3-azaspiro [5.5] undecan-9-one
To a solution of tert-butyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (1.0 g, 3.74 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 2 mL) . The resulting mixture was stirred
at 25℃ for 2hrs. The reaction mixture was concentrated in vacuo to give a crude. The crude product was applied to the next step without further purification.
Step B: benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate
To a solution of 3-azaspiro [5.5] undecan-9-one (630 mg, 3.09 mmol, HCl salt) and CbzCl (791.38 mg, 4.64 mmol) in DCM (10 mL) was added TEA (938.84 mg, 9.28 mmol) and . The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was treated with water (100 mL) and extracted with EA (3*50 mL) . The organic layer combined was washed with brine (3*200mL) , dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by chromatography on silica gel column eluting PE: EA=10: 1~2: 1 to give benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate. LC/MS: MS (ESI) M/Z 302.3 [M+H] +.
Step C: benzyl 9- (2- (tert-butoxy) -2-oxoethylidene) -3-azaspiro [5.5] undecane-3-carboxylate
To a solution of tert-butyl 2-diethoxyphosphorylacetate (987.62 mg, 3.92 mmol) in THF (10 mL) was added NaH (156.61 mg, 3.92 mmol, 60%purity) at 0℃. After 0.5h, benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (590 mg, 1.96 mmol) was added to mixture and stirred at 25 ℃ for 18 hrs. The reaction mixture was quenched with water (100mL) and extracted with EA (3*30mL) . The organic layer combined was washed with brine (100mL*3) , dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by chromatography on silica gel column eluting PE: EA=50: 1~15: 1 to give benzyl 9- (2-tert-butoxy-2-oxo-ethylidene) -3-azaspiro [5.5] undecane-3-carboxylate. LC/MS: MS (ESI) M/Z 422.3 [M+Na] +.
Step D: tert-butyl 2- (3-azaspiro [5.5] undecan-9-yl) acetate
To a solution of benzyl 9- (2-tert-butoxy-2-oxo-ethylidene) -3-azaspiro [5.5] undecane-3-carboxylate (530 mg, 1.33 mmol) in MeOH (20 mL) was added Pd/C (128.89 mg, 10%w/w) . The resulting mixture was degassed under vacuum and purged with H2 for 3 times. The mixture was stirred under H2 at 25 ℃ for 6 hrs. The reaction mixture was filtered through Celite pad and the filter cake was washed with MeOH (3*20mL) . The filtrate combined was concentrated to dryness in vacuo to give tert-butyl 2- (3-azaspiro [5.5] undecan-9-yl) acetate. The crude product was applied to the next step without further purification. LC/MS: MS (ESI) M/Z 268.4 [M+H] +.
Step E: tert-butyl 2- (3- (prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetate
To a suspension of tert-butyl 2- (3-azaspiro [5.5] undecan-9-yl) acetate (480 mg, 1.80 mmol) in MeOH (10 mL) was added K2CO3 (297.70 mg, 2.15 mmol) at 0℃. After 0.1h, 3-bromoprop-1-yne (256.24 mg, 2.15 mmol, 185.68 μL) was added and stirred at 0 ℃ for 1 hr. The reaction mixture was warmed to rt and treated with water and extracted with DCM. The organic phase was washed with brine and concentrated to give a crude. The residue was purified by column chromatography PE: EA=15: 1~2: 1 to afford tert-butyl 2- (3-prop-2-ynyl-3-
azaspiro [5.5] undecan-9-yl) acetate. 1H-NMR (400 MHz, CDCl3) δ 3.28 (t, J = 2.3 Hz, 2H) , 2.51-2.46 (m, 4H) , 2.24-2.21 (m, 2H) , 2.09 (d, J = 7.1 Hz, 2H) , 1.70-1.62 (m, 2H) , 1.57-1.49 (m, 4H) , 1.44-1.39 (m, 11H) , 1.16-1.09 (m, 4H) .
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- (tert-butoxy) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 2- (3-prop-2-ynyl-3-azaspiro [5.5] undecan-9-yl) acetate (128.96 mg, 422.18 μmol) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (150 mg, 211.09 μmol) in DMF (10 mL) was added CuI (20.10 mg, 105.54 μmol) , Pd (PPh3) 4 (121.96 mg, 105.54 μmol) and DIEA (109.13 mg, 844.35 μmol) . The tube was degassed and backfilled with N2 for 5 times. The resulting mixture was stirred at 60℃ for 4 hrs under N2. The reaction mixture was cooled to RT, quenched with water (100mL) and extracted with EA (3*30mL) . The organic layer combined was washed with brine (3*100 mL) , dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by chromatography on silica gel column eluting DCM: MeOH=50: 1~5: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 445.4 [M+2H] +/2.
Step G: 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (135 mg, 152.00 μmol) in FA (5 mL) was stirred at 40 ℃ for 4 hrs. The reaction mixture was concentrated in vacuo to give 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetic acid. LC/MS: MS (ESI) M/Z 417.1 [M+2H] +/2.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a mixture of 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid (140 mg, 168.26 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-
dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (144.89 mg, 336.52 μmol) in DMF (5 mL) was added HATU (319.89 mg, 841.31 μmol) and DIEA (217.46 mg, 1.68 mmol) . The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was quenched with water and extracted with EA (3*25mL) . The organic layer combined was washed with saturated NH4Cl solution, brine, dried over Na2SO4 and concentrated to dryness. The residue obtained was purified by Prep-TLC (MeOH/DCM=1: 10) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate as off-white solid. LC/MS: MS (ESI) M/Z 622.9 [M+2H] +/2.
Step I: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (75 mg, 60.26 μmol) in MeOH (5 mL) and THF (5 mL) was added LiOH (7.20 mg, 301.30 μmol) . The resulting mixture was stirred at 25 ℃ for 2 hrs. The resulting mixture was stirred at 25℃ for 2 hrs. The pH value of the reaction mixture was adjusted to pH=3 with 0.1M HCl solution and extracted with DCM (3*25mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LC/MS: MS (ESI) M/Z 616.4 [M+2H] +/2. 1H-NMR (400 MHz, CDCl3) δ8.67 (s, 1H) , 7.85 (d, J = 8.5 Hz, 1H) , 7.61 (s, 2H) , 7.32-7.26 (m, 11H) , 7.17 (d, J = 0.8 Hz, 1H) , 6.74 (d, J = 8.5 Hz, 2H) , 6.44 (d, J = 7.1 Hz, 1H) , 4.88 (t, J = 17.5 Hz, 2H) , 4.67 (t, J = 7.8 Hz, 1H) , 4.59-4.51 (m, 3H) , 4.27 (d, J = 15.4 Hz, 1H) , 4.11 (d, J = 12.6 Hz, 1H) , 3.91 (t, J = 6.0 Hz, 2H) , 3.77 (d, J = 6.0 Hz, 2H) , 3.59 (d, J = 7.7 Hz, 2H) , 3.27 (s, 2H) , 3.01 (t, J = 5.8 Hz, 2H) ,
2.72 (s, 3H) , 2.48 (s, 4H) , 2.06 (d, J = 6.3 Hz, 4H) , 1.54 (m, 9H) , 1.26 (s, 2H) , 1.05-0.93 (m, 14H) .
Example 14: Compound 14
Step A: methyl 1- (4- (2- (tert-butoxy) -2-oxoethyl) cyclohexyl) azetidine-3-carboxylate
To a solution of tert-butyl 2- (4-oxocyclohexyl) acetate (8.25 g, 38.86 mmol) and methyl azetidine-3-carboxylate (4.07 g, 35.33 mmol) in DCE (200 mL) was added NaBH (OAc) 3 (22.47 g, 105.99 mmol) and AcOH (2.12 g, 35.33 mmol) slowly at 0 ℃. The resulting mixture was stirred at 25 ℃ for 6 h. The reaction mixture was quenched by addition of H2O (120 mL) , extracted with DCM (100 mL*3) . The combined organic layers were washed with brine (60 mL*2) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~50%EtOAc) to afford methyl 1- [4- (2-tert-butoxy-2-oxo-ethyl) cyclohexyl] azetidine-3-carboxylate. LC/MS: MS (ESI) M/Z 312.3 [M+H] +.
Step B: tert-butyl 2- (4- (3-formylazetidin-1-yl) cyclohexyl) acetate
To a solution of methyl 1- [4- (2-tert-butoxy-2-oxo-ethyl) cyclohexyl] azetidine-3-carboxylate (2.30 g, 7.39 mmol) in dry DCM (100 mL) was added DIBAL-H in toluene (18.5 mL, 18.5 mmol) dropwise at -78 ℃ under N2 atmosphere. The resulting mixture was stirred at -78 ℃ for 30 min. The reaction mixture was quenched by addition of sodium sulfate decahydrate (~6 g) and stirred at -78 ℃ for 30 min. The reaction mixture was filtered through a Celite pad and the filter cake was washed with DCM (3*80 mL) . The filtrate combined was concentrated to give tert-butyl 2- (4- (3-formylazetidin-1-yl) cyclohexyl) acetate, which was used for the next step without further purification. LC/MS: MS (ESI) M/Z 282.4 [M+H] +.
Step C: tert-butyl 2- (4- (3-ethynylazetidin-1-yl) cyclohexyl) acetate
To a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (1.30 g, 6.83 mmol) in MeOH (60 mL) was added K2CO3 (943 mg, 6.83 mmol) . The mixture was stirred at 25 ℃ for 0.5 h. Tert-butyl 2- [4- (3-formylazetidin-1-yl) cyclohexyl] acetate (1.61 g, 5.69 mmol) was added. The resulting mixture was stirred at 25 ℃ for 11.5 h. The reaction mixture was quenched by addition of H2O (100 mL) , extracted with DCM (100 mL*3) . The combined organic layers were washed with brine (50 mL*2) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluant: Petroleum Ether with 0~20%EtOAc) to afford tert-butyl 2- [4- (3-ethynylazetidin-1-yl) cyclohexyl] acetate. LC/MS: MS (ESI) M/Z 278.3 [M+H] +.
Step D: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [4- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] cyclohexyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 13. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H) , 7.89 (d, J = 7.2 Hz, 1H) , 7.75 (d, J = 8.4 Hz, 1H) , 7.61 (d, J = 7.2 Hz, 1H) , 7.44 -7.28 (m, 10 H) , 6.82 (d, J = 7.6 Hz, 2H) , 4.99 -4.90 (m, 4 H) , 4.63 -4.30 (m, 7H) , 4.19 -4.15 (m, 2 H) , 3.98 -3.95 (m, 2 H) , 3.89 -3.76 (m, 5 H) , 3.35 -3.31 (m, 2 H) , 3.25 -3.21 (m, 2 H) , 3.06 -3.03 (m, 2H) , 2.44 (s, 3 H) , 2.28 -2.03 (m, 6 H) , 1.78 –1.27 (m, 6H) , 1.01 (s, 9H) . LC/MS: MS (ESI) M/Z 1202.6 [M+H] +.
Example 15: Compound 15
Step A: tert-butyl 1- (1- ( (benzyloxy) carbonyl) azetidin-3-yl) piperidine-4-carboxylate
To a suspension of benzyl 3-oxo azetidine-1-carboxylate (5.02 g, 24.39 mmol) and tert-butyl piperidine-4-carboxylate (5.40 g, 24.37 mmol) in THF (100 mL) was added AcOH (731.6 mg, 12.18 mmol) . The resulting mixture was stirred at R. T for 5 min. Then NaBH (OAc) 3 (15.49 g, 73.10 mmol) was added. The resulting mixture was stirred at 25 ℃ for 4 h. The mixture was added H2O (80 mL) , extracted with EtOAc (3*80 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~50%EtOAc) to give tert-butyl 1- (1-benzyloxycarbonylazetidin-3-yl) piperidine-4-carboxylate. LCMS: MS (ESI) M/Z: 375.3 [M+H] +.
Step B: tert-butyl 1- (azetidin-3-yl) piperidine-4-carboxylate
To a solution of tert-butyl 1- (1-benzyloxycarbonylazetidin-3-yl) piperidine-4-carboxylate (4.80 g, 12.82 mmol) in MeOH (100 mL) was added Pd/C (1.21 g, 50%purity) and AcOH (2.31 g, 38.45 mmol) . The resulting mixture was degassed under vacuum and purged with H2 for 3 times. The mixture was stirred under H2 at rt for 1 h. The reaction mixture was filtered through a celite pad and the filter cake was washed with MeOH (3*30 mL) . The filtrate combined was
concentrated to give tert-butyl 1- (azetidin-3-yl) piperidine-4-carboxylate. LC/MS: MS (ESI) M/Z 241.3 [M+H] +.
Step C: tert-butyl 1- (1- (prop-2-yn-1-yl) azetidin-3-yl) piperidine-4-carboxylate
To a suspension of tert-butyl 1- (azetidin-3-yl) piperidine-4-carboxylate (2.5 g, 8.32 mmol, AcOH salt) and K2CO3 (3.45 g, 24.97 mmol) in CH3CN (100 mL) was added a solution of 3-bromoprop-1-yne (990 mg, 8.32 mmol) in CH3CN (5 mL) dropwise at 0 ℃. The resulting mixture was stirred at 25 ℃ for 2 h. The solid was removed by filtration and washed with EtOAc (2*10 mL) . The filtrate was concentrated to dryness. The residue was purified by column chromatography (sical gel, eluant: DCM with 0~5%MeOH) to afford tert-butyl 1- (1-prop-2-ynylazetidin-3-yl) piperidine-4-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 3.44-3.48 (m, 2 H) , 3.26 (d, J =2.4Hz, 2 H) , 3.02-3.06 (m, 2 H) , 2.89-2.95 (m, 1 H) , 2.67-2.70 (m, 2 H) , 2.22 (t, J =2.4 Hz, 1 H) , 2.07-2.19 (m, 2 H) , 1.81-1.86 (m, 4 H) , 1.63-1.73 (m, 2 H) , 1.41 (s, 9 H) . LC/MS: MS (ESI) M/Z 279.3 [M+H] +.
Step D: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 13. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.57 (t, J =6.0 Hz, 1H) , 8.02 (d, J =7.6 Hz,1H) , 7.78 (d, J =8.4 Hz, 2H) , 7.67 (d, J =7.6 Hz, 1H) , 7.32-7.49 (m, 11H) , 6.89 (d, J =8.8 Hz, 2H) , 4.83 (s, 1H) , 4.52 (d, J =9.2 Hz, 1H) , 4.40-4.45 (m, 2H) , 4.34 (m, 1H) , 4.18-4.24 (m, 1H) , 3.98 (t, J =6.4 Hz, 2H) , 3.71 (t, J =6.0 Hz, 2H) , 3.60-3.68 (m, 2H) , 3.33 (t, J =6.4 Hz, 5H) , 3.16 (t, J =7.6 Hz, 2H) , 2.98-3.03 (m, 4H) , 2.79-2.86 (m, 1H) , 2.69-2.73 (m, 2H) , 2.44 (s, 3H) , 2.31-2.39 (m, 1H) , 1.96-2.01 (m, 3H) , 1.86-1.92 (m, 1H) , 1.65-1.75 (m, 3H) , 1.45-1.54 (m, 3H) , 0.92 (s, 9H) . LC/MS: 1023.70 [M+H] +.
Example 16: Compound 16
Step A: tert-butyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of methoxymethyl (triphenyl) phosphonium (4.30 g, 12.54 mmol) in THF (60 mL) was added t-BuOK (2.11 g, 18.80 mmol) at 0℃. After 0.5 h, the mixture was added tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (1.5 g, 6.27 mmol) and stirred at 70 ℃ for 4 hrs. The reaction mixture was treated with water (100 mL) and extracted with EA (3 *50 mL) . The organic layer combined was washed with brine (3 *200 mL) , dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by chromatography on silica gel column eluting PE: EA=20: 1~8: 1 to give tert-butyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 5.76 (s, 1H) , 3.59 (s, 4H) , 3.51 (s, 3H) , 2.14 (s, 2H) , 1.92-1.89 (m, 2H) , 1.64-1.61 (m, 4H) , 1.43 (s, 9H) .
Step B: tert-butyl 7-formyl-2-azaspiro [3.5] nonane-2-carboxylate
To a solution of tert-butyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate (1.47 g, 5.50 mmol) in DCM (10 mL) was added TFA: H2O=1: 10 (5 mL) . The mixture was stirred at room temperature for 4 hrs. The reaction mixture was treated with water (100 mL) and extracted with DCM (3*50 mL) . The organic layer combined was washed with brine (3*200 mL) , dried over Na2SO4 and concentrated in vacuo to give the title compound as a crude product, which was used in next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 9.62 (s, 1H) , 3.57 (d, J = 2.5 Hz, 4H) , 2.23-2.18 (m, 1H) , 1.89-1.84 (m, 4H) , 1.55-1.48 (m, 4H) , 1.43 (s, 9H) .
Step C: tert-butyl 7-ethynyl-2-azaspiro [3.5] nonane-2-carboxylate
To a solution of tert-butyl 7-formyl-2-azaspiro [3.5] nonane-2-carboxylate (1.2 g, 4.74 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.36 g, 7.11 mmol) in MeOH (20 mL) was added K2CO3 (981.97 mg, 7.11 mmol) . The resulting mixture was allowed to stir at room temperature for 1 hr. The reaction mixture was quenched with water (80 mL) and extracted with EA (3*30 mL) . The organic layer combined was washed with brine (3*100 mL) , dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by chromatography on silica gel column eluting PE: EA=50: 1~10: 1 to give tert-butyl 7-ethynyl-2-azaspiro [3.5] nonane-2-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 3.56 (d, J = 16.2 Hz, 4H) , 2.36 (s, 1H) , 2.03 (d, J = 2.5 Hz, 1H) , 1.89-1.83 (m, 2H) , 1.74 (s, 2H) , 1.53-1.46 (m, 4H) , 1.42 (s, 9H) .
Step D: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (tert-butoxycarbonyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 7-ethynyl-2-azaspiro [3.5] nonane-2-carboxylate (210.54 mg, 844.35 μmol) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (300 mg, 422.18 μmol) in DMF (5 mL)
was added CuI (40.20 mg, 211.09 μmol. ) , Pd (PPh3) 4 (243.93 mg, 211.09 μmol) and DIEA (218.25 mg, 1.69 mmol) at room temperature. The resulting mixture was degassed under vacuum and purged with N2 for 3 times. The resulting mixture was allowed to stir at 60℃ for 4 hrs under N2. The reaction mixture was quenched with water (50 mL) and extracted with EA (3*30 mL) . The organic layer combined was washed with brine (3*100mL) , dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by chromatography on silica gel column eluting DCM: MeOH=100: 1~20: 1 and Prep-TLC to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- (2-tert-butoxycarbonyl-2-azaspiro [3.5] nonan-7-yl) ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 833.4 [M+H] +.
Step E: methyl 5- (3- (4- (2-azaspiro [3.5] nonan-7-ylethynyl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- (2-tert-butoxycarbonyl-2-azaspiro [3.5] nonan-7-yl) ethynyl] phenoxy] propyl] thiazole-4-carboxylate (460 mg, 552.86 μmol) was added FA (5 mL) . The resulting mixture was allowed to stir at room temperature for 18 hrs. The reaction mixture was concentrated in vacuo to give methyl 5- [3- [4- [2- (2-azaspiro [3.5] nonan-7-yl) ethynyl] phenoxy] propyl] -2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] thiazole-4-carboxylate, which was used in next step without further purification. LC/MS: MS (ESI) M/Z 366.8 [M+2H] +/2.
Step F: 2- (7- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) -2-azaspiro [3.5] nonan-2-yl) acetic acid
To a solution of 2- (7- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) -2-azaspiro [3.5] nonan-2-yl) acetic acid and oxaldehydic acid (788.98 mg, 10.66 mmol) in DMF (5 mL) and DCE (5 mL) was added AcOH (95.99 mg, 1.60 mmol) and NaBH (OAc) 3 (173.74 mg, 819.76 μmol) . The resulting mixture was allowed to stir at room temperature for 2hrs. The reaction mixture was concentrated in vacuo to give a crude. The crude reaction mixture was filtered and purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [7- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] -2-azaspiro [3.5] nonan-2-yl] acetic acid. LC/MS: MS (ESI) M/Z 395.4 [M+2H] +/2.
Step G: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- [7- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] -2-azaspiro [3.5] nonan-2-yl] acetic acid (25 mg, 31.65 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (16.35 mg, 37.98 μmol) in DMF (1 mL) was added EDCI (30.33 mg, 158.24 μmol) , , HOBT (21.45 mg, 158.88 μmol) and DIEA (40.90 mg, 316.47 μmol) . The resulting mixture was allowed to stir at room temperature for 18 hrs. The reaction mixture was quenched with water (50mL) and extracted with EA (3*20mL) . The organic layer combined was washed with brine (3*100 mL) , dried over Na2SO4 and concentrated in vacuo. The reaction mixture was purified by Prep-TLC to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-7-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 417.1 [M+2H] +/2.
Step H: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-7-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-7-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate (16 mg, 13.31 μmol) in MeOH (1 mL) and THF (1 mL) was added LiOH (3.19 mg, 133.06 μmol) . The resulting mixture was allowed to stir at room temperature for 4 hrs. The reaction mixture was concentrated in vacuo. The pH value of the reaction mixture was adjusted to pH=4-5 with 0.1M HCl solution. The reaction mixture was filtered and the filter cake was washed with H2O (3*1 mL) to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-7-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid . LC/MS: MS (ESI) M/Z 1189.7 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H) , 10.30 (s, 1H) , 8.95
(s, 1H) , 8.57 (t, J = 5.9 Hz, 1H) , 8.00 (d, J = 8.0 Hz, 1H) , 7.75 (d, J = 8.2 Hz, 1H) , 7.63 (d, J = 7.1 Hz, 1H) , 7.46-7.30 (m, 9H) , 7.21 (d, J = 8.5 Hz, 2H) , 6.81 (d, J = 8.8 Hz, 2H) , 5.14 (s, 1H) , 4.79 (s, 2H) , 4.50 (d, J = 9.6 Hz, 1H) , 4.43-4.33 (m, 3H) , 4.19 (dd, J = 15.8, 5.1 Hz, 1H) , 3.93 (t, J = 6.2 Hz, 2H) , 3.69-3.63 (m, 3H) , 3.54 (d, J = 10.2 Hz, 1H) , 3.12 (t, J = 7.4 Hz, 2H) , 2.98 (t, J = 5.9 Hz, 2H) , 2.40 (s, 3H) , 2.04-1.87 (m, 6H) , 1.68-1.41 (m, 6H) , 1.19 (s, 6H) , 1.12 (d, J = 7.4 Hz, 1H) , 0.91 (s, 9H)
Example 17: Compound 17
Step A: tert-butyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of (methoxymethyl) (methyl) diphenylphosphonium chloride (4.30 g, 1.25 mol) in THF (50 mL) was added t-BuOK (1.5 g, 1.34 mmol) . The reaction was stirred at 15 ℃for 0.5 h under N2. Then tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (2.0 g, 835.7 mmol) was added. The resulting solution was stirred at 70 ℃ for another 2 h under N2. The mixture was cooled to R. T. The reaction mixture was quenched by addition of H2O (40 mL) , extracted with EtOAc (3*50 mL) . The combined organic layers were washed with brine (2*40 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~30%EtOAc) to afford tert-butyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate.
Step B: tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate
To a solution of tert-butyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate (2.01 g, 7.49 mmol) in MeCN (30 mL) and H2O (7.5 mL) was added TFA (0.3 mL) . The mixture was stirred at R. T for 2 h. The pH value of the resulting mixture was adjusted to 9 by using saturated Na2CO3. The mixture was extracted with EtOAc (3*30 mL) . The combined organic layers were washed with brine (2*20 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate (1.99 g, crude) , which was used for next step without purification.
Step C: tert-butyl 2-ethynyl-7-azaspiro [3.5] nonane-7-carboxylate
To a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (1.82 g, 9.47 mmol) in MeOH (20 mL) was added K2CO3 (1.31 g, 9.47 mmol) . The resulting solution was stirred at R. T for 0.5 h. Then tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate (2.01 g, 7.89 mmol) was added. The mixture was stirred at R. T for another 1.5 h. The mixture was added H2O (60 mL) and extracted with EtOAc (3 *60 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluant: Petroleum Ether with 0~20%EtOAc) to afford tert-butyl 2-ethynyl-7-azaspiro [3.5] nonane-7-carboxylate.
Step D: 2-ethynyl-7-azaspiro [3.5] nonane
To a solution of tert-butyl 2-ethynyl-7-azaspiro [3.5] nonane-7-carboxylate (400 mg, 1.61 mmol) in DCM (5 mL) was added TFA (1 mL) . The mixture was stirred at 30 ℃ for 2 h. The mixture was concentrated under reduced pressure to afford crude 2-ethynyl-7-azaspiro [3.5] nonane (410 mg, TFA salt) as a yellow oil which was used for next step without purification.
Step E: tert-butyl 3- (2-ethynyl-7-azaspiro [3.5] nonan-7-yl) propanoate
To a solution of crude 2-ethynyl-7-azaspiro [3.5] nonane (400 mg, TFA salt) and tert-butyl 3-bromopropanoate (476 mg, 2.28 mmol) in MeCN (10 mL) was added TEA (615 mg, 6.08 mmol, 847.70 μL) . The mixture was stirred at 30 ℃ for 16 h. The mixture was concentrated in vacuum. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~40%EtOAc) to afford tert-butyl 3- (2-ethynyl-7-azaspiro [3.5] nonan-7-yl) propanoate. LC/MS: MS (ESI) M/Z 278.3 [M+H] +.
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (7- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropyl) -7-azaspiro [3.5] nonan-2-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 13. 1H-NMR (400 MHz, CD3OD) δ 8.78 (s, 1H) , 8.54 (t, J = 6.0 Hz, 1H) , 8.07 (d, J = 8.0 Hz,
1H) , 7.83 (d, J = 8.0 Hz, 1H) , 7.68 (d, J = 8.4 Hz, 1H) , 7.54 (d, J = 7.2 Hz, 1H) , 7.38-7.23 (m, 8H) , 7.12 (d, J = 8.4 Hz, 2H) , 6.70 (d, J = 8.8 Hz, 2H) , 4.80 (s, 1H) , 4.50-4.43 (m, 4H) , 4.34-4.23 (m, 1H) , 3.90-3.85 (m, 3H) , 3.73-3.66 (m, 3H) , 3.40-3.27 (m, 4H) , 3.16 (t, J = 7.2 Hz, 2H) , 2.97 (t, J = 6.0 Hz, 2H) , 2.89-2.83 (m, 2H) , 2.76-2.67 (m, 1H) , 2.37-1.70 (m, 14H) , 1.29-1.13 (m, 4H) , 0.977 (s, 9H) . LC/MS: MS (ESI) M/Z 1202.6 [M+H] +.
Example 18: Compound 18
Step A: tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate
To a solution of (methoxymethyl) triphenylphosphonium chloride (15.11 g, 44.06 mmol) in THF (150 mL) was added potassium tert-butoxypotassium (5.27 g, 47.00 mmol) at 0 ℃. The mixture was stirred for 30 mins at 0 ℃ under N2, and then stirred for 60 mins at rt under N2. The mixture was cooled to 0 ℃ and tert-butyl 3-oxocyclobutanecarboxylate (5 g, 29.38 mmol) was added as a solution in THF (3mL) . The result mixture was stirred at rt for 3 hours, then for another three hours at 70℃. The mixture was diluted with EtOAc (50 mL) and washed with saturate aq. NH4Cl (50mL) . The organic layer was separated and dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography, (EtOAc/heptane, 0 to 80%) to give tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate. 1H NMR (400 MHz, CDCl3) δ 5.80-5.78 (m, 1H) , 3.54 (s, 3H) , 3.08-3.00 (m, 1H) , 2.92-2.75 (m, 4H) , 1.46-1.42 (s, 9H) .
Step B: tert-butyl 3-formylcyclobutanecarboxylate
To a solution of tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate (1.5 g, 7.57 mmol) in DCM (60 mL) was added H2O: TFA=25: 1 (15 mL) at rt, the resulting mixture was stirred at rt for 16 hr. The resulting mixture was extracted with DCM (3*20 mL) . The combined organic layers were washed with brine (2*10 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE/EtOAc=20/1 to give tert-butyl 3-formylcyclobutanecarboxylate. 1H NMR (400 MHz, CDCl3) δ 9.69 (d, 1H) , 3.10-2.98 (m, 2H) , 2.49-2.36 (m, 4H) , 1.44 (m, 9H)
Step C: tert-butyl 4-ethynylpiperidine-1-carboxylate
To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (11.71 g, 60.95 mmol) in MeOH (100 mL) was added K2CO3 (12.96 g, 93.78 mmol) . The resulting mixture was stirred at rt for 1h and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10 g, 46.89 mmol) in THF (20 mL) was added. The reaction solution was stirred at rt 16 hr. The resulting mixture was concentrated under reduced pressure. The mixture was added H2O (200 mL) , extracted with EA (3*100 mL) . The combined organic layer was washed with water (3*10 mL) , brine (3*20 mL) , dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc 0~10/1) to give tert-butyl 4-ethynylpiperidine-1-carboxylate. LC/MS: MS (ESI) M/Z 154.2 [M+H-t-Bu] +.
Step D: 4-ethynylpiperidine hydrochloride
To a solution of tert-butyl 4-ethynylpiperidine-1-carboxylate (2.5 g, 11.95 mmol) in dioxane-HCl (4M, 20 mL) at rt, the resulting mixture was stirred at rt for 3hr. The reaction mixture was concentrated to give 4-ethynylpiperidine hydrochloride (1.70 g, crude) and used for the next step without further purification.
Step E: tert-butyl 3- [ (4-ethynyl-1-piperidyl) methyl] cyclobutanecarboxylate
To a solution of 4-ethynylpiperidine hydrochloride (513.80 mg) and tert-butyl 3-formylcyclobutanecarboxylate (500 mg, 2.71 mmol, 0.76 equiv) in DCE: MeOH=1: 1 (4 mL) was stirred at rt for 1hr. Then sodium triacetoxyborohydride (1.16 g, 5.43 mmol) was added, the mixture was stirred at rt for 16 hr. Brine (80 mL) was added, extracted with EA (3*50mL) . The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography eluted with (DCM/MeOH= 20/1) to give tert-butyl 3- [ (4-ethynyl-1-piperidyl) methyl] cyclobutanecarboxylate. LC/MS: MS (ESI) M/Z 278.3 [M+H] +.
Step F: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-
propyl] carbamoyl] cyclobutyl] methyl] -4-piperidyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 13.LC/MS: MS (ESI) M/Z 1203.6 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H) , 7.84 (d, J = 8.0 Hz, 1H) , 7.68 (d, J = 8.2 Hz, 1H) , 7.53 (d, J = 7.1 Hz, 1H) , 7.38-7.16 (m, 13H) , 6.71 (d, J = 8.5 Hz, 2H) , 4.57-4.42 (m, 4H) , 3.88 (m, 2H) , 3.72 (m, 3H) , 3.55-3.60 (m, 1H) , 3.11-2.96 (m, 7H) , 2.38-2.30 (m, 4H) , 2.16-2.09 (m, 1H) , 2.02-1.97 (m, 6H) , 1.92-1.84 (m, 3H) , 1.36 (s, 1H) , 1.30-1.20 (m, 9H) , 1.18-1.14 (m, 1H) , 0.94-0.91 (m, 9H) .
Example 19: Compound 19
Step A: benzyl 4-vinylpiperidine-1-carboxylate
To a solution of methyltriphenylphosphonium bromide (21.67 g, 60.66 mmol) in THF (100 mL) was cooled to 0℃ and added slowly t-BuOK (7.25 g, 64.70 mmol) , then stirred for 1h at 25 ℃. benzyl 4-formylpiperidine-1-carboxylate (10.0 g, 40.44 mmol) was added and the mixture was stirred for 2 hr at 25 ℃. The mixture was quenched with NH4Cl (aq) and diluted with EA, the mixture was extracted with EA (3*200 ml) and combined with the organic layer and washed with brine, concentrated on vacuum and the crude was purified by silica gel column chromatography using PE: EA=5: 1 to afford benzyl 4-vinylpiperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 246.2 [M+H] +.
Step B: benzyl 4- (2, 2-dichloro-3-oxocyclobutyl) piperidine-1-carboxylate
To a solution of benzyl 4-vinylpiperidine-1-carboxylate (4.5 g, 18.34 mmol) in dioxane (50 mL) was added POCl3 (3.09 g, 20.18 mmol) and Zn-Cu couple (9.47 g, 73.37 mmol) and the mixture was cooled to 0℃. 2, 2, 2-trichloroacetyl chloride (13.34 g, 73.37 mmol) was added dropwise and the mixture was stirred for 16 hr at 25 ℃. The mixture was quenched with NaHCO3 (aq) in ice water, then was extracted with EA (3*100 ml) , combined with organic layer
and washed with brine, dried over Na2SO4, concentrated on vacuum to afford benzyl 4- (2, 2-dichloro-3-oxocyclobutyl) piperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 356.2 [M+H] +.
Step C: benzyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate
To a solution of benzyl 4- (2, 2-dichloro-3-oxocyclobutyl) piperidine-1-carboxylate (7.5 g, 21.05 mmol) in methanol (100 mL) and water (10 mL) was added Zn (4.10 g, 63.15 mmol) , NH4Cl (4.50 g, 84.20 mmol) , then the mixture was stirred for 16 hr at 25 ℃. The mixture was filtered and the filter was concentrated on vacuum, the crude was purified by silica gel column chromatography using PE: EA=4: 1 to give benzyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 288.3 [M+H] +.
Step D: tert-butyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate
To a solution of benzyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate (4.7 g, 16.36 mmol) in methanol (150 mL) was added Pd/C (500 mg, 10%w/w) , Di-tert-butyl dicarbonate (3.75 g, 17.17 mmol, 1.05 equiv) and TEA (4.14 g, 40.89 mmol) , the mixture was stirred for 16 hr at 25 ℃ under H2. The mixture was filtered and the filter was concentrated on vacuum and the crude was purified by silica gel column chromatography using PE: EA = 8: 1 to afford tert-butyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 239.2 [M+H-t-Bu+MeCN] +.
Step E: tert-butyl 4- (3- (methoxymethylene) cyclobutyl) piperidine-1-carboxylate
To a solution of (methoxymethyl) triphenylphosphonium bromide (4.59 g, 11.84 mmol) in THF (20 mL) was cooled to 0℃ and was added t-BuONa (1.16 g, 12.63 mmol) , then stirred for 1 h at rt. tert-butyl 4- (3-oxocyclobutyl) piperidine-1-carboxylate (2.0 g, 7.89 mmol) was added at 0℃, the mixture was stirred for 16 hr at 25℃. The mixture was quenched with NH4Cl (aq) and extracted with EA (3*50 mL) . The organic layer was combined, then was washed with brine and concentrated on vacuum, the crude was purified by silica gel column chromatography using PE: EA=5: 1 to afford tert-butyl 4- (3- (methoxymethylene) cyclobutyl) piperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 226.3 [M+H] +.
Step F: tert-butyl 4- (3-formylcyclobutyl) piperidine-1-carboxylate
To a solution of tert-butyl 4- (3- (methoxymethylene) cyclobutyl) piperidine-1-carboxylate (1.6 g, 5.69 mmol) in ACN (15 mL) was added TFA (10%in water, 5 mL) , the mixture was stirred for 16 hr at 25 ℃. The mixture was added NaHCO3 (aq) and extracted with EA (3*20 mL) , combined the organic layer, concentrated on vacuum to afford tert-butyl 4- (3-formylcyclobutyl) piperidine-1-carboxylate. LCMS: MS (ESI) M/Z: 253.3 [M+H-56+41] +.
Step G: tert-butyl 4- (3-ethynylcyclobutyl) piperidine-1-carboxylate
To a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (2.30 g, 11.97 mmol) in methanol (20 mL) was added K2CO3 (2.48 g, 17.95 mmol) and stirred for 30 mins at rt, tert-butyl 4- (3-formylcyclobutyl) piperidine-1-carboxylate (1.6 g, 5.98 mmol) was added and the mixture was stirred for 5 hr at 25 ℃. the mixture was concentrated on vacuum and the mixture was purified by silica gel column chromatography using PE: EA=5: 1 to afford tert-butyl 4- (3-ethynylcyclobutyl) piperidine-1-carboxylate.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (300 mg, 422.18 μmol) and tert-butyl 4- (3-ethynylcyclobutyl) piperidine-1-carboxylate (166.79 mg, 633.26 μmol) in DMF (5 mL) was added Pd (PPh3) 2Cl2 (59.19 mg, 84.44 μmol) , CuI (32.16 mg, 168.87 μmol) and DIEA (164.65 mg, 1.27 mmol) , then the mixture was stirred for 16 hr at 25 ℃. The mixture was diluted with NH4Cl (aq. ) , the water was extracted with EA (3*20ml) , combined the organic layer and washed with brine, dried over Na2SO4 and concentrated on vacuum, the crude was purified by Prep-TLC using DCM: MeOH=20: 1 to afford methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 846.4 [M+H] +.
Step I: methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
The solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (160 mg, 189.11 μmol) in FA (3 mL) was stirred for 0.5 hr at 30℃ and the mixture was concentrated on vacuum to afford methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 746.4 [M+H] +.
Step J: 2- (4- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclobutyl) piperidin-1-yl) acetic acid
To a solution of methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (140 mg, 187.68 μmol) and glyoxylic acid monohydrate (34.55 mg, 375.36 μmol) in methanol
(5 mL) was added AcOH (33.78 mg, 563.04 μmol) . Then the mixture was stirred for 30min at room temperature and added NaBH3CN (29.56 mg, 469.20 μmol) stirred for 16 hr at 25 ℃. The mixture was filtered and the filter cake was concentrated on vacuum to afford 2- (4- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclobutyl) piperidin-1-yl) acetic acid. LCMS: MS (ESI) M/Z: 804.4 [M+H] +.
Step K: methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- (4- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclobutyl) piperidin-1-yl) acetic acid (90 mg, 111.94 μmol, 1.0 equiv. ) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (48.20 mg, 111.94 μmol) in DMF (2 mL) was added DIEA (43.66 mg, 335.83 μmol) and HATU (51.05 mg, 134.33 μmol) , then was stirred for 1 hr at 25 ℃. The mixture was diluted with EA and water and the water layer was extracted with EA (3*30 mL) , the organic layer was washed with brine and dried over Na2SO4 and concentrated on vacuum. The crude was purified by Prep-TLC using MeOH: DCM=1: 10 to afford methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1216.7 [M+H] +.
Step L: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (72 mg, 59.18 μmol) in dioxane (2 mL) was added aq. NaOH (2 M, 591.85 μL) , the mixture was stirred for 2 hr at 25 ℃. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of
50%MeCN in water to 55%MeCN in water over a 7 min period, where both solvents contain 0.1%TFA) to afford 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (1- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperidin-4-yl) cyclobutyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid. LCMS: MS (ESI) M/Z: 1202.7 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 12.72-13.09 (m, 1H) , 9.00 (s, 1H) , 8.80-8.61 (m, 2H) , 8.04 (d, J = 7.4 Hz, 1H) , 7.80 (d, J = 8.0 Hz, 1H) , 7.67 (d, J = 7.7 Hz, 1H) , 7.50-7.34 (m, 8H) , 7.26 (q, J = 9.1 Hz, 2H) , 6.88-6.83 (m, 2H) , 4.83 (s, 2H) , 4.59 (d, J = 9.1 Hz, 1H) , 4.49-4.37 (m, 3H) , 4.26-4.19 (m, 1H) , 4.05-3.96 (m, 4H) , 3.73-3.60 (m, 4H) , 3.51-3.43 (m, 2H) , 3.16 (t, J = 7.4 Hz, 3H) , 3.07-2.95 (m, 5H) , 2.45 (s, 3H) , 2.40-2.33 (m, 1H) , 2.13-1.88 (m, 6H) , 1.77-1.74 (m, 4H) , 1.53-1.23 (m, 3H) , 0.95 (s, 9H) .
Example 20: Compound 20
Step A: tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate
To a solution of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (3.0 g, 13.08 mmol) in dry DCM (30 mL) was added DMP (6.10 g, 14.39 mmol) slowly under nitrogen atmosphere at 25 ℃, and the reaction mixture was stirred at 25 ℃ for 8 h. The reaction mixture was diluted with H2O (50 mL) and the pH value of the solution was adjusted to 5-6 with NaHCO3 (aqu) . Then it was extracted with ethyl acetate (3*50 mL) . The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate. LC/MS: MS (ESI) M/Z 172.1 [M+H-Boc] +.
Step B: tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate
To a solution of dimethyl (1-Diazo-2-oxopropyl) phosphonate (1.81 g, 9.40 mmol) in dry MeOH (20 mL) was added K2CO3 (2.16 g, 15.66 mmol) slowly under nitrogen atmosphere at 25 ℃, and the reaction mixture was stirred at 25 ℃ for 30 min. Then a solution of tert-butyl4- (2-oxoethyl) piperidine-1-carboxylate (1.78 g, 7.83 mmol) in dry MeOH (20 mL) was added and the mixture stirred for an additional 8 hr. The reaction mixture was concentrated to dryness and was diluted with H2O (200 mL) . Then it was extracted with ethyl acetate (3*200 mL) . The combined organic layer was dried over Na2SO4 and concentrated. The crude product was
purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate. LC/MS: MS (ESI) M/Z 168.1 [M+H-Boc] +.
Step C: 4-prop-2-ynylpiperidine
A solution of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (1.484 g, 3.06 mmol) in dioxane (1 mL) was added HCl-dioxane (4 M, 1 mL) at 25℃, the resulting mixture was stirred at 25℃ for 2 hr in N2. The reaction mixture was concentrated to dryness to give product 4-prop-2-ynylpiperidine (1.047 g, crude) and used for the next step without further purification. LC/MS: MS (ESI) M/Z 168.1 [M+H-Boc] +.
Step D: tert-butyl 3- (4-prop-2-ynyl-1-piperidyl) cyclobutanecarboxylate
To a solution of tert-butyl 3-oxocyclobutanecarboxylate (755.32 mg, 4.44 mmol) in dry DCE (10 mL) was added 4-prop-2-ynylpiperidine (497 mg, 4.03 mmol) under nitrogen atmosphere at 50 ℃, and the reaction mixture was stirred at 50 ℃ for 30 min. Then a solution of sodium triacetoxyhydroborate (1.71 g, 8.07 mmol) in dry was added and the mixture stirred at 50 ℃ for an additional 8 hr. The reaction mixture was diluted with H2O (10 mL) and the pH value of the solution was adjusted to 7-8 with aqueous NaHCO3. Then it was extracted with DCM (3*10 mL) . The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give tert-butyl 3- (4-prop-2-ynyl-1-piperidyl) cyclobutanecarboxylate.
Step E: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- (3-tert-butoxycarbonylcyclobutyl) -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (200 mg, 281.45 μmol) and tert-butyl 3- (4-prop-2-ynyl-1-piperidyl) cyclobutanecarboxylate (195.19 mg, 703.63 μmol) in THF (4 mL) was added tetrakis (triphenylphosphine) palladium (32.52 mg, 28.15 μmol) and CuI (10.72 mg, 56.29 μmol) at 25 ℃, the resulting mixture was stirred at 60 ℃ for 2 hr in N2. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1: 2 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- (3-tert-butoxycarbonylcyclobutyl) -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 430.8 [M/2+H] +.
Step F: 3- [4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -1-piperidyl] cyclobutanecarboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- (3-tert-butoxycarbonylcyclobutyl) -4-piperidyl] prop-1-
ynyl] phenoxy] propyl] thiazole-4-carboxylate (110 mg, 127.89 μmol) in HCOOH (9 mL) at 25 ℃, the resulting mixture was stirred at rt for 7 hr in N2. The reaction mixture was concentrated to dryness to give product 3- [4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -1-piperidyl] cyclobutanecarboxylic acid (88.00 mg, crude) and used for the next step without further purification. LC/MS: MS (ESI) M/Z 403.1 [M/2+H] +
Step G: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (47.13 mg, 109.45 μmol) and 3- [4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -1-piperidyl] cyclobutanecarboxylic acid (88 mg, 109.45 μmol) in DMF (4 mL) was added DIEA (42.44 mg, 328.36 μmol) and HATU (61.94 mg, 164.18 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 2 hr under N2 atmosphere. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 61.5%MeCN in water to 81.5%MeCN in water over a 10 min period, where both solvents contain 0.05%NH3H2O) to provide methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 609.1 [M/2+H] +
Step H: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5 - [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (20 mg, 16.44 μmol) in dioxane (2 mL) was added LiOH·H2O (1.38 mg, 32.88 μmol) in H2O (0.4 mL) at 25 ℃, the resulting mixture was stirred at 25℃ for 2 hr in N2. The reaction mixture
was diluted with H2O (1 mL) and the pH value of the solution was adjusted to 5-6 with aqueous HCl (1M) . The reaction mixture was filtered and dried under vacuum to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [1- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] -4-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LC/MS: MS (ESI) M/Z 1203.6 [M+H] +
1H-NMR (400 MHz, CD3OD) δ 8.84 (d, J = 2.7 Hz, 1H) , 7.88 (d, J = 7.7 Hz, 1H) , 7.72 (d, J = 8.0 Hz, 1H) , 7.58 (dd, J = 7.0, 1.8 Hz, 1H) , 7.44-7.27 (m, 8H) , 7.21-7.17 (m, 2H) , 6.79-6.74 (m, 2H) , 4.71 (s, 2H) , 4.61 (s, 1H) , 4.55-4.46 (m, 2H) , 3.94 (t, J = 6.5 Hz, 2H) , 3.76 (dd, J = 10.7, 4.1 Hz, 3H) , 3.22 (q, J = 7.1 Hz, 2H) , 3.02 (t, J = 5.9 Hz, 2H) , 2.89-2.77 (m, 2H) , 2.72-2.64 (m, 1H) , 2.44 (s, 3H) , 2.31-2.15 (m, 5H) , 2.12-1.98 (m, 6H) , 1.86-1.78 (m, 4H) , 1.41-1.35 (m, 1H) , 1.31-1.24 (m, 5H) , 0.98 (d, J = 9.3 Hz, 9H) .
Example 21: Compound 21
Step A: 3-azaspiro [5.5] undecan-9-one hydrochloride
To a solution of tert-butyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (2.0 g, 7.48 mmol) in DCM (60.0 mL) was added HCl (4 M in dioxane, 18.70 mL) at 25 ℃. The mixture was stirred for 2 h at 25 ℃. TLC showed that the reaction was completed. The reaction solution was concentrated under reduced pressure to afford the title 3-azaspiro [5.5] undecan-9-one (1.50 g, crude, HCl) and directly used in next reaction without further purification. LCMS: MS (ESI) M/Z: 168.2 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H) , 3.03 (d, J = 1.6Hz, 4H) , 2.25 (t, J = 6.8Hz, 4H) , 1.74-1.69 (m, 8H) .
Step B: benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate
To a solution of 3-azaspiro [5.5] undecan-9-one hydrochloride (1.4 g, 6.87 mmol) and NaHCO3 (1.73 g, 20.62 mmol) in THF (30 mL) was added CbzCl (1.41 g, 8.25 mmol) at 0 ℃. The mixture was stirred for 16 h at 25℃. The reaction solution was filtered and washed with EA (30 mL) . The combined organic layer was concentrated and purified by silica gel chromatography eluted with PE: EtOAc=2: 1 to afford benzyl 9-oxo-3-azaspiro [5.5] undecane-3-
carboxylate. LCMS: MS (ESI) M/Z: 302.2 [M+H] +. 1H-NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 5H) , 5.14 (s, 2H) , 3.53-3.50 (m, 4H) , 2.36-2.32 (m, 4H) , 1.78-1.75 (m, 4H) , 1.57 (s, 4H) .
Step C: benzyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate
To a solution of (methoxymethyl) triphenylphosphonium chloride (1.71 g, 4.98 mmol) in THF (20.0 mL) was added KHMDS in THF (1.00 M, 6.64 mL) at -30 ℃ under N2. The mixture was stirred for 0.5 h at -30℃. After 0.5 h, to a solution of benzyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (1.00 g, 3.32 mmol) in THF (5.0 mL) was above the mixture (10 mL) at -30 ℃ under N2. The mixture was stirred at -30 ℃ for 0.5 h and stirred at 25 ℃ for 2 h. After cooled to 0 ℃, the reaction mixture was quenched with 5.0 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (2*10 mL) . The combined organic layers were washed with water (10 ml) and brine (10 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography eluted with PE: EtOAc=3: 1 to afford the title benzyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate. LCMS: MS (ESI) M/Z: 330.3 [M+H] +. 1H-NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5H) , 5.77 (s, 1H) , 5.12 (s, 2H) , 3.53 (s, 3H) , 3.46 (t, J = 2.0Hz, 4H) , 2.18 (t, J = 6.4Hz, 2H) , 1.95 (t, J = 6.4Hz, 2H) , 1.44-1.39 (m, 8H) .
Step D: benzyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate
To a solution of benzyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate (900.0 mg, 2.73 mmol) in THF (10.0 mL) at 25℃ was added 1M aq. HCl (1.0 M, 5.46 mL) and the mixture was stirred at 25 ℃ for 16 hr. The mixture was diluted with sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3*20 mL) . The combined organic layers was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the benzyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate. LCMS: MS (ESI) M/Z: 316.3 [M+H] +.
Step E: 3- ( (benzyloxy) carbonyl) -3-azaspiro [5.5] undecane-9-carboxylic acid
To a solution of benzyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate (900 mg, 2.85 mmol) and KMnO4 (901.70 mg, 5.71 mmol) in acetone (20 mL) was added NaOH (114.14 mg, 2.85 mmol) and H2O (20 mL) at 0 ℃. The mixture was stirred at 25 ℃ for 4 h. The mixture was acidified to pH ~2 with HCl (2M) and extracted with ethyl acetate (3*30 mL) . The combined organic layers was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title crude 3-benzyloxycarbonyl-3-azaspiro [5.5] undecane-9-carboxylic acid.
LCMS: MS (ESI) M/Z: 332.3 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H) , 7.35-7.26 (m, 5H) , 5.02 (s, 2H) , 3.29 (s, 4H) , 2.06 (d, J = 12.8Hz, 1H) , 1.61-1.21 (m, 10H) , 1.09 (d, J = 6.4Hz, 2H) .
Step F: 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate
To a solution of 3-benzyloxycarbonyl-3-azaspiro [5.5] undecane-9-carboxylic acid (900.0 mg, 2.72 mmol) and DMAP (66.36 mg, 543.14 μmol) in THF (20.00 mL) was added (Boc) 2O (710.43 mg, 3.26 mmol) at 25 ℃ under N2. The mixture was stirred at 25 ℃ for 3 h. After cooled to 0 ℃, the reaction mixture was quenched with 5.0 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (2*10 mL) . The combined organic layers were washed with water (10 ml) and brine (10 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography eluted with PE:EtOAc=3: 1 to afford the title 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate. LCMS: MS (ESI) M/Z: 388.3 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 7.39-7.31 (m, 5H) , 5.05 (s, 2H) , 3.37-3.32 (m, 4H) , 2.14 (d, J = 3.2 Hz, 1H) , 1.63-1.61 (m, 4H) , 1.42-1.40 (m, 13H) , 1.27-1.24 (m, 2H) , 1.22-1.12 (m, 2H) .
Step G: 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate
To a stirred solution of 3-benzyl 9-tert-butyl 3-azaspiro [5.5] undecane-3, 9-dicarboxylate (530 mg, 1.37 mmol) in MeOH (20 mL) was added Pd/C (166.11 mg, 10%w/w) at 25 ℃. The reaction was stirred at room temperature for 16 hrs under H2. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purification by flash silica gel chromatography eluted with DCM: MeOH=0-5%to afford the title tert-butyl 3-azaspiro [5.5] undecane-9-carboxylate. LCMS: MS (ESI) M/Z: 254.3 [M+H] +.
Step H: tert-butyl 3- (prop-2-yn-1-yl) -3-azaspiro [5.5] undecane-9-carboxylate
To a solution of tert-butyl 3-azaspiro [5.5] undecane-9-carboxylate (100.0 mg, 394.67 μmol) in ACN (2.0 mL) was added DIEA (56.00 mg, 434.13 μmol) at 0 ℃. After stirred at 0 ℃for 10 min, 3-bromoprop-1-yne (46.95 mg, 394.67 μmol) was added dropwise to above mixture at 0 ℃ for 20 min. The reaction was stirred at 25 ℃ for 1 h. After completion, the reaction mixture was quenched by the addition of the solution of NH4Cl (2.0 mL) and extracted with DCM (2*5.0 mL) . The organic layers were combined, dried and concentrated under vacuum at 25 ℃ to afford the title tert-butyl 3-prop-2-ynyl-3-azaspiro [5.5] undecane-9-carboxylate. LCMS: MS (ESI) M/Z: 292.3 [M+H] +.
Step I: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (tert-butoxycarbonyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (243.84 mg, 343.14 μmol) in anhydrous DMF (2.00 mL) was added Pd (PPh3) 2Cl2 (24.33 mg, 34.31 μmol) , CuI (13.07 mg, 68.63 μmol) , TEA (104.17 mg, 1.03 mmol) and tert-butyl 3-prop-2-ynyl-3-azaspiro [5.5] undecane-9-carboxylate (100.0 mg, 343.14 μmol) at 25 ℃. The reaction mixture
was stirred at 25 ℃ for 16 hrs under N2. After completion, the reaction mixture was poured by addition H2O (50.0 mL) , and filtered. The combined organic solid were washed with water (5.0 mL) and concentrated under reduced pressure. The residue was purified by Prep_HPLC to afford the title product methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (9-tert-butoxycarbonyl-3-azaspiro [5.5] undecan-3-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 874.7 [M+H] +.
Step J: 3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecane-9-carboxylic acid
The solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (9-tert-butoxycarbonyl-3-azaspiro [5.5] undecan-3-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (40 mg, 45.76 μmol) in FA (0.5 mL) under N2 was stirred at 30 ℃ for 2 hrs. After completion, the reaction mixture was concentrated under vacuum at 25 ℃ to afford the 3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecane-9-carboxylic acid. LCMS: MS (ESI) M/Z: 818.5 [M+H] +
Step K: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
The solution of 3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecane-9-carboxylic acid (38.00 mg, 46.45 μmol) , HATU (22.95 mg, 60.39 μmol) , DIEA (17.98 mg, 139.36 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (22.00 mg, 51.10 μmol) in anhydrous DMF (4.0 mL) was stirred at room temperature for 16 hrs. After completion, the mixture was poured into water (20.0 mL) , and extracted with EA (3*5.0 mL) . The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by Prep_HPLC to afford the product methyl 2- [8- (5, 6-dihydro-1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1230.7 [M+H] +
Step L: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -
3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (39.93 mg, 32.45 μmol) in dioxane: H2O (v: v = 1: 1, 4.0 mL) was added NaOH (1.0 mL, 2 M) at 25 ℃. The resulting mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (3 mL) and the pH value of the solution was adjusted to 6 with aqueous HCl (1M) and extracted with DCM. The organic layers were combined, dried and concentrated under vacuum at 25 ℃. The crude was purified by Prep-HPLC and lyophilization to afford the title 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy ] propyl] thiazole-4-carboxylic acid. LCMS: MS (ESI) M/Z: 1216.7 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.03 (d, J = 8.0 Hz, 1H) , 7.79 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H) , 7.44 -7.38 (m, 10H) , 6.94 (d, J = 8.8 Hz, 2H) , 4.82 (s, 2H) , 4.51 (s, 1H) , 4.40-4.29 (m, 6H) , 3.71-3.62 (m, 4H) , 3.52 (s, 4H) , 3.16-3.02 (m, 5H) , 2.43 (s, 3H) , 2.33 (s, 1H) , 2.01-1.99 (m, 6H) , 1.52-1.31 (m, 7H) , 1.22 (s, 3H) , 7.25 (dd, J = 14.6, 8.8 Hz, 2H) , 0.91 (d, J = 8.8 Hz, 9H) .
Example 22: Compound 22
Step A: tert-butyl 2- (2-ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of ethyl 2- (diethoxyphosphoryl) acetate (14.01 g, 62.7 mmol) in DMF (150 mL) was added NaH (2.50 g, 62.7 mmol, 60%purity) in portions at 0 ℃. The mixture was stirred for 20 min at the same temperature. Then tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (10.0 g, 41.8 mmol) in THF (30 mL) was added dropwise under N2. The reaction mixture was stirred at R.T for 2 h. The reaction mixture was quenched by addition of H2O (600 mL) , extracted with EtOAc (3 *200 mL) . The combined organic layers were washed with brine (2*100 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 0~40%EtOAc) to afford tert-butyl 2- (2-ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate. LC/MS: MS (ESI) M/Z 295.3 [M-t-Bu+MeCN+H] +.
Step B: tert-butyl 2- (2-ethoxy-2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of tert-butyl 2- (2-ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate (9.02 g, 29.3 mmol) in MeOH (90 mL) was added Pd/C (2.0 g, 50%purity) under N2. The suspension was degassed under vacuum and purged with H2 three times. The resulting mixture was stirred at R.T for 1 h under H2. The reaction mixture was filtered through a Celite pad and the filter cake was washed with MeOH (3*100 mL) . The filtrate combined was concentrated to afford tert-butyl 2- (2-ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate.
Step C: tert-butyl 2- (2- (methoxy (methyl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of tert-butyl 2- (2-ethoxy-2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate (2.01 g, 6.41 mmol) and N, O-dimethylhydroxylamine hydrochloride (1.25 g, 12.8 mmol) in THF (35 mL) was added i-PrMgCl (2 M, 16 mL, 32.0 mmol) in portions at 0 ℃. The reaction mixture was stirred at R.T for 2 h. under N2. The reaction mixture was quenched by addition of NH4Cl (60 mL) , extracted with EtOAc (3*80 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2- (2- (methoxy (methyl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate.
Step D: tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of tert-butyl 2- (2- (methoxy (methyl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate (1.71 g, 5.24 mmol) in DCM (20 mL) was added DABAI-H in toluene (1 M, 6.2 mL, 6.20 mmol) in portions at 0 ℃, the reaction mixture was stirred at R.T for 1 h under N2. The reaction mixture was quenched by addition of H2O (0.3 mL) , 15%NaOH in H2O (0.3 mL) , and H2O (1 mL) and stirred at for 10 min. The mixture was extracted with EtOAc (3*60 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~60%EtOAc) to afford tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate.
Step E: tert-butyl 2- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of Bestmann-Ohira reagent (1.0 g, 5.41 mmol) in MeOH (20 mL) was added K2CO3 (1.24 g, 9.02 mmol) . The reaction mixture was stirred for 20 min at R.T. tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate (1.21 g, 4.51 mmol) in MeOH (2 mL) was added. The reaction mixture was stirred for 1 h at R.T. The reaction mixture was quenched by addition of H2O (60 mL) , extracted with DCM (3*80 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 0~30%EtOAc) to afford tert-butyl 2- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate.
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (tert-butoxycarbonyl) -7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (160 mg, 225.16 μmol) and tert-butyl 2-prop-2-ynyl-7-azaspiro [3.5] nonane-7-carboxylate (89 mg, 337.74 μmol) in DMF (4 mL) was added Pd (PPh3) 2Cl2 (15 mg, 21.10 μmol) , DIEA (116 mg, 900.64 μmol, 4.0
equiv. ) and CuI (22 mg, 112.58 μmol) . The resulting mixture was stirred at 100 ℃ for 5 h under N2. The mixture was added H2O (30 mL) , extracted with EtOAc (3*40 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~60%EtOAc) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (7-tert-butoxycarbonyl-7-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 846.3 [M+H] +.
Step G: methyl 5- (3- (4- (3- (7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (7-tert-butoxycarbonyl-7-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (140 mg, 165.47 μmol) in DCM (5 mL) was added FA (72 mg, 827.36 μmol) . The resulting mixture was stirred for 16 h at R.T. The solution was concentrated in vacuum to give methyl 5- [3- [4- [3- (7-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] -2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl]thiazole-4-carboxylate, which was used to next step directly without purification.
Step H: 2- (2- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -7-azaspiro [3.5] nonan-7-yl) acetic acid
To a solution of methyl 5- [3- [4- [3- (7-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] -2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] thiazole-4-carboxylate (140 mg, 176.77 μmol, FA salt) and oxaldehydic acid (26 mg, 353.55 μmol) in DCE (5 mL) was added NaBH3CN (375 mg, 1.77 mmol) and AcOH (32 mg, 530.32 μmol) . The resulting mixture was stirred for 16 h at R.T. The solid was removed and the solution was concentrated. The residue was purification reverse phase preparative HPLC (YMC-Actus Triart C18, 150*20mm, 5um; 0.05%NH3H2O-10 mmol/L NH4HCO3-ACN, 48-68%flow: 20 mL/min) to give 2- [2- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -7-azaspiro [3.5] nonan-7-yl] acetic acid. LC/MS: MS (ESI) M/Z 804.4 [M+H] +.
Step I: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of 2- [2- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -7-azaspiro [3.5] nonan-7-yl] acetic acid (80 mg, 99.50 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (56 mg, 119.41 μmol) in DMF (3 mL) was added HATU (56 mg, 149.26 μmol) and DIEA (39 mg, 298.51 μmol) . The resulting mixture was stirred for 2 h at R.T. The mixture was added H2O (20 mL) , extracted with EtOAc (3*30 mL) . The organic layer combined was washed with brine (2*10 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=10: 1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 608.9 [M/2+H] +.
Step J: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (70 mg, 57.54 μmol) in MeOH (1 mL) , THF (1 mL) and H2O (1 mL) was added LiOH. H2O (12 mg, 287.70 μmol) . The resulting mixture was stirred for 4 h at R.T. The pH value of the resulting mixture was adjusted to 5 by using 0.5 M HCl and extracted with DCM (3*25 mL) . The organic layer combined was washed with brine (2*10 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (YMC-Actus Triart C18, 150*20mm, 5um; 0.05%NH3H2O -10 mmol/L NH4HCO3-ACN, 56%-76%; flow: 20 mL/min) . The eluent was concentrated in under reduced pressure and freeze-dried to give 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -7-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H) , 9.81 (s, 1H) , 8.99 (s, 1H) , 8.61 (t, J = 6.4 Hz, 1H) , 8.04 (d, J = 7.6 Hz, 1H) , 7.80 (d, J = 8.0 Hz, 1H) , 7.68 (d, J = 7.2 Hz, 1H) , 7.50 -7.35 (m, 9H) , 7.28 (d, J = 8.8 Hz, 2H) , 6.87 (d, J = 8.8 Hz, 2H) , 5.19 (s, 1H) , 4.84 (s, 2H) , 4.58 -4.54 (m, 1H) , 4.47 -4.38 (m, 3H) , 4.27 -4.22 (m, 1H) , 3.98 (t, J = 6.4 Hz, 2H) , 3.74 -
3.69 (m, 3H) , 3.52 -3.48 (m, 1H) , 3.17 (t, J = 7.2 Hz, 2H) , 3.04 (t, J = 5.6 Hz, 2H) , 2.48 -2.45 (m, 5H) , 2.09 -1.48 (m, 10H) , 1.31 -1.18 (m, 9H) , 0.94 (s, 9H) ; LC/MS: MS (ESI) M/Z 1202.7 [M+H] +.
Example 23: Compound 23
Step A: 7-azaspiro [3.5] nonan-2-one hydrochloride
To a solution of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (5.01 g, 20.89 mmol) in DCM (20 mL) was added was added HCl/dioxane (10.5 mL, 417.87 mmol, 4.0 M) dropwise at 0 ℃. The reaction mixture was stirred at R.T for 2 h. The solution was concentrated in vacuum to give crude 7-azaspiro [3.5] nonan-2-one hydrochloride (3.01 g, crude, HCl salt) , which was used to next step directly without purification.
Step B: benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate
To a solution of 7-azaspiro [3.5] nonan-2-one hydrochloride (1.02 g, 5.71 mmol) in THF (7 mL) and saturated NaHCO3 (5 mL) was added Cbz-Cl (1.74 g, 10.25 mmol) dropwise at 0 ℃. The resulting mixture was then stirred at 25 ℃ for 3 h. H2O (20 mL) was added and the mixture was extracted with EA (3*40 mL) . The combined organic layers were washed with brine (2*20 mL) , dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (sical gel, eluant: Petroleum Ether with 5~30%EtOAc) to afford benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate. LC/MS: MS (ESI) M/Z 274.3 [M+H] +.
Step C: benzyl 2- (2-tert-butoxy-2-oxo-ethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (700 mg, 2.56 mmol) and tert-butyl 2-diethoxyphosphorylacetate (969 mg, 3.84 mmol) in THF (10 mL) was added NaH (93 mg, 3.84 mmol, 60%purity) at 0 ℃. The resulting mixture was stirred at R.T for 2 h. The reaction mixture was quenched by addition of H2O (20 mL) , extracted with EtOAc (3*40 mL) . The combined organic layers were washed with brine (3*20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~30%EtOAc) to afford benzyl 2- (2- (tert-butoxy) -2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate. LC/MS: MS (ESI) M/Z 394.4 [M+Na] +.
Step D: tert-butyl 2- (7-azaspiro [3.5] nonan-2-yl) acetate
To a solution of benzyl 2- (2-tert-butoxy-2-oxo-ethylidene) -7-azaspiro [3.5] nonane-7-carboxylate (500 mg, 1.35 mmol) in MeOH (10 mL) was added Pd/C (500 mg, 50%purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at R.T for 2 h. under H2 balloon. The suspension was filtered through Celite and filter cake was washed with MeOH (3*20 mL) . The combined filtrates were concentrated to give tert-butyl 2- (7-azaspiro [3.5] nonan-2-yl) acetate.
Step E: tert-butyl 2- (7- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonan-2-yl) acetate
To a solution of tert-butyl 2- (7-azaspiro [3.5] nonan-2-yl) acetate (250 mg, 1.04 mmol) and 3-bromoprop-1-yne (149 mg, 1.25 mmol) in DMF (5 mL) was added K2CO3 (173 mg, 1.25 mmol) at 0 ℃. The resulting mixture was stirred at R.T for 0.5 h. The mixture was added H2O (20 mL) , extracted with EtOAc (3*40 mL) . The combined organic layers were washed with brine (2*20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~50%EtOAc) to afford tert-butyl 2- (7-prop-2-ynyl-7-azaspiro [3.5] nonan-2-yl) acetate. LC/MS: MS (ESI) M/Z 278.2 [M+H-Boc] +.
Step F: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1H-NMR (400 MHz, CD3OD) δ 8.82 (s, 1H) , 7.82 (d, J = 7.6 Hz, 1H) , 7.70 -7.67 (m, 1H) , 7.55 (d, J = 7.2 Hz, 1H) , 7.37 -7.23 (m, 10H) , 6.78 (d, J = 8.4 Hz, 2H) , 4.82 -4.77 (m, 3H) , 4.54 -4.52 (m, 1H) , 4.46 -4.39 (m, 3H) , 4.26 -4.23 (m, 1H) , 4.10 (s, 2H) , 3.91 (t, J = 5.4 Hz, 2H) , 3.79 -3.67 (m, 3H) , 3.52 -3.45 (m, 2H) , 3.16 (t, J = 7.2 Hz, 2H) , 2.99 -2.90 (m, 4H) , 2.58 -
2.54 (m, 1H) , 2.37 (s, 3H) , 2.31 -2.27 (m, 2H) , 2.14 -1.88 (m, 7H) , 1.70 -1.52 (m, 5H) , 0.92 (s, 9H) . LC/MS: MS (ESI) M/Z 1224.6 [M+Na] +.
Example 24: Compound 24
Step A: tert-butyl 3-ethynylazetidine-1-carboxylate
To a solution of tert-butyl 3-formylazetidine-1-carboxylate (5.0 g, 26.99 mmol) in MeOH (125 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (7.8 g, 40.49 mmol)
and K2CO3 (5.6g, 40.49 mmol) . The resulting mixture was stirred at RT for 16 h. The reaction mixture was then poured into H2O (100 mL) and extracted with EA (3*80 mL) , washed with brine (2*50 mL) . The organic layers were combined and concentrated. The residue obtained was purified by TLC (1/10PE/EA) to afford tert-butyl 3-ethynylazetidine-1-carboxylate. LC/MS: MS (ESI) M/Z 181.1 [M+H] +.
Step B: 3-ethynylazetidine
The solution of tert-butyl 3-ethynylazetidine-1-carboxylate (3.7g, 20.44 mmol) in FA (30 mL) was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo to afford 3-ethynylazetidine (1.5 g, 90.90%) . LC/MS: MS (ESI) M/Z 81.1 [M+H] +.
Step C: tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate
To a solution of methoxymethyl (triphenyl) -phosphane (9.5g, 30.85 mmol) in THF (60 mL) was added t-BuOK (3.7 g, 32.90 mmol) at 0℃. The resulting mixture was stirred at 0℃for 0.5 h. Then a solution of tert-butyl 3-oxocyclobutanecarboxylate (3.5 g, 20.56 mmol) in dry THF (10 mL) was added under nitrogen atmosphere at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 min. The reaction mixture was stirred at 70 ℃ for 3 h. After cooled to RT, the reaction mixture was quenched with (50 mL) of saturated aqueous NH4Cl. The resulting mixture was extracted with EA (3*50 mL) . The organic layers were combined, washed with brine (2*35 mL) . The residue obtained was purified by TLC (1: 20PE/EA) to afford tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate. LC/MS: MS (ESI) M/Z 198.1 [M+H] +.
Step D: tert-butyl 3-formylcyclobutanecarboxylate
To a solution of tert-butyl 3- (methoxymethylene) cyclobutanecarboxylate (2.2 g, 11.10 mmol) in DCM (20 mL) was added TFA: H2O=1: 20 (25 mL) at RT. The resulting mixture was stirred at RT for 2 h. The resulting mixture was extracted with DCM (3*50 mL) . The organic layers were combined, washed with brine (2*35 mL) . The residue obtained was purified by TLC (1: 30PE/EA) to afford tert-butyl 3-formylcyclobutanecarboxylate. LC/MS: MS (ESI) M/Z 184.1 [M+H] +
Step E: tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) cyclobutanecarboxylate
To a solution of tert-butyl 3-formylcyclobutanecarboxylate (1.1g, 6.61 mmol) in DCM/MeOH=1/1 (20 mL) was added NaBH3CN (1.55 g, 24.66 mmol) , 3-ethynylazetidine (500 mg, 6.16 mmol) and AcOH (0.1 mL) . The resulting mixture was stirred at 25 ℃for 16 h. The reaction was quenched with H2O (10 mL) . The resulting mixture was extracted with DCM (3*30 mL) . The organic layers were combined, washed with brine (4*15 mL) . The residue obtained was purified by TLC (1: 50 DCM/MeOH) to afford tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) cyclobutanecarboxylate. LC/MS: MS (ESI) M/Z 249.2 [M+H] +
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- (tert-butoxycarbonyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) cyclobutanecarboxylate (200 mg, 0.80 mmol) in DMF (6 mL) was added methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (570 mg, 0.80 mmol) and Pd (PPh3) 2Cl2 (56mg, 0.08 mmol, 0.1 equiv. ) , CuI (31mg, 0.16 mmol) and DIEA (517mg, 4.00mmol) . The resulting mixture was stirred at 60℃ for 4 h. The reaction was quenched with H2O (10 mL) . The resulting mixture was extracted with EA (3*20 mL) . The residue obtained was purified by TLC (1: 50 DCM/MeOH) to afford methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- (tert-butoxycarbonyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 847.3 [M+H] +.
Step G: 3- ( (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) methyl) cyclobutanecarboxylic acid
The solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- (tert-butoxycarbonyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (200mg, 0.24 mmol) in FA (10 mL) was stirred at RT for 10 h. The reaction mixture was concentrated in vacuo to afford3- ( (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) methyl) cyclobutanecarboxylic acid. LC/MS: MS (ESI) M/Z 791.8 [M+H] +.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 3- ( (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) methyl) cyclobutanecarboxylic acid (0.18g, 0.22 mmol) in DMF (3 mL) was added (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (0.11g, 0.23 mmol) , HATU (0.19 g, 0.44 mmol) and DIEA (0.17 g, 1.10 mmol) . The resulting mixture was stirred at 25 ℃ for 2 h. The reaction was quenched with H2O (5 mL) . The resulting mixture was extracted with EA (3*15 mL) . The residue obtained was purified by TLC (1: 10 DCM/MeOH) to afford methyl 2- (8-
(benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 1187.4 [M+H] +.
Step I: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (0.27 g, 0.23 mmol) in THF (3 mL) and MeOH (3 mL) was added LiOH. H2O (98.9 mg, 2.30 mmol) and H2O (3 mL) . The resulting mixture was stirred at 25 ℃for 4 h. The reaction was quenched with H2O (5 mL) . The resulting mixture was extracted with EtOAc (3*15 mL) . The organic layers were combined, washed with brine (4*15 mL) . The residue obtained was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water with 10 mmol/L NH4HCO3+0.1%NH3. H2O, Mobile Phase B: CH3CN (15 %to 45%in 11 min, 45 %to 100 %in 0.1 min, 100 %to 100 %in 2 min, 100%to 30 %in 0.1 min, 30 %to 30 %in 1 min; Detector, UV 254 nm to afford2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- ( (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclobutyl) methyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid. 1H-NMR (400 MHz, CD3OD) δ 8.89 (d, J = 8.5 Hz, 1H) , 7.89 (d, J = 7.7 Hz, 1H) , 7.75 (d, J = 8.0 Hz, 1H) , 7.63 (d, J = 7.1 Hz, 1H) , 7.45-7.37 (m, 7H) , 7.34-7.25 (m, 3H) , 6.83-6.77 (m, 2H) , 5.00-4.88 (m, 3H) , 4.64-4.09 (m, 9H) , 3.99-3.76 (m, 7H) , 3.24 (t, J = 7.4 Hz, 3H) , 3.18-3.05 (m, 3H) , 2.52-2.43 (m, 4H) , 2.40-2.17 (m, 3H) , 2.13-1.94 (m, 5H) , 0.99 (s, 9H) .
Example 25: Compound 25
Step A: tert-butyl 3- ( (3- (methoxycarbonyl) azetidin-1-yl) methyl) azetidine-1-carboxylate
To a solution tert-butyl 3-formylazetidine-1-carboxylate (6.11 g, 32.98 mmol) , methyl azetidine-3-carboxylate (5.01 g, 32.98 mmol) in THF (100 mL) was added NaBH (OAc) 3 (17.48 g, 82.46 mmol) and HOAc (5 mL) . The mixture was stirred at 30 ℃ for 3 h. The reaction mixture was quenched by addition of H2O (40 mL) , extracted with EtOAc (3*80 mL) . The combined organic layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~40%EtOAc) to give tert-butyl 3- [ (3-methoxycarbonylazetidin-1-yl) methyl] azetidine-1-carboxylate.
Step B: tert-butyl 3- ( (3- (methoxycarbonyl) azetidin-1-yl) methyl) azetidine-1-carboxylate
To a solution tert-butyl 3- [ (3-methoxycarbonylazetidin-1-yl) methyl] azetidine-1-carboxylate (2.00 g, 7.03 mmol) in DCM (40 mL) was added DIBAL-H (1 M, 14.07 mL) at -78 ℃ under N2. The mixture was stirred at -78 ℃ for 1 h. The reaction mixture was quenched by addition of Sodium sulfate decahydrate (~8 g) and stirred at -78 ℃ for 30 min. The reaction mixture was filtered through a Celite pad and the filter cake was washed with DCM (3*80 mL) . The filtrate combined was concentrated to afford tert-butyl 3- [ (3-formylazetidin-1-yl) methyl] azetidine-1-carboxylate.
Step C: tert-butyl 3- ( (3-ethynylazetidin-1-yl) methyl) azetidine-1-carboxylate
To a solution (1-diazo-2-oxo-propyl) -phosphonic acid dimethyl ester (1.18 g, 6.13 mmol) in MeOH (8 mL) was added K2CO3 (848 mg, 6.13 mmol) . The mixture was stirred at 30 ℃ for 0.5 h. Then tert-butyl 3- [ (3-formylazetidin-1-yl) methyl] azetidine-1-carboxylate (1.31 g, 5.12 mmol) was added. The mixture was stirred at 30 ℃ for 15.5 h. The reaction mixture was quenched by addition of H2O (60 mL) , extracted with EtOAc (2*80 mL) . The combined organic
layers were washed with brine (2*30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 0~50%EtOAc) to afford tert-butyl 3- [ (3-ethynylazetidin-1-yl) methyl] azetidine-1-carboxylate.
Step D: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [ [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] methyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
The compound was prepared following the similar procedure as described in Example 1. 1H-NMR (400 MHz, CD3OD) δ 8.84 (s, 1H) , 7.89 (d, J = 8.0 Hz, 1H) , 7.74 (d, J = 8.4 Hz, 1H) , 7.60 (d, J = 7.6 Hz, 1H) , 7.47-7.24 (m, 10H) , 6.84-6.77 (m, 2H) , 4.86-4.86 (1H) , 4.59-4.48 (m, 3H) , 4.39-4.24 (m, 5H) , 4.12-3.94 (m, 7H) , 3.86-3.75 (m, 4H) , 3.62-3.47 (m, 2H) , 3.22 (t, J = 7.2 Hz, 2H) , 3.16-3.11 (m, 1H) , 3.08-2.93 (m, 2H) , 2.44 (s, 3H) , 2.38-1.97 (m, 4H) , 1.44-1.18 (m, 4H) , 1.02 (s, 9H) . LC/MS: 1189.60 [M+H] +.
Example 26: Compound 26
Step A: tert-butyl 2- (3- (benzyloxy) cyclobutylidene) acetate
To a solution of tert-butyl 2- (diethoxyphosphoryl) acetate (5.00 g, 34.05 mmol) in THF (60 mL) was added NaH (1.36 g, 34.05 mmol, 60%purity, ) in portions at 0 ℃. The mixture was stirred for 20 min at the same temperature. Then 3- (benzyloxy) cyclobutanone (5.01 g, 28.38 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at R.T for 2 h. The reaction mixture was quenched by addition of H2O (40 mL) , extracted with EtOAc (3*60 mL) . The combined organic layers were washed with brine (2*40 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 0~20%EtOAc) to afford tert-butyl 2- (3- (benzyloxy) cyclobutylidene) acetate.
Step B: tert-butyl 2- (3-hydroxycyclobutyl) acetate
To a solution of tert-butyl 2- (3-benzyloxycyclobutylidene) acetate (5.0 g, 18.22 mmol) in MeOH (70 mL) was added Pd/C (500 mg, 50%purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at R.T for 16 h. under H2 balloon. The suspension was filtered through Celite and filter cake was washed with
MeOH (3*40 mL) . The combined filtrates were concentrated to give tert-butyl 2- (3-hydroxycyclobutyl) acetate.
Step C: tert-butyl 2- (3-oxocyclobutyl) acetate
To a solution of tert-butyl 2- (3-hydroxycyclobutyl) acetate (3.02 g, 16.14 mmol) in DCM (40 mL) was added DMP (8.22 g, 19.36 mmol) . The reaction mixture was stirred for 2 h at R.T. The mixture was added aq. Na2S2O4 (40 mL) , NaHCO3 (50 mL) , extracted with DCM (2*50 mL) . The combined organic layers were washed with brine (2*40 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 0~30%EtOAc) to afford tert-butyl 2- (3-oxocyclobutyl) acetate.
Step D: tert-butyl 2- (3- (3-ethynylazetidin-1-yl) cyclobutyl) acetate
To a solution of tert-butyl 2- (3-oxocyclobutyl) acetate (150 mg, 814.19 μmol) and 3-ethynylazetidine (125 mg, 977.03 μmol) in DCM (5 mL) and methanol (5 mL) was added AcOH (147 mg, 2.44 mmol) and NaBH3CN (101 mg, 1.63 mmol) . The resulting mixture was stirred at R.T for 3 h. The mixture was added aq. NaHCO3 (20 mL) , extracted with EtOAc (2*40 mL) . The combined organic layers were washed with brine (2*20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (sical gel, eluant: Petroleum Ether with 10~70%EtOAc) to afford tert-butyl 2- (3- (3-ethynylazetidin-1-yl) cyclobutyl) acetate.
Step E: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- (3- (2- (tert-butoxy) -2-oxoethyl) cyclobutyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4-iodophenoxy) propyl) thiazole-4-carboxylate (160 mg, 225.16 μmol) and tert-butyl 2- [3- (3-ethynylazetidin-1-yl) cyclobutyl] acetate (141 mg, 562.90 μmol) in DMF (5 mL) was added Pd (PPh3) 2Cl2 (92 mg, 112.58 μmol) and CuI (21 mg, 112.58 μmol) and DIEA (116 mg, 900.64 μmol) . The resulting mixture was stirred at 60 ℃ for 3 h under N2. The mixture was added H2O (20 mL) and extracted with EtOAc (3*40 mL) . The combined organic layer was washed with brine (3*20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [3- (2-tert-butoxy-2-oxo-ethyl) cyclobutyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 832.3 [M+H] +
Step F: 2- (3- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) azetidin-1-yl) cyclobutyl) acetic acid
A solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- (3- (2- (tert-butoxy) -2-oxoethyl) cyclobutyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate (150 mg, 180.28 μmol) in FA (3 mL) was stirred at R.T for 16 h. The solution was concentrated in vacuum to give 2- [3- [3- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] azetidin-1-yl] cyclobutyl] acetic acid (120 mg, crude, FA salt) , which was used to next step directly without purification. LC/MS: MS (ESI) M/Z 388.8 [M/2+H] +
Step G: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (1- (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) cyclobutyl) azetidin-3-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (85 mg, 182.49 μmol, HCl salt) and 2- [3- [3- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] azetidin-1-yl] cyclobutyl] acetic acid (100 mg, 121.66 μmol) in DMF (2 mL) was added DIEA (63 mg, 486.64 μmol) and HATU (60 mg, 158.16 μmol) . The resulting mixture was stirred at R.T for 2 h. The mixture was added H2O (20 mL) and extracted with EtOAc (3*40 mL) . The combined organic layer was washed with brine (3*20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [1- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] cyclobutyl] azetidin-3-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 595.0 [M/2+H] +
Example 27: Compound 27
Step A: ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate
A solution of ethyl 4-oxocyclohexanecarboxylate (800 g, 4.70 mol) , TosOH (81 g, 0.47 mol) and ethylene glycol (350.08 g, 5.64 mol) in toluene (5500 mL) was refluxed at 110 ℃ for 16 hr and water was removed by Dean-Stark trap. The mixture was cooled to rt, washed with saturated NaHCO3 aqueous, the organic layers was dried over Na2SO4 and concentrated under vacuo. The crude oil was purified by chromatography column using PE/EA=30/1 to obtain ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate. LC/MS: MS (ESI) M/Z 215.2 [M+H] +.
Step B: diethyl 1, 4-dioxaspiro [4.5] decane-8, 8-dicarboxylate
To a solution of HTMP (257.44 g, 1.82 mol) in dry THF (1500 mL) was added n-BuLi (2.5 M, 729.03 mL) dropwise slowly under nitrogen atmosphere at -78 ℃, and the reaction mixture was stirred at -78 ℃ for 30 min. Then a solution of ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate (355 g, 1.66 mol) in dry THF (1000 mL) was added dropwise slowly under nitrogen atmosphere at -78℃ during 1.5 h, then a solution of ethyl carbonochloridate (269.72 g,
2.49 mol) in dry THF (500 mL) was added dropwise slowly under nitrogen atmosphere at -78 ℃ and the mixture stirred for a further 1 hr. The mixture was quenched with saturated NH4Cl aqueous, extracted with EA (3×1000 mL) , the organic layers was dried over Na2SO4 and concentrated, the crude oil was purified by chromatography column using PE/EA=50/1 to obtain diethyl 1, 4-dioxaspiro [4.5] decane-8, 8-dicarboxylate.
Step C: 1, 4-dioxaspiro [4.5] decane-8, 8-diyldimethanol
To a solution of LiAlH4 (99.42 g, 2.62 mol) in dry THF (1500 mL) was added a solution of diethyl 1, 4-dioxaspiro [4.5] decane-8, 8-dicarboxylate (250 g, 873.15 mmol) in dry THF (500 mL) slowly under nitrogen atmosphere at 0℃ for 2 hrs, and the reaction mixture was stirred at 0-10 ℃ for an additional 5 hr . The mixture was quenched with H2O (100 mL) , 15%NaOH aqueous (100 mL) and H2O (300 mL) at 0-10℃, then Na2SO4 was added and stirred at 10℃ for 15 min, the solid was filtered, the filtrate was concentrated [8- (hydroxymethyl) -1, 4-dioxaspiro [4.5] decan-8-yl] methanol.
Step D: 2- [ (2, 4-dimethoxyphenyl) methyl] -8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane
To a suspension of [8- (hydroxymethyl) -1, 4-dioxaspiro [4.5] decan-8-yl] methanol (60 g, 296.67 mmol) and DIEA (115.03 g, 890.00 mmol) in dry CH3CN (1000 mL) was added Tf2O (167.40 g, 593.33 mmol, 2.0 equiv. ) dropwise at -40 ~ -30 ℃. The reaction mixture was stirred at -40 ~ -30 ℃ for 1 hr. To the resulting brown solution was added DIEA (115.03 g, 890.00 mmol) in one portion and (3, 4-dimethoxyphenyl) methanamine (49.60 g, 296.67 mmol) dropwise in 5 min at -40 ~ -30 ℃. The flask containing the reaction mixture was transferred to an oil bath, and stirred at 75~80 ℃ for 12 hr. The reaction mixture was diluted with H2O (600 mL) and extracted with EA (2*600 mL) . The organic layer combined was washed with brine (2*600 mL) , dried over Na2SO4 and concentrated to dryness in vacuo. The residue was purified by column chromatography (Silica gel, MeOH/DCM=0~10%) to give 2- [ (3, 4-dimethoxyphenyl) methyl] -8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane. LC/MS: MS (ESI) M/Z 334.3 [M+H] +.
Step E: tert-butyl 8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane-2-carboxylate
To a solution of 2- [ (2, 4-dimethoxyphenyl) methyl] -8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane (3 g, 9.00 mmol) and tert-butoxycarbonyl tert-butyl carbonate (3.93 g, 18.00 mmol) in MeOH (60 mL) was added TEA (2.73 g, 26.99 mmol) , Pd/C (600.00 mg, 10%w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 60℃ for 16hr. The suspension was filtered through Celite and filter cake was washed with MeOH. The combined filtrates were concentrated, the crude oil was purified by chromatography column using PE/EA=4/1 to give tert-butyl 8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane-2-carboxylate.
Step F: tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate
A solution of tert-butyl 8, 11-dioxa-2-azadispiro [3.2.47.24] tridecane-2-carboxylate (2.54 g, 8.96 mmol) in acetone (50 mL) and H2O (5 mL) was added TsOH. H2O (341.01 mg, 1.79 mmol) , the resulting mixture was stirred at 45 ℃ for 16 hr. The mixture was cooled to rt, concentrated under vacuo, the crude oil was purified by chromatography column using PE/EA=4/1 to obtain tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate.
Step G: tert-butyl 7- (2-ethoxy-2-oxoethylidene) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of ethyl 2-diethoxyphosphorylacetate (3.23 g, 14.42 mmol) in dry THF (50 mL) was added NaH (768.88 mg, 19.22 mmol, 60%purity) in portions under nitrogen atmosphere at 0℃, and the reaction mixture was stirred at 0℃ for 30 min. Then a solution of tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (2.3 g, 9.61 mmol, 1.0 equiv. ) in dry THF (50 mL) was added and the mixture stirred for a further 3 hr at 0℃-10℃. Saturated NH4Cl aqueous was added to quench the solution, and extracted with EA (2*100 mL) . The organic layers were dried over Na2SO4 and concentrated to obtain tert-butyl 7- (2-ethoxy-2-oxo-ethylidene) -2-azaspiro [3.5] nonane-2-carboxylate (3.20 g, crude) .
Step H: tert-butyl 7- (2-ethoxy-2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of tert-butyl 7- (2-ethoxy-2-oxo-ethylidene) -2-azaspiro [3.5] nonane-2-carboxylate (3 g, 9.70 mmol) in MeOH (150 mL) was added Pd/C (600.00 mg, 10%w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 20 ℃ for 3 hr. The suspension was filtered through Celite and filter cake was washed with MeOH (3*20 mL) . The combined filtrates were concentrated, the crude oil was purified by chromatography column using PE/EA=4/1 to obtain tert-butyl 7- (2-ethoxy-2-oxo-ethyl) -2-azaspiro [3.5] nonane-2-carboxylate. LC/MS: MS (ESI) M/Z 256.2 [M+H-t-Bu] +.
Step I: tert-butyl 7- (2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of tert-butyl 7- (2-ethoxy-2-oxo-ethyl) -2-azaspiro [3.5] nonane-2-carboxylate (1 g, 3.21 mmol) in dry DCM (10 mL) was added DIBAL-H (1 M, 4.82 mL) dropwise during 30 min under nitrogen atmosphere at -78 ℃, and the mixture stirred for an additional 30 min. The mixture was quenched with saturated NaHCO3 aqueous, extracted with DCM (3*50 mL) , the organic layers was dried, concentrated to obtain tert-butyl 7- (2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate.
Step J: tert-butyl7- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (862.24 mg, 4.49 mmol) in dry MeOH (20 mL) was added K2CO3 (930.46 mg, 6.73 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Then a solution of tert-butyl 7- (2-oxoethyl) -2-azaspiro [3.5] nonane-2-carboxylate (1.2 g, 4.49 mmol) in dry MeOH (20 mL) was added and the mixture stirred for a further 16 hr. The reaction mixture was concentrated,
purified by chromatography column using PE/EA=4/1 to obtain tert-butyl 7-prop-2-ynyl-2-azaspiro [3.5] nonane-2-carboxylate.
Step K: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
The compound was prepared following the similar procedure as described in Example 22. 1H NMR (400 MHz, DMSO-d6) δ 12.96 (brs, 1H) , 10.57 (s, 1H) , 9.03 (s, 1H) , 8.66-8.54 (m, 1H) , 8.00 (d, J = 6.4 Hz, 1H) , 7.76 (d, J = 7.2 Hz, 1H) , 7.63 (d, J = 6.8 Hz, 1H) , 7.47-7.29 (m, 8H) , 7.22 (d, J = 8.0 Hz, 2H) , 6.88 (d, J = 8.4 Hz, 2H) , 4.85 (s, 2H) , 4.51 (d, J = 8.4 Hz, 4H) , 4.42-4.28 (m, 4H) , 4.26-3.98 (m, 4H) , 3.96-3.84 (m, 6H) , 3.18 (s, 2H) , 3.05 (s, 2H) , 2.46 (s, 3H) , 2.26-1.82 (m, 8H) , 1.76-1.58 (m, 2H) , 1.45-1.17 (m, 5H) , 0.95 (s, 9H) . LCMS: MS (ESI) M/Z: 1202.7 [M+H] +.
Example 28: Compound 28
Step A: tert-butyl 3- (2- ( ( (3S, 7aR) -3- ( ( (tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 10- {4- [3- (2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -4- (methoxycarbonyl) -1, 3-thiazol-5-yl) propoxy] phenyl} dec-9-ynoic acid (300 mg, 0.400 mmol) in DMF (5 mL) was added (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethylbutanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (266.42 mg, 0.600 mmol) , HATU (227.86 mg, 0.600 mmol and DIEA (154.90 mg, 1.200 mmol) . The mixture was stirred at r. t. for 1 h. The reaction was quenched with water (5 mL) . The mixture was extracted with EA (3 x 20 mL) and the resulting mixture was washed with 3 x 20 mL of water, The organic layer was dried over Na2SO4 and filtered. The organic layers were concentrated. The crude product was purified with silica gel column. The organic layers were concentrated under reduced pressure to afford methyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1S) -1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] ethyl] carbamoyl} pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1177 [M+H] +.
Step B: tert-butyl 3- (2- ( ( (3S, 7aR) -3- ( ( (tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of methyl 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1S) -1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] ethyl] carbamoyl} pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylate (300 mg, 0.255 mmol) in MeOH (2 mL) and THF (4 mL) was added aqueous NaOH (2N, 2 mL) . The mixture was stirred at 50℃ for 1 h. The mixture was concentrated under reduced pressure to removed MeOH. The pH value of the solution was adjusted to 4~5 with 2 M HCl. The mixture was extracted with EA (10 mL x 2) . The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 51%B to 71%B in 7 min, 71%B; Wave Length: 254 nm; RT1 (min) : 4.95; Number Of Runs: 0. After lyophilization, it was afforded 2- {8- [ (1, 3-benzothiazol-2-yl) carbamoyl] -3, 4-dihydro-1H-isoquinolin-2-yl} -5- {3- [4- (9- { [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1S) -1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl] ethyl] carbamoyl} pyrrolidin-1-yl] -3, 3-dimethyl-1-oxobutan-2-yl] carbamoyl} non-1-yn-1-yl) phenoxy] propyl} -1, 3-thiazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.38 (d, J = 7.8 Hz, 1H) , 8.01 (d, J = 8.1 Hz, 1H) , 7.73 -7.85 (m, 2H) , 7.63 -7.72 (m, 1H) , 7.18 -7.52 (m, 10H) , 6.85 (d, J = 8.7 Hz, 2H) , 4.75 -5.00 (m, 4H) , 4.48 -4.56 (m, 1H) , 4.36 -4.48 (m, 1H) , 4.23 -4.33 (m, 1H) , 3.95 (t, J = 6.3 Hz, 2H) , 3.66 -3.79 (m, 2H) , 3.55 -
3.66 (m, 2H) , 3.16 (t, J = 6.3 Hz, 2H) , 3.03 (t, J = 6.3 Hz, 2H) , 2.44 (s, 3H) , 2.34 (t, J = 6.9 Hz, 2H) , 2.18 -2.32 (m, 1H) , 2.07 -2.17 (m, 1H) , 1.93 -2.06 (m, 3H) , 1.72 -1.86 (m, 1H) , 1.43 -1.59 (m, 4H) , 1.32 -1.43 (m, 5H) , 1.19 -1.32 (m, 4H) , 0.93 (s, 9H) . LCMS: MS (ESI) M/Z: 1163.45 [M+H] +.
Example 29: Compound 29
Step A: tert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate
To a solution of tert-butyl 4-oxocyclohexanecarboxylate (6.23 g, 31.42 mmol) in THF (65.43 mL) was added LiHMDS in THF (1 M, 34.57 mL) at -78℃, the mixture was stirred at -78 ℃ for 1 hr, 1, 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (12.35 g, 34.57 mmol) was added and the mixture was stirred at 28 ℃ for 16 hr. The resulting solution was extracted with EA (10 mL *3) . The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 1: 0 to give tert-butyl 4- (trifluoromethylsulfonyloxy) cyclohex-3-ene-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 5.80-5.75 (m, 1H) , 2.57-2.31 (m, 5H) , 2.14-2.04 (m, 1H) , 1.95-1.82 (m, 1H) , 1.46-1.42 (m, 9H) .
Step B: benzyl 4- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate
A solution of tert-butyl 4- (trifluoromethylsulfonyloxy) cyclohex-3-ene-1-carboxylate (4 g, 12.11 mmol) in water (10 mL) and dioxane (80 mL) was added benzyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (2.91 g, 8.48 mmol) , 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.00 g, 1.21 mmol) and potassium acetate (3.57 g, 36.33 mmol) , the resulting mixture was stirred at90 ℃ for 16 hr in N2. The resulting solution was extracted with EA (10 mL *3) . The combined organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluted with PE: EtOAc =20: 1 to give
benzyl 4- (4-tert-butoxycarbonylcyclohexen-1-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate. LCMS: MS (ESI) M/Z: 420.1 [M+Na] +
Step C: tert-butyl 4- (piperidin-4-yl) cyclohexanecarboxylate
To a solution of benzyl 4- (4-tert-butoxycarbonylcyclohexen-1-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (3.23 g, 8.13 mmol) in MeOH (120 mL) was added Pd/C (2.16 g, 10%purity) , the resulting mixture was stirred at 70 ℃ for16 hr under H2 atmosphere. The reaction mixture was concentrated to dryness and the crude product was used in next step without further purification.
Step D: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- (tert-butoxycarbonyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- (3-chloroprop-1-ynyl) phenoxy] propyl] thiazole-4-carboxylate (24.58 mg) and tert-butyl 4- (4-piperidyl) cyclohexanecarboxylate (20 mg, 74.79 μmol) in DMF (0.2 mL) was added cesium carbonate (73.11 mg, 224.38 μmol) , the resulting mixture was stirred at 25 ℃ for 16 hrs under N2 atmosphere. The reaction mixture was filtered and the crude product was purified by HPLC (mobile phase: 0.05%NH3H2O-10 mmol/l NH4HCO3-ACN; Chromatographic column: YMC-Actus Triart C18, 150*20mm, 5um; Current Speed (ml/min) : 20; Gradient (%) : 46.2-66.2; Running time (min) : 14; Peak time (min) : 8.7) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (4-tert-butoxycarbonylcyclohexyl) -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 888.6 [M+H] +
Step E: 4- (1- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) piperidin-4-yl) cyclohexanecarboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (4-tert-butoxycarbonylcyclohexyl) -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (177 mg, 199.29 μmol) in FA (3 mL) was stirred at 25 ℃ for16 hr. The reaction mixture was concentrated under reduced pressure to give 4- [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] cyclohexanecarboxylic acid, which was used in next step without further purification. LCMS: MS (ESI) M/Z: 832.50 [M+H] +
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-
yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
The solution of 4- [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] cyclohexanecarboxylic acid (165.82 mg) , HATU (90.93 mg, 239.15 μmol) , DIEA (77.27 mg, 597.88 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (85.81 mg, 199.29 μmol) in anhydrous DMF (2 mL) was stirred at 25℃ for 16 hr. The crude reaction mixture was filtered and purified by HPLC (mobile phase: 0.1%TFA-ACN; Chromatographic column: Prep Fluoro-Phenyl, 150*19mm, 5um; Current Speed (ml/min) : 20; Gradient (%) : 72.5-85.5; Running time (min) : 15; Peak time (min: 7.5) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexyl] -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1244.89 [M+H] +
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexyl] -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (19 mg, 15.27 μmol) in dioxane: H2O (240.00 μL) was added NaOH (6.11 mg, 152.66 μmol) , the resulting mixture was stirred at 40 ℃ for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC (mobile phase: 0.1%TFA-ACN; Chromatographic column: X select CSH Prep Fluoro-Phenyl, 150*19mm, 5um; Current Speed (ml/min) : 20; Gradient (%) : 55.2-75.2; Running time (min) : 11; Peak time (min) : 8.2) to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexyl] -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, CD3OD) δ 8.94 (s, 1H) , 7.91 (d, J = 7.7 Hz, 1H) , 7.77 (d, J = 8.2 Hz, 1H) , 7.65 (d, J = 7.4 Hz, 1H) , 7.46-7.39 (m, 10H) , 6.88 (d, J = 8.8 Hz, 2H) , 4.97 (t, J = 15.3 Hz, 4H) , 4.65-4.46 (m, 5H) , 4.36-4.29 (m, 1H) , 4.25-4.20 (m, 2H) , 4.04-3.97 (m, 2H) , 3.88-3.78 (m, 4H) , 3.69 (d, J = 11.8 Hz, 1H) , 3.13-3.02 (m,
4H) , 2.47 (d, J = 3.0 Hz, 3H) , 2.29-2.02 (m, 7H) , 1.93-1.78 (m, 2H) , 1.66-1.26 (m, 10H) , 1.01 (d, J = 9.3 Hz, 9H) . LCMS: MS (ESI) M/Z: 1230.70 [M+H] +
Example 30: Compound 30
Step A: Tert-butyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate
To a solution of (methoxymethyl) triphenylphosphonium chloride (1.67 g, 4.86 mmol) in THF (20 mL) was added t-BuOK (608.56 mg, 5.42 mmol) at 25 ℃ and stirred for 30 mins. A solution of tert-butyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (1 g, 3.74 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred at 25 ℃ for 16 hr. The mixture reaction was filtered and the filtrate was diluted with EtOAc (80 mL) . The organic layer was washed with H2O (15 mL) . The aqueous layer was extracted with EtOAc (80 mL *2) . The
combined organic layers was washed with brine (100 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate, which was used in next step without further purification.
Step B: tert-butyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate
To a solution of tert-butyl 9- (methoxymethylene) -3-azaspiro [5.5] undecane-3-carboxylate (1.1 g) in THF (15 mL) was added aqueous solution of HCl (1 M, 11.17 mL) and the mixture was stirred at 25℃ for 16 hr. The mixture was diluted with aq. sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL *3) . The combined organic layers was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound, which was used in next step without further purification.
Step C: tert-butyl 9-ethynyl-3-azaspiro [5.5] undecane-3-carboxylate
To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.00 g) in methanol (15 mL) was added potassium carbonate (1.44 g, 10.45 mmol) at room temperature stirred for 30 min. A solution of tert-butyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate (735 mg, 2.61 mmol) in methanol (15 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was filtered and the filtrate was diluted with EtOAc (15 mL) . The organic layer was washed with H2O (30 mL) . The aqueous layer was extracted with EtOAc (15 mL *2) . The combined organic layer was washed with brine (20 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 10: 1 to give tert-butyl 9-ethynyl-3-azaspiro [5.5] undecane-3-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 3.40-3.33 (m, 4H) , 2.04 (d, J = 2.5 Hz, 1H) , 1.78-1.39 (m, 18H) , 1.38-1.14 (m, 5H)
Step D: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (tert-butoxycarbonyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (300 mg, 422.18 μmol) and tert-butyl 9-ethynyl-3-azaspiro [5.5] undecane-3-carboxylate (175.67 mg, 633.26 μmol) in THF (10 mL) was added CuI (16.08 mg, 84.44 μmol) , TEA (213.60 mg, 2.11 mmol, 293.41 μL) and Bis (triphenylphosphine) palladium (II) chloride (148.16 mg, 211.09 μmol) , the resulting mixture was stirred at 60 ℃ for 3 hr under N2 atmosphere. The reaction mixture was concentrated to dryness and the residue was purification by prep-TLC (SiO2, DCM: MeOH = 25: 1 ) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -
5- [3- [4- [2- (3-tert-butoxycarbonyl-3-azaspiro [5.5] undecan-9-yl) ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) m/z: 860.60 [M+H] +
Step E: methyl 5- (3- (4- (3-azaspiro [5.5] undecan-9-ylethynyl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- (3-tert-butoxycarbonyl-3-azaspiro [5.5] undecan-9-yl) ethynyl] phenoxy] propyl] thiazole-4-carboxylate (400 mg, 465.07 μmol) in FA (2 mL) was stirred at 28 ℃ for 1 h. The reaction mixture was concentrated to dryness to give the title compound, which was used in next step without further purification. LCMS MS [ESI] m/z: 760.4 [M+H] +
Step F: 2- (9- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) -3-azaspiro [5.5] undecan-3-yl) acetic acid
To a solution of methyl 5- [3- [4- [2- (3-azaspiro [5.5] undecan-9-yl) ethynyl] phenoxy] propyl] -2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] thiazole-4-carboxylate (353 mg) , glyoxylic acid monohydrate (85.51 mg, 928.98 μmol) and acetic acid (139.46 mg, 2.32 mmol) in DMF (3 mL) was added sodium cyanoborohydride (87.57 mg, 1.39 mmol) and the mixture was stirred at rt for 5 min. The mixture was diluted with EtOAc (30 mL) . The organic layer was washed H2O (30 mL) . The aqueous layer was extracted with EtOAc (30 mL *2) . The combined organic layers were washed with brined (30 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was filtered and purified by HPLC (mobile phase: 0.1%TFA-ACN; Chromatographic column: YMC-Actus Triart C18, 150 *20 mm, 5um; Current Speed (ml/min) : 20; Gradient (%) : 43.5-63.5; Running time (min) : 12; Peak time (min) : 9.5) to provide 2- [9- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] -3-azaspiro [5.5] undecan-3-yl] acetic acid. LCMS: MS (ESI) M/Z: 818.4 [M+H] +
Step G: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
A solution of 2- [9- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] -3-azaspiro [5.5] undecan-3-yl] acetic acid (55 mg, 67.24 μmol) , HATU (30.68 mg, 80.68 μmol) , DIEA (43.45 mg, 336.18 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-
hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (43.42 mg, 100.85 μmol) in anhydrous DMF (0.1 mL) was stirred at room temperature for 2 h. The crude reaction mixture was filtered and purified by HPLC to provide methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-9-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1230.7 [M+H] +
Step H: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-9-yl) ethynyl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-9-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate (30 mg, 24.38 μmol) in dioxane (2 mL) and H2O (2 mL) was added NaOH (1.95 mg, 48.76 μmol) at 25 ℃, the resulting mixture was stirred at 28 ℃ for 5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (3 mL) and the pH value of the solution was adjusted to 5 -6 with aqueous HCl (1M) , filtered, and the solid dried over air to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-9-yl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LCMS: MS (ESI) m/z: 1216.6 [M+H] +. 1H-NMR (400 MHz, METHANOL-D4) δ 8.93 (s, 1H) , 7.91 (d, J = 8.2 Hz, 1H) , 7.76 (d, J = 8.2 Hz, 1H) , 7.65 (d, J = 7.7 Hz, 1H) , 7.47-7.39 (m, 7H) , 7.33 (t, J = 7.4 Hz, 1H) , 7.20 (d, J = 8.5 Hz, 2H) , 6.78 (d, J = 8.8 Hz, 2H) , 4.95 (s, 3H) , 4.63 (s, 1H) , 4.56-4.51 (m, 3H) , 4.34 (d, J = 15.7 Hz, 1H) , 4.03-3.78 (m, 8H) , 3.69-3.65 (m, 2H) , 3.41 (s, 2H) , 3.27-3.07 (m, 5H) , 2.59 (s, 1H) , 2.45 (d, J = 5.5 Hz, 3H) , 2.23-2.07 (m, 4H) , 1.94 (s, 2H) , 1.84-1.60 (m, 8H) , 1.33 (d, J = 41.8 Hz, 4H) , 1.04 (d, J = 12.9 Hz, 9H)
Example 31: Compound 31 (Compound 31-A and 31-B)
Step A. tert-butyl 4-hydroxycyclohexanecarboxylate
A solution of 4-hydroxycyclohexanecarboxylic acid (2.0 g, 13.87 mmol) and 1, 1-ditert-butoxy-N, N-dimethyl-methanamine (5.64 g, 27.75 mmol) in toluene (20 mL) was stirred at 80℃ for 12 hr. the reaction mixture was quenched with water and extracted with EA, the organic layer was concentrated, and the crude product was purified by pre-TLC to afford tert-butyl 4-hydroxycyclohexanecarboxylate.
Step B. tert-butyl 4-prop-2-ynoxycyclohexanecarboxylate
To a solution of NaH (181.75 mg, 4.54 mmol, 60%purity) in THF (7 mL) was added tert-butyl 4-hydroxycyclohexanecarboxylate (0.7 g, 3.50 mmol) and the mixture was stirred at 0-20℃ for 30 min. To the above solution was added 3-bromoprop-1-yne (540.53 mg, 4.54 mmol) at 0-20℃ and the mixture was stirred at 0-20℃ for 2 hr. the reaction mixture was quenched with water and extracted with MTBE, the organic layer was concentrated, the crude product was purified by pre-TLC to afford tert-butyl 4-prop-2-ynoxycyclohexanecarboxylate.
Step C. methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (4-tert-butoxycarbonylcyclohexoxy) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (0.488 g, 686.74 μmol) and tert-butyl 4-prop-2-ynoxycyclohexanecarboxylate (0.18 g, 755.41 μmol) in DMF (5mL) was added Pd (PPh3) 2Cl2 (96.28 mg, 137.35 μmol) and CuI (52.32 mg, 274.70 μmol) and DIEA (265.77 mg, 2.06 mmol) at room temperature and the mixture was stirred at room temperature for 5 hr. the reaction mixture was quenched with water and extracted with EA, the organic layer was concentrated, the crude product was purified by pre-TLC to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (4-tert-butoxycarbonylcyclohexoxy) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) m/z: 821 [M+H] +.
Step D. 4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynoxy] cyclohexanecarboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (4-tert-butoxycarbonylcyclohexoxy) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (150 mg, 182.70 μmol) in HCOOH (2 mL) was stirred at 40℃ for 2 hr. the reaction mixture concentrated to afford 4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynoxy] cyclohexanecarboxylic acid. LCMS: MS (ESI) m/z: 765 [M+H] +.
Step F. 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1R) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
To a solution of 4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-
ynoxy] cyclohexanecarboxylic acid (150 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (130.78 mg, 294.15 μmol) in DMF (2 mL) was added HATU (111.78 mg, 294.15 μmol) and DIEA (75.89 mg, 588.31 μmol) at room temperature and the mixture was stirred at room temperature for 12 hr. the mixture was quenched with water and extracted with EA, the organic layer was concentrated, the crude product was purified by silica gel chromatography to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1191 [M+H] +.
Step G: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (80 mg, 67.14 umol) and NaOH (26.86 mg, 671.40 μmol) in MeOH (1 mL) and water (1 mL) was stirred at 20-30 ℃ for 3 hr. the mixture was quenched with HCl (2N) and purified by pre-HPLC to give (Compound 31, Isomer 1) and (Compound 31, Isomer 2) .
Compound 31, Isomer 1:
1H-NMR (400 MHz, CDCl3) δ 8.96 (s, 1H) , 7.91-7.86 (m, 3H) , 7.61-7.32 (m, 10H) , 6.78 (d, J = 8.5 Hz, 2H) , 6.26 (d, J = 8.2 Hz, 1H) , 5.10-4.97 (m, 3H) , 4.72 (t, J = 7.8 Hz, 1H) , 4.51 (d, J = 8.0 Hz, 2H) , 4.36 (s, 2H) , 4.14-3.97 (m, 3H) , 3.77 (t, J = 5.5 Hz, 2H) , 3.59-3.48 (m, 2H) , 3.30 (t, J = 7.4 Hz, 2H) , 3.07 (t, J = 5.8 Hz, 2H) , 2.53 (d, J = 11.0 Hz, 3H) , 2.15-1.92 (m, 8H) , 1.54-1.45 (m, 4H) , 1.31-1.25 (m, 5H) , 1.03 (s, 9H) ; LCMS: MS (ESI) M/Z: 1177 [M+H] +; HPLC: RT = 9.374 min, Method: 1.0ml-15min-5-70-95%ACN-H3PO4.
Compound 31, Isomer 2
1H-NMR (400 MHz, DMSO-d6, ) δ 8.94 (s, 1H) , 8.33 (d, J = 8.0 Hz, 1H) , 8.00 (d, J = 7.7 Hz, 1H) , 7.75 (d, J = 8.0 Hz, 1H) , 7.64-7.57 (m, 1H) , 7.46-7.29 (m, 9H) , 6.85 (d, J = 8.8 Hz, 2H) , 4.89-4.79 (m, 3H) , 4.46-4.24 (m, 4H) , 3.95 (t, J = 6.2 Hz, 2H) , 3.68 (t, J = 5.6 Hz, 4H) , 3.14-2.97 (m, 4H) , 2.63 (s, 1H) , 2.41 (s, 2H) , 2.29 (s, 1H) , 1.99-1.94 (m, 3H) , 1.87-1.74 (m, 2H) , 1.63 (d, J = 8.0 Hz, 2H) , 1.49-1.32 (m, 6H) , 1.20 (s, 4H) , 0.89-0.80 (m, 9H) ; LCMS: MS
(ESI) M/Z: 1177 [M+H] +; HPLC: RT = 9.562 min, Method: 1.0ml-15min-5-70-95%ACN-H3PO4.
Example 33: Compound 33
Step A: 2-azaspiro [3.5] nonan-7-one
A solution of tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (2 g, 8.36 mmol) in DCM (2 mL) was added HCl/Dioxane (7 mL) , the resulting mixture was stirred at 25 ℃ for 1
hr. The reaction mixture was concentrated to dryness and the crude was used directly without further purification.
Step B: benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate
A solution of 2-azaspiro [3.5] nonan-7-one (1.0 g) in DCM (3 mL) was added CbzCl (2.44 g, 14.38 mmol) and TEA (2.90 g, 28.76 mmol) at 15 ℃, the resulting mixture was stirred at 15 ℃ for 16 hr. The mixture was then poured into water (10 mL) , and the resulting mixture was extracted with DCM (20 mL*3) . The organic layer was concentrated to dryness, the crude product was purified by silica gel (PE/EA=10/1-5/1) to give the title compound.
Step C: benzyl 7- (2- (tert-butoxy) -2-oxoethylidene) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of tert-butyl 2-diethoxyphosphorylacetate (922.87 mg, 3.66 mmol) in dry THF (8 mL) was added NaH (146.35 mg, 3.66 mmol, 60%purity) under nitrogen atmosphere at 0 ℃, and the reaction mixture was stirred at 0 ℃ for 30 min. Then a solution of benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (0.5 g, 1.83 mmol) in dry THF (2 mL) was added and the mixture stirred for an additional 3.5 hr . The mixture was then poured into water (10 mL) , and the resulting mixture was extracted with EA (10 mL*3) . The organic layer was concentrated to dryness, the crude product was purified on silica gel (PE/EA=15/1-10/1) to give the title compound.
Step D: tert-butyl 2- (2-azaspiro [3.5] nonan-7-yl) acetate
To a solution of benzyl 7- (2-tert-butoxy-2-oxo-ethylidene) -2-azaspiro [3.5] nonane-2-carboxylate (0.45 g, 1.21 mmol) in MeOH (5 mL) was added Pd/C (50 mg, 10%w/w? ) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at 25 ℃ for 6 hr. The suspension was filtered through Celite, and filter cake was washed with MeOH (10 mL×3) . The combined filtrates were concentrated to give tert-butyl 2- (2-azaspiro [3.5] nonan-7-yl) acetate.
Step E: tert-butyl 2- (2- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonan-7-yl) acetate
To a solution of tert-butyl 2- (2-azaspiro [3.5] nonan-7-yl) acetate (0.19 g) and 3-bromoprop-1-yne (94.43 mg, 793.81 μmol) in DMF (5 mL) was added K2CO3 (219.09 mg, 1.59 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 2 hr. The mixture was then poured into water (10 mL) , and the resulting mixture was extracted with EA (10 mL*3) . The organic layer was concentrated to dryness, the crude product was purified on silica gel (PE/EA=20/1-15/1) to give the title compound.
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- (tert-butoxy) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (256.16 mg) and tert-butyl 2- (2-prop-2-ynyl-2-azaspiro [3.5] nonan-7-yl) acetate (100 mg, 360.49 μmol) in DMF (5 mL) was added CuI (68.66 mg, 360.49 μmol) , Pd (PPh3) 4 (208.18 mg, 180.24 μmol) and DIEA (186.01 mg, 1.44 mmol) at 25 ℃, the resulting mixture was stirred at 60 ℃ for 3 hrs under N2 atmosphere. The mixture was cooled to rt and diluted with EA. The organic layer was washed with brine and H2O, dried and concentrated. The crude was purified by Prep-TLC using DCM/MeOH=20/1 to obtain methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- (2-tert-butoxy-2-oxo-ethyl) -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 860.3 [M+H] +.
Step G: 2- (2- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -2-azaspiro [3.5] nonan-7-yl) acetic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- (2-tert-butoxy-2-oxo-ethyl) -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (150 mg, 174.40 μmol) in FA (6 mL) was stirred at 25 ℃ for 16 hr in N2. The reaction was concentrated under vacuo to give 2- [2- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -2-azaspiro [3.5] nonan-7-yl] acetic acid as a crude product. LC/MS: MS (ESI) M/Z 402.8 [M/2 +H] +.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of 2- [2- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -2-azaspiro [3.5] nonan-7-yl] acetic acid (110 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (353.45 mg, 820.91 μmol) in DMF (5 mL) was added EDCI (262.28 mg, 1.37 mmol) , HOBT (184.87 mg, 1.37 mmol) and DIEA (176.83 mg, 1.37 mmol) . The resulting mixture was stirred at room temperature for 5 hr under N2 atmosphere. The mixture was diluted with EA (50 mL) , washed with brine (30 mL) and H2O (30 mL) , the organic layers was dried over Na2SO4 and concentrated. The crude product was purified by Prep-TLC using DCM/MeOH=10/1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-
yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 1216.7 [M+H] +.
Step I: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 82.20 μmol) in THF (1.5 mL) , MeOH (1.5 mL) and H2O (1.5 mL) was added LiOH (39.37 mg, 1.64 mmol) , the resulting mixture was stirred at 25℃ for 4 hr under N2 atmosphere. The pH value was adjusted to 3-4 with 1N HCl, concentrated, the crude reaction mixture was filtered and purified by HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where water contain 0.1%formic acid) to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H) , 8.95 (s, 1H) , 8.53 (s, 1H) , 7.99 (d, J = 7.6 Hz, 1H) , 7.83-7.74 (m, 2H) , 7.62 (s, 1H) , 7.43-7.35 (m, 10H) , 6.97-6.87 (m, 2H) , 4.78 (s, 2H) , 4.50-4.29 (m, 10H) , 3.83-3.60 (m, 8H) , 3.13 (s, 2H) , 2.98 (s, 2H) , 2.40 (s, 3H) , 2.15-1.80 (m, 9H) , 1.59-1.19 (m, 6H) , 0.89 (s, 9H) . LC/MS: MS (ESI) M/Z 1202.7 [M+H] +.
Example 34: Compound 34
Step A: benzyl 4- (3-tert-butoxy-3-oxo-propoxy) piperidine-1-carboxylate
To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 21.25 mmol) and tert-butyl 3-bromopropanoate (4.44 g, 21.25 mmol) in THF (100 mL) was added NaH (849.98 mg, 21.25 mmol, 60%purity) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 15 hr in N2. The reaction mixture was diluted with H2O (100 mL) . Then it was extracted with ethyl acetate (200mL×3) . The combined organic layers was washed with brine (100 mL) , dried over Na2SO4,
then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give the title compound. LC/MS: MS (ESI) M/Z 308.3 [M-56+H] +.
Step B: tert-butyl 3- (4-piperidyloxy) propanoate
To a solution of benzyl 4- (3-tert-butoxy-3-oxo-propoxy) piperidine-1-carboxylate (2.0 g, 5.50 mmol) in ethanol (25 mL) was added Pd/C (668.32 mg, 10%w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at 30 ℃ for 10 hr. The resulting mixture was filtered, the filter cake was washed with EtOH (20 mL×3) . The filtrate was concentrated under reduced pressure to give the title compound.
Step C: tert-butyl 3- [ (1-prop-2-ynyl-4-piperidyl) oxy] propanoate
A solution of tert-butyl 3- [ (1-prop-2-ynyl-4-piperidyl) oxy] propanoate (1.0 g) and 3-bromoprop-1-yne (415.01 mg, 3.4mmol) , K2CO3 (902.69 mg, 6.54 mmol) in MeCN (10 mL) was stirred for 2 hr at 25 ℃. The reaction mixture was diluted with H2O (20 mL) . Then it was extracted with ethyl acetate (30 mL×3) . The combined organic layers was washed with brine (30 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give the title compound. LC/MS: MS (ESI) M/Z 268.20 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (3-tert-butoxy-3-oxo-propoxy) -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (300 mg, 422.18 μmol) and tert-butyl 3- [ (1-prop-2-ynyl-4-piperidyl) oxy] propanoate (225.75 mg, 844.35 μmol) in DMF (5 mL) was added DIEA (163.38 mg, 1.27 mmol) , CuI (32.16 mg, 168.87 μmol) and Pd (PPh3) Cl2 (59.27 mg, 84.44 μmol) . The mixture was stirred for 5 hr at room temperature. The resulting mixture was diluted with ethyl acetate (30 mL) , washed with water (30 mL×3) . The combined organic layers was washed with brine (30 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1: 1 to give the title compound. LCMS: MS (ESI) M/Z 850.5 [M+H] +.
Step E: 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] oxy] propanoic acid
The solution of 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] oxy] propanoic acid (260 mg, 305.86 μmol) in FA (5 mL) was stirred for 12 hr at 25 ℃. The resulting mixture was concentrated in vacuo. The crude product was used in the next step directly without further purification. LCMS: MS (ESI) M/Z 794.4 [M+H] +
Step F: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -4-piperidyl] oxy] propanoic acid (150 mg, 188.93 μmol) , DIEA (259 mg, 2.0 mmoL) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (84.00 mg, 188.93 μmol) and HATU (150 mg, 399 μmol) in DMF (2 mL) was stirred for 2 hr at 25 ℃. The reaction system was slowly added dropwise to the ice water (10 mL) and the solid was precipitated. The precipitated solids were collected by filtration and washed with water (10 mL) to give the tile compound. LCMS: MS (ESI) M/Z 1220.7 [M+H] +
Step G: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -3-oxo-propoxy] -1-piperidyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid (90 mg, 73.74 μmol) and NaOH (8.85 mg, 221.22 μmol) in dioxane (10 mL) and H2O (2 mL) was stirred for 2 hr at 25℃. The crude reaction mixture was filtered and subjected to reverse phase preparative MPLC (Prep-C18, 20-45μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 35%MeCN in water to 45%TFA in water over a 7 min period, where both solvents contain 0.1%formic acid) to provide the title compound. LC/MS: MS (ESI) M/Z [M+H] +1206.6. 1H-NMR (400 MHz, DMSO-D6) δ 8.92 (d, J = 9.1 Hz, 1H) , 8.34 (s, 1H) , 7.99 (d, J = 7.8 Hz, 1H) , 7.79 (d, J = 28.9 Hz, 2H) , 7.62 (d, J = 8.8 Hz, 1H) , 7.47-7.34 (m, 8H) , 6.90 (s, 2H) , 5.28 (s, 1H) , 4.86-4.76 (m, 3H) , 4.48-4.25 (m, 4H) , 3.95 (s, 2H) , 3.06 (d, J = 56.3 Hz,
5H) , 2.63 (s, 2H) , 2.31 (s, 2H) , 2.14-1.71 (m, 7H) , 1.49-1.32 (m, 6H) , 1.19 (s, 9H) , 0.88 (d, J = 8.0 Hz, 9H) .
Example 35: Compound 35
Step A: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (150 mg, 211.09 μmol) and tert-butyl 2- (3-prop-2-ynyl-3-azaspiro [5.5] undecan-9-yl) acetate (128.96 mg, 422.18 μmol) in DMF (5 mL) was added Pd (PPh3) 4 (121.80 mg, 105.54 μmol) , DIEA (136.15 mg, 1.06 mmol) and CuI (40.20 mg, 211.09 μmol) at 25 ℃. The resulting mixture was stirred at 60 ℃ for 3 hr under N2 atmosphere. The mixture was cooled to rt and diluted with EA (50 mL) , washed
with brine and H2O, dried and concentrated. The residue was purified by Prep-TLC using DCM/MeOH=20/1 to obtain methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 888.3 [M+H] +.
Step B: 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (150 mg, 168.89 μmol) in HCOOH (5 mL) was stirred at 25 ℃ for 8 hr under N2 atmosphere. The mixture was concentrated to obtain 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid. LC/MS: MS (ESI) M/Z 832.3 [M+H] +.
Step C: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid (150 mg, 180.28 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (320.60 mg, 721.12 μmol) in DMF (5 mL) was added EDCI (172.80 mg, 901.40 μmol) , HOBT (122 mg, 903.70 μmol) and DIEA (186.05 mg, 1.44 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 5 hr. The reaction was diluted with EA (50 mL) , washed with H2O and brine, the organic layers was dried and concentrated. The residue was purified by Prep-TLC using DCM/MeOH=9/1 to obtain methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 629.9 [M+H/2] +.
Step D: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 79.45 μmol) in THF (1.5 mL) , MeOH (1.5 mL) and H2O (1.5 mL) was added LiOH. H2O (66.68 mg, 1.59 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 3 hr. The reaction mixture was concentrated to remove solvent and diluted with H2O (5 mL) , the pH value of the solution was adjusted to 5-6 with aqueous HCl (1M) . Then it was concentrated under reduced pressure. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where water contain 0.1%formic acid) to obtain 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 9.83 (s, 1H) , 8.96 (s, 1H) , 8.34 (d, J = 6.8 Hz, 1H) , 8.00 (d, J = 8.0 Hz, 1H) , 7.76 (d, J = 8.0 Hz, 2H) , 7.64 (d, J = 8.0 Hz, 1H) , 7.46-7.27 (m, 10H) , 6.91 (d, J = 8.8 Hz, 2H) , 4.91-4.79 (m, 3H) , 4.48 (d, J = 8.8 Hz, 1H) , 4.37 (t, J = 8.0 Hz, 1H) , 4.30-4.18 (m, 3H) , 3.97 (t, J = 6.4 Hz, 2H) , 3.68 (t, J = 5.6 Hz, 2H) , 3.56 (s, 2H) , 3.38 (s, 2H) , 3.15-2.97 (m, 7H) , 2.41 (s, 3H) , 2.19-2.14 (m, 1H) , 2.03-1.91 (m, 5H) , 1.78-1.72 (m, 1H) , 1.61-1.42 (m, 5H) , 1.34-0.96 (m, 10H) , 0.89 (s, 9H) . LC/MS: MS (ESI) M/Z 1244.8 [M+H] +.
Example 36: Compound 36
Step A: 9- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) non-8-ynoic acid
To a solution of non-8-ynoic acid (52.08 mg, 337.746 μmol, 1.5 eq) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (160 mg, 225.16 μmol) in DMF (3 mL) was added Pd (PPh3) 2Cl2 (31.61 mg, 45.03 μmol) , CuI (17.15 mg, 90.06 μmol, 0.4 eq) and DIEA (87.81 mg, 675.48 μmol) , the mixture was stirred for 1 hr at room temperature under N2. The mixture was diluted with EA and water and the water phase was extracted with EA (50 ml*3) , combined the organic layer and washed with brine, dried over Na2SO4 and concentrated on vacuum to afford the title compound. LCMS: MS (ESI) M/Z: 737.4 [M+H] +.
Step B: methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 9- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) non-8-ynoic acid (180 mg) and
(2S, 4R) -1- [ (2S) -2 -amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (130.32 mg, 293.12 μmol) in DMF (3 mL) was added DIEA (95.26 mg, 732.80 μmol) and HATU (111.39 mg, 293.12 μmol) . The mixture was stirred for 1 hr at 25 ℃. The mixture was diluted with EA and water, water phase was extracted with EA (50 ml*3) and combined the organic layer and washed with brine, dried over Na2SO4 and concentrated on vacuum. The crude was purified by Prep-TLC using MeOH: DCM=1: 15 to afford the title compound. LCMS: MS (ESI) M/Z: 1163.6 [M+H] +.
Step C: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (180 mg, 154.71 μmol) in dioxane (3 mL) and water (0.6 mL) was added LiOH (22.23 mg, 928.26 μmol) and stirred for 2 hr at 40 ℃. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 45%MeCN in water to 50%MeCN in water over a 7 min period, where both solvents contain 0.1%TFA) to afford 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid. LCMS: MS (ESI) M/Z: 1149.7 [M+H] +. 1H-NMR (400 MHz, DMSO-D6) δ 12.90 (s, 1H) , 8.99 (s, 1H) , 8.38 (d, J = 8.0 Hz, 1H) , 8.04 (d, J = 7.6 Hz, 1H) , 7.82-7.78 (m, 2H) , 7.67 (d, J = 7.2 Hz, 1H) , 7.50-7.32 (m, 8H) , 7.28-7.23 (m, 2H) , 6.87-6.82 (m, 2H) , 5.18-4.83 (m, 4H) , 4.53-4.48 (m, 1H) , 4.42 (t, J = 8.4 Hz, 1H) , 4.28 (s, 1H) , 3.99-3.94 (t, J=6.0 Hz, 2H) , 3.72 (t, J = 6.0 Hz, 2H) , 3.62 (s, 2H) , 3.16 (t, J = 7.6 Hz, 2H) , 3.03 (t, J = 5.6 Hz, 2H) , 2.45 (s, 3H) , 2.38-3.34 (m, 2H) , 2.30-2.22 (m, 1H) , 2.16-2.09 (m, 1H) , 2.03-1.96 (m, 3H) , 1.82-1.76 (m, 1H) , 1.56-1.45 (m, 4H) , 1.40-1.36 (m, 5H) , 1.32-1.19 (m, 3H) , 0.89 (s, 9H) .
Example 37: Compound 37
Step A: benzyl 3- (hydroxymethyl) azetidine-1-carboxylate
To a solution of 1-benzyloxycarbonylazetidine-3-carboxylic acid (10 g, 42.51 mmol) in THF (40 mL) was added borane-tetrahydrofuran complex (1 M, 127.53 mL) at 0~10 ℃ dropwise over 10 mins. The resulting mixture was stirred at 0~25 ℃ for 16 hr under N2. To the resulting mixture was added NaOH solution (4M, 100 mL) dropwise at 0-10℃ over 30 mins. The resulting mixture was extracted with EA (100 mL*2) . The organic layer was combined,
washed with brine (50 mL*2) , dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 200~300 mesi, EA/PE=0~50%) to afford benzyl 3- (hydroxymethyl) azetidine-1-carboxylate. LCMS: MS (ESI) M/Z: 222.1 [M+H] +.
Step B: benzyl 3- (bromomethyl) azetidine-1-carboxylate
To a solution of benzyl 3- (hydroxymethyl) azetidine-1-carboxylate (1.0 g, 4.52 mmol) in DCM (10 mL) was added a solution of PPh3 (1.66 g, 6.33 mmol) in DCM (10 mL) dropwise at 0~10 ℃ over 5 mins. The resulting mixture was stirred at 0~10 ℃ for 20 mins. To the mixture was added a solution of CBr4 (1.80 g, 5.42 mmol) in DCM (10 mL) dropwise at 0~10 ℃ over 5 mins. The resulting mixture was stirred at room temperature for 18h. The reaction mixture was concentrated to dryness under reduced pressure at 40~45℃. The residue was purified by column chromatography (silica gel, 200~300 mesi, EA/PE=0~20%) to give benzyl 3- (bromomethyl) azetidine-1-carboxylate. LCMS: MS (ESI) M/Z: 286.0, 284.1 [M+H] +.
Step C: benzyl 3- [ [bromo (triphenyl) -phosphanyl] methyl] azetidine-1-carboxylate
To a solution of benzyl 3- (bromomethyl) azetidine-1-carboxylate (0.72 g, 2.53 mmol) in toluene (10 mL) was added PPh3 (731.06 mg, 2.79 mmol) at 10~20 ℃. The resulting mixture was stirred at 80 ℃ for 72 hr under N2. The reaction mixture was concentrated to dryness under reduced pressure. The residue was triturated in MTBE (25mL) and filtrated to afford benzyl 3- [ [bromo (triphenyl) -phosphanyl] methyl] azetidine-1-carboxylate. LC/MS: MS (ESI) M/Z 466.2 [M+H-Br] +.
Step D: benzyl 3- [ (3-tert-butoxycarbonylcyclobutylidene) methyl] azetidine-1-carboxylate
To a suspension of benzyl 3- [ [bromo (triphenyl) -phosphanyl] methyl] azetidine-1-carboxylate (1.09 g, 1.99 mmol) in dry THF (30 mL) was added LiHMDS in THF (1 M, 1.99 mL) dropwise at -40~-30 ℃ under N2. The reaction mixture was stirred at -40~-30 ℃ for 1hr. a solution of benzyl 3- [ [bromo (triphenyl) -phosphanyl] methyl] azetidine-1-carboxylate (1.09 g, 1.99 mmol) in THF (0.5 mL) was added dropwise at -40~-30 ℃. The resulting mixture was allowed to warm-up to room temperature overnight. The reaction mixture was quenched by saturated NH4Cl solution (30mL) and extracted with DCM (30mL*2) . The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure at 40℃. The residue was purified by prep-TLC (EA/PE=1: 5) to give benzyl 3- [ (3-tert-butoxycarbonylcyclobutylidene) methyl] azetidine-1-carboxylate. LC/MS: MS (ESI) M/Z 302.2 [M+H-56] +.
Step E: tert-butyl 2- (3- (3- (prop-2-yn-1-yl) azetidin-1-yl) cyclobutyl) acetate
To a solution of benzyl 3- [ (3-tert-butoxycarbonylcyclobutylidene) methyl] azetidine-1-carboxylate (200.00 mg, 559.53 μmol) in i-PrOH (30 mL) was added Pd/C (20 mg, 10%w/w) and Pd (OH) 2/C (20 mg, 10%w/w) at room temperature. The resulting mixture was degassed and backfilled with H2 for 3 times. The resulting mixture was stirred at 25 ℃ for 16 hr under H2. The reaction mixture was filtered through a celite pad and washed with EA. The filtrate was concentrated to dryness under reduced pressure at 40℃. The resulting crude was used in next step without further purification. LC/MS: MS (ESI) M/Z 226.3 [M+H] +.
Step F: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ (3-tert-butoxycarbonylcyclobutyl) methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- (3-chloroprop-1-ynyl) phenoxy] propyl] thiazole-4-carboxylate (235.00 mg, 357.58 μmol) and tert-butyl 3- (azetidin-3-ylmethyl) cyclobutanecarboxylate (80.57 mg, 357.58 μmol) in DMF (7 mL) was added Cs2CO3 (349.52 mg, 1.07 mmol) at room temperature. The resulting mixture was stirred at 25 ℃ for 48 hr. The reaction mixture was diluted with H2O (50mL) and extracted with DCM (25mL*3) . The combined organic layers was washed with brine (25mL*2) , dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by prep-TLC (MeOH/DCM=1: 20) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ (3-tert-butoxycarbonylcyclobutyl) methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 424.0 [M/2+H] +.
Step G: 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] azetidin-3-yl] methyl] cyclobutanecarboxylic acid
The solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ (3-tert-butoxycarbonylcyclobutyl) methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (52.0 mg, 61.46 μmol) in HCOOH (3 mL) was stirred for 16 hr at 40 ℃ under N2. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (3 mL) and concentrated to dryness under reduced pressure. This procedure was repeated for 3 times. The resulting crude product was used in next step without further purification. LC/MS: MS (ESI) M/Z 395.8 [M/2+H] +.
Step H: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-
propyl] carbamoyl] cyclobutyl] methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of 3- [ [1- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] azetidin-3-yl] methyl] cyclobutanecarboxylic acid (58 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (59.74 mg, 138.76 μmol) in DCM (6 mL) was added DIEA (35.87 mg, 277.52 μmol) and HATU (55.40 mg, 145.70 μmol) at room temperature. The resulting mixture was stirred at 25℃ for 1.5 hr. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL*2) . The organic layer combined was washed with brine (10 mL*2) , dried over Na2SO4 and concentrated to dryness under reduce pressure. The residue was purified by Prep-TLC (MeOH/DCM=1: 25) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 601.8 [M/2+H] +.
Step I: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methyl carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (68.0 mg, 56.55 μmol) in a mixture of THF (2 mL) /MeOH (2 mL) and H2O (1 mL) was added LiOH H2O (23.73 mg, 565.49 μmol) at room temperature. The resulting mixture was stirred at 25℃ for 8 hr. The reaction mixture was concentrated to dryness under reduce pressure. The residue purified by prep-HPLC (0.1%TFA-ACN, YMC-Actus Triart C18, 150*20mm, 5um) and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [ [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclobutyl] methyl] azetidin-1-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LC/MS: MS (ESI) M/Z 1188.6 [M+H] +. 1H-NMR (400 MHz, DMSO-D2O) δ1H-NMR (400 MHz, DMSO-D2O) δ 8.99 (s, 1H) , 8.04 (d, J = 7.7 Hz, 1H) , 7.81 (d, J = 8.0 Hz,
1H) , 7.67 (d, J = 7.4 Hz, 1H) , 7.51-7.35 (m, 10H) , 6.95 (d, J = 8.8 Hz, 2H) , 4.84 (s, 2H) , 4.53-4.08 (m, 8H) , 4.01 (t, J = 6.2 Hz, 2H) , 3.88-3.80 (m, 2H) , 3.72 (t, J = 6.0 Hz, 3H) , 3.18 (t, J = 7.4 Hz, 2H) , 3.02-3.05 (m, 3H) , 2.76-2.66 (m, 1H) , 2.45 (s, 3H) , 2.21-1.88 (m, 7H) , 1.78-1.63 (m, 4H) , 1.54 (d, J = 6.9 Hz, 1H) , 1.23 (s, 1H) , 0.91 (s, 9H) .
Example 38: Compound 38
Step A: methyl 2-chloro-5- (3- (2-fluoro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (1 g, 4.24 mmol, 1.00 equiv. ) and 2-fluoro-4-iodo-phenol (1.01 g, 4.24 mmol) in THF (20 mL) was added PPh3 (1.11 g, 4.24 mmol) and DEAD (738.92 mg, 4.24 mmol) . The mixture was stirred at room temperature for 4 hrs. The reaction mixture was treated with water (100mL) and extracted with EA (3*50mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE=0~10%) to give methyl 2-chloro-5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 456.0 [M+H] +.
Step B: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (857.65 mg, 2.48 mmol, HCl salt) and methyl 2-chloro-5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (1.13 g, 2.48 mmol) in DMA (10 mL) was added KI (411.66 mg, 2.48 mmol) and Cs2CO3 (2.42 g, 7.44 mmol) . The mixture was stirred at 70 ℃ for 18 hrs. The reaction mixture was treated with water (100mL) and extracted with EA (3*50mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash column chromatography (MeOH/DCM=0~90%) and prep-TLC DCM: MeOH=70: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 728.9 [M+H] +.
Step C: 9- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) -3-fluorophenyl) non-8-ynoic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (350 mg, 480.39 μmol) and non-8-ynoic acid (148.14 mg, 960.75 μmol) in DMF (5 mL) was added CuI (36.59 mg, 192.15 μmol) , Pd (PPh3) 2Cl2 (67.43 mg, 96.09 μmol) and DIEA (182.25 mg, 1.44 mmol) . The mixture was degassed and backfilled with N2 for 6 times. The resulting mixture was stirred at 60℃ for 1 hr. The reaction mixture was treated with water (50mL) and extracted with EA(5*20mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-fluoro-phenyl] non-8-ynoic acid as a crude product, which was used in next step without further purification. LC/MS: MS (ESI) M/Z 755.5 [M+H] +.
Step D: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-
yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-fluoro-phenyl] non-8-ynoic acid (200 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (185.60 mg, 397.41 μmol, HCl salt) in DCM (5 mL) was added HATU (151.11 mg, 397.41 μmol) and DIEA (102.72 mg, 794.82 μmol) . The mixture was stirred at room temperature for 2 hrs. The reaction mixture was treated with water (50mL) and extracted with DCM (3*20mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by prep-TLC (MeOH/DCM=20: 1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 584.3 [M+2H] /2+.
Step E: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (140 mg, 119.92 μmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.5 mL) was added LiOH (86.16 mg, 3.60 mmol) . The mixture was stirred at room temperature for 2 hrs. The pH value of the reaction mixture was adjusted to 3 with 0.1M HCl solution and extracted with DCM (25mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H) , 8.52 (t, J = 6.0 Hz, 1H) , 8.00 (d, J = 7.6 Hz, 1H) , 7.81 (d, J = 9.2 Hz, 1H) , 7.75 (d, J = 8.0 Hz, 1H) , 7.63 (d, J = 7.2 Hz, 1H) , 7.45-7.30 (m, 8H) , 7.19-7.14 (m, 1H) , 7.09-7.01 (m, 2H) , 4.79 (s, 2H) , 4.51 (d, J = 9.2 Hz, 1H) , 4.42-4.36 (m, 2H) , 4.31 (s,
1H) , 4.20-4.16 (m, 1H) , 4.01 (t, J = 6.4 Hz, 2H) , 3.69-3.61 (m, 4H) , 3.12 (t, J = 7.6 Hz, 2H) , 2.98 (t, J = 5.6 Hz, 2H) , 2.40 (s, 3H) , 2.32 (t, J = 6.8 Hz, 2H) , 2.22 (q, J = 7.2 Hz, 1H) , 2.12-2.05 (m, 1H) , 1.98 (d, J = 7.2 Hz, 2H) , 1.86 (t, J = 8.4 Hz, 1H) , 1.45 (q, J = 6.8 Hz, 3H) , 1.38-1.31 (m, 1H) , 1.23 (q, J = 7.2 Hz, 2H) , 0.89 (s, 9H) . LC/MS: MS (ESI) M/Z 1154.6 [M+H] +.
Example 39: Compound 39
Step A: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-fluoro-phenyl] non-8-ynoic acid (150 mg, 198.71 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (143.38 mg, 298.06 μmol, HCl salt) in DCM (5 mL) was added HATU (113.33 mg, 298.06 μmol) and DIEA (77.04 mg, 596.12 μmol) . The mixture was stirred at room temperature for 2 hrs. The reaction mixture was treated with water (50mL) and extracted with DCM (3*20mL) . The organic layer combined
was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by prep-TLC (MeOH/DCM=20: 1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 591.4 [M+2H] /2+.
Step B: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxonon-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (130 mg, 110.03 μmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.5 mL) was added LiOH (79.06 mg, 3.30 mmol) . The mixture was stirred at room temperature for 2 hrs. The pH value of the reaction mixture was adjusted to 3 with 0.1M HCl solution and extracted with DCM (25mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 8.99 (s, 1H) , 8.37 (d, J = 8.0 Hz, 1H) , 8.04 (d, J = 8.0 Hz, 1H) , 7.79 (d, J = 7.6 Hz, 2H) , 7.67 (d, J = 7.2 Hz, 1H) , 7.49-7.32 (m, 8H) , 7.20 (d, J = 12.4 Hz, 1H) , 7.14-7.05 (m, 2H) , 4.95-4.88 (m, 1H) , 4.84 (s, 2H) , 4.52 (d, J = 9.2 Hz, 1H) , 4.42 (t, J = 8.0 Hz, 1H) , 4.28 (s, 1H) , 4.05 (t, J = 6.4 Hz, 2H) , 3.72 (t, J = 5.6 Hz, 2H) , 3.60 (s, 2H) , 3.17 (t, J = 7.6 Hz, 2H) , 3.03 (t, J = 5.6 Hz, 2H) , 2.45 (s, 3H) , 2.37 (t, J = 6.8 Hz, 2H) , 2.29-2.20 (m, 1H) , 2.18-2.09 (m, 1H) , 2.05-1.98 (m, 3H) , 1.83-1.76 (m, 1H) , 1.52-1.47 (m, 3H) , 1.37 (d, J = 6.8 Hz, 3H) , 1.30-1.23 (m, 2H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1168.6 [M+H] +.
Example 40: Compound 40
Step A: tert-butyl 3- ( ( ( (trifluoromethyl) sulfonyl) oxy) methyl) azetidine-1-carboxylate
To a solution of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (10 g, 53.41 mmol) and DIEA (13.81 g, 106.82 mmol, 18.61 mL) in dry DCM (111.96 mL) was added Tf2O (15.82 g, 56.08 mmol, 9.43 mL) dropwise under nitrogen atmosphere at -75 ~ -70 ℃. The reaction mixture was stirred at -75 ~ -70 ℃ for 1h. The reaction mixture was quenched by adding 40 mL H2O at -75 ~ -70 ℃. The resulting mixtures was extracted with DCM (100mL*2) at 0-5 ℃. The organic layer combined was washed with water (100mL*1) , brine (100mL*1) , dried over Na2SO4 and concentrated to dryness at 20 ℃. The residue was purified by column chromatography (silica gel, 200-300 mesi, DCM/PE= 10%~ 100%) to give tert-butyl 3- ( ( ( (trifluoromethyl) sulfonyl) oxy) methyl) azetidine-1-carboxylate. LCMS: MS (ESI) M/Z: 264.0 [M-56+H] +.
Step B: tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine-1-carboxylate
To a solution of ethynyl (trimethyl) silane (20.30 g, 206.71 mmol, 29.21 mL) in anhydrous THF (200 mL) was added n-BuLi (206.70 mmol, 18.8 mL, THF solution) dropwise under nitrogen atmosphere at -30 ~ -20 ℃. The reaction mixture was stirred at -30 ~ -20 ℃ for 30 min. To the reaction mixture was added DMPU (20 mL) at -30 ~ -20℃, followed by addition of a solution of tert-butyl 3- ( ( ( (trifluoromethyl) sulfonyl) oxy) methyl) azetidine-1-carboxylate (11 g, 34.45 mmol) in anhydrous THF (20 mL) dropwise in 30 min at -30 ~ -20 ℃. The resulting mixture was stirred for an additional 0.5 hr at -30 ~ -20℃. The reaction mixture was quenched by conc. NH3H2O (20 mL) and MeOH (20mL) at -30 ~ -20 ℃. The resulting mixture was warmed to room temperature over 10 min. The reaction mixture was diluted with
EA(60 mL) and H2O (30 mL) . The organic layer combined was washed with water (60 mL*1) , brine (60 mL*1) , dried over Na2SO4 and concentrated to dryness in vacuo at 40 ℃. The residue was purified by column chromatography (Silica gel, DCM/PE=0~10%) to give tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine-1-carboxylate. LC/MS: MS (ESI) M/Z 253.1 [M-56+ACN+H] +.
Step C: 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine
To a solution of tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine-1-carboxylate (4.0 g, 14.96 mmol) in dioxane (12 mL) was added HCl-dioxane (4 M, 12 mL) at room temperature. The resulting mixture was stirred at 10~20℃ for 3 hr. The reaction mixture was concentrated to dryness under reduced pressure to afford 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine, which was used in next step without further purification. LC/MS: MS (ESI) M/Z 168.2 [M+H] +.
Step D: tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidine] -1'-carboxylate
To a solution of 3- (3- (trimethylsilyl) prop-2-yn-1-yl) azetidine (3.0 g) and tert-butyl 3-oxoazetidine-1-carboxylate (2.52 g, 14.72 mmol) in dry DCM (90 mL) was added NaBH (OAc) 3 (9.36 g, 44.16 mmol) in one portion at 10~20 ℃. The resulting mixture was stirred for 16 hr. To the mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (2.52 g, 14.72 mmol) and NaBH (OAc) 3 (1.56 g, 7.36 mmol) . The resulting mixture was stirred for an additional 3 hr. The reaction mixture was quenched with saturated NaHCO3 solution (45 mL) and extracted with DCM(45 mL*3) . The organic layer combined was washed with brine (90mL) , dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesi, MeOH/DCM=0~10%) to afford tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidine] -1'-carboxylate. LC/MS: MS (ESI) M/Z 323.3 [M+H] +.
Step E: 3- (3- (trimethylsilyl) prop-2-yn-1-yl) -1, 3'-biazetidine
To a solution of tert-butyl 3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidine] -1'-carboxylate (2 g, 6.20 mmol) in dioxane (6 mL) was added HCl-dioxane (4 M, 6.00 mL) at rt. The resulting mixture was stirred at 25℃ for 4 hr. The reaction mixture was concentrated to dryness under reduced pressure to afford 3- (3- (trimethylsilyl) prop-2-yn-1-yl) -1, 3'-biazetidine as a crude product, which was used in next step without further purification. LC/MS: MS (ESI) M/Z 223.2 [M+H] +.
Step F: tert-butyl 2- (3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidin] -1'-yl) acetate
To a solution of 3- [1- (azetidin-3-yl) azetidin-3-yl] prop-1-ynyl-trimethyl-silane (1.6 g) in anhydrous DMF (32 mL) was added K2CO3 (2.14 g, 15.45 mmol) at 0~10 ℃. After stirred at 0~10 ℃ for 10 min, a solution of tert-butyl 2-bromoacetate (1.21 g, 6.18 mmol) in CH3CN (1
mL) was added at 0-10℃. The reaction was stirred at 80℃ for 1 hr. The reaction mixture was diluted with H2O (100mL) and extracted with DCM (100mL*3) . The organic layer combined was washed with brine (10mL*1) , dried over Na2SO4 and concentrated to dryness under reduced pressure at 40 ℃. The residue was purified by column chromatography (silica gel, 200-300 mesi, MeOH/DCM=0~10%) . The eluent was concentrated under reduced pressure. The desired eluent was combined and concentrated to dryness under reduced pressure to afford tert-butyl 2- (3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidin] -1'-yl) acetate. LC/MS: MS (ESI) M/Z 337.2 [M+H] +.
Step G: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- (tert-butoxy) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (330.00 mg, 464.39 μmol) and tert-butyl 2- (3- (3- (trimethylsilyl) prop-2-yn-1-yl) - [1, 3'-biazetidin] -1'-yl) acetate (187.55 mg, 557.27 μmol) in DMF (6.6 mL) in a 50-mL flask was added Pd (PPh3) 4 (53.66 mg, 46.44 μmol) , CuI (17.69 mg, 92.88 μmol) and DIEA (180.06 mg, 1.39 mmol, 248.01 μL) at room temperature. The flask was degassed and backfilled with N2 for 3 times. TBAF (1 M, 557.27 μL) was added. The flask was degassed and backfilled with N2 for 3 times. The resulting mixture was stirred at 70 ℃ under N2 for 3 hr. The reaction mixture was diluted with H2O (100mL) and extracted with DCM (50mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by prep-TLC(MeOH/DCM=1: 30) to afford methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- (tert-butoxy) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 847.3 [M+H] +, 424.5 [M/2+H] +.
Step H: 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) - [1, 3'-biazetidin] -1'-yl) acetic acid
To methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- (tert-butoxy) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (150 mg, 177.08 μmol) was added HCOOH (5 mL) at room temperature. The resulting mixture was stirred at 40 ℃ for 5 hr under N2. The reaction mixture was concentrated to dryness to give a crude product, which was used in next step without further purification. LC/MS: MS (ESI) M/Z 396.6 [M/2+H] +.
Step I: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) - [1, 3'-biazetidin] -1'-yl) acetic acid (180.00 mg, 227.58 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (212.57 mg, 455.15 μmol, HCl salt) in DCM (6 mL) was added DIEA (88.24 mg, 682.73 μmol, 121.54 μL) and HATU (173.06 mg, 455.15 μmol) at room temperature. The resulting mixture was stirred at 25℃ for 2 hr. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse phase Column Chromatography (C18-ODS, ACN/H2O (0.1%TFA) ) = 0~100%) to afford methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 602.4 [M/2+H] +.
Step J: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1 H) -yl) -5- (3- (4- (3- (1'- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (60.00 mg, 49.85 μmol) in a mixture of THF (0.6 mL) and MeOH (0.6 mL) was added LiOH H2O (20.92 mg, 498.55 μmol) at room temperature. The resulting mixture was stirred at 25℃ for 4 hr. The reaction mixture was concentrated to dryness under reduced pressure. The residue was redissolved in DCM/MeOH (10: 1) , filtered and concentrated to dryness. The residue was purified by prep-HPLC (0.05%NH3H2O-10mmol/L NH4HCO3-ACN, YMC-Actus Triart C18, 150*20mm, 5um) and freeze-dried to afford 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (1'- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) - [1, 3'-biazetidin] -3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid. LC/MS: MS (ESI) M/Z 1189.7 [M+H] +. 1H-NMR (400 MHz, DMSO-D6) δ 8.96 (s, 1H) , 8.60 (t, J = 5.9 Hz, 1H) , 8.02 (d, J =
8.0 Hz, 1H) , 7.77 (d, J = 8.0 Hz, 1H) , 7.66 (d, J = 7.4 Hz, 1H) , 7.54 (d, J = 9.6 Hz, 1H) , 7.48-7.32 (m, 9H) , 7.25 (d, J = 8.5 Hz, 2H) , 6.83 (d, J = 8.8 Hz, 2H) , 4.81 (s, 2H) , 4.48 (d, J = 9.6 Hz, 1H) , 4.44-4.33 (m, 3H) , 4.21-4.26 (m, 1H) , 3.95 (t, J = 6.2 Hz, 2H) , 3.71-3.55 (m, 6H) , 3.16-2.95 (m, 12H) , 2.66-2.53 (m, 3H) , 2.43 (s, 3H) , 2.06-1.85 (m, 4H) , 1.22 (s, 2H) , 0.90 (s, 9H) .
Example 41: Compound 41
Step A: benzyl 4- ( (2- (tert-butoxy) -2-oxoethoxy) methyl) piperidine-1-carboxylate
To a solution of benzyl 4- (hydroxymethyl) piperidine-1-carboxylate (3 g, 12.03 mmol) and tert-butyl 2-bromoacetate (3.52 g, 18.05 mmol) in toluene (30 mL) was added TBAB (3.88
g, 12.03 mmol) and NaOH (50%aq. ) (2.41 g, 60.17 mmol) . The resulting mixture was stirred at 25 ℃ for 18 hr. The reaction mixture was treated with water (100mL) and extracted with DCM (3*50mL) . The organic phase was washed with brine (2*100mL) and concentrated in vacuo to give a crude. The residue was purified by chromatography on silica gel column eluting PE: EA=5: 1 to give the title product. LCMS: MS (ESI) M/Z 363.4 [M+H]
Step B: tert-butyl 2- (piperidin-4-ylmethoxy) acetate
To a solution of benzyl 4- ( (2- (tert-butoxy) -2-oxoethoxy) methyl) piperidine-1-carboxylate (1.2 g, 3.30 mmol) in MeOH (50 mL) was added Pd/C (400 mg, 10%w/w) . The mixture was stirred at 25 ℃ for 4 hr under H2. The reaction mixture was filtered through a pad of celite and filtrate was concentrated in vacuum to give the crude product. LCMS: MS (ESI) M/Z 229.3 [M+H] .
Step C: tert-butyl 2- ( (1- (prop-2-yn-1-yl) piperidin-4-yl) methoxy) acetate
To a solution of tert-butyl 2- (piperidin-4-ylmethoxy) acetate (740 mg) in THF (20 mL) was added K2CO3 (535.19 mg, 3.87 mmol) at 0 ℃. After 0.1 h, 3-bromoprop-1-yne (460.66 mg, 3.87 mmol) was added and the mixture was stirred at 0 ℃ for 4 hr. The reaction mixture was warmed to rt, treated with water and extracted with DCM . The organic phase was washed with saturated NaCl and concentrated in vacuo. The residue was purified by prep-TLC PE: EA=2: 1 to give the title compound. LCMS: MS (ESI) M/Z 267.4 [M+H] .
Step D. methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- ( (2- (tert-butoxy) -2-oxoethoxy) methyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 2- ( (1- (prop-2-yn-1-yl) piperidin-4-yl) methoxy) acetate (112.87 mg, 422.18 μmol) , methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4-iodophenoxy) propyl) thiazole-4-carboxylate, CuI (40.20 mg, 211.09 μmol) and Pd (PPh3) 4 (243.93 mg, 211.09 μmol) in DMF (3 mL) was added DIEA (218.25 mg, 1.69 mmol) at 25 ℃. The resulting mixture was stirred at 60 ℃ for 16 hr. he resulting mixture was stirred at 60 ℃ for 16 hr. The reaction was concentrated and purified by Prep-TLC using DCM/MeOH =25/1 to afford the title compound. LCMS: MS (ESI) M/Z 850.1 [M+1] .
Step E: 2- ( (1- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) piperidin-4-yl) methoxy) acetic acid
The solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- ( (2- (tert-butoxy) -2-oxoethoxy) methyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (200 mg, 235.28 μmol) in FA (5 mL) was stirred at
25 ℃ for 16 hr. The mixture was concentrated under reduced pressure to get the crude product , which was used directly in next step. LCMS: MS (ESI) M/Z 794.0 [M+H] /
Step F. methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- ( (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) methyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- ( (1- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) piperidin-4-yl) methoxy) acetic acid (180 mg) and (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutanoyl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (112.56 mg) in DCM (8 mL) was added HATU (144.30 mg, 379.8 μmol) and DIEA (81.65 mg, 632.94 μmol) , and the resulting mixture was stirred at 25℃ for 4 hr. The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) , washed with brine (4*30 mL) . The organic layers were combined and concentrated. The crude product was purified by silica gel chromatography eluted with DCM: MeOH=1: 1 to give the title product. LCMS: MS (ESI) M/Z 1220.5 [M+H] +.
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- ( (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) methyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- ( (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) methyl) piperidin-1-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (150 mg, 122.90 μmol) in THF/MeOH/H2O (V1: V2: V3=2: 2: 1, 3 mL) was added LiOH (25.78 mg, 614.49 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 4 hr. The reaction was concentrated, the pH value was adjusted to 3 with 1N HCl, extracted with DCM (25mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) to give the title product. LCMS: MS (ESI) M/Z 1206.5 [M+H] +. 1H-NMR (400 MHz, DMSO-D6) δ 12.92 (brs, 1H) , 10.04 (brs, 1H) , 8.99 (s, 1H) , 8.83 (brs, 1H) , 8.43 (d, J = 7.7 Hz, 1H) , 8.03 (d, J = 7.7 Hz, 1H) , 7.80 (d, J = 7.7 Hz, 1H) , 7.67 (d, J = 7.4 Hz, 1H) , 7.50-7.34 (m, 11H) , 6.95 (d, J = 8.2 Hz, 2H) , 4.93-4.83 (m, 3H) , 4.58-4.54 (m, 1H) , 4.44 (t, J = 8.1 Hz, 1H) , 4.31 (s, 3H) , 4.03-3.96 (m, 4H) , 3.73-3.55 (m, 5H) , 3.30-3.45 (m, 2H) , 3.17 (t, J = 7.1 Hz, 2H) , 3.11-3.03 (m, 3H) , 2.45 (s, 3H) , 2.10-1.76
(m, 8H) , 1.52 (d, J = 6.9 Hz, 2H) , 1.48-1.44 (m, 2H) , 1.36 (d, J = 6.6 Hz, 2H) , 1.23 (s, 1H) , 0.94 (s, 9H)
Example 42: Compound 42
Step A: 7-azaspiro [3.5] nonan-2-one hydrochloride
A solution of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (4 g, 16.71 mmol) in DCM (50 mL) and HCl/dioxane (10 mL) was stirred at room temperature for 3 hr . The reaction mixture was concentrated to dryness and used in next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (s, 4H) , 2.86 (s, 4H) , 1.84 (t, J = 4.0 Hz, 4H) .
Step B: benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate
A solution of 7-azaspiro [3.5] nonan-2-one (2.9 g, HCl salt) in THF (14 mL) was added CbzCl (5.07 g, 29.72 mmol) and NaHCO3 (1.39 g, 16.51 mmol) at 0 ℃, the resulting mixture was stirred at 0-20 ℃ for 2 hr. The reaction mixture was quenched with 30 mL H2O. The resulting solution was extracted with EA (30 mL*3) . The combined organic layers was washed with brine (30 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. 1H NMR (400 MHz, DMSO-d6) δ 7.34 (m, 5H) , 5.12 (s, 2H) , 3.40 (m, 4H) , δ 2.80 (s, 4H) , 1.70 (s, 4H) . LC/MS: MS (ESI) M/Z 274.2 [M+H] +.
Step C: benzyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate
To a solution of methoxymethyl (triphenyl) phosphonium (7.15 g) in THF (30 mL) was added t-BuOK (2.50 g, 22.24 mmol, 1.6 equiv) under N2. The suspension was degassed under vacuum and purged with N2 several times. Then the mixture was added benzyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (3.8 g, 13.90 mmol, 1.5 equiv) and stirred at 70℃ for 2h. The reaction mixture was quenched with 20 mL H2O. The resulting solution was extracted with EA (20 mL*3) . The combined organic layers was washed with brine (20mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=5: 1 to give benzyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (m, 5H) , 5.83 (s, 1H) , 3.54-3.40 (m, 7H) , 2.42-2.33 (m, 4H) , 1.56 (s, 4H) . LC/MS: MS (ESI) M/Z 302.2 [M+H] +.
Step D: benzyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate
To a solution of benzyl 2- (methoxymethylene) -7-azaspiro [3.5] nonane-7-carboxylate (4 g, 13.27 mmol) in MeCN (8 mL) , H2O (2 mL) was added TFA (0.2 mL) and the resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with H2O (1 mL) and the pH value of the solution was adjusted to 9 with saturated Na2CO3 solution. Then it was extracted with EtOAc (10 mL*3) . The combined organic layer was washed with brine (10 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was used in next step without further purification. LC/MS: MS (ESI) M/Z 288.2 [M+H] +.
Step E: 7- ( (benzyloxy) carbonyl) -7-azaspiro [3.5] nonane-2-carboxylic acid
A solution of benzyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate (2.3 g) in MeCN (15 mL) and H2O (15 mL) was added KMnO4 (1.90 g, 12.01 mmol) at 25 ℃, the resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated. The
reaction mixture was diluted with H2O (3 mL) and the pH value of the solution was adjusted to 3-4 with aqueous HCl (1M) . Then it was extracted with EtOAc (20 mL*3) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction mixture was dried under vacuum to afford 7-benzyloxycarbonyl-7-azaspiro [3.5] nonane-2-carboxylic acid. LC/MS: MS (ESI) M/Z 304.2 [M+H] +.
Step F: 7-benzyl 2-tert-butyl 7-azaspiro [3.5] nonane-2, 7-dicarboxylate
A solution of 7-benzyloxycarbonyl-7-azaspiro [3.5] nonane-2-carboxylic acid (800 mg) and tert-butoxycarbonyl tert-butyl carbonate (1.15 g, 5.27 mmol) in DCM (20 mL) was added DMAP (161.09 mg, 1.32 mmol) and TEA (533.72 mg, 5.27 mmol) at room temperature, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with 5 mL H2O. The resulting solution was extracted with DCM (10 mL*3) , the combined organic layers were washed with brine (10 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give 7-benzyl 2-tert-butyl 7-azaspiro [3.5] nonane-2, 7-dicarboxylate. LC/MS: MS (ESI) M/Z 360.2 [M+H] +.
Step G: tert-butyl 7-azaspiro [3.5] nonane-2-carboxylate
A solution of 7-benzyl 2-tert-butyl 7-azaspiro [3.5] nonane-2, 7-dicarboxylate (1.7 g, 4.73 mmol) in MeOH (30 mL) was added Pd/C (574.38 mg, 10%w/w) at 20 ℃. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature for 2 hr. The suspension was filtered through celite and filter cake was washed with MeOH (5 mL*3) . The combined filtrates were concentrated to dryness to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.96-2.756 (m, 5H) , 1.994-1.952 (m, 4H) , 1.588-1.512 (m, 5H) , 1.42 (s, 9H) .
Step H: tert-butyl 7- (prop-2-yn-1-yl) -7-azaspiro [3.5] nonane-2-carboxylate
A solution of tert-butyl 7-azaspiro [3.5] nonane-2-carboxylate (860 mg, 3.82 mmol, 1 equiv) and 3-bromoprop-1-yne (454.03 mg, 3.82 mmol, 1 equiv) in DMF (10 mL) was added K2CO3 (1.06 g, 7.63 mmol, 2 equiv) at 0 ℃, the resulting mixture was stirred at 20 ℃ for 0.5 hr. The reaction mixture was quenched with 10 mL H2O. The resulting solution was extracted with DCM (10mL*3) . The combined organic layers were washed with brine (10mL) , dried over Na2SO4, , filtered and concentrated under reduced pressure. The crude product was used in next step without further purification. LC/MS: MS (ESI) M/Z 264.3 [M+H] +.
Step I: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (2- (tert-butoxycarbonyl) -7-azaspiro [3.5] nonan-7-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of tert-butyl 7-prop-2-ynyl-7-azaspiro [3.5] nonane-2-carboxylate (277.98 mg) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (500 mg, 703.63 μmol) in DMF (8 mL) was added DIPEA (363.75 mg, 2.81 mmol) , CuI (67.00 mg, 351.81 μmol) and Pd (PPh3) 4 (406.54 mg, 351.81 μmol) at 25 ℃, the resulting mixture was stirred at 60 ℃ for 3 hr under N2 atmosphere. Water (20 mL) was added and the mixture was extracted with DCM (20mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with DCM: MeOH=20: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (2-tert-butoxycarbonyl-7-azaspiro [3.5] nonan-7-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 846.6 [M+H] +.
Step J: 7- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -7-azaspiro [3.5] nonane-2-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (2-tert-butoxycarbonyl-7-azaspiro [3.5] nonan-7-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (230 mg, 271.85 μmol) in FA (5 mL) was stirred at 40 ℃ for 1 hr. The reaction mixture was concentrated to dryness and used in next step without further purification. LC/MS: MS (ESI) M/Z 790.3 [M+H] +.
Step K: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -7-azaspiro [3.5] nonan-7-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of 7- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -7-azaspiro [3.5] nonane-2-carboxylic acid (150 mg) and DIPEA (368.11 mg, 2.85 mmol) in DMF (8 mL) was added HATU (144.31 mg, 379.77 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (422.10 mg, 949.42 μmol) at 20 ℃, the resulting mixture was stirred at 20 ℃ for 3 hr. Water (20 mL) was added and the mixture was extracted with DCM (20mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Prep-C18, 20-45μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where both solvents contain 0.1%formic acid) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-
isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 608.8 [M/2+H] +.
Step L: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -7-azaspiro [3.5] nonan-7-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 82.20 μmol) in THF (4 mL) , MeOH (4 mL) and H2O (4 mL) was added LiOH (19.69 mg, 822.01 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 3 hr. The reaction mixture was diluted with H2O (4 mL) and the pH value of the solution was adjusted to 4-5 with aqueous HCl (1M) . The reaction mixture was filtered and the precipitated solid was washed with H2O (5 mL*3) and dried under vacuum to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 8.94 (s, 1H) , 8.34 (d, J = 8.0 Hz, 1H) , 8.00 (d, J = 7.2 Hz, 1H) , 7.84 (t, J = 6.0 Hz, 1H) , 7.78-7.74 (m, 2H) , 7.62 (d, J = 7.2 Hz, 1H) , 7.54-7.28 (m, 9H) , 7.23-7.18 (m, 2H) , 6.82-6.76 (m, 2H) , 4.91-4.84 (m, 1H) , 4.75 (s, 2H) , 4.49-4.44 (m, 1H) , 4.23 (s, 1H) , 3.91 (t, J = 6.4 Hz, 2H) , 3.77 (t, J = 6.0 Hz, 2H) , 3.58 (s, 2H) , 3.21-2.98 (m, 5H) , 2.64-2.61 (m, 1H) , 2.40 (d, J = 8.0 Hz, 3H) , 2.34-2.28 (m, 2H) , 2.23-1.90 (m, 4H) , 1.78-1.72 (m, 1H) , 1.52-1.12 (m, 14H) , 0.97-0.88 (m, 12H) . LC/MS: MS (ESI) M/Z 1202.6 [M+H] +.
Example 43: Compound 43
Step A: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of 7- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -7-azaspiro [3.5] nonane-2-carboxylic acid (170 mg, 215.20 μmol) and DIPEA (278.13 mg, 2.15 mmol) in DMF (8 mL) was added HATU (122.66 mg, 322.80 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (138.99 mg, 322.80 μmol) at 20 ℃ room temperature, the resulting mixture was stirred at room temperature for 3 hr. Water (30 mL) was added and extracted with EA (20mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC with DCM: MeOH=20: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-
propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 609.9 [M/2+H] +.
Step B: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 83.16 μmol) in THF (0.5 mL) /MeOH (0.5 mL) /H2O (0.5 mL) was added LiOH (19.92 mg, 831.60 μmol) at room temperature, the resulting mixture was stirred at 25 ℃ for 3 hr. The reaction mixture was diluted with H2O (4 mL) and the pH value of the solution was adjusted to 4-5 with aqueous HCl (1M) . The reaction mixture was filtered and the precipitated solid was washed with H2O (5 mL*3) and dried under vacuum to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -7-azaspiro [3.5] nonan-7-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 12.59-13.28 (s, 1H) , 9.89 (s, 1H) , 8.95 (s, 1H) , 8.53 (m, 1H) , 7.99 (d, J = 8.0 Hz, 1H) , 7.77-7.63 (m, 3H) , 7.47-7.30 (m, 10H) , 6.92-6.87 (m, 2H) , 4.79 (s, 2H) , 4.51-4.15 (m, 7H) , 3.99-3.92 (m, 2H) , 3.70-3.38 (m, 6H) , 3.22-2.61 (m, 7H) , 2.39 (s, 3H) , 2.09-1.59 (m, 12H) , 1.19 (s, 1H) , 0.93-0.79 (m, 9H) . LC/MS: MS (ESI) M/Z 1188.6 [M+H] +.
Example 44: Compound 44
Step A: methyl 2-chloro-5- (3- (2-fluoro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (1 g, 4.24 mmol) and 2-fluoro-4-iodo-phenol (1.01 g, 4.24 mmol) in THF (20 mL) was added PPh3 (1.11 g, 4.24 mmol) and DEAD (738.92 mg, 4.24 mmol) . The mixture was stirred at room temperature for 4 hrs. The reaction mixture was treated with water (100mL) and extracted with EA (3*50mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in
vacuo to give a crude. The crude was purified by flash column chromatography (EA/PE=0~10%) to give the title compound. LC/MS: MS (ESI) M/Z: 456.0 [M+H] +.
Step B: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (857.65 mg, 2.48 mmol, HCl salt) and methyl 2-chloro-5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (1.13 g, 2.48 mmol) in DMA (10 mL) was added KI (411.66 mg, 2.48 mmol) and Cs2CO3 (2.42 g, 7.44 mmol) . The mixture was stirred at 70 ℃ for 18 hrs. The reaction mixture was treated with water (100mL) and extracted with EA (3 *50 mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM=0~90%) and prep-TLC DCM: MeOH=70: 1 to afford the title compound. LC/MS: MS (ESI) M/Z: 728.9 [M+H] +.
Step C: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] -2-fluoro-phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (2-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (450 mg, 617.63 μmol) and tert-butyl 2- (3-prop-2-ynyl-3-azaspiro [5.5] undecan-9-yl) acetate (282.98 mg, 926.44 μmol) in DMF (8 mL) was added CuI (47.05 mg, 247.05 μmol) , Pd (PPh3) 2Cl2 (86.69 mg, 123.53 μmol) and DIEA (239.47 mg, 1.85 mmol) . The mixture was degassed and backfilled with N2 for 6 times. The resulting mixture was stirred at 60℃ for 1 hrs. The reaction mixture was treated with water (100mL) and extracted with EA (5*50mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by prep-TLC DCM: MeOH=20: 1 to afford the title compound. LC/MS: MS (ESI) M/Z: 454.0 [M/2+H] +.
Step D: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (carboxymethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) -2-fluorophenoxy) propyl) thiazole-4-carboxylic acid
The solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [9- (2-tert-butoxy-2-oxo-ethyl) -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] -2-fluoro-phenoxy] propyl] thiazole-4-carboxylate (290 mg, 320.04 μmol) in FA (3 mL) was stirred at 40 ℃ for 4 hrs. The reaction mixture was concentrated in vacuo to give 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (carboxymethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) -2-fluorophenoxy) propyl) thiazole-
4-carboxylic acid. The crude product was used in next step without further purification. LC/MS: MS (ESI) M/Z: 851.5 [M+H] +.
Step E: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-fluoro-phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid (100 mg, 117.64 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (274.71 mg, 588.21 μmol, HCl salt) in DCM (3 mL) was added HATU (223.66 mg, 588.21 μmol) and DIEA (152.04 mg, 1.18 mmol) . The mixture was stirred at room temperature for 2 hrs. The reaction mixture was treated with water (50mL) and extracted with DCM (3 *20mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by prep-TLC (MeOH/DCM=10: 1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z: [M/2+H] +.
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (75 mg, 59.40 μmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.5 mL) was added LiOH (142.69 mg, 1.78 mmol) . The mixture was stirred at room temperature for 2 hrs. The pH value of the reaction mixture was adjusted to pH=3 with 0.1M HCl solution and extracted with DCM (25mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-
isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 9.97 (s, 1H) , 8.95 (s, 1H) , 8.47-8.56 (m, 1H) , 7.99 (d, J = 7.6 Hz, 1H) , 7.80-7.74 (m, 2H) , 7.63 (d, J = 7.2 Hz, 1H) , 7.45-7.30 (m, 9H) , 7.27-7.23 (m, 1H) , 7.15-7.10 (m, 1H) , 4.79 (s, 2H) , 4.51 (d, J = 9.2 Hz, 1H) , 4.42-4.36 (m, 2H) , 4.29 (d, J = 18.0 Hz, 3H) , 4.18 (dd, J = 15.6, 5.6 Hz, 1H) , 4.06 (t, J = 6.4 Hz, 2H) , 3.68 (t, J = 6.0 Hz, 2H) , 3.62 (s, 2H) , 3.38 (s, 2H) , 3.15-2.97 (m, 6H) , 2.40 (s, 3H) , 2.18 (dd, J = 13.6, 7.6 Hz, 1H) , 2.01-1.83 (m, 7H) , 1.61-1.45 (m, 5H) , 1.32-1.19 (m, 4H) , 1.06-0.98 (m, 3H) , 0.90 (s, 9H) . LC/MS: MS (ESI) M/Z: 1248.70 [M+H] +.
Example 45: Compound 45
Step A: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-fluoro-phenyl] prop-2-ynyl] -3-azaspiro [5.5] undecan-9-yl] acetic acid (140 mg, 164.70 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-
dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (118.84 mg, 247.05 μmol, HCl salt) in DCM (3 mL) was added HATU (93.94 mg, 247.05 μmol) and DIEA (63.86 mg, 494.10 μmol) . The mixture was stirred at room temperature for 2 hrs. The reaction mixture was treated with water (50mL) and extracted with DCM (3*20mL) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude. The crude was purified by prep-TLC (MeOH/DCM=10: 1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z: 1277.8 [M+H] /+.
Step B: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-fluoro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 78.33 μmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.5 mL) was added LiOH. H2O (52.28 mg, 2.38 mmol) . The mixture was stirred at room temperature for 2 hrs. The pH value of the reaction mixture was adjusted to pH=3 with 0.1M HCl solution and extracted with DCM (25mL*3) . The organic layer combined was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (10 mmol/L NH4HCO3-ACN, 66%-86%; YMC-Actus Triart C18, 150*20mm, 5um; flow: 20 mL/min) . The eluent was concentrated in vacuo and freeze-dried to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-fluoro-4- [3- [9- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] -3-azaspiro [5.5] undecan-3-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 12.92 (s, 0H) , 10.00 (s, 1H) , 9.00 (s, 1H) , 8.38 (d, J = 7.6 Hz, 1H) , 8.04 (d, J = 7.6 Hz, 1H) , 7.80 (d, J = 8.0 Hz, 2H) , 7.68 (d, J = 6.8 Hz, 1H) , 7.50-7.29 (m, 10H) , 7.18 (t, J = 8.8 Hz, 1H) , 4.95-4.88 (m, 1H) , 4.84 (s, 2H) , 4.53 (d, J = 9.2 Hz, 1H) , 4.42 (t, J = 8.0 Hz, 2H) , 4.30 (d, J = 11.6 Hz, 3H) , 4.10 (t, J = 6.4 Hz, 2H) , 3.72 (t, J = 6.0 Hz, 2H) , 3.61 (s, 2H) , 3.42 (s, 2H) , 3.20-3.02 (m, 6H) , 2.46 (s, 3H) , 2.21 (dd, J = 13.6, 7.7 Hz, 1H) , 2.05-1.99 (m, 6H) , 1.83-1.46 (m, 5H) , 1.38 (d,
J = 7.2 Hz, 3H) , 1.34-1.23 (m, 4H) , 1.11-1.05 (m, 3H) , 0.94 (s, 9H) . LC/MS: MS (ESI) M/Z: 632.5 [M/2+H] +.
Example 46: Compound 46
Step A: 7- (2-chloropyrimidin-5-yl) hept-6-enoic acid
To a solution 5-bromo-2-chloro-pyrimidine (9.06 g, 46.81 mmol) , hept-6-enoic acid (5 g, 39.01 mmol) in DMF (50 mL) was added PPh3 (511.60 mg, 1.95 mmol) , Pd (OAc) 2 (437.92 mg, 1.95 mmol) , TEA (11.84 g, 117.03 mmol) , the mixture was stirred at 100℃ for 3h. water (100 mL) was added to the reaction mixture. The resulting solution was extracted with EA (4*40 mL) . The combined organic layers was washed with water (2*50 mL) and brine (70mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with (3: 1 PE: EtOAc) to give 7- (2-chloropyrimidin-5-yl) hept-6-enoic acid. LC/MS: 241.1 [M+H] +.
Step B: tert-butyl 7- (2-chloropyrimidin-5-yl) hept-6-enoate
To a solution of 7- (2-chloropyrimidin-5-yl) hept-6-enoic acid (3 g, 12.46 mmol) in DCM (35 mL) was added tert-butyl alcohol (923.88 mg, 12.46 mmol, 20 mL) , DCC (7.72 g, 37.39 mmol) and DMAP (1.52 g, 12.46 mmol) . The mixture was stirred at 15℃ for 16h. Water (30 mL) was added to the reaction mixture. The resulting solution was extracted with DCM (4*30 mL) . The combined organic layers was washed with water (2*20 mL) and brine (30mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with (3: 1 PE: EtOAc) to give tert-butyl - (2-chloropyrimidin-5-yl) hept-6-enoate. LC/MS: MS (ESI) M/Z 297.2 [M+H] +.
Step C: tert-butyl 7- (2- (4-hydroxyphenyl) pyrimidin-5-yl) hept-6-enoate
To a solution (4-hydroxyphenyl) boronic acid (1.27 g, 9.20 mmol) , tert-butyl (E) -7- (2-chloropyrimidin-5-yl) hept-6-enoate (2.1 g, 7.08 mmol) in H2O (1.5 mL) , dioxane (8 mL) was added Pd (PPh3) 2Cl2 (496.64 mg, 707.57 μmol) and Na2CO3 (1.87 g, 17.69 mmol) , the mixture was stirred at 90℃ (or 80℃) for 4 h under N2. Water (30 mL) was added to the reaction
mixture. The resulting solution was extracted with EA (3*30 mL) . The combined organic layers were washed with water (2*30 mL) and brine (30mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with (3: 1 PE: EtOAc) to give tert-butyl 7- (2- (4-hydroxyphenyl) pyrimidin-5-yl) hept-6-enoate. LC/MS: MS (ESI) M/Z 355.2 [M+H] +.
Step D: tert-butyl 7- (2- (4-hydroxyphenyl) pyrimidin-5-yl) heptanoate
To a solution of tert-butyl 7- (2- (4-hydroxyphenyl) pyrimidin-5-yl) hept-6-enoate (500 mg, 1.41 mmol) in EA (10 mL) was added Pd/C (50 mg, 10%purity) , the mixture was stirred at 10℃ for 0.5h under H2 (15psi) . The suspension was filtered through celite and filter cake was washed with EA (2*10 mL) . The combined filtrates were concentrated to give tert-butyl 7- (2- (4-hydroxyphenyl) pyrimidin-5-yl) heptanoate. LC/MS: MS (ESI) M/Z 357.2 [M+H] +.
Step E: methyl 5- (3- (4- (5- (7- (tert-butoxy) -7-oxoheptyl) pyrimidin-2-yl) phenoxy) propyl) -2-chlorothiazole-4-carboxylate
To a solution of tert-butyl 7- [2- (4-hydroxyphenyl) pyrimidin-5-yl] heptanoate (300 mg, 841.62 μmol) , methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (198.36 mg, 841.62 μmol) in THF (8 mL) was added PPh3 (375.26 mg, 1.43 mmol) , then DEAD (249.17 mg, 1.43 mmol) was added dropwise. The mixture was stirred at 15℃ for 2h. Water (30 mL) was added to the reaction mixture. The resulting solution was extracted with EA (4*30 mL) . The combined organic layers was washed with brine (50mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with (20: 1 PE: EtOAc) to give methyl 5- (3- (4- (5- (7- (tert-butoxy) -7-oxoheptyl) pyrimidin-2-yl) phenoxy) propyl) -2-chlorothiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 574.2 [M+H] +.
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (7- (tert-butoxy) -7-oxoheptyl) pyrimidin-2-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (118.55 mg, 383.19 μmol) , methyl 5- [3- [4- [5- (7-tert-butoxy-7-oxo-heptyl) pyrimidin-2-yl] phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (200 mg, 348.35 μmol) in dioxane (10 mL) was added SPhos (14.30 mg, 34.84 μmol) , t-BuOK (58.63 mg, 522.53 μmol) and Pd2 (dba) 3 (20.03 mg, 34.84 μmol) , the mixture was stirred at 90℃ for 6h. Water (30 mL) was added to the reaction mixture. The resulting solution was extracted with EA (3*30 mL) . The combined organic layers were washed with brine (50mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (1: 1 PE: EtOAc) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (7-tert-butoxy-7-oxo-heptyl) pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 847.3 [M+H] +.
Step G: 7- (2- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) pyrimidin-5-yl) heptanoic acid
The solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (7-tert-butoxy-7-oxo-heptyl) pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate (150 mg, 177.08 μmol) in FA (5 mL) was stirred at 40℃ for 1h. The mixture was concentrated under reduce pressure to give 7- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] pyrimidin-5-yl] heptanoic acid. LC/MS: MS (ESI) M/Z 791.3 [M+H] +.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (7- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptyl) pyrimidin-2-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 7- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] pyrimidin-5-yl] heptanoic acid (130 mg) in DMF (7 mL) was added HATU (93.69 mg, 246.54 μmol) and DIEA (106.01 mg, 821.80 μmol) , the mixture was stirred at 15℃ for 0.5h. Then (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (87.69 mg, 197.23 μmol) was added. The mixture was stirred at 15℃ for another 2h. Water (30 mL) was added to the reaction mixture. The resulting solution was extracted with EA (4*30 mL) . The combined organic layers was washed with water (2*30 mL) and brine (30mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (0.1%TFA-ACN, Xselect CSH prep Fluoro-Phenyl, 150*19mm, 5um, 20 33.0-63.0 13 9.1) to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -7-oxo-heptyl] pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 609.5 [M/2+H] +.
Step I: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (7- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptyl) pyrimidin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -7-oxo-heptyl] pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate (0.11 g, 90.35 μmol) in THF (1.5
mL)/MeOH (1.5 mL) /H2O (1.5 mL) was added LiOH (113.84 mg, 2.71 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuum, water (3mL) was added, then pH value was adjusted to 3 using 1M HCl. The mixture was filtrated and the cake was concentrated in vacuum to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -7-oxo-heptyl] pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 12.52-13.25 (brs, 1H) , 8.94 (s, 1H) , 8.65 (s, 1H) , 8.33 (d, J = 8.0 Hz, 1H) , 8.23 (d, J = 8.8 Hz, 2H) , 7.99 (d, J = 7.6 Hz, 1H) , 7.76 (d, J = 6.4 Hz, 2H) , 7.63 (d, J = 7.6 Hz, 1H) , 7.45-7.29 (m, 9H) , 6.98 (d, J = 9.2 Hz, 2H) , 4.87 (t, J = 6.8 Hz, 1H) , 4.80 (s, 2H) , 4.50-4.43 (m, 1H) , 4.38 (t, J = 8.0 Hz, 1H) , 4.24 (s, 1H) , 4.02 (t, J = 6.0 Hz, 2H) , 3.68 (t, J = 6.0 Hz, 2H) , 3.56 (s, 2H) , 3.16 (t, J = 7.2 Hz, 2H) , 2.98 (t, J = 5.6 Hz, 2H) , 2.63-2.52 (m, 1H) , 2.41 (s, 3H) , 2.29-1.94 (m, 7H) , 1.78-1.72 (m, 1H) , 1.55-1.19 (m, 12H) , 0.89 (s, 9H) . LC/MS: MS (ESI) M/Z 1203.7 [M+H] +.
Example 47: Compound 47
Step A: 2-azaspiro [3.5] nonan-7-one hydrochloride
A solution of tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (5.00 g, 20.92 mmol) in DCM (40 mL) was added HCl/dioxane (4M, 6.27 mL) at 25℃, the resulting mixture was stirred at 25℃ for 4 hr. The reaction mixture was concentrated to dryness and used in next step without further purification.
Step B: benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate
To a solution of 2-azaspiro [3.5] nonan-7-one hydrochloride (3.3 g) in dry THF (20 mL) was added NaHCO3 (1.99 g, 23.71 mmol) at 0℃, and the reaction mixture was stirred at 0℃ for 30 min. Then benzyl carbonochloridate (7.28 g, 42.67 mmol) was added and the mixture was stirred for an additional 2 hr at 25℃. The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) . The organic layers were combined and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1: 1 to give benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate. LC/MS: MS (ESI) M/Z 274.2 [M+H] +.
Step C: benzyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate
To a solution of (methoxymethyl) triphenylphosphonium (6.21 g, 18.11 mmol) in dry THF (20 mL) was added t-BuOK (2.16 g, 19.32 mmol) under nitrogen atmosphere at 25 ℃, and the reaction mixture was stirred at 25 ℃ for 30 min. Then a solution of benzyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (3.3 g, 12.07 mmol) in dry THF (20 mL) was added and the mixture stirred for an additional 1 hr under nitrogen atmosphere at 70℃. After cooling down to 25℃, the reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) . The organic layer was washed with brine (4*10 mL) and concentrated. The residue was purified by
silica gel chromatography eluted with PE: EtOAc=10: 1 to give benzyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate. LC/MS: MS (ESI) M/Z 302.2 [M+H] +.
Step D: benzyl 7-formyl-2-azaspiro [3.5] nonane-2-carboxylate
A solution of benzyl 7- (methoxymethylene) -2-azaspiro [3.5] nonane-2-carboxylate (2.2 g, 7.30 mmol, ) in ACN (8 mL) and water (2 mL) was added TFA (832.34 mg, 7.30 mmol, 1 mL) at 25℃, and the resulting mixture was stirred at 25 ℃ for 2 hr. The reaction was extracted with DCM (3*10 mL) . The organic layers were combined and concentrated to dryness, the residue was used for the next step without further purification. LC/MS: MS (ESI) M/Z 288.2 [M+H] +.
Step E: 2- ( (benzyloxy) carbonyl) -2-azaspiro [3.5] nonane-7-carboxylic acid
A solution of benzyl 7-formyl-2-azaspiro [3.5] nonane-2-carboxylate (2.0 g, 6.96 mmol) in acetone (10 mL) and water (10 mL) was added KMnO4 (1.65 g, 10.44 mmol) at 25℃, the resulting mixture was stirred at 25℃ for 2 hr. The reaction mixture was filtered and the filtrate was dried under vacuum to afford 2-benzyloxycarbonyl-2-azaspiro [3.5] nonane-7-carboxylic acid. LC/MS: MS (ESI) M/Z 304.2 [M+H] +.
Step F: 2-benzyl 7-tert-butyl 2-azaspiro [3.5] nonane-2, 7-dicarboxylate
A solution of 2-benzyloxycarbonyl-2-azaspiro [3.5] nonane-7-carboxylic acid (1.1 g) and di-tert-butyl dicarbonate (3.17 g, 14.50 mmol) in DCM (20 mL) was added DMAP (221.50 mg, 1.81 mmol) and TEA (1.47 g, 14.50 mmol) at 25℃, the resulting mixture was stirred at 25℃ for 16 hr . The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) , washed with brine (4*30 mL) . The organic layers were combined and concentrated. The residue was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give 2-benzyl 7-tert-butyl 2-azaspiro [3.5] nonane-2, 7-dicarboxylate. LC/MS: MS (ESI) M/Z 360.2 [M+H] +.
Step G: tert-butyl 2-azaspiro [3.5] nonane-7-carboxylate
To a solution of 2-benzyl 7-tert-butyl 2-azaspiro [3.5] nonane-2, 7-dicarboxylate (0.3 g, 834.59 μmol, 1.0 equiv. ) in ethyl acetate (60 mL) was added Pd/C (88.47 mg, 10%w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at 25℃ for 1 hr. The suspension was filtered through celite and filter cake was washed with EA (10mLx2) . The combined filtrates was concentrated to dryness to give tert-butyl 2-azaspiro [3.5] nonane-7-carboxylate. LC/MS: MS (ESI) M/Z 226.3 [M+H] +.
Step H: tert-butyl 2- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonane-7-carboxylate
To a solution of tert-butyl 2-azaspiro [3.5] nonane-7-carboxylate (0.188 g) and 3-bromoprop-1-yne (99.25 mg, 834.35 μmol) in DMF (2 mL) was added K2CO3 (230.28 mg, 1.67 mmol) at 0℃, and the resulting mixture was stirred at 25℃ for 0.3 hr. The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) , washed with brine (4*30
mL) . The organic layers were combined and concentrated to give tert-butyl 2- (prop-2-yn-1-yl) -2-azaspiro [3.5] nonane-7-carboxylate. LC/MS: MS (ESI) M/Z 264.3 [M+H] +.
Step I: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- (tert-butoxycarbonyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (0.17 g, 239.23 μmol) and tert-butyl 2-prop-2-ynyl-2-azaspiro [3.5] nonane-7-carboxylate (126.02 mg, 478.47 μmol) in DMF (3 mL) was added CuI (22.78 mg, 119.62 μmol) , Pd (PPh3) 4 (138.28 mg, 119.62 μmol) and DIEA (123.44 mg, 956.93 μmol) at 25℃, and the resulting mixture was stirred at 50 ℃ for 1.5 hr in N2. The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) , washed with brine (4*10 mL) . The organic layers were combined and concentrated. The crude product was purified by silica gel chromatography eluted with DCM: MeOH=20: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (7-tert-butoxycarbonyl-2-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 846.5 [M+H] +.
Step J: 2- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) -2-azaspiro [3.5] nonane-7-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- (7-tert-butoxycarbonyl-2-azaspiro [3.5] nonan-2-yl) prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (0.07 g, 82.74 μmol) in FA (3 mL) was stirred at 40 ℃ for 3 hr. The reaction mixture was concentrated to dryness and the residue was used in next step without further purification. LC/MS: MS (ESI) M/Z 790.4 [M+H] +.
Step K: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of 2- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] -2-azaspiro [3.5] nonane-7-carboxylic acid (0.05 g) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (112.56 mg, 253.18 μmol) in DMF (3 mL) was added HATU (48.10 mg, 126.59 μmol) and DIEA (81.65 mg, 632.94 μmol) at 25℃, and the resulting mixture was stirred at 25℃ for 2 hr. The reaction was quenched with H2O (10 mL) , then extracted with DCM (3*10 mL) ,
washed with brine (4*30 mL) . The organic layers were combined and concentrated. The residue was purified by silica gel chromatography eluted with DCM: MeOH=1: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z 608.9 [M/2+H] +.
Step L: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (7- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) -2-azaspiro [3.5] nonan-2-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (0.06 g, 49.32 μmol) in THF (1.5 mL) , MeOH (1.5 mL) and H2O (1.5 mL) was added LiOH/H2O (62.14 mg, 1.48 mmol) at 25℃. The resulting mixture was stirred at 25℃ for 2 hr. The reaction mixture was concentrated and subjected to reverse phase preparative to provide 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -2-azaspiro [3.5] nonan-2-yl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-D6) δ12.95 (s, 1H) , 10.62 (s, 1H) , 8.99 (s, 1H) , 8.35 (d, J = 7.60 Hz, 1H) , 8.03 (d, J = 7.60 Hz, 1H) , 7.79 (d, J = 8.0 Hz, 1H) , 7.72-7.67 (m, 2H) , 7.50-7.23 (m, 10H) , 6.97-6.94 (m, 2H) , 5.16-4.90 (m, 1H) , 4.83 (s, 2H) , 4.50-4.28 (m, 5H) , 4.03-3.51 (m, 8H) , 3.19-2.89 (m, 4H) , 2.73-2.53 (m, 1H) , 2.47-2.28 (m, 6H) , 2.07-1.99 (m, 4H) , 1.83-1.23 (m, 11H) , 0.93 (s, 9H) . LC/MS: MS (ESI) M/Z 1202.7 [M+H] +.
Example 48: Compound 48
Step A: methyl 2-chloro-5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (0.35 g, 1.49 mmol) , 3-fluoro-4-iodo-phenol (424.12 mg, 1.78 mmol) and PPh3 (505.80 mg, 1.93 mmol) in THF (4 mL) was added DEAD (310.07 mg, 1.78 mmol) at 20-30 ℃ dropwise and the mixture was stirred at 20-30 ℃ for 2 hr. the product was purified by Pre-TLC to obtain methyl 2-chloro-5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z 456 [M+H] +.
Step B: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (0.2 g, 438.91 μmol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (203.69 mg, 658.37 μmol) in DMA (2 mL) was added Cs2CO3 (429.26 mg, 1.32 mmol) and KI (72.86 mg, 438.91 μmol) at 20 ℃, the mixture was stirred at 70℃ for 18 hr. the reaction mixture was quenched with water and extracted with EA, dried over Na2SO4, filtered, concentrated. The residue was purified by pre-TLC to obtain methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 729 [M+H] +.
Step C: 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-fluoro-phenyl] non-8-ynoic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (3-fluoro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (0.14 g, 192.15 μmol) and non-8-ynoic acid (59.26 mg, 384.30 μmol) in DMF (1 mL) was added DIEA (74.36 mg, 576.45 μmol) , CuI (14.64 mg, 76.86 μmol) and Pd (PPh3) 2Cl2 (26.94 mg, 38.43 μmol) at 20-30 ℃ and the mixture was stirred at 20-30℃ for 2 hr. the reaction mixture was quenched with water and extracted with EA, the solvent was concentrated. The residue was purified by the silica gel chromatography to obtain 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-fluoro-phenyl] non-8-ynoic acid. LCMS: MS (ESI) M/Z: 755 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-fluoro-phenyl] non-8-ynoic acid (0.14 g, 185.46 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (103.94 mg, 222.55 μmol, HCl salt) in DMF (2 mL) was added HATU (84.57 mg, 222.55 μmol) and DIEA (56.19 mg, 450.22 μmol) at 20-30℃ and the mixture was stirred at 25℃ for 2 hr. the reaction mixture was quenched with water and extracted with EA, the solvent was concentrated. The residue was purified by the silica gel chromatography to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1167 [M+H] +
Step E: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (0.08 g, 68.53 μmol) and aq. NaOH (2N, 0.35 mL) in H2O (0.8 mL) and THF (0.8 mL) was stirred at 25℃ for 5 hr. the reaction mixture was quenched with diluted HCl and the product was purified by pre-HPLC to obtain 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 8.94 (d, J = 4.9 Hz, 1H) , 8.51 (t, J = 6.0 Hz, 1H) , 7.99 (d, J = 7.3 Hz, 1H) , 7.81-7.74 (m, 2H) , 7.63 (d, J = 6.6 Hz, 1H) , 7.46-7.24 (m, 10H) , 6.80 (dd, J = 11.8, 2.5 Hz, 1H) , 6.67 (dd, J = 8.5, 2.2 Hz, 1H) , 4.79 (s, 2H) , 4.49 (t, J = 9.5 Hz, 1H) , 4.42-4.31 (m, 3H) , 4.18 (dd, J = 15.9, 5.5 Hz, 1H) , 3.95 (q, J = 6.2 Hz, 2H) , 3.69-3.59 (m, 4H) , 3.12 (t, J = 7.4 Hz, 2H) , 2.99 (t, J = 5.9 Hz, 2H) , 2.40-2.34 (m, 5H) , 2.29-2.19 (m, 1H) , 2.12-1.83 (m, 5H) , 1.52-1.19 (m, 10H) , 0.88 (d, J = 7.7 Hz, 9H) . LCMS: MS (ESI) M/Z: 1154 [M+H] +.
Example 49: Compound 49
Step A: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (28.27 mg, 63.59 μmol) and 9- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-fluoro-phenyl] non-8-ynoic acid (0.04 g, 52.99 μmol) in DMF (0.5mL) was added HATU (24.16 mg, 63.59 μmol) and DIEA (20.51 mg, 158.96 μmol) at 20-30℃ and the mixture was stirred at 25℃ for 2 hr. the reaction mixture was quenched with water and extracted with EA, the solvent was concentrated. The residue was purified by silica gel chromatography to obtain methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 1181 [M+H] +
Step B: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1R) -1- [4- (4-methylthiazol-5-
yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (50.60 mg, 42.83 μmol) and aq. NaOH (2N, 0.21 mL) in water (0.5 mL) and MeOH (0.5 mL) was stirred at 25℃ for 3 hr. The reaction mixture was quenched with diluted HCl and the product was purified by pre-HPLC to obtain 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-fluoro-4- [9- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1R) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -9-oxo-non-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO-D6) δ 8.94 (d, J = 6.9 Hz, 1H) , 8.33 (d, J = 7.7 Hz, 1H) , 8.00 (d, J = 7.7 Hz, 1H) , 7.69 (dd, J = 49.3, 7.6 Hz, 3H) , 7.45-7.26 (m, 10H) , 6.82-6.66 (m, 2H) , 4.89-4.79 (m, 3H) , 4.49-4.36 (m, 2H) , 3.96 (t, J = 6.0 Hz, 3H) , 3.68 (t, J = 5.9 Hz, 2H) , 3.56 (s, 2H) , 3.14-2.97 (m, 4H) , 2.63 (s, 1H) , 2.41-2.35 (m, 5H) , 2.29-2.06 (m, 2H) , 1.99-1.92 (m, 3H) , 1.78-1.72 (m, 1H) , 1.50-1.19 (m, 12H) , 0.84 (d, J = 39.0 Hz, 9H) . LCMS: MS (ESI) M/Z: 1167 [M+H] +.
Example 50: Compound 50
Step A. methyl 2-chloro-5- (3- (2-chloro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (650 mg, 2.76 mmol) , 2-chloro-4-iodo-phenol (701.75 mg, 2.76 mmol) and PPh3 (723.35 mg, 2.76 mmol) in THF (4 mL) was added DEAD (480.30 mg, 2.76 mmol) at 25℃, the resulting mixture was
stirred at 25 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give the crude product. The crude was purified by chromatography on silica gel column eluting PE/EA =10: 1 to give the title compound. LCMS: MS (ESI) M/Z 472.1 [M+H] +
Step B: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4-iodophenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2-chloro-5- (3- (2-chloro-4-iodophenoxy) propyl) thiazole-4-carboxylate (614.31 mg, 1.30 mmol) , N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (450 mg, 1.30 mmol, HCl salt) in DMA (5 mL) was added KI (431.98 mg, 2.60 mmol) and Cs2CO3 (1.27 g, 3.90 mmol) at 25 ℃, and the resulting mixture was stirred at 70 ℃ for 16 hr. The mixture was extracted with EA (300 mL × 3) and dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography by silica gel column eluting PE/EA =10/1 to give the title compound. LCMS: MS (ESI) M/Z: 745.0 [M+H] +
Step C: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- (tert-butoxy) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) -2-chlorophenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 2- (3-prop-2-ynyl-3-azaspiro [5.5] undecan-9-yl) acetate (166.04 mg, 543.59 μmol) , Pd (PPh3) 2Cl2 (50.87 mg, 72.48 μmol) , CuI (27.61 mg, 144.96 μmol) and tert-butyl 2- (3-prop-2-ynyl-3-azaspiro [5.5] undecan-9-yl) acetate (166.04 mg, 543.59 μmol) in DMF (5 mL) was added methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (2-chloro-4-iodo-phenoxy) propyl] thiazole-4-carboxylate (270 mg, 362.39 μmol) , DIEA (188 mg, 1.45 mmol) at 25 ℃, the resulting mixture was stirred at 60 ℃ for 2 hr under N2 atmosphere. The mixture was diluted with EA (50 mL) . The organic layer was washed H2O (300 mL) . The water layer was extracted with EA (300 mL) and dried over Na2SO4, filtered and concentrated. The reaction was purified by Prep-TLC using DCM/MeOH=20/1 to afford the title compound. LCMS: MS (ESI) M/Z: 922.6 [M+H] +
Step D: 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) -3-chlorophenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetic acid
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (9- (2- (tert-butoxy) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) -2-chlorophenoxy) propyl) thiazole-4-carboxylate (150 mg, 162.59 μmol) in FA (3 mL) at 25 ℃, the resulting mixture was stirred at 40 ℃ for 2 hr. The mixture was concentrated under reduced pressure to get the title compound, which was used in next step without further purification. LCMS: MS (ESI) M/Z: 866.5 [M+H] +
Step E: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 2- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) -3-chlorophenyl) prop-2-yn-1-yl) -3-azaspiro [5.5] undecan-9-yl) acetic acid (80 mg, ) , (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (64.68 mg, 138.49 μmol, HCl salt) and HATU (52.66 mg, 138.57 μmol) in DCM (3 mL) was added DIEA (35.80 mg, 276.98 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 2 hr. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified Prep-TLC using DCM/MeOH=10/1 to the title compound. LCMS: MS (ESI) M/Z: 1279.0 [M/2+H]
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (3- (9- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) -3-azaspiro [5.5] undecan-3-yl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate (56 mg, 43.78 μmol) in THF/MeOH/H2O (V1: V2: V3=1: 1: 2, 1.25 mL) was added LiOH (20.97 mg, 875.66 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 3 hr in N2. The mixture was quenched with 1N HCl (pH value adjusted to around 4) , then the mixture was concentrated and the crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where water contain 0.1%TFA) to provide to get the title compound. LCMS: MS (ESI) M/Z: 1265.0 [M/2+H] . 1H-NMR (400 MHz, DMSO-D6) δ 12.87 (brs, 1H) , 9.98 (brs, 1H) , 8.95 (d, J = 1.6 Hz, 1H) , 8.81 (brs, 1H) , 8.53 (s, 1H) , 8.00 (d, J = 7.6 Hz, 1H) , 7.80 (d, J = 8.0 Hz, 1H) , 7.76 (d, J = 8.0 Hz, 1H) , 7.64-7.56 (m, 2H) , 7.46-7.30 (m, 9H) , 7.11 (d, J = 7.2 Hz, 1H) , 4.79 (s, 2H) , 4.56-4.50 (m, 1H) , 4.42-4.06 (m, 7H) , 3.69-3.59 (m, 4H) , 3.39 (brs, 2H) , 3.17-2.98 (m, 6H) , 2.41 (s, 3H) , 2.19-2.16 (m, 1H) , 2.01-1.91 (m, 5H) , 1.89-1.83 (m, 1H) , 1.62-1.47 (m, 6H) , 1.33-1.19 (m, 5H) , 1.05-1.02 (m, 3H) , 0.90 (s, 9H)
Example 51: Compound 51 (Compound 51-A and 51-B)
Step A: tert-butyl 4-hydroxycyclohexanecarboxylate
A solution of 1, 1-ditert-butoxy-N, N-dimethyl-methanamine (6.35 g, 31.21 mmol) and 4-hydroxycy clohexanecarboxylic acid (3 g, 20.81 mmol) in toluene (30 mL) was stirred at 90 ℃ for 12 hr in N2. The mixture was evaporated. The residue was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give tert-butyl 4-hydroxycyclohexanecarboxylate. 1H-NMR (400 MHz, DMSO-D6) δ 1.94-2.07 (1H) , 1.65-1.83 (6H) , 1.38-1.48 (2H) , 1.31-1.37 (9H) , 1.17-1.31 (2H) LCMS: MS (ESI) M/Z: 215.2 [M+H] +.
Step B: tert-butyl 4- (allyloxy) cyclohexanecarboxylate
A solution of tert-butyl 4-hydroxycyclohexanecarboxylate (100 mg, 499.32 μmol) in THF (3 mL) was added NaH (39.95 mg, 998.63 μmol, 60%purity) at 25 ℃, the resulting mixture was stirred at 20 ℃ for 30 min, then 3-bromoprop-1-ene (72.49 mg, 599.18 μmol) was added and the mixture was stirred for 5 h at 35℃. The reaction mixture was diluted with H2O (3 mL) . Then it was extracted with ethyl acetate (10mL*3) . The combined organic layers was washed with brine (10mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 5.81-6.02 (1H) , 5.10-5.34 (2H) , 3.91-4.09 (2H) , 3.16-3.33 (1H) , 1.85-2.30 (5H) , 1.19-1.52 (13H) .
Step C: tert-butyl 4- (3-hydroxypropoxy) cyclohexanecarboxylate
A solution of tert-butyl 4-allyloxycyclohexanecarboxylate (50 mg, 208.04 μmol) in THF (2.44 mL) was added borane-tetrahydrofuran complex (1 M, 416.08 μL, 60%purity) at 25℃, the resulting mixture was stirred at 25℃ for 1h, then hydrogen peroxide (536.09 mg, 5.20 mmol, 33%purity) and NaOH (10 M, 145.63 μL) was added at 0℃, and the mixture was stirred for 1 h at rt. After cooled to 20 ℃, the reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) . The resulting solution was extracted with EA (10 mL×3) . The combined organic layers was washed with water (10mL) and brine (10mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1: 1 to give tert-butyl 4- (3-hydroxypropoxy) cyclohexanecarboxylate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.58-3.71 (2H) , 3.35-3.49 (2H) , 1.93-2.09 (2H) , 1.78-1.84 (1H) , 1.49-1.70 (5H) , 1.41-1.45 (9H) , 1.30-1.41 (2H) , 1.17-1.29 (2H) .
Step D: tert-butyl 4- (3-oxopropoxy) cyclohexanecarboxylate
A solution of tert-butyl 4- (3-hydroxypropoxy) cyclohexanecarboxylate (35 mg, 135.47 μmol) in DCM (3 mL) was added Dess-Martin periodinane (114.92 mg, 270.95 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 2 h The mixture was filtered, and organic layer was concentrated and diluted with H2O (30 mL) , extracted with EA (10mL×3) , The combined organic layers were washed with water (30mL) and brine (30mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product.
Step E: tert-butyl 4- (but-3-yn-1-yloxy) cyclohexanecarboxylate
A solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (281.04 mg, 1.46 mmol) in MeOH (3 mL) was added potassium carbonate (404.38 mg, 2.93 mmol) at 25 ℃, the resulting mixture was stirred at 20 ℃ for 30 min, tert-butyl-4- (3-oxopropoxy) cyclohexanecarboxylate (250 mg, 975.28 μmol) was added and the mixture was stirred for 16 h at 25℃. The reaction mixture was diluted with H2O (10 mL) . Then it was extracted with ethyl acetate (10 mL*3) . The combined organic layers was washed with brine (10mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure to give crude product.
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (4- ( (4- (tert-butoxycarbonyl) cyclohexyl) oxy) but-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (100 mg, 140.73 μmol) , tert-butyl 4-but-3-ynoxy cyclohexanecarboxylate (35.51 mg) and 1, 1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (58.31 mg, 70.36 μmol) in THF (20 mL) was added CuI (5.36 mg, 28.15 μmol) and TEA (71.20 mg, 703.63
μmol) , the resulting mixture was stirred at room temperature for 1 hr in N2. The resulting solution was extracted with EA (10 mL×3) . The combined organic layer was dried over Na2SO4 and concentrated to give the crude product. The residue was purified by silica gel chromatography eluted with PE : EtOAc=10 : 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- (4-tert-butoxycarbonylcyclohexoxy) but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 835.6 [M+H] +
Step G: 4- ( (4- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) but-3-yn-1-yl) oxy) cyclohexanecarboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- (4-tert-butoxycarbonylcyclohexoxy) but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (64 mg, 76.64 μmol) in FA (3 mL) was stirred at 25 ℃ for 6 hr. The mixture was evaporated to give the crude product. LCMS: MS (ESI) M/Z: 779.4 [M+H] + .
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (4- ( (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) oxy) but-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylth iazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (77.05 mg, 173.31 μmol) and 4- [4- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] but-3-ynoxy] cyclohexanecarboxylic acid (135 mg, ) in DMF (5 mL) was added [dimethylamino- (3-oxido-2, 3-dihydrotriazolo [4, 5-b] pyridin-3-ium-1-yl) methylene] -dimethyl-ammonium; hexafluorophosphate (131.80 mg, 346.63 μmol) and DIPEA (112.00 mg, 866.57 μmol) at 25 ℃, the resulting mixture was stirred at 30 ℃ for 12 hr. The resulting solution was extracted with EA (10 mL×3) . The combined organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluted with DCM : MeOH =20 : 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexox] but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. The mixture was repurified by HPLC to give isomer 1 and isomer 2.
Step I: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (4- ( (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-
yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) cyclohexyl) oxy) but-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (Compound 51, isomer 1) in NaOH 3N (0.2 mL) /Dioxane (3 mL) was stirred at 25 ℃ for 2 hr. The resulting solution was concentrated and acid with HCl (3M) till PH ~ 4 and extract with EA (30 mL*3) . The combined organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by HPLC to give 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-meth ylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid.
(Compound 51, isomer 1) . LCMS: MS (ESI) M/Z: 1191.7 [M+1] + . 1H-NMR (400 MHz, DMSO-D6) δ 8.92-8.98 (m, 1H) , 8.31-8.42 (m, 1H) , 7.94-8.05 (m, 1H) , 7.57-7.79 (m, 3H) , 7.19-7.47 (m, 11H) , 6.78-6.89 (m, 2H) , 6.56-6.64 (m, 1H) , 5.04-5.33 (m, 1H) , 4.74-4.92 (m, 3H) , 4.34-4.48 (m, 2H) , 4.18-4.27 (m, 1H) , 3.88-3.99 (m, 2H) , 3.63-3.73 (m, 2H) , 3.47-3.60 (m, 3H) , 3.08-3.16 (m, 1H) , 2.95-3.03 (m, 1H) , 1.91-2.03 (m, 6H) , 1.56-1.80 (m, 3H) , 1.02-1.43 (m, 16H) , 0.79-0.95 (m, 9H) ; HPLC: RT = 9.652 min, Method: 1.0ml-15min-5-70-95%ACN-H3PO4.
2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid (Compound 51, isomer 2) was prepared following the similar procedure described as above using methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] cyclohexoxy] but-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (Compound 51, isomer 2) as starting material. LCMS: MS (ESI) M/Z: 1191.7 [M+H] +. 1H-NMR (400 MHz, DMSO-D6) δ 8.91-8.97 (m, 1H) , 8.29-8.39 (m, 1H) , 7.96-8.04 (m, 1H) , 7.72-7.79 (m, 1H) , 7.51-7.66 (m, 2H) , 7.14-7.47 (m, 11H) , 6.78-6.87 (m, 2H) , 6.55-6.67 (m, 1H) , 5.21-5.38 (m, 1H) , 5.03-5.13 (m, 1H) , 4.76-4.90 (m, 2H) , 4.32-4.49 (m, 2H) , 4.20-4.30 (m, 1H) , 3.87-4.00 (m, 2H) , 3.63-3.80 (m, 2H) , 3.44-3.59 (m, 3H) , 3.09-3.15 (m, 1H) , 2.96-3.01 (m, 1H) , 1.88-2.02 (m, 4H) , 1.57-1.84 (m,
5H) , 1.29-1.39 (m, 5H) , 1.17-1.24 (m, 11H) , 0.78-0.92 (m, 9H) ; HPLC: RT = 9.998 min, Method: 1.0ml-15min-5-70-95%ACN-H3PO4.
Example 53: Compound 53
Step A: methyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate
To a solution of ethyl 4-oxocyclohexanecarboxylate (20 g, 117.51 mmol) in toluene (100 mL) was added ethylene glycol (36.47 g, 587.53 mmol, 5.0 equiv. ) and p-Toluenesulfonic acid (2.02 g, 11.75 mmol) at 25 ℃, the resulting mixture was stirred at 120 ℃ for 24 hr under
N2 atmosphere. The resulting solution was extracted with EA (100 mL×3) . The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate. LCMS: MS (ESI) M/Z: 215.2 [M+1] +.
Step B: 1, 4-dioxaspiro [4.5] decan-8-ylmethanol
To a solution of ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate (16 g, 74.68 mmol) in THF (200 m L) was added Lithium aluminum hydride (3.99 g, 89.61 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 1 hr under N2 atmospheres. After cooled to 0 ℃, the reaction mixture was quenched with 3 mL of saturated aqueous NaOH 10%. The resulting mixture was diluted with EA (50 mL) and filtered. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give 1, 4-dioxaspiro [4.5] decan-8-ylmethanol. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.85-4.00 (4H) , 3.42-3.54 (2H) , 1.68-1.84 (4H) , 1.40-1.59 (4H) , 1.26-1.32 (1H) .
Step C: 1, 4-dioxaspiro [4.5] decane-8-carbaldehyde
To a solution of 1, 4-dioxaspiro [4.5] decan-8-ylmethanol (300 mg, 1.74 mmol) in DCM (3 mL) was added (1, 1-diacetoxy-3-oxo-1, 2-benziodoxol-1-yl) acetate (1.11 g, 2.61 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 12 hr under N2 atmosphere. After cooled to 10 ℃, the reaction mixture was quenched with 10 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (5mL×3) . The combined organic layers was washed with water (10mL) and brine (5mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure, the crude product was used in next step.
Step D: 8-ethynyl-1, 4-dioxaspiro [4.5] decane
To a solution of 1, 4-dioxaspiro [4.5] decane-8-carbaldehyde (2.1 g) in methanol (3 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (2.84 g, 14.81 mmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 12 hr in N2. The resulting solution was extracted with EA (20 mL×3) and dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give 8-ethynyl-1, 4-dioxaspiro [4.5] decane. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.31-3.57 (2H) , 2.99-3.13 (2H) , 2.46-2.60 (1H) , 1.91-2.28 (9H) .
Step E: 4-ethynylcyclohexanone
The solution of 8-ethynyl-1, 4-dioxaspiro [4.5] -decane (4.0 g) in FA (3 mL) was stirred at 25 ℃ for 12 hr in N2. The mixture was evaporated to give the crude product used for next step.
Step F: tert-butyl 1- (4-ethynylcyclohexyl) piperidine-4-carboxylate
To a solution of tert-butyl piperidine-4-carboxylate (1.09 g, 4.91 mmol, HCl salt) and 4-ethynylcyclohexanone (0.49 g) in THF (10 mL) was added zinc chloride (1 M, 12.28 mL in THF) , sodium cyanoborohydride (925.93 mg, 14.73 mmol) at 55℃, the resulting mixture was stirred at 55 ℃ for 4 hr in N2. The resulting solution was extracted with EA (10 mL×3) . The combined organic layer was dried over Na2SO4 and concentrated to give tert-butyl 1- (4-ethynylcyclohexyl) piperidine-4-carboxylate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.45-3.73 (4H) , 3.09-3.37 (4H) , 2.60-2.78 (1H) , 2.15-2.32 (3H) , 1.43-1.52 (17H) .
Step G: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (4- (4- (tert-butoxycarbonyl) piperidin-1-yl) cyclohexyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 1- (4-ethynylcyclohexyl) piperidine-4-carboxylate (100 mg) , methyl2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (120 mg, 168.87 μmol) and TEA (85.44 mg, 844.35 μmol) in THF (1.93 mL) was added cuprous iodide (6.43 mg, 33.77 μmol) and Bis (triphenylphosphine) palladium (II) chloride (59.26 mg, 84.44 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 3 hr in N2. The mixture was diluted with DCM (5 mL) . The organic layer was added H2O (5 mL) and extracted with DCM (5 mL *2) . The collected organic layers were washed with brined (30 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated and purified by column to give the title compound.
Step H: 1- (4- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclohexyl) piperidine-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [4- (4-tert-butoxycarbonyl-1-piperidyl) cyclohexyl] ethynyl] phenoxy] propyl] thiazole-4-carboxy late (30 mg, 34.32 μmol) in FA (2 mL) was stirred at 25 ℃ for 12 hr in N2. The mixture was evaporated to give the crude product. LCMS: MS (ESI) M/Z: 409.8 [M/2] + .
Step I: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) piperidin-1-yl) cyclohexyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 1- [4- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] cyclohexyl] piperidine-4-carboxylic acid (27 mg) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-
yl) phenyl] methyl] pyrrolidine-2-carboxamide (28.42 mg, 66.01 μmol) in DMF (1 mL) was added HATU (25.23 mg, 66.01 μmol) and DIEA (21.33 mg, 165.03 μmol) at 25 ℃, the resulting mixture was stirred at room temperature for 12 hr in N2. The mixture was diluted with DCM (5 mL) . The organic layer was added H2O (5 mL) . The water layer was extracted with DCM (5 mL *2) . The collected organic layers were washed with brined (5 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound.
Step J: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- ( (4- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) piperidin-1-yl) cyclohexyl) ethynyl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methyl carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] cyclohexyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate (20 mg, ) in dioxane (2 mL) was added aq. NaOH (2N, 0.1 mL) and H2O (1 mL) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 12 hr. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5μM X Bridge column, 19× 150 mm, Waters; gradient elution of 35 %MeCN in water to 43 %MeCN in water over a 7 min period, where water contain 0.1%formic acid) to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [4- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] cyclohexyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LCMS: MS (ESI) M/Z: 1216.8 [M+1] + . 1H-NMR (400 MHz, METHANOL-D4) δ 8.86-8.85 (m, , 1H) , 8.67-8.62 (m, 1H) , 7.94-7.89 (m, 2H) , 7.75-7.59 (m, 2H) , 7.44-7.24 (m, 8H) , 6.83-6.75 (m, 2H) , 4.59-4.48 (m, 5H) , 3.94-3.79 (m, 5H) , 3.58-3.46 (m, 2H) , 3.21-3.11 (m, 1H) , 3.11-3.03 (m, 4H) , 2.45-2.43 (m, J = 6.9 Hz, 4H) , 2.19-1.98 (m, 14H) , 1.63-1.26 (m, 8H) , 1.01 (s, 9H) .
Example 54: Compound 54
Step A: tert-butyl 3- (3-ethynylcyclobutyl) azetidine-1-carboxylate
A solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (577.99 mg, 3.01 mmol) in MeOH (20 mL) was added K2CO3 (618.28 mg, 4.51 mmol) at 25℃, the resulting mixture was stirred at 25℃ for 30 mins. then tert-butyl 3- (3-formylcyclobutyl) azetidine-1-carboxylate (360 mg, 1.50 mmol) was added. The reaction mixture was stirred for16hr at 25 ℃. H2O (30 mL) was added and the resulting solution was extracted with EA (50mL×3) . The combined organic layer was washed with brine (20mL) , dried over Na2SO4, filtered and concentrated under reduced
pressure. The reaction mixture was concentrated to dryness to afford the title compound, which was used in next step without further purification. LC/MS: MS (ESI) M/Z: 180 [M+H-t-Bu] +.
Step B: methyl2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- (1-tert-butoxycarbonylazetidin-3-yl) cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of tert-butyl 3- (3-ethynylcyclobutyl) azetidine-1-carboxylate (198 mg) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (298.95 mg, 420.70 μmol) in DMF (15 mL) was added DIEA (162.81 mg, 1.26 mmol) , CuI (40mg) and Pd (PPh3) 4 (97.18 mg, 84.14 μmol) at 25℃, and the resulting mixture was stirred at 30℃ for 16 hr in N2. After cooled to 20℃, the reaction mixture was quenched with 40 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (50 mL×3) . The combined organic layers were washed with brine (50mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=1: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- (1-tert-butoxycarbonylazetidin-3-yl) cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z: 818 [M+H] +.
Step C: methyl5- (3- (4- ( (3- (azetidin-3-yl) cyclobutyl) ethynyl) phenoxy) propyl) -2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) thiazole-4-carboxylate
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- (1-tert-butoxycarbonylazetidin-3-yl) cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate (290 mg, 354.52 μmol) in FA (10 mL) was stirred at 25℃ for 1 hr in N2. The reaction mixture was concentrated to dryness and the crude product was used in next step without further purification. LC/MS: MS (ESI) M/Z: 718 [M+H] +.
Step D: methyl 2- (3- (3- ( (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) ethynyl) cyclobutyl) azetidin-1-yl) acetic acid
A solution of methyl 5- [3- [4- [2- [3- (azetidin-3-yl) cyclobutyl] ethynyl] phenoxy] propyl] -2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] thiazole-4-carboxylate (200 mg) in MeOH (20 mL) was added AcOH (50 mg, 835.77 μmol) , the reaction was stirred for 30 min at 30℃ , then added NaBH3CN (43 mg, 696.47 μmol) . The resulting mixture was stirred at room temperature for 3 hr under N2 atmosphere. The reaction mixture was quenched with 20 mL of H2O. The resulting solution was extracted with EA (30 mL×3) . The combined organic layers were washed with brine (20mL) , dried over Na2SO4, then filtered and
concentrated under reduced pressure. The reaction mixture was concentrated to dryness and the residue was used in next step without further purification. LC/MS: MS (ESI) M/Z: 776 [M+H] +.
Step E: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of 2- [3- [3- [2- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] ethynyl] cyclobutyl] azetidin-1-yl] acetic acid (140 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (93.22mg, 216.51 μmol) in DMF (8 mL) was added DIEA (46.55 mg, 360.86 μmol) and HATU (95.99 mg, 252.60 μmol) at 25 ℃, the resulting mixture was stirred at room temperature for 1hr in N2.20 mL of H2O was added and the resulting solution was extracted with EA (20 mL×3) . The combined organic layers were washed with brine (20mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where water contain 0.1%formic acid) to afford methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate.
Step F: 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylate (70 mg, 58.90 μmol) in dioxane/H2O (10: 1) (1 mL) was added NaOH (5.89 mg, 147.25 μmol) at 25°, the resulting mixture was stirred at 25℃ for 16hr under N2 atmosphere. The pH value of the solution was adjusted to 6-7 with aqueous HCl (1M) . Then it was concentrated under reduced pressure. The crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, Waters; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where water contain 0.1%formic acid) to
provide 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [2- [3- [1- [2- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -2-oxo-ethyl] azetidin-3-yl] cyclobutyl] ethynyl] phenoxy] propyl] thiazole-4-carboxylic acid. LC/MS: MS (ESI) M/Z: 1173 [M+H] +. 1H-NMR (400 MHz, DMSO-D6) δ 8.94 (s, 1H) , 8.61 (dd, J = 20.2, 8.4 Hz, 1H) , 7.99 (d, J = 8.0 Hz, 1H) , 7.76-7.61 (m, 2H) , 7.45-7.20 (m, 9H) , 6.81 (d, J = 8.0 Hz, 2H) , 4.77 (s, 2H) , 4.51-4.31 (m, 4H) , 4.18-3.15 (m, 16H) , 3.43-2.88 (m, 4H) , 2.62-2.28 (m, 3H) , 2.14-1.68 (m, 7H) , 1.18 (s, 1H) , 0.90-0.80 (s, 9H)
Example 55: Compound 55
Step A: methyl 2- (3- (benzyloxy) cyclobutylidene) acetate
To a solution of methyl 2-dimethoxyphosphorylacetate (12.40 g, 68.10 mmol) in THF (80 mL) was added NaH (2.72 g, 68.10 mmol, 60%purity) at 0 ℃, the resulting mixture was stirred at 0~20 ℃ for 1 hr. Then 3- (benzyloxy) cyclobutanone (10 g, 56.75 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with 40mL H2O. The resulting solution was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=5: 1 to give methyl 2- (3-benzyloxycyclobutylidene) acetate.
Step B: methyl 2- (3-hydroxycyclobutyl) acetate
To a solution of methyl 2- (3-benzyloxycyclobutylidene) acetate (8 g, 34.44 mmol) in MeOH (250 mL) was added Pd/C (836.60 mg, 10%w/w) . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 60 ℃ for 2 hrs. The suspension was filtered through celite and filter cake was washed with MeOH (10mL*3) . The combined filtrates was concentrated to give methyl 2- (3-hydroxycyclobutyl) acetate. 1H-
NMR (400 MHz, CDCl3) δ 4.19-4.08 (m, 1H) , 3.67 (s, 3H) , 2.67-2.36 (m, 4H) , 2.15-1.96 (m, 3H) , 1.61-1.54 (m, 1H) .
Step C: methyl 2- (3-oxocyclobutyl) acetate
A solution of methyl 2- (3-hydroxycyclobutyl) acetate (4.7 g) in DCM (50 mL) was added DMP (16.59 g, 39.12 mmol) at 0 ℃, the resulting mixture was stirred at room temperature for 2 hr. The mixture was poured into water (10mL) , extracted with EA (20mL*3) . The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column (PE: EtOAc=12: 1) to afford the product methyl 2- (3-oxocyclobutyl) acetate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 4.25 (m, 1H) , 3.67 (s, 3H) , 2.49-2.37 (m, 1H) , 2.36-2.30 (m, 2H) , 2.15-2.07 (m, 2H) , 1.56-1.59 (m, 1H) .
Step D: tert-butyl 1- (3- (2-methoxy-2-oxoethyl) cyclobutyl) piperidine-4-carboxylate
A solution of methyl 2- (3-oxocyclobutyl) acetate (3.74 g, 26.31 mmol) and tert-butyl piperidine-4-carboxylate (6.42 g, 28.94 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH3CN (4.97 g, 78.93 mmol) and AcOH (1.58 g, 26.31 mmol) at 20 ℃, the resulting mixture was stirred at room temperature for 3 hr. After completion, the mixture was poured into water (50mL) , extracted with EA (50mL*3) . The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give tert-butyl 1- [3- (2-methoxy-2-oxo-ethyl) cyclobutyl] piperidine-4-carboxylate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.69-3.62 (s, 3H) , 3.48-3.18 (m, 3H) , 2.82-2.03 (m, 14H) , 1.45 (s, 9H) .
Step E: tert-butyl 1- (3- (2-hydroxyethyl) cyclobutyl) piperidine-4-carboxylate
To a solution of CaCl2 (3.21 g, 28.90 mmol) and NaBH4 (1.82 g, 48.17 mmol, ) in EtOH (30 mL) was added tert-butyl 1- [3- (2-methoxy-2-oxo-ethyl) cyclobutyl] piperidine-4-carboxylate (3 g, 9.63 mmol, 1 equiv) at 0 ℃, the resulting mixture was stirred at 60 ℃ for 16 hr. The reaction mixture was concentrated to dryness. The reaction mixture was quenched with 40 mL H2O, extracted with EA (50 mL*3) . The combined organic layers was washed with brine (30 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with DCM: MeOH = 50: 1 to give tert-butyl 1- [3- (2-hydroxyethyl) cyclobutyl] piperidine-4-carboxylate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 3.63-3.46 (m, 3H) , 2.93-2.58 (m, 4H) , 2.32-1.65 (m, 13H) , 1.40 (s, 9H) .
Step F: tert-butyl 1- (3- (2-oxoethyl) cyclobutyl) piperidine-4-carboxylate
To a solution tert-butyl 1- [3- (2-hydroxyethyl) cyclobutyl] piperidine-4-carboxylate (300 mg, 1.06 mmol) in DCM (5 mL) was added DMP (673.24 mg, 1.59 mmol) at 0 ℃, the reaction was stirred at 25 ℃ for 2 hr. Saturated aqueous NaHCO3 (20 mL) was added to the reaction mixture and extracted with DCM (20 mL *3) . The organic layer was washed with brine (300 ml
*1) , dried over anhydrous Na2S04 and concentrated in vacuo. The mixture was purified by column chromatography (PE: EA=70: 1) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 9.70 (s, 1H) , 3.47 (s, 3H) , 2.97-2.21 (m, 8H) , 2.08-1.87 (m, 6H) , 1.40 (s, 9H)
Step G: tert-butyl 1- (3- (prop-2-yn-1-yl) cyclobutyl) piperidine-4-carboxylate
To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (341.36 mg, 3.34 mmol) and K2CO3 (245.58 mg, 3.34 mmol) in MeOH (6 mL) was added tert-butyl 1- [3- (2-oxoethyl) cyclobutyl] piperidine-4-carboxylate (250 mg, 1.67 mmol) in MeOH (4mL) , the resulting mixture was stirred at room temperature for another 16 hrs. The mixture was purified by column chromatography (PE: EA=20: 1) . The product tert-butyl 1- (3- (prop-2-yn-1-yl) cyclobutyl) piperidine-4-carboxylate. 1H-NMR (400 MHz, CHLOROFORM-D) δ 5.25 (s, 1H) , 3.59-3.46 (m, 2H) , 2.91-2.41 (m, 3H) , 2.22-1.53 (m, 12H) , 1.35 (s, 9H) .
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (3- (4- (tert-butoxycarbonyl) piperidin-1-yl) cyclobutyl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of tert-butyl 1- (3-prop-2-ynylcyclobutyl) piperidine-4-carboxylate (87.83 mg, 316.63 μmol) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (150 mg, 211.09 μmol in DMF (10 mL) was added DIPEA (108.92 mg, 844.35 μmol) , CuI (20.10 mg, 105.54 μmol) and Pd (PPh3) 4 (48.76 mg, 42.22 μmol) at 25 ℃. The resulting mixture was stirred at 50 ℃for 3 hr under N2 atmosphere. The reaction mixture was quenched with 5 mL H2O. The resulting solution was extracted with EA (10 mL*3) . The combined organic layers was washed with brine (10 mL) , dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- (4-tert-butoxycarbonyl-1-piperidyl) cyclobutyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z: 430.7 [M/2+H] +.
Step I: 1- (3- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) cyclobutyl) piperidine-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- (4-tert-butoxycarbonyl-1-piperidyl) cyclobutyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (40 mg, 46.51 μmol) in FA (5 mL) was stirred at 40 ℃ for 1.5 hr. The reaction mixture was concentrated to dryness and the crude product was used in next step without further purification. LC/MS: MS (ESI) M/Z: 402.9 [M/2+H] +.
Step J: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (3- (4- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) piperidin-1-yl) cyclobutyl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of 1- [3- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] cyclobutyl] piperidine-4-carboxylic acid (40 mg) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (21.42 mg, 49.75 μmol) in DMF (5 mL) was added DIPEA (64.30 mg, 497.52 μmol) , HOBT (67.23 mg, 497.52 μmol) and EDCI (95.37 mg, 497.52 μmol) at 25 ℃, the resulting mixture was stirred at 25 ℃ for 3 hr. The reaction mixture was quenched with 3 mL H2O. The resulting solution was extracted with EA (5 mL*3) . The organic layer was concentrated and subjected to reverse phase preparative HPLC (Prep-C18, 20-45μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 35%MeCN in water to 43%MeCN in water over a 7 min period, where both solvents contain 0.1%formic acid) to provide methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] cyclobutyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LC/MS: MS (ESI) M/Z: 608.8 [M/2+H] +.
Step K: 4- {4- [4- ( {1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl} amino) phenyl] piperazin-1-yl} butanoic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] cyclobutyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (25 mg, 20.55 μmol) in H2O (1 mL) and THF (1 mL) /MeOH (1 mL) was added LiOH (4.92 mg, 205.50 μmol) at room temperature, the resulting mixture was stirred at room temperature for 5 hr. The pH value of the resulting mixture was adjusted to 4 by using 1N HCl solution. The resulting mixture was filtered to afford 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [3- [4- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] -1-piperidyl] cyclobutyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, MeOH-d4) δ 8.84 (s, 1H) , 7.88 (d, J = 8.0 Hz, 1H) , 7.72 (d, J = 7.2 Hz, 1H) , 7.58 (d, J = 7.2 Hz, 1H) , 7.44-7.28 (m, 8H) , 7.19 (d, J = 8.8 Hz, 2H) , 6.74 (d, J = 8.8 Hz, 2H) , 4.60-4.46 (m, 5H) , 4.35-4.25 (m, 1H) , 3.93-3.76 (m, 6H) , 3.46-3.32 (m, 4H) , 3.26-3.10 (m, 3H) , 3.08-2.96 (m,
2H) , 2.53-2.39 (m, 5H) , 2.27-2.13 (m, 2H) , 2.09-1.83 (m, 9H) , 1.23 (brs, 4H) , 0.99 (s, 9H) . LC/MS: MS (ESI) M/Z: 1202.7 [M+H] +.
Example 56: Compound 56
Step A: ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-ylidene) acetate
To a solution of ethyl 2- (diethoxyphosphoryl) acetate (34.45 g, 153.67 mmol, 30.49 mL) in THF (200 mL) was added NaH (6.66 g, 166.48 mmol, 60%purity) at 25 ℃ stirred for 1 h. The solution of 1, 4-dioxaspiro [4.5] decan-8-one (20 g, 128.06 mmol) in THF (200 mL) was added dropwise. The resulting mixture was stirred at 25 ℃ for 2 hr. The mixture was diluted with EtOAc (200 mL) . The organic layer was washed H2O (300 mL) . The water layer was extracted with EtOAc (200 mL *2) . The collected organic layers were washed with brined (200 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was used in next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.62 (s, 1H) , 6.13-6.08 (m, 2H) , 5.93 (t, J = 2.9 Hz, 4H) , 4.98-4.94 (m, 2H) , 4.35-4.32 (m, 2H) , 3.75-3.69 (m, 4H) , 3.25-3.20 (m, 4H) .
Step B: ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate
To a solution of ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-ylidene) acetate (28.98 g, 128.08 mmol) in ethanol (300 mL) under N2 and was added Pd/C (6.82 g, 10%purity) at 25 ℃. Then the reaction was replaced three times with hydrogen and stirred at 25 ℃ for 16 hr. The mixture reaction was filtered and concentrated in vacuo to give the crude product, which was used in next step without further purification.
Step C: 2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanol
To a solution of ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate (29.24 g) in THF (300 mL) at 0 ℃ under N2 was added LiAlH4 (1 M, 128.09 mL, THF solution) in 10 min. The resulting mixture was stirred at 0 ℃ for 1 hr. The mixture was quenched by addition of H2O (6 mL) , NaOH (18 mL of a 15%aqueous solution) and an additional portion of H2O (6 mL) . The solids were filtered and the filtrate was concentrated under reduced pressure. The mixture was diluted with EtOAc (100 mL) . The organic layer was washed H2O (200 mL) . The aqueous layer was extracted with EtOAc (100 mL *2) . The collected organic layers were washed with brine (1000 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography eluted with PE: EtOAc (0 ~ 50%) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 3.91 (t, J = 6.7 Hz, 4H) , 3.66 (t, J = 6.6 Hz, 2H) , 1.73-1.66 (m, 5H) , 1.55-1.40 (m, 5H) , 1.29-1.18 (m, 2H) .
Step D: 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetaldehyde
To a solution of 2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanol (13.1 g, 70.34 mmol) in dichloromethane (90 mL) was added (1, 1-diacetoxy-3-oxo-1, 2-benziodoxol-1-yl) acetate (35.80 g, 84.40 mmol) at 0℃, the resulting mixture was stirred at 25 ℃ for16 hr under N2 atmosphere. The mixture reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc =10: 1 to give 2- (1, 4-
dioxaspiro [4.5] decan-8-yl) acetaldehyde. 1H-NMR (400 MHz, CDCl3) δ 9.76 (t, J = 2.1 Hz, 1H) , 3.96-3.90 (m, 4H) , 2.37-2.27 (m, 2H) , 1.98-1.90 (m, 1H) , 1.80-1.72 (m, 4H) , 1.61-1.51 (m, 2H) , 1.38-1.17 (m, 2H) .
Step E: 8- (prop-2-yn-1-yl) -1, 4-dioxaspiro [4.5] decane
To a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (6.26 g, 32.57 mmol) in methanol (55 mL) was added potassium carbonate (11.25 g, 81.42 mmol) at 25 ℃ and the mixture was stirred for 30 min. A solution of 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetaldehyde (5 g, 27.14 mmol) in methanol (55 mL) was added dropwise. The resulting mixture was stirred at 25 ℃ for16 hr. The mixture reaction was filtered and the filtrate was diluted with EtOAc (80 mL) . The organic layer was washed with H2O (15 mL) . The water layer was extracted with EtOAc (80 mL*2) . The collected organic layers were washed with brine (100 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by purified by silica gel chromatography eluted with PE: EtOAc=20: 1to give 8-prop-2-ynyl-1, 4-dioxaspiro [4.5] decane. 1H-NMR (400 MHz, CDCl3) δ 3.96-3.91 (m, 4H) , 2.12 (dd, J = 6.7, 2.6 Hz, 2H) , 1.96 (td, J = 2.7, 0.7 Hz, 1H) , 1.83-1.72 (m, 4H) , 1.59-1.49 (m, 3H) , 1.38-1.24 (m, 2H) .
Step F: 4- (prop-2-yn-1-yl) cyclohexanone
To a solution of 8-prop-2-ynyl-1, 4-dioxaspiro [4.5] decane (880 mg, 4.88 mmol) in FA (5 mL) at 20 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure. The reaction mixture was concentrated to give 4-prop-2-ynylcyclohexanone as a crude product, which was used for the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 2.46-2.28 (m, 4H) , 2.25-2.21 (m, 2H) , 2.19-2.10 (m, 2H) , 2.07-1.93 (m, 2H) , 1.63-1.46 (m, 2H) .
Step G: tert-butyl 1- (4- (prop-2-yn-1-yl) cyclohexyl) azetidine-3-carboxylate
To a solution of 4-prop-2-ynylcyclohexanone (1.32 g) and tert-butyl azetidine-3-carboxylate (1.53 g, 9.71 mmol) in anhydrous methanol : THF (30 mL, v: v = 1: 1) was added dropwise ZnCl2 (1 M, 24.28 mL, THF solution) at 55 ℃ under N2. After stirring for 15 min, sodium cyanoborohydride (1.53 g, 24.28 mmol) was added and the mixture was stirred at 55 ℃ for 4 hr. The mixture was diluted with NaHCO3 (50 mL) . The water layer was extracted with EtOAc (30 mL *3) . The collected organic layers were washed with brined (30 mL) , dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crudetert-butyl 1- (4-prop-2-ynylcyclohexyl) azetidine-3-carboxylate. LCMS: MS (ESI) M/Z: 278.2 [M+H] +.
Step H: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (3- (tert-butoxycarbonyl) azetidin-1-yl) cyclohexyl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- (4-iodophenoxy) propyl] thiazole-4-carboxylate (50 mg, 70.36 μmol) , tert-butyl 1- (4-prop-2-ynylcyclohexyl) azetidine-3-carboxylate (29.28 mg) and cuprous iodide (2.68 mg, 14.07 μmol) in anhydrous DMF (1.5 mL) was added dropwise TEA (21.36 mg, 211.09 μmol) at 20℃ under N2. Bis (triphenylphosphine) palladium (II) chloride (24.69 mg, 35.18 μmol) was added and the mixture was stirred at 28 ℃ for 2 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which the crude reaction mixture was filtered and subjected to reverse phase preparative HPLC (mobile phase: 0.05%NH3H2O-10mmol/L NH4HCO3-CAN; Chromatographic column: YMC-Actus Triart C18, 150*20 mm, 5 um; Current Speed (ml/min) : 20; Gradient (%) : 59.25-79.25; Running time (min) : 12; Peak time (min) : 9.5) to provide methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (3-tert-butoxycarbonylazetidin-1-yl) cyclohexyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 860.50 [M+H] +.
Step I: 1- (4- (3- (4- (3- (2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (methoxycarbonyl) thiazol-5-yl) propoxy) phenyl) prop-2-yn-1-yl) cyclohexyl) azetidine-3-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- (3-tert-butoxycarbonylazetidin-1-yl) cyclohexyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (50 mg, 58.13 μmol) in FA (0.3 mL) at 25℃ was stirred at 25 ℃ for 2 hr. The reaction mixture was concentrated to dryness and the product was used in next step without further purification. LCMS: MS (ESI) M/Z: 804.6 [M+H] +.
Step J: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) azetidin-1-yl) cyclohexyl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylate
A solution of 1- [4- [3- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] prop-2-ynyl] cyclohexyl] azetidine-3-carboxylic acid (50 mg, ) , DIEA (24.11 mg, 186.57 μmol) , HATU (118.23 mg, 310.95 μmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (26.78 mg, 62.19 μmol) in anhydrous DMF (1.5 mL) was stirred at 30 ℃ for 16 hr. The crude reaction mixture was filtered and subjected to reversed-phase preparative HPLC (mobile phase: 0.1%TFA-ACN; Chromatographic column: Prep Fluoro-Phenyl, 150*19mm, 5um; Current Speed (ml/min) : 20; Gradient (%) : 43.5-63.5; Running time (min) : 12; Peak time (min) : 8.5) to provide methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [3- [ [ (1S) -1-
[ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] azetidin-1-yl] cyclohexyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate. LCMS: MS (ESI) M/Z: 609.1 [M/2+H] +
Step K: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3- (4- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamoyl) azetidin-1-yl) cyclohexyl) prop-1-yn-1-yl) phenoxy) propyl) thiazole-4-carboxylic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] azetidin-1-yl] cyclohexyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylate (16.1 mg, 13.23 μmol) in dioxane (1 mL) was added NaOH (2M, aqueous solution, 66.17 μL) at 25℃, the resulting mixture was stirred at 30 ℃ for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was filtered and subjected to reverse phase preparative HPLC (mobile phase: 0.1%TFA-ACN; Chromatographic column: Prep Fluoro-Phenyl, 150 *19mm, 5 um; Current Speed (ml/min) : 20; Gradient (%) : 37.65-57.65; Running time (min) : 12; Peak time (min) : 9.5) to provide 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3- [4- [3- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [4- (4-methylthiazol-5-yl) phenyl] methylcarbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] carbamoyl] azetidin-1-yl] cyclohexyl] prop-1-ynyl] phenoxy] propyl] thiazole-4-carboxylic acid. 1H-NMR (400 MHz, CD3OD) δ 8.91 (s, 1H) , 8.65-8.62 (m, 1H) , 8.17-8.14 (m, 1H) , 7.91-7.89 (d, J = 8.0 Hz, 1H) , 7.75-7.73 (d, J = 7.1 Hz, 1H) , 7.61-7.60 (d, J = 6.9 Hz, 1H) , 7.50-7.35 (m, 6H) , 7.25 (m, 2H) , 6.83-6.81 (d, J = 8.5 Hz, 2H) , 5.02-4.94 (m, 3H) , 4.64-4.55 (m, 4H) , 4.40-4.32 (m, 5H) , 4.01-3.94 (m, 3H) , 3.83-3.82 (m, 3H) , 3.61-3.46 (m, 1H) , 3.28 (s, 2H) , 3.16-3.08 (m, 2H) , 2.49 (s, 3H) , 2.42-2.36 (m, 2H) , 2.28-2.23 (m, 1H) , 2.15-1.96 (m, 5H) , 1.69-1.47 (m, 5H) , 1.36-1.32 (m, 1H) , 1.25-1.22 (m, 1H) , 1.06 (s, 9H) . LCMS: MS (ESI) M/Z: 1202.7 [M+H] +.
Example 57: Compound 75
Following the similar procedure as shown in Example 46, Compound 75 was prepared.
1H-NMR (400 MHz, DMSO-D6) δ 8.94 (s, 1H) , 8.67-8.61 (m, 2H) , 8.34 (d, J = 8.0 Hz, 1H) , 8.25-8.22 (m, 2H) , 7.97 (d, J = 7.6 Hz, 1H) , 7.79-7.71 (m, 2H) , 7.64 (d, J = 6.0 Hz, 1H) , 7.44-7.25 (m, 9H) , 6.99-6.96 (m, 2H) , 4.91-4.84 (m, 1H) , 4.80 (s, 2H) , 4.51-4.45 (m, 1H) , 4.43-4.36 (m, 1H) , 4.26-4.19 (m, 1H) , 4.01 (t, J = 6.0 Hz, 2H) , 3.67 (t, J = 6.0 Hz, 2H) , 3.56 (s, 2H) , 3.15 (t, J = 7.6 Hz, 2H) , 2.98 (t, J = 5.6 Hz, 2H) , 2.54 (t, J = 7.2 Hz, 1H) , 2.40 (s, 3H) , 2.25-2.15 (m, 1H) , 2.11-1.95 (m, 4H) , 1.78-1.72 (m, 1H) , 1.55-1.37 (m, 5H) , 1.33 (d, J = 6.9 Hz, 3H) , 1.25-1.19 (m, 7H) , 0.88 (s, 9H) . LCMS: MS (ESI) M/Z: 1217.7 [M+H] +.
Example 58: Compound 74
Step A: methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate
To a solution of tert-butyl nitrite (5.94 g, 57.57 mmol) in MeCN (140 mL) was added CuCl2 (6.19 g, 46.1 mmol) under N2. The mixture was stirred at 25 ℃ for 10 min. To the mixture was added methyl 2-amino-5- (3-hydroxypropyl) thiazole-4-carboxylate (8.30 g, 38.4 mmol) . The mixture was stirred at 25 ℃ for 2 h. The mixture was diluted with water (150 mL) , and extracted with EtOAc (100 mL) twice. The organic layer was washed with brine (150 mL) , and concentrated to give crude. The crude was purified by Combi-flash (silica gel, 0~10%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 258.1 [M+H] +. 1H NMR (400MHz, CDCl3) δ3.95 (s, 3H) , 3.67 (t, J = 5.6 Hz, 2H) , 3.40 (t, J = 7.2 Hz, 2H) , 1.87-1.99 (m, 2H) .
Step B: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a solution of tert-butyl 8- [6- (4-hydroxyphenyl) -3-pyridyl] octanoate (1.2 g, 3.25 mmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (804 mg, 3.41 mmol) in THF (12 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (2.74 g, 11.37 mmol) under N2. The mixture was stirred at 80 ℃ for 16 h. The mixture was concentrated to remove the solvent. The residue was purified by Combi-flash (silica gel, 10~20%EtOAc in PE) to afford the desired product. LCMS: MS (ESI) m/z 587.3 [M+H] +.
Step C: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (1.00 g, 1.70 mmol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (707 mg, 2.04 mmol, HCl) in dioxane (12 mL) were added Pd2 (dba) 3 (780 mg, 852 μmol) , SPhos (349 mg, 851 μmol) , t-BuOK (478 mg, 4.26 mmol) under N2. The mixture was stirred at 90 ℃ for 2 h. The yellow suspension was diluted with EtOAc (110 mL) , and filtered with celite. The filter cake was washed with EtOAc (50 mL) . The filtrate was concentrated to give crude (15.5 g) as a yellow gum. The crude was purified by Combi-flash (silica gel, 0~10%MeOH in DCM) . 6.30 g of yellow gum was obtained. The gum was purified by Combi-flash (silica gel, 30~100%EtOAc in PE) to afford the desired product. LCMS: MS (ESI) m/z 860.4 [M+H] +.
Step D: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -3-pyridyl] octanoic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] phenoxy] propyl] thiazole-4-
carboxylate (1.40 g, 1.63 mmol) in formic acid (75 mL) was stirred at 25 ℃ for 15 h. The solution was concentrated to afford the desired product. LCMS: MS (ESI) m/z 804.4 [M+H] +.
Step E: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -3-pyridyl] octanoic acid (950 mg, 1.18 mmol) in DMF (10 mL) was added HATU (584 mg, 1.54 mmol) under N2. The mixture was stirred at 25 ℃ for 15 min. To the mixture was added (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (551 mg, 1.24 mmol) and TEA (359 mg, 3.54 mmol) . The mixture was stirred at 25 ℃ for 1 h. The yellow solution was diluted with water (30 mL) and filtered. The filter cake was dried under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 1230.6 [M+H] +.
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (950 mg, 772 μmol) in THF (5 mL) and MeOH (5 mL) was added LiOH. H2O (162 mg, 3.86 mmol) in H2O (2 mL) . The mixture was stirred at 25 ℃ for 16 h. The mixture was treated with 1N HCl aq. to adjust pH to 6. The mixture was concentrated to give crude. The crude was purified by prep-HPLC: column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 35%-95%, 9 min. The fractions were concentrated to remove the solvent, and the remaining was dried by lyophilization to afford Compound 74. LCMS: MS (ESI) m/z 1216.9 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ12.93 (brs, 1H) , 8.99 (s, 1H) , 8.48 (s, 1H) , 8.37 (d, J = 7.6 Hz, 1H) , 8.03 (d, J = 7.6 Hz, 1H) , 7.97 (d, J = 8.8 Hz, 2H) , 7.74-7.87 (m, 4H) , 7.66 (d, J = 6.8 Hz, 1H) , 7.31-7.49 (m, 8H) , 7.01 (d, J = 8.0 Hz, 2H) , 4.93 (t, J = 7.2 Hz, 1H) , 4.88 (m, 2H) , 4.51 (d, J = 9.2 Hz, 1H) , 4.42 (t, J = 8.0 Hz, 1H) , 4.21-4.29 (m, 1H) , 4.05 (t, J = 6.0 Hz, 2H) , 3.72 (t, J = 6.0 Hz, 2H) , 3.55-3.62 (m, 2H) , 3.19 (t, J = 7.6 Hz, 2H) , 3.19 (t, J = 7.6 Hz, 2H) , 3.03 (t, J = 6.0 Hz, 2H) , 2.62 (t, J = 7.6 Hz,
2H) , 2.46 (m, 3H) , 2.17-2.28 (m, 1H) , 1.94-2.13 (m, 4H) , 1.72-1.82 (m, 1H) , 1.55-1.63 (m, 2H) , 1.43-1.53 (m, 2H) , 1.52 (d, J = 7.2 Hz, 3H) , 1.22-1.33 (m, 6H) , 0.93 (s, 9H) .
Example 59: Compound 126
Following the similar procedure as shown in Example 1, Compound 126 was prepared.
1H-NMR (400 MHz, DMSO-D6) δ 8.97 (d, J = 5.2 Hz, 1H) , 8.02 (d, J = 7.7 Hz, 1H) , 7.82-7.66 (m, 3H) , 7.48-7.23 (m, 9H) , 6.85 (d, J = 8.5 Hz, 2H) , 4.91 (t, J = 7.1 Hz, 1H) , 4.52-4.40 (m, 2H) , 4.27 (s, 1H) , 3.96 (t, J = 6.0 Hz, 2H) , 3.71 (t, J = 5.6 Hz, 2H) , 3.60 (s, 2H) , 3.17-3.00 (m, 4H) , 2.63 (d, J = 37.4 Hz, 1H) , 2.45-1.96 (m, 12H) , 1.82-1.75 (m, 1H) , 1.52-1.23 (m, 18H) , 0.93-0.83 (m, 9H) . LCMS: MS (ESI) M/Z: 1177.6 [M+H] +.
Example 60: Compound 172
Following the similar procedure as shown in Example 1, Compound 172 was prepared.
1H-NMR (400 MHz, METHANOL-D4) δ 8.93 (d, J = 11.0 Hz, 1H) , 7.90 (d, J = 7.4 Hz, 1H) , 7.75 (t, J = 7.3 Hz, 2H) , 7.66 (d, J = 7.1 Hz, 1H) , 7.48-7.32 (m, 8H) , 7.23 (dd, J = 21.0, 8.7 Hz, 3H) , 6.76 (d, J = 8.0 Hz, 2H) , 5.09 (s, 2H) , 5.01-4.94 (m, 1H) , 4.61-4.53 (m, 2H) , 4.41 (s, 1H) , 3.95 (t, J = 5.6 Hz, 1H) , 3.91-3.85 (m, 2H) , 3.75-3.72 (m, 1H) , 3.12 (d, J = 6.3 Hz, 3H) , 2.46 (s, 3H) , 2.35 (t, J = 6.7 Hz, 2H) , 2.27 (q, J = 7.4 Hz, 1H) , 2.17 (dd, J = 14.8, 8.0 Hz, 1H) , 2.06-1.93
(m, 3H) , 1.65-1.43 (m, 8H) , 1.40-1.29 (m, 7H) , 1.01 (d, J = 9.1 Hz, 9H) . LCMS: MS (ESI) M/Z: 1143.7 [M+H] +.
Example 61: Compound 231
Following the similar procedure as shown in Example 50, Compound 231 was prepared.
1H-NMR (400 MHz, DMSO-D6) δ 12.90 (brs, 1H) , 9.97 (brs, 1H) , 8.99 (s, 1H) , 8.37 (d, J = 7.7 Hz, 1H) , 8.04 (d, J = 8.0 Hz, 1H) , 7.79 (m, 2H) , 7.68 (d, J = 7.4 Hz, 1H) , 7.61 (s, 1H) , 7.50-7.32 (m, 9H) , 7.17-7.14 (m, 1H) , 4.95-4.88 (m, 1H) , 4.83 (s, 2H) , 4.57-4.48 (m, 1H) , 4.42 (t, J = 8.1 Hz, 1H) , 4.31-4.24 (m, 3H) , 4.11 (t, J = 5.9 Hz, 2H) , 3.73-3.36 (m, 6H) , 3.22-3.01 (m, 6H) , 2.46 (s, 3H) , 2.24-2.18 (m, 1H) , 2.07-1.99 (m, 6H) , 1.66-1.04 (m, 16H) , 0.94 (s, 9H)
Example 62: Compound 229
Step A: (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoic acid
A mixture of 5-bromo-2-chloro-pyrimidine (3.6 g, 18.61 mmol) , oct-7-enoic acid (2.20 g, 15.45 mmol) , PPh3 (244.08 mg, 0.930 mmol) and TEA (5.65 g, 55.83 mmol, 7.77 mL) in DMF (20 mL) was added Pd (OAc) 2 (208.92 mg, 0.930 mmol) . The mixture was stirred at 100 ℃ for 16 hr
under N2. The mixture was poured into water (200 mL) and extracted with EtOAc (300 mL × 2) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (42%EtOAc in petroleum ether) , then concentrated to afford the desired product. LCMS: MS (ESI) m/z 255.2 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 2H) , 7.27 (s, 1H) , 6.34–6.44 (m, 1 H) , 6.25–6.32 (m, 1H) , 2.35–2.38 (m, 2H) , 2.25–2.30 (m, 2H) , 1.66–1.70 (m, 2H) , 1.49–1.55 (m, 2H) , 1.39–1.44 (m, 2H) .
Step B: tert-butyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate
A mixture of (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoic acid (1.70 g, 6.67 mmol) , DCC (4.13 g, 20.02 mmol, 4.05 mL) , and DMAP (815.37 mg, 6.67 mmol) in t-BuOH (8 mL) and DCM (10 mL) . The mixture was stirred at 25 ℃ for 16 hr under N2 atmosphere. The mixture was poured into water (100 mL) and extracted with DCM (100 mL × 2) . The combined organic layers were washed with brine (50 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (13%EtOAc in petroleum ether) , then concentrated to afford the desired product. LCMS: MS (ESI) m/z 255.0 [M+H-tBu] +.
Step C: tert-butyl (E) -8- [2- (4-hydroxyphenyl) pyrimidin-5-yl] oct-7-enoate
A mixture of tert-butyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate (900 mg, 2.90 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (955.86 mg, 4.34 mmol) , Pd (PPh3) 2Cl2 (203.24 mg, 289.56 umol) , Na2CO3 (920.70 mg, 8.69 mmol) in dioxane (6 mL) and H2O (1 mL) was purged with N2 for 3 times. The mixture was stirred at 90 ℃ for 16 hr under N2 atmosphere. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (23%EtOAc in petroleum ether) , then concentrated to afford the desired product. LCMS: MS (ESI) m/z 370.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H) , 8.84 (s, 2H) , 8.19–8.23 (m, 2H) , 6.85–6.88 (m, 2H) , 6.50–6.64 (m, 1H) , 6.33–6.47 (m, 1H) , 2.16–2.24 (m, 4H) , 1.44–1.53 (m, 4H) , 1.38 (s, 9H) , 1.30–1.35 (m, 2H) .
Step D: tert-butyl 8- [2- (4-hydroxyphenyl) pyrimidin-5-yl] octanoate
To a solution of tert-butyl (E) -8- [2- (4-hydroxyphenyl) pyrimidin-5-yl] oct-7-enoate (900 mg, 2.44 mmol) in EtOAc (5 mL) was added Pd/C (0.3 g, 2.44 mmol, 10%wt loading) under H2. The mixture was stirred at 25 ℃ for 2 hr under H2 (15 Psi) . The reaction mixture was filtered, washed with EtOAc (500 mL) and concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (26%EtOAc in Petroleum ether) and then purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 um) ; mobile phase: [0.1%NH3H2O EtOH] ; B%: 35%-35%, min) and dried by lyophilization to afford the
desired product. LCMS: MS (ESI) m/z 371.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H) , 8.19 (d, J = 8.8 Hz, 2H) , 6.87 (d, J = 8.8 Hz, 2H) , 4.61 (s, 1H) , 2.65 (t, J = 7.6 Hz, 2H) , 2.21 (t, J = 7.2 Hz, 2H) , 1.62–1.73 (m, 2H) , 1.57 (t, J = 14.4, 7.2 Hz, 2H) , 1.43 (s, 9H) , 1.30–1.42 (m, 6H) .
Step E: methyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate
A mixture of tert-butyl 8- [2- (4-hydroxyphenyl) pyrimidin-5-yl] octanoate (25.52 mg, 68.89 umol) , methyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- (3-methylsulfonyloxypropyl) pyridine-2-carboxylate (20 mg, 34.44 umol) and K2CO3 (23.80 mg, 172.21 umol) in DMF (3 mL) was stirred at 60 ℃ for 16 hr under N2 atmosphere. The mixture was concentrated to give a residue, which was purified by column chromatography on silica gel (4%MeOH in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 855.4 [M+H] +.
Step F: 8- [2- [4- [3- [6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -2-methoxycarbonyl-3-pyridyl] propoxy] phenyl] pyrimidin-5-yl] octanoic acid
To a solution of methyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate (30 mg, 35.09 umol) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) . The mixture was stirred at 25 ℃ for 2 hr. The mixture was concentrated to afford the desired product. LCMS: MS (ESI) m/z 799.4 [M+H] +.
Step G: methyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate
A mixture of {8- [2- [4- [3- [6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -2-methoxycarbonyl-3-pyridyl] propoxy] phenyl] pyrimidin-5-yl] octanoic acid (20 mg, 25.03 umol) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5yl) phenyl] ethyl] pyrrolidine-2-carboxamide (13.36 mg, 30.04 umol) , HATU (14.28 mg, 37.55 umol) and DIEA (9.71 mg, 75.10 umol, 13.08 uL) in DMF (3 mL) was stirred at 25℃ for 2 hr. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated to afford the desired product. LCMS: MS (ESI) m/z 1225.5 [M+H] +.
Step H: 6- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (3- (4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-
yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) phenoxy) propyl) picolinic acid
A mixture of methyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate (20.23 mg, 16.51 umol) and LiOH. H2O (40 mg, 953.29 umol) in MeOH (1 mL) , THF (1 mL) and H2O (0.5 mL) was stirred at 25 ℃ for 16 hr. The mixture was concentrated to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (FA) -ACN] ; B%: 65%-85%, 11 min) and dried by lyophilization to afford Compound 229. LCMS: MS (ESI) m/z 1211.6 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H) , 8.62 (m, 2H) , 8.55 (d, J = 6.0 Hz, 1H) , 8.21 (d, J = 8.8 Hz, 2H) , 7.91 (d, J = 7.6 Hz, 1H) , 7.81 (s, 1H) , 7.77 (d, J = 7.6 Hz, 1H) , 7.62 (s, 1H) , 7.59 (s, 1H) , 7.32–7.47 (m, 9H) , 7.05 (d, J = 8.8 Hz, 1H) , 6.93 (d, J = 8.8 Hz, 2H) , 5.03 (m, 2H) , 4.59–4.61 (m, 4H) , 4.42 (m, 1H) , 4.03 (t, J = 6.0 Hz, 2H) , 3.84–3.94 (m, 3H) , 3.74 (dd, J = 11.2, 3.6 Hz, 1H) , 3.03–3.15 (m, 5 H) , 2.61–2.68 (m, 2H) , 2.46 (m, 3H) , 2.23–2.32 (m, 2H) , 2.05–2.10 (m, 2H) , 1.89–1.99 (m, 1H) , 1.60–1.68 (m, 4H) , 1.49 (d, J = 7.2 Hz, 3H) , 1.35–1.41 (m, 4H) , 1.27–1.31 (m, 3H) , 1.02 (s, 9H) .
Example 63: Compound 173
Step A: (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoic acid
To a solution of oct-7-enoic acid (2.20 g, 15.45 mmol, 0.83 eq) and 5-bromo-2-chloro-pyrimidine (3.6 g, 18.61 mmol) in DMF (30 mL) was added Pd (OAc) 2 (208.92 mg, 930.57 umol) , Et3N (7.53 g, 74.45 mmol, 10.36 mL) and PPh3 (244.08 mg, 930.57 umol) under N2 atmosphere. The mixture was stirred at 110 ℃ for 16 hr. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =1: 1) to afford the desired product. LCMS: MS (ESI) m/z 255.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H) , 8.83 (s, 2H) , 6.64 (t, J = 16.0, 6.8 Hz, 1H) , 6.40 (d, J = 16.0 Hz, 1H) , 2.18–2.24 (m, 4H) , 1.49–1.57 (m, 2H) , 1.42–1.48 (m, 2H) , 1.30–1.35 (m, 2H) .
Step B: tert-butyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate
To a solution of (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoic acid (1 g, 3.93 mmol) in DCM (17.5 mL) was added t-BuOH (10 mL) , DCC (2.43 g, 11.78 mmol, 2.38 mL) and DMAP (479.63 mg, 3.93 mmol) . The mixture was stirred at 15℃ for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =3: 1) to afford the desired product. LCMS: MS (ESI) m/z 311.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 2H) , 6.57–6.69 (m, 1H) , 6.40 (d, J = 16.0 Hz, 1H) , 2.16–2.22 (m, 4H) , 1.49–1.53 (m, 2H) , 1.43–1.47 (m, 2H) , 1.37 (s, 9H) , 1.30–1.34 (m, 2H) .
Step C: tert-butyl (E) -8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] oct-7-enoate To a solution of (4-hydroxy-3-methyl-phenyl) boronic acid (156.44 mg, 1.03 mmol) and tert-butyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate (160 mg, 514.77 umol) in H2O (0.5 mL) and dioxane (5 mL) was added Na2CO3 (109.12 mg, 1.03 mmol) and RuPhos Pd G3 (21.53 mg, 25.74 umol) under N2 atmosphere. The mixture was stirred at 80 ℃ for 4 hr. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =3: 1) to afford the desired product. LCMS: MS (ESI) m/z 383.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H) , 8.82 (s, 2H) , 8.10–8.14 (m, 1H) , 8.02–8.06 (m, 1H) , 6.86–6.89 (m, 1H) , 6.46–6.62 (m, 1H) , 6.33–6.43 (m, 1H) , 2.21–2.25 (m, 2H) , 2.19 (s, 3H) , 2.14–2.19 (m, 2H) , 1.50–1.56 (m, 2H) , 1.44–1.48 (m, 2H) , 1.38 (s, 9H) , 1.31–1.35 (m, 2H) .
Step D: tert-butyl 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoate
To a solution of tert-butyl (E) -8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] oct-7-enoate (110 mg, 287.59 umol) in EtOAc (5 mL) was added Pd/C (50 mg, 287.59 umol, 10%wt
loading) . The mixture was stirred at 25 ℃ for 0.5 hr under H2 (15 Psi) atmosphere. The mixture was diluted with EtOAc (100 mL) , filtered via celite pad and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 385.2 [M+H] +.
Step E: 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoic acid
A mixture of tert-butyl 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoate (80 mg, 208.06 umol) in DCM (1 mL) and TFA (0.5 mL) was stirred at 25 ℃ for 16 hr. The reaction mixture was lyophilized directly to afford the desired product. LCMS: MS (ESI) m/z 329.3 [M+H] +.
Step F: (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide; hydrochloride (95.21 mg, 197.93 umol) and 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoic acid (65 mg, 197.93 umol) in DMF (1 mL) and DIEA (255.80 mg, 1.98 mmol, 344.74 uL) was added HATU (112.89 mg, 296.89 umol) . The mixture was stirred at 25 ℃ for 16 hr. The mixture was poured into water (100 mL) and extracted with EtOAc (30 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (5%Methanol in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 755.4 [M+H] +.
Step G: tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -2-methyl-phenoxy] propyl] pyridine-2-carboxylate
To a solution of tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- (3-methylsulfonyloxypropyl) pyridine-2-carboxylate (47.14 mg, 58.28 umol, 77%purity) in DMF (1.5 mL) was added K2CO3 (24.16 mg, 174.84 umol) and (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (50 mg, 58.28 umol, 88%purity) . The mixture was stirred at 60 ℃ for 16 h under N2. The residue was diluted with water (10.0 mL) and freeze-dried in vacuum to afford the desired product. LCMS: MS (ESI) m/z 1281.4 [M+H] +.
Step H: 6- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (3- (4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-
yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) -2-methylphenoxy) propyl) picolinic acid
A mixture of tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -2-methyl-phenoxy] propyl] pyridine-2-carboxylate (100 mg, 21.07 umol, 27%purity) in DCM (4 mL) and TFA (1.6 mL) . The mixture was stirred at 25 ℃ for 6 hr. The reaction mixture was adjusted to pH = 8 with Et3N solution, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (FA) -ACN] ; B%: 65%-85%, 11 min) to afford Compound 173. LCMS: MS (ESI) m/z 1225.5 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H) , 8.60 (s, 2H) , 8.53–8.57 (m, 1H) , 8.06–8.10 (m, 2H) , 7.91 (d, J = 8.0 Hz, 1H) , 7.76–7.80 (m, 2H) , 7.60 (d, J = 6.4 Hz, 1H) , 7.56 (d, J = 7.6 Hz, 1H) , 7.42–7.48 (m, 3H) , 7.40 (d, J = 3.6 Hz, 4H) , 7.32–7.37 (m, 2H) , 6.98 (d, J = 7.6 Hz, 1H) , 6.90 (d, J = 8.8 Hz, 1H) , 5.00 (m, 2H) , 4.59 (m, 4H) , 4.42 (s, 1H) , 4.04 (t, J = 6.0 Hz, 2H) , 3.85–3.93 (m, 3H) , 3.74 (dd, J = 10.8, 4.0 Hz, 1H) , 3.05–3.09 (dd, J = 10.4, 5.6 Hz, 5H) , 2.64 (t, J = 8.0 Hz, 2H) , 2.46 (m, 3H) , 2.25–2.30 (m, 2H) , 2.21 (m, 3H) , 2.09–2.13 (m, 2H) , 1.90–1.98 (m, 1H) , 1.64–1.68 (m, 2H) , 1.59–1.63 (m, 2H) , 1.48 (d, J = 7.2 Hz, 3H) , 1.36–1.38 (m, 4H) , 1.29 (d, J = 4.4 Hz, 3H) , 1.02 (s, 9H) .
Example 64: Compound 205
Step A: ethyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate
To a solution of ethyl 7- [bromo (triphenyl) -λ5-phosphanyl] heptanoate (2.38 g, 4.77 mmol) in THF (20 mL) were added K2CO3 (898.51 mg, 6.50 mmol) and 18-Crown-6 (229.11 mg, 866.80 umol) under N2 at 0 ℃. After being stirred at 0 ℃ for 10 min, 2-chloropyrimidine-5-carbaldehyde (617.78 mg, 4.33 mmol) was added. The mixture was stirred at 60 ℃ for 16 h under N2. The yellow suspension was filtered. The filter cake was washed with EtOAc (10 mL) . The filtrate was concentrated to give crude. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =5: 1) to afford the desired product. LCMS: MS (ESI) m/z 283.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.66–8.87 (m, 2H) , 6.35–6.44 (m, 1H) , 5.93–5.99 (m, 1H) , 4.01–4.06 (m, 2H) , 2.22–2.30 (m, 4H) , 1.48–1.58 (m, 2H) , 1.39–1.45 (m, 2H) , 1.26–1.34 (m, 2H) , 1.16 (t, J = 7.2 Hz, 3H) .
Step B: ethyl (E) -8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] oct-7-enoate
To a solution of ethyl (E) -8- (2-chloropyrimidin-5-yl) oct-7-enoate (175 mg, 618.89 umol) and 2-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (236.28 mg, 928.33 umol) in H2O (0.5 mL) and dioxane (5 mL) was added Na2CO3 (131.19 mg, 1.24 mmol) and RuPhos Pd G3 (25.88 mg, 30.94 umol under N2 atmosphere. The mixture was stirred at 85 ℃ for 16 hr. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate =5: 1) to afford the desired product. LCMS: MS (ESI) m/z 375.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H) , 8.75–8.88 (m, 2H) , 8.28–8.32 (m, 1H) , 8.14–8.20 (m, 1H) , 7.02–7.15 (m, 1H) , 6.32–6.48 (m, 1H) , 5.82–5.99 (m, 1H) , 4.02–4.07 (m, 2H) , 2.22–2.33 (m, 4H) , 1.49–1.59 (m, 2H) , 1.40–1.48 (m, 2H) , 1.27–1.35 (m, 2H) , 1.16 (t, J = 7.2 Hz, 3H) .
Step C: ethyl 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoate
To a solution of ethyl (E) -8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] oct-7-enoate (150 mg, 400.15 umol in EtOH (3 mL) was added PtO2 (45.43 mg, 200.07 umol) . The mixture was stirred at 25 ℃ for 0.5 hr under H2 (15 Psi) atmosphere. The mixture was diluted with EtOH (100 mL) , filtered via celite pad and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 377.2 [M+H] +.
Step D: 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoic acid
To a solution of ethyl 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoate (50 mg, 106.14 umol, 80%purity) in H2O (0.5 mL) , THF (1 mL) and MeOH (1 mL) was added LiOH. H2O (22.27 mg, 530.68 umol) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was lyophilized directly to afford the desired product. LCMS: MS (ESI) m/z 349.2 [M+H] +.
Step E: (2S, 4R) -1- [ (2S) -2- [8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide; hydrochloride (132.39 mg, 275.21 umol) and 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoic acid (80 mg, 183.47 umol, 80%purity) in DCM (3 mL) was added EDCI (70.34 mg, 366.95 umol) , HOBt (37.19 mg, 275.21 umol) and TEA (37.13 mg, 366.95 umol, 51.07 uL) . The mixture was stirred at 25 ℃ for 16 hr. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column
chromatography on silica gel (10%Methanol in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 775.3 [M+H] +.
Step F: tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate
To a solution of tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- (3-methylsulfonyloxypropyl) pyridine-2-carboxylate (56.82 mg, 91.24 umol) in DMF (1.5 mL) was added K2CO3 (26.74 mg, 193.45 umol) and (2S, 4R) -1- [ (2S) -2- [8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (50 mg, 64.48 umol) . The mixture was stirred at 60 ℃ for 16 h. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (4%Methanol in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 1301.3 [M+H] +.
Step G: 6- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (3- (2-chloro-4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) phenoxy) propyl) picolinic acid
A mixture of tert-butyl 6- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -3- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] pyridine-2-carboxylate (30 mg, 23.04 umol) in HFIP (1 mL) and TFA (0.1 mL) . The mixture was stirred at 25 ℃ for 4 hr. The reaction mixture was adjusted to pH = 8 with Et3N solution, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (FA) -ACN] ; B%: 73%-93%, 11 min) to afford Compound 205. LCMS: MS (ESI) m/z 1245.5 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H) , 8.62 (m, 2H) , 8.51–8.57 (m, 1H) , 8.29 (d, J = 2.0 Hz, 1H) , 8.19 (dd, J = 8.8, 2.0 Hz, 1H) , 7.90 (d, J = 8.0 Hz, 1H) , 7.78 (dd, J = 12.8, 9.2 Hz, 2H) , 7.58–7.62 (m, 2H) , 7.41–7.47 (m, 3H) , 7.40 (d, J = 3.2 Hz, 4H) , 7.34–7.38 (m, 2H) , 7.06 (d, J = 8.8 Hz, 1H) , 7.03 (d, J = 8.4 Hz, , 1H) , 5.01 (m, 2H) , 4.60 (m, 4H) , 4.41–4.44 (m, 1H) , 4.09 (t, J = 6.0 Hz, 2H) , 3.86–3.91 (m, 3H) , 3.70–3.77 (m, 1H) , 3.10–3.17 (m, 2H) , 3.07 (t, J = 6.0 Hz, 2H) , 2.61–2.67 (m, 2H) , 2.46 (s, 3H) , 2.25–2.31 (m, 2H) , 2.13–2.15 (m, 2H) , 1.90–2.00 (m, 1H) , 1.60–1.69 (m, 5H) , 1.48 (d, J = 7.2 Hz, 3H) , 1.36–1.38 (m, 4H) , 1.29 (m, 3H) , 1.02 (s, 9H)
Example 65: Compound 185,
Step A: ethyl 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoate
A mixture of ethyl 8- (2-chloropyrimidin-5-yl) octanoate (400 mg, 1.40 mmol) , 2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (394.57 mg, 1.69 mmol) and K3PO4 (1.19 g, 5.62 mmol) in THF (4 mL) and H2O (1 mL) was added [2- (2-aminophenyl) phenyl] palladium (1+) ; bis (1-adamantyl) -butyl-phosphane; methanesulfonate (153.44 mg, 210.69 umol) . The mixture was stirred at 60 ℃ for 16 hr. The mixture was poured into water (200 mL) and extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (19%EtOAc in petroleum ether) , then concentrated to afford the desired product. LCMS: MS (ESI) m/z 357.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H) , 8.64 (m, 2H) , 8.11 (d, J = 1.6 Hz, 1H) , 8.03 (dd, J = 8.4, 2.0 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 4.00 -4.06 (m, 2H) , 2.57 (t, J = 7.6 Hz, 2H) , 2.26 (t, J = 7.6 Hz, 2H) , 2.19 (m, 3H) , 1.54–1.63 (m, 2H) , 1.46–1.53 (m, 2H) , 1.14–1.18 (m, 3H) , 1.07 (s, 6H) .
Step B: 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoic acid
To a solution of ethyl 8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoate (280 mg, 785.51 umol) in MeOH (1 mL) , THF (1 mL) , H2O (0.5 mL) was added LiOH. H2O (164.81 mg, 3.93 mmol) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was acidified with 2 M HCl to pH = 6 and concentrated to afford the desired product. LCMS: MS (ESI) m/z 329.2 [M+H] +.
Step C: (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
A mixture of {8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoic acid (280 mg, 852.61 umol) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (398.01 mg, 895.24 umol) , TEA (431.37 mg, 4.26 mmol, 593.36 uL) , HOBt (172.81 mg, 1.28 mmol) and EDCI (326.89 mg, 1.71 mmol) in DMF (5 mL) was stirred at 25℃ for 3 hr. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (6%MeOH in Dichloromethane) , then concentrated to afford the desired product. LCMS: MS (ESI) m/z 755.4 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -2-methyl-phenoxy] propyl] thiazole-4-carboxylate
A mixture of (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-3-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (20 mg, 26.49 umol) , methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate (20 mg, 34.09 umol) , Cs2CO3 (4.32 mg, 13.25 umol) and K2CO3 (7.32 mg, 52.98 umol) in DMF (2 mL) was stirred at 60 ℃ for 16 hr. The mixture was poured into water (100 mL) and extracted with DCM (100 mL × 2) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (5%MeOH in Dichloromethane) and concentrated to afford the desired product. LCMS: MS (ESI) m/z 1245.8 [M+H] +.
Step E: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) -2-methylphenoxy) propyl) thiazole-4-carboxylic acid
A mixture of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -2-methyl-phenoxy] propyl] thiazole-4-carboxylate (150 mg, 120.43 umol) , LiOH. H2O (25.27 mg, 602.13 umol) in THF (1 mL) , MeOH (1 mL) , H2O (0.5 mL) was stirred at 25 ℃ for 16 hr. The reaction mixture was acidified with HCl/dioxane (4 M) to pH = 6, and concentrated to give a residue, which was purified by prep-HPLC (column: C18-1 150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 24%-64%, 9 min) and dried by lyophilization to afford Compound 185. LCMS: MS (ESI) m/z 1231.3 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H) , 8.61 (m, 2H) , 8.06 (m, 2H) , 7.92 (d, J = 8.4 Hz, 1H) , 7.77 (d, J = 8.0 Hz, 2H) , 7.59 (d, J = 8.0 Hz, 1H) , 7.43–7.47 (m, 2H) , 7.38–7.42 (m, 5H) , 7.31–7.38 (m, 3H) , 6.91 (d, J = 8.0 Hz, 1H) , 4.60–4.61 (m, 3H) , 4.40–4.44 (m, 1H) , 4.07 (t, J = 6.4 Hz, 2H) , 3.87 (d, J = 12.0 Hz, 1H) , 3.82 (t, J = 5.6 Hz, 2H) , 3.71–3.77 (m, 1H) , 3.02–3.07 (m, 2H) , 2.62–2.67 (m, 2H) , 2.47 (m, 3H) , 2.25–2.30 (m, 2H) , 2.22 (s, 3H) , 2.11–2.18 (m, 3H) , 1.90–1.98 (m, 1H) , 1.57–1.71 (m, 5H) , 1.49 (d, J = 6.8 Hz, 3H) , 1.27–1.41 (m, 10H) , 1.19 (s, 1H) , 1.03 (s, 9H) .
Example 66: Compound 184
Step A: methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate
To a solution of tert-butyl nitrite (5.94 g, 57.57 mmol) in MeCN (140 mL) was added CuCl2 (6.19 g, 46.06 mmol) under N2. The mixture was stirred at 25 ℃ for 10 min. To the mixture was added methyl 2-amino-5- (3-hydroxypropyl) thiazole-4-carboxylate (8.30 g, 38.38 mmol) . The
mixture was stirred at 25 ℃ for 2 h. The mixture was diluted with water (150 mL) , extracted with EtOAc (100 mL) twice. The organic layer was washed with brine (150 mL) , concentrated to give crude. The crude was purified by Combi-flash (silica gel, 0~10%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 258.1 [M+Na] +. 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H) , 3.67 (t, J = 6.0 Hz, 2H) , 3.34 (t, J = 7.2 Hz, 2H) , 1.89-1.99 (m, 2H) .
Step B: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-hydroxypropyl) thiazole-4-carboxylate
To a solution of N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (3.00 g, 8.67 mmol, HCl salt) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (2.25 g, 9.54 mmol) in DMF (45 mL) was added Cs2CO3 (12.72 g, 39.03 mmol) . The mixture was stirred at 70 ℃ for 2 h under N2. The mixture was stirred at 70 ℃ for another 4 h under N2. The yellow suspension was cooled down to 25 ℃, and then filtered. The filtrate was concentrated to give crude (7.20 g) as a yellow gum. The crude was purified by Combi-flash (silica gel, 0~12%MeOH in DCM) to give product (2.24 g) as a yellow gum. The impure was purified by Combi-flash (silica gel, 0~12%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 509.1 [M+H] +.
Step C: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-hydroxypropyl) thiazole-4-carboxylate (1.06 g, 2.08 mmol) and methylsulfonyl methanesulfonate (1.09 g, 6.27 mmol) in DCM (10 mL) was added Et3N (742 mg, 7.34 mmol) at 0 ℃ and the solution was stirred at 20 ℃ for 16 h. The mixture was diluted with water (15 mL) , extracted with DCM (10 mL x3) . The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude. The crude product was purified by column chromatography (SiO2, Methanol: Dichloromethane = 0%to 3%) to afford the desired product. LCMS: MS (ESI) m/z 587.1 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 7.81-7.89 (m, 1H) , 7.60 (d, J = 6.8 Hz, 1H) , 7.39-7.47 (m, 1H) , 7.30-7.37 (m, 3H) , 7.23-7.27 (m, 1H) , 4.91 (s, 2H) , 4.27 (t, J = 6.4 Hz, 2H) , 3.85 (t, J = 6.0 Hz, 2H) , 3.82 (s, 3H) , 3.21 (t, J = 8.0 Hz, 2H) , 3.05 (t, J = 8.0 Hz, 2H) , 2.99 (s, 3H) , 2.06-2.14 (m, 2H) .
Step D: ethyl 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoate
To a solution of ethyl 8- (2-chloropyrimidin-5-yl) octanoate (400 mg, 1.40 mmol) and 2-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (536.24 mg, 2.11 mmol) in H2O (1 mL) and THF (4 mL) was added K3PO4 (1.19 g, 5.62 mmol) and [2- (2-aminophenyl) phenyl] palladium (1+) ; bis (1-adamantyl) -butyl-phosphane; methanesulfonate (153.44 mg, 210.69 umol) . The mixture was stirred at 60 ℃ for 16 hr under N2. The mixture
was poured into water (50 mL × 2) and extracted with EtOAc (100 mL) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (14%Ethyl acetate in Petroleum ether) to afford the desired product. LCMS: MS (ESI) m/z 377.2 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.59 (m, 2H) , 8.45 (d, J = 2.0 Hz, 1H) , 8.28 (dd, J = 8.8, 2.0 Hz, 1H) , 7.12 (d, J = 8.8 Hz, 1H) , 5.81 (s, 1H) , 4.10–4.16 (m, 2H) , 2.62 (t, J = 7.6 Hz, 2H) , 2.30 (t, J = 7.6 Hz, 2H) , 1.61–1.66 (m, 3H) , 1.34–1.38 (m, 4H) , 1.24–1.29 (m, 6H) .
Step E: 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoic acid
To a solution of ethyl 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoate (200 mg, 424.54 umol, 80%purity) in H2O (1 mL) , THF (2 mL) and MeOH (2 mL) was added LiOH. H2O (89.07 mg, 2.12 mmol) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was added EtOAc (2 mL) , acidified with 4 M HCl/dioxane to pH = 6, concentrated to afford the desired product. LCMS: MS (ESI) m/z 349.2 [M+H] +.
Step F: (2S, 4R) -1- [ (2S) -2- [8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide; hydrochloride (358.56 mg, 745.36 umol) and 8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoic acid (200 mg, 573.36 umol) in DMF (4 mL) was added EDCI (219.83 mg, 1.15 mmol) , HOBt (116.21 mg, 860.03 umol) and TEA (290.09 mg, 2.87 mmol, 399.02 uL) . The mixture was stirred at 40 ℃ for 6 h. The mixture was poured into water (50 mL × 2) and extracted with EtOAc (100 mL × 2) . The combined organic layers were washed with brine (50 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (6%Methanol in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 775.3 [M+H] +.
Step G: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate (10 mg, 17.04 umol) and (2S, 4R) -1- [ (2S) -2- [8- [2- (3-chloro-4-hydroxy-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (15 mg, 19.34 umol) in DMF (1.5 mL) was added K2CO3 (5.35 mg, 38.69 umol)
and Cs2CO3 (3.15 mg, 9.67 umol) . The mixture was stirred at 60 ℃ for 16 h. The mixture was poured into water (50 mL × 2) and extracted with EtOAc (100 mL × 2) . The combined organic layers were washed with brine (50 mL × 2) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (7%Methanol in Dichloromethane) to afford the desired product. LCMS: MS (ESI) m/z 1265.2 [M+H] +.
Step H: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] phenoxy] propyl] thiazole-4-carboxylate (260 mg, 205.37 umol) in H2O (1 mL) , THF (2 mL) and MeOH (2 mL) was added LiOH. H2O (43.09 mg, 1.03 mmol) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was added EtOAc (2 mL) , acidified with aq. HCl (1M) to pH = 6, was filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 34%-54%, 8 min) to afford Compound 184. LCMS: MS (ESI) m/z 1251.3 [M+H] +. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H) , 8.62 (m, 2H) , 8.32 (d, J = 1.6 Hz, 1H) , 8.18–8.23 (m, 1H) , 7.92 (d, J = 8.0 Hz, 1H) , 7.76 (d, J = 8.0 Hz, 1H) , 7.58 (d, J = 6.8 Hz, 1H) , 7.42–7.47 (m, 2H) , 7.41 (m, 4H) , 7.38 (d, J = 3.2 Hz, 2H) , 7.31–7.36 (m, 2H) , 7.09 (d, J = 8.8 Hz, 1H) , 5.16–5.20 (m, 1H) , 5.00 (m, 2H) , 4.60 (m, 4H) , 4.41–4.44 (m, 1H) , 4.13 (t, J = 6.0 Hz, 2H) , 3.87 (d, J = 11.2 Hz, 1H) , 3.81 (t, J = 6.0 Hz, 2H) , 3.74 (dd, J = 11.2, 3.2 Hz, 1H) , 3.04 (t, J = 5.2 Hz, 2H) , 2.63–2.69 (m, 2H) , 2.47 (m, 3H) , 2.24–2.30 (m, 2H) , 2.14–2.19 (m, 3H) , 1.91–1.99 (m, 1H) , 1.58–1.67 (m, 4H) , 1.49 (m, 3H) , 1.30–1.40 (m, 8H) , 1.03 (s, 9H) .
Example 67: Compound 232
Step A: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (7-tert-butoxy-1-methyl-7-oxo-heptyl) -3-fluoro-2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a mixture of tert-butyl 7- [5-fluoro-6- (4-hydroxyphenyl) -3-pyridyl] octanoate (90 mg, 0.232 mmol) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate (177 mg, 0.302 mmol) in DMF (2 mL) was added K2CO3 (65 mg, 0.470 mmol) , Cs2CO3 (38 mg, 0.117 mmol) under N2 and the solution was stirred at 60 ℃ for 16 h. The mixture was filtered and washed with DMF (5 mL) . The filtrate was concentrated under reduced pressure to give crude as light brown oil. The crude was purified by Combi Flash (silica gel 12 g, 35 mL/min, 30-60%ethyl acetate in petroleum ether) to afford the desired product. LCMS: MS (ESI) m/z 878.6 [M+H] +.
Step B: 7- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -5-fluoro-3-pyridyl] octanoic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (7-tert-butoxy-1-methyl-7-oxo-heptyl) -3-fluoro-2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (100 mg, 0.119 mmol) in HCOOH (2 mL) under N2 and the solution was stirred at 20 ℃ for 16 h. The crude was dissolved in DCM (10 mL) and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 822.5 [M+H] +.
Step C: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-fluoro-5- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -1-methyl-7-oxo-heptyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a compound of 7- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -5-fluoro-3-pyridyl] octanoic acid (100 mg, 0.122 mmol) in DMF (1 mL) was added HATU (56 mg, 0.147 mmol) under N2 and the solution was stirred at 20 ℃ for 1 h. (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (81 mg, 0.182 mmol) was added the solution and the solution was stirred at 20 ℃ for 0.5 h. DIEA (63 mg, 0.487 mmol) was added the solution and the solution was stirred at 20 ℃ for 15 h. The solution was diluted with water (3 mL) and extracted with EtOAc (3 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 1248.7 [M+H] +.
Step D: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctan-2-yl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl]-5- [3- [4- [3-fluoro-5- [7- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -1-methyl-7-oxo-heptyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (195 mg, 0.156 mmol) in THF (2 mL) , EtOH (2 mL) , H2O (1 mL) was added LiOH. H2O (28 mg, 0.667 mmol) at 20 ℃ under N2 and the solution was stirred at 20 ℃ for 24 h. The solution was acidified with HCl (2 M) until pH~7. The solution was concentrated under reduced pressure to give crude as yellow oil. The crude was diluted with MeOH (2.0 mL) , DMF (1.5 mL) and purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 65%-85%, 9
min) . The desired fractions was concentrated under reduced pressure to afford Compound 232. LCMS: MS (ESI) m/z 618.0 [M/2+H] +. 1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H) , 8.28-8.41 (m, 1H) , 7.82-7.91 (m, 3H) , 7.64 (m, 2H) , 7.28-7.40 (m, 11H) , 6.83-7.00 (m, 2H) , 6.30-6.46 (m, 1H) , 5.00-5.10 (m, 1H) , 4.89 (m, 2H) , 4.63-4.75 (m, 1H) , 4.45-4.62 (m, 2H) , 3.70-4.12 (m, 4H) , 3.57 (d, J = 7.2 Hz, 1H) , 3.30 (m, 2H) , 3.01 (m, 2H) , 2.79 (m, 2H) , 2.51 (m, 6H) , 2.07-2.20 (m, 6H) , 1.52-1.60 (m, 3H) , 1.41-1.48 (m, 3H) , 1.22-1.29 (m, 6H) , 1.04 (s, 9H) .
Example 68: Compound 233
Step A: tert-butyl 7-bromoheptanoate
A solution of 7-bromoheptanoic acid (10.0 g, 47.8 mmol) in DCM (100 mL) was added TFAA (20.1 g, 95.7 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 2 h. Then t-BuOH (10.6 g, 143 mmol) was added to the mixture and the mixture was stirred at 25 ℃ for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (50 mL *2) . The combined organic layer were washed with brine (50 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to afford the desired product. 1H NMR (400MHz, CDCl3) δ 3.41 (t, J =6.8 Hz, 2H) , 2.22 (t, J =7.6 Hz, 2H) , 1.83-1.90 (m, 2H) , 1.56-1.65 (m, 2H) , 1.38-1.51 (m, 11H) , 1.29-1.38 (m, 2H) .
Step B: tert-butyl 7- [bromo (triphenyl) -λ5-phosphanyl] heptanoate
To a solution of tert-butyl 7-bromoheptanoate (12.5 g, 47.1 mmol) in MeCN (150 mL) was added PPh3 (12.4 g, 47.1 mmol) at 25 ℃. The mixture was stirred at 80 ℃ for 16 h. The reaction was concentrated to give a crude product. The crude product was triturated with PE (50 mL *2) at 25 ℃ for 5 min to afford the desired product. 1H NMR (400MHz, DMSO-d6) δ
11.99 (s, 1H) , 7.87-7.95 (m, 5H) , 7.78-7.84 (m, 10H) , 3.47-3.66 (m, 4H) , 2.09-2.24 (m, 4H) , 1.50-1.55 (m, 2H) , 1.37 (s, 9H) , 1.26-1.28 (m, 2H) .
Step C: tert-butyl (E) -8- (6-chloro-5-fluoro-3-pyridyl) oct-7-enoate
A solution of tert-butyl 7- [bromo (triphenyl) -λ5-phosphanyl] heptanoate (1.59 g, 3.01 mmol) in THF (15 mL) were added K2CO3 (519 mg, 3.76 mmol) and 18-crown-6 (133 mg, 0.501 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 10 min. Then 6-chloro-5-fluoro-pyridine-3-carbaldehyde (400 mg, 2.51 mmol) was added to the mixture and the mixture was stirred at 60 ℃ for 16 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (20 mL *2) . The combined organic were washed with brine (15 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (12.0 g Silica Flash Column, EtOAc /PE with EtOAc from 0~15%, flow rate = 35 mL/min, 254 nm) to afford the desired product. 1H NMR (400MHz, CDCl3) δ 8.08-8.16 (m, 1H) , 7.33-7.49 (m, 1H) , 6.31-6.36 (m, 1H) , 5.83-6.31 (m, 1H) , 2.19-2.32 (m, 4H) , 1.60-1.67 (m, 1H) , 1.50-1.56 (m, 1H) , 1.43-1.50 (m, 11H) , 1.33-1.41 (m, 2H) .
Step D: tert-butyl (E) -8- [6- (3-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] oct-7-enoate
A solution of tert-butyl (E) -8- (6-chloro-5-fluoro-3-pyridyl) oct-7-enoate (250 mg, 0.763 mmol) and (3-chloro-4-hydroxy-phenyl) boronic acid (131 mg, 0.763 mmol) in dioxane (4 mL) and H2O (1 mL) were added Pd (dppf) Cl2 (84 mg, 0.114 mmol) and K3PO4 (648 mg, 3.05 mmol) at 25 ℃. The mixture was stirred at 80 ℃ for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (25 mL *2) . The combined organic layer were washed with brine (15 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (12.0 g Silica Flash Column, 0~30%EtOAc in PE, flow rate = 35 mL/min, 254 nm) to afford the desired product. LCMS: MS (ESI) m/z 420.1 [M+H] +.
Step E: tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] octanoate
A solution of tert-butyl (E) -8- [6- (3-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] oct-7-enoate (177 mg, 0.421 mmol) in EtOAc (2 mL) was added Pd/C (50 mg, 0.422 mmol, 5%loaded) at 25 ℃. The mixture was stirred at 25 ℃ for 1 h under H2 at 15 psi. The reaction mixture was filtered and the filtrate was concentrated to afford the desired product. LCMS: MS (ESI) m/z 422.1 [M+H] +.
Step F: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -2-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a solution of tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] octanoate (100 mg, 0.237 mmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (56 mg, 0.237 mmol) in THF (1 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (172 mg, 0.713
mmol) under N2. The mixture was stirred at 80 ℃ for 2 h. The mixture was concentrated to give crude. The crude was purified by Combi-flash (silica gel, 5~30%EtOAc in PE) to afford the desired product. LCMS: MS (ESI) m/z 639.1 [M+H] +.
Step G: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -2-chloro-phenoxy] propyl] thiazole-4-carboxylate
To a solution of N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (50 mg, 0.145 umol, 1 eq, HCl) and methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -2-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (93 mg, 0.145 mmol) in dioxane (1 mL) were added SPhos (30 mg, 73.08 umol) , Pd2 (dba) 3 (66 mg, 72.07 umol) , t-BuOK (33 mg, 294.09 umol) under N2. The mixture was stirred at 90 ℃ for 3 h. The dark mixture was concentrated to give crude. The crude was purified by Combi-flash (silica gel, 0~10%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 912.4 [M+H] +. 1H NMR (400MHz, CDCl3) δ8.30 (s, 1H) , 8.02 (s, 1H) , 7.79-7.88 (m, 2H) , 7.28-7.48 (m, 4H) , 7.21-7.25 (m, 1H) , 7.06-7.16 (m, 1H) , 6.95 (d, J = 8.8 Hz, 1H) , 6.60 (d, J = 8.0 Hz, 1H) , 4.91 (s, 1H) , 4.11 (t, J = 7.2 Hz, 1H) , 3.78-3.91 (m, 2H) , 3.58-3.74 (m, 5H) , 3.48 (m, 2H) , 3.27-3.37 (m, 1H) , 2.93-3.06 (m, 1H) , 2.65 (t, J = 7.6 Hz, 2H) , 2.21 (t, J = 7.6 Hz, 2H) , 1.52-1.71 (m, 8H) , 1.57 (s, 9H) , 1.29-1.40 (m, 4H) .
Step H: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-chloro-phenyl] -5-fluoro-3-pyridyl] octanoic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -2-chloro-phenoxy] propyl] thiazole-4-carboxylate (90 mg, 0.099 mmol) in formic acid (3 mL) was stirred at 25 ℃ for 1 h. The yellow solution was concentrated to afford the desired product. LCMS: MS (ESI) m/z 856.4 [M+H] +.
Step I: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
A solution of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-chloro-phenyl] -5-fluoro-3-pyridyl] octanoic acid (90 mg, 0.105 mmol) in DMF (2 mL) was added HATU (52 mg, 0.136 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 0.5 h. Then (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (61 mg, 0.137 mmol) and DIEA (54 mg, 0.420 mmol) were added to the mixture and the mixture was
stirred at 25 ℃ for 16 h. The reaction mixture was diluted with aqueous NH4Cl (25 mL) and extracted with EtOAc (15 mL *2) . The combined organic layer were washed with brine (20 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (4.0 g Silica Flash Column, MeOH /DCM with MeOH from 0~8%, flow rate = 30 mL/min, 254 nm) to afford the desired product. LCMS: MS (ESI) m/z 1282.8 [M+H] +.
Step J: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (61 mg, 0.048 mmol) in MeOH (1 mL) and H2O (0.2 mL) was added LiOH. H2O (10 mg, 0.238 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h. The colorless solution was treated with 1N HCl aq. until pH to 7. The suspension was concentrated to give crude. The crude was purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 73%-93%, 9 min) . The fraction was concentrated to remove most of the solvent, and the remaining was dried by lyophilization to afford Compound 233. LCMS: MS (ESI) m/z 1268.5 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ 8.86-9.10 (m, 1H) , 8.24-8.49 (m, 2H) , 7.89-8.09 (m, 2H) , 7.73-7.89 (m, 3H) , 7.60-7.73 (m, 2H) , 7.16-7.56 (m, 9H) , 5.01-5.21 (m, 1H) , 4.74-5.01 (m, 3H) , 4.46-4.61 (m, 1H) , 4.37-4.46 (m, 1H) , 4.25-4.36 (m, 1H) , 4.09-4.22 (m, 2H) , 3.57-3.75 (m, 2H) , 3.10-3.22 (m, 4H) , 2.63-2.93 (m, 6H) , 2.40-2.44 (m, 3H) , 1.96-2.12 (m, 3H) , 1.72-1.86 (m, 1H) , 1.54-1.68 (m, 2H) , 1.42-1.54 (m, 2H) , 1.31-1.41 (m, 4H) , 1.16-1.31 (m, 6H) , 0.92 (s, 9H) .
Example 69: Compound 234
Step A: tert-butyl 8- [5-fluoro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] oct-7-enoate
To a mixture of tert-butyl 8- (6-chloro-5-fluoro-3-pyridyl) oct-7-enoate (300 mg, 0.915 mmol) and (4-hydroxy-2-methyl-phenyl) boronic acid (209 mg, 1.38 mmol) in H2O (0.6 mL) , dioxane (2.4 mL) was added Pd (dppf) Cl2 (101 mg, 0.138 mol) , K3PO4 (777 mg, 3.66 mmol) under N2 and the solution was stirred at 80 C for 16 h. The solution was diluted with water (5 mL) and extracted with EtOAc (5 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude as black brown oil. The crude was purified by Combi-flash (silica gel 12 g, 30 mL/min, 0-30 %ethyl acetate in petroleum ether) to afford the desired product.
1H NMR (400MHz, CDCl3) δ 8.38-8.46 (m, 1H) , 7.38-7.50 (m, 1H) , 7.18-7.25 (m, 1H) , 6.65-6.73 (m, 2H) , 6.36-6.42 (m, 1H) , 5.81-5.93 (m, 1H) , 2.27-2.41 (m, 2H) , 2.18-2.25 (m, 5H) , 1.58-1.63 (m, 2H) , 1.49-1.55 (m, 2H) , 1.44-1.47 (s, 9H) , 1.36-1.42 (m, 2H) .
Step B: tert-butyl 8- [5-fluoro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] octanoate
To a compound of tert-butyl 8- [5-fluoro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] oct-7-enoate (300 mg, 0.751 mmol) in MeOH (8 mL) was added Pd/C (50 mg, 10%purity) under H2 (15 psi) for three times and the mixture was stirred at 20 ℃ for 1 h. The mixture was filtered and washed with MeOH (15 mL) . The filtrate was concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 402.2 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.32 (s, 1H) , 7.32 (d, J = 8.8 Hz, 1H) , 7.18 (d, J = 7.6 Hz, 1H) , 6.63-6.69 (m, 2H) , 2.68 (t, J = 8.0 Hz, 2H) , 2.22 (t, J = 7.2 Hz, 2H) , 2.17 (m, 3H) , 1.64-1.73 (m, 4H) , 1.57-1.62 (m, 2H) , 1.45 (s, 9H) , 1.35-1.40 (m, 4H) .
Step C: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-methyl-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a mixture of tert-butyl 8- [5-fluoro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] octanoate (300 mg, 0.747 mmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (230 mg, 0.976 mmol) in THF (3.2 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (540 mg, 2.24 mmol) under N2 and the solution was stirred at 80 ℃ for 22 h. The mixture was concentrated under reduced pressure to give crude as brown oil, and the crude product was purified by column chromatography (SiO2, ethyl acetate in petroleum ether= 0%to 59%) to afford the desired product. LCMS: MS (ESI) m/z 619.6 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.36 (s, 1H) , 7.29-7.38 (m, 2H) , 6.79-6.84 (m, 2H) , 4.07 (t, J = 6.0 Hz, 2H) , 3.93 (m, 3H) , 3.43 (t, J = 7.6 Hz, 2H) , 2.70 (t, J = 7.2 Hz, 2H) , 2.26 (m, 3H) , 2.19-2.24 (m, 4H) , 1.66-1.72 (m, 2H) , 1.60-1.63 (m, 2H) , 1.45 (s, 9H) , 1.34-1.41 (m, 6H) .
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate
To a mixture of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-methyl-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (306 mg, 0.494 mmol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (188 mg, 0.544 mmol, HCl) in dioxane (3 mL) was added Pd2 (dba) 3 (226.3 mg, 0.247 mmol, ) , tBuOK (139 mg, 1.24 mmol) , SPhos (101.4 mg, 0.247 mmol) under N2 and the solution was stirred at 90 ℃ for 3 h. The mixture was concentrated under reduced pressure to give crude as brown oil and the crude was purified by Combi-flash (silica gel 12 g, 25 mL/min, 0-7 %dichloromethane in methanol, 254, 280 nm, UV) to afford the desired product. LCMS: MS (ESI) m/z 892.5 [M+H] +.
Step E: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-methyl-phenyl] -5-fluoro-3-pyridyl] octanoic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate (177 mg, 0.198 mmol) in HCOOH (3 mL) under N2 and the solution was stirred at 25 ℃ for 16 h. The crude was dissolved in DCM (15 mL) and concentrated under reduced pressure to remove residual FA for two times to afford the desired product. LCMS: MS (ESI) m/z 836.5 [M+H] +.
Step F: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) -3-methylphenoxy) propyl) thiazole-4-carboxylate
To a mixture of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-methyl-phenyl] -5-fluoro-3-pyridyl] octanoic acid (175 mg, 0.113 mmol, 54%purity) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (71 mg, 0.160 mmol) in DMF (2 mL) was added HOBt (23 mg, 0.170 mmol) , EDCI (44 mg, 0.230 mmol) , DIEA (60 mg, 0.464 mmol) under N2 and the solution was stirred at 25 ℃ for 4 h. The solution was diluted with water (4 mL) and extracted with EtOAc (4 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude as brown oil. The crude was purified by Combi-flash (silica gel 4 g, 20 mL/min, 0-5 %dichloromethane in methanol) to afford the desired product. LCMS: MS (ESI) m/z 632.2 [M/2+H] +.
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-
yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) -3-methylphenoxy) propyl) thiazole-4-carboxylic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate (91 mg, 0.072 mmol) in THF (1 mL) , EtOH (1 mL) , H2O (0.5 mL) was added LiOH. H2O (22 mg, 0.524 mmol) under N2 and the solution was stirred at 25 ℃ for 16 h. The solution was diluted with EtOH (2.0 mL) , and acidified with HCl (2 M) until pH~7. The solution was concentrated under reduced pressure to give crude as yellow oil. The crude was diluted with MeOH (1.0 mL) , DMF (0.5 mL) and purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 65%-85%, 9 min) . The desired fractions was lyophilized under reduced pressure to afford Compound 234. LCMS: MS (ESI) m/z 1248.4 [M+H] +. 19F NMR (400MHz, CD3Cl) : δ = -122.562. 1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H) , 8.34 (s, 1H) , 7.85 (d, J = 8.0 Hz, 1H) , 7.61-7.72 (m, 2H) , 7.45-7.51 (m, 1H) , 7.27-7.42 (m, 10H) , 7.21 (d, J = 8.0 Hz, 1H) , 6.67-6.79 (m, 2H) , 6.31 (d, J = 8.4 Hz, 1H) , 5.28-5.53 (m, 2H) , 5.07 (t, J = 7.2 Hz, 1H) , 4.92 (m, 2H) , 4.71 (brs, 1H) , 4.59 (d, J = 8.4 Hz, 1H) , 4.48 (s, 1H) , 4.10 (d, J = 12.0 Hz, 1H) , 3.98 (t, J = 6.0 Hz, 2H) , 3.76-3.84 (m, 2H) , 3.57 (d, J = 9.6 Hz, 1H) , 3.29 (t, J = 6.8 Hz, 2H) , 3.01-3.07 (m, 2H) , 2.66 (t, J = 7.2 Hz, 2H) , 2.43-2.54 (m, 4H) , 2.21-2.24 (m, 2H) , 2.17 (m, 3H) , 2.12-2.15 (m, 2H) , 2.00-2.03 (m, 2H) , 1.61-1.68 (m, 4H) , 1.46 (d, J = 6.8 Hz, 2H) , 1.31-1.34 (m, 5H) , 1.04 (s, 9H) .
Example 70: Compound 235
Step A: tert-butyl (E) -8- [5-chloro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] oct-7-enoate
To a solution of tert-butyl (E) -8- (5, 6-dichloro-3-pyridyl) oct-7-enoate (200 mg, 0.580 mmol) in dioxane (2 mL) and H2O (0.5 mL) was added (4-hydroxy-2-methyl-phenyl) boronic acid (97 mg, 0.640 mmol) , K3PO4 (493 mg, 2.32 mmol) , and Pd (dppf) Cl2 (64 mg, 0.09 mmol) at 25 ℃. The mixture was stirred at 80 ℃ for 16 h under N2. The mixture was added (4-hydroxy-2-methyl-phenyl) boronic acid (27 mg, 0.17 mmol) and Pd (dppf) Cl2 (85 mg, 0.12 mmol) and stirred at 80 ℃ for 2 hr under N2. The mixture was diluted with (20 mL) and extracted with EtOAc (30 mL *3) . The organic phase was wash with rine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~35%Ethyl acetate/Petroleum ethergradient @35 mL/min) to afford the desired product. LCMS: MS (ESI) m/z 416.4 [M+H] +.
Step B: tert-butyl 8- [5-chloro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] octanoate
To a solution of tert-butyl (E) -8- [5-chloro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] oct-7-enoate (120 mg, 0.289 mmol) in EtOAc (1 mL) was added Pd/C (50 mg, 0.289 mmol, 10%purity) at 25 ℃. The mixture was stirred at 25 ℃ for 1 h under H2 at 15 psi. The mixture was filtered and concentrated reduced to afford the desired product. LCMS: MS (ESI) m/z 418.4 [M+H] +.
Step C: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-methyl-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a solution of tert-butyl 8- [5-chloro-6- (4-hydroxy-2-methyl-phenyl) -3-pyridyl] octanoate (120 mg, 287 umol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (68 mg, 288
umol) in THF (1.2 mL) was dded 2- (tributyl-λ5-phosphanylidene) acetonitrile (277 mg, 1.15 mmol) under N2. The mixture was stirred at 80 ℃ for 16 h. The solution was concentrated to give a residue. The residue was purified by Combi-flash (silica gel, 5~30%EtOAc in PE) to afford the desired product. LCMS: MS (ESI) m/z 635.1 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-methyl-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (115 mg, 181 umol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (63 mg, 182 umol, HCl salt) in dioxane (1.2 mL) were added Pd2 (dba) 3 (82 mg, 89 umol) , SPhos (37 mg, 90 umol) , t-BuOK (51 mg, 454 umol) under N2. The mixture was stirred at 90 ℃ for 3 h. TThe mixture was diluted with EtOAc (6 mL) , and filtered. The filtrate was concentrated to give crude (305 mg) as a yellow gum. The crude was purified by Combi-flash (silica gel, 0~4%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 908.5 [M+H] +.
Step E: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-methyl-phenyl] -5-chloro-3-pyridyl] octanoic acid
A solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate (80 mg, 0.0881 mmol) in HCOOH (1 mL) at 25 ℃. The mixture was stirred at 25 ℃ for 2 h. The reaction was concentrated to afford the desired product. LCMS: MS (ESI) m/z 852.2 [M+H] +.
Step F: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-chloro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate
A solution of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-methyl-phenyl] -5-chloro-3-pyridyl] octanoic acid (70 mg, 0.0821 mmol) , (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (44 mg, 0.0985 mmol) and HOBt (17 mg, 0.123 mmol) , EDCI (325 mg, 0.164 mmol) in DMF (1 mL) was added DIEA (43 mg, 0.328 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL *2) . The combined organic
layer were washed with brine (15 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to afford the desired product. LCMS: MS (ESI) m/z 640.5 [1/2 M+H] +
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3-chloro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) -3-methylphenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-chloro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate (100 mg, 0.0782 mmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.4 mL) was added LiOH. H2O (16 mg, 0.391 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h. The colorless solution was treated with 1N HCl aq. until pH to 7. The suspension was concentrated to give crude. The crude was purified by prep-HPLC. (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 45%-65%, 9 min) . The fraction was concentrated to remove most of the solvent, and the remaining was dried by lyophilization to afford Compound 235. LCMS: MS (ESI) m/z 1264.4 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.35-8.44 (m, 2H) , 7.93-7.99 (m, 1H) , 7.84-7.89 (m, 1H) , 7.77-7.83 (m, 1H) , 7.67-7.77 (m, 2H) , 7.32-7.51 (m, 8H) , 7.25-7.32 (m, 1H) , 7.03-7.11 (m, 1H) , 6.80-6.88 (m, 1H) , 4.82-4.99 (m, 3H) , 4.49-4.56 (m, 1H) , 4.38-4.46 (m, 1H) , 4.25-4.31 (m, 1H) , 3.99-4.04 (m, 2H) , 3.65-3.81 (m, 2H) , 3.58-3.63 (m, 1H) , 3.14-3.22 (m, 1H) , 2.99-3.07 (m, 3H) , 2.60-2.72 (m, 2H) , 2.42-2.47 (m, 6H) , 2.23-2.39 (m, 2H) , 2.08-2.17 (m, 1H) , 1.97-2.02 (m, 5H) , 1.72-1.84 (m, 1H) , 1.58-1.67 (m, 2H) , 1.43-1.51 (m, 2H) , 1.34-1.39 (m, 3H) , 1.28-1.32 (m, 4H) , 1.18-1.24 (m, 2H) , 0.92 (s, 9H) .
Example 71: Compound 236
Step A: 3-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol
To a mixture of 4-bromo-3-chloro-phenol (800 mg, 3.86 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1.18 g, 4.63 mmol) in dioxane (10 mL) was added KOAc (946 mg, 9.64 mmol) , Pd (dppf) Cl2 (282 mg, 0.386 mmol) under N2 and the solution was stirred at 100 ℃ for 3 h. The solution was diluted with water (15 mL) and filtered. The filtrate was extracted with EtOAc (15 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude as brown oil. The crude was purified by Combi-flash (silica gel 40 g, 40 mL/min, 0-10 %ethyl acetate in petroleum ether, 220, 254 nm, UV) to afford the desired product. 1H NMR (400MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 1H) , 6.85 (d, J = 2.0 Hz, 1H) , 6.70 (dd, J = 2.4, 8.0 Hz, 1H) , 1.36 (s, 12H) .
Step B: tert-butyl 8- [6- (2-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] oct-7-enoate
To a mixture of tert-butyl 8- (6-chloro-5-fluoro-3-pyridyl) oct-7-enoate (250 mg, 0.763 mmol) and 3-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (276 mg, 1.08 mmol) in H2O (0.6 mL) , dioxane (2.4 mL) was added Pd (dppf) Cl2 (83.7 mg, 0.1149 mmol) , K3PO4 (648 mg, 3.05 mmol) under N2 and the solution was stirred at 80 ℃ for 16 h. The solution was diluted with water (5 mL) and extracted with EtOAc (5 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude oil. The crude was purified by Combi-flash (silica gel 12 g, 30 mL/min, 0-17 %ethyl acetate in petroleum ether, 254, 280 nm, UV) to afford the desired product. LCMS: MS (ESI) m/z 420.4 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.42 (s, 1H) , 7.42-7.53 (m, 1H) , 7.28-7.32 (m, 1H) , 6.91-6.96 (m, 1H) , 6.75-6.81 (m, 1H) , 6.36-6.44 (m, 1H) , 5.84-5.95 (m, 1H) , 2.28-2.41 (m, 2H) , 2.20-2.26 (m, 2H) , 1.51-1.54 (m, 2H) , 1.45 (s, 9H) , 1.36-1.42 (m, 2H) , 1.25-1.29 (m, 2H) .
Step C: tert-butyl 8- [6- (2-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] octanoate
To a compound of tert-butyl 8- [6- (2-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] oct-7-enoate (258 mg, 0.614 mmol) in EtOAc (10 mL) was added Pd/C (60 mg, 10%purity) under H2 (15 psi) for three times and the mixture was stirred at 25 ℃ for 1 h. The mixture was filtered and washed with EtOAc (15 mL) . The filtrate was concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 423.3 [M+H] +.
Step D: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a mixture of tert-butyl 8- [6- (2-chloro-4-hydroxy-phenyl) -5-fluoro-3-pyridyl] octanoate (258 mg, 0.611 mmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (230 mg, 0.976 mmol) in THF (3 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (750 mg,
3.11 mmol) under N2 and the solution was stirred at 80 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude as brown oil. The crude product was purified by column chromatography (SiO2, ethyl acetate in petroleum ether = 0%to 25%) to afford the desired product. LCMS: MS (ESI) m/z 639.3 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.34 (s, 1H) , 7.39 (d, J = 8.4 Hz, 1H) , 7.33 (d, J = 9.2 Hz, 1H) , 7.01-7.03 (m, 1H) , 6.90 (dd, J = 2.4, 8.8 Hz, 1H) , 4.07 (t, J = 6.0 Hz, 2H) , 3.93 (s, 3H) , 3.43 (t, J = 7.6 Hz, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.18-2.24 (m, 4H) , 1.65-1.71 (m, 2H) , 1.56-1.62 (m, 4H) , 1.45 (s, 9H) , 1.35-1.39 (m, 4H) .
Step E: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-chloro-phenoxy] propyl] thiazole-4-carboxylate
To a mixture of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (295 mg, 0.461 mmol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (176 mg, 0.509 mmol, HCl salt) in dioxane (3 mL) was added Pd2 (dba) 3 (211 mg, 0.230. mmol) , tBuOK (130 mg, 1.16 mmol) , SPhos (95 mg, 0.231 mmol) under N2 and the solution was stirred at 90 ℃ for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude oil. The crude was purified by Combi-flash (silica gel 20 g, 30 mL/min, 0-8 %dichloromethane in methanol) to give an impure product. The impure product was second purified by Combi-flash (silica gel 12 g, 30 mL/min, 0-5 %dichloromethane in methanol) to afford the desired product. LCMS: MS (ESI) m/z 912.7 [M+H] +.
Step F: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-chloro-phenyl] -5-fluoro-3-pyridyl] octanoic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] -3-chloro-phenoxy] propyl] thiazole-4-carboxylate (194 mg, 0.2123 mmol) in HCOOH (3 mL) under N2 and the solution was stirred at 25 ℃ for 16 h. The crude was dissolved in DCM (15 mL) and concentrated under reduced pressure to remove residual FA for three times to afford the desired product. LCMS: MS (ESI) m/z 856.6 [M+H] +.
Step G: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-chloro-4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a mixture of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-chloro-phenyl] -5-fluoro-3-pyridyl] octanoic
acid (155 mg, 0.181 mmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (112 mg, 0.252 mmol) in DMF (2 mL) was added DIEA (94 mg, 0.727 mmol) , HATU (83 mg, 0.218 mmol) under N2 and the solution was stirred at 25℃ for 16 h. The solution was diluted with water (2 mL) and extracted with EtOAc (2 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude as brown oil. The crude product was purified by column chromatography (SiO2, methanol : dichloromethane= 0%to 6%) to afford the desired product. LCMS: MS (ESI) m/z 1283.6 [M+H] +.
Step H: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (3-chloro-4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-chloro-4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (120 mg, 0.094 mmol) in THF (1 mL) , EtOH (1 mL) , H2O (0.5 mL) was added LiOH. H2O (30 mg, 0.715 mmol) under N2 and the solution was stirred at 25 ℃ for 16 h. The solution was diluted with EtOH (2.0 mL) , acidified with HCl (2 M) until pH~7. The solution was concentrated under reduced pressure to give crude as yellow oil. The crude was diluted with MeOH (1.0 mL) , DMF (0.5 mL) and purified by prep-HPLC (column: Boston Uni C18 40 *150 *5 um; mobile phase: [water (FA) -ACN] ; B%: 73%-93%, 9 min) . The desired fractions were lyophilized under reduced pressure to afford Compound 236. LCMS: MS (ESI) m/z 1290.4 [M+Na] +. 19F NMR (400MHz, CDCl3) : δ = -120.781. 1H NMR (400MHz, CDCl3) δ 8.69 (s, 1H) , 8.36 (s, 1H) , 7.83-7.89 (m, 1H) , 7.63-7.74 (m, 2H) , 7.32-7.52 (m, 13H) , 6.94 (s, 1H) , 6.28-6.84 (m, 1H) , 4.91-5.11 (m, 2H) , 4.67-4.78 (m, 1H) , 4.46-4.64 (m, 2H) , 3.88-4.16 (m, 3H) , 3.76-3.84 (m, 1H) , 3.53-3.63 (m, 1H) , 2.99-3.37 (m, 3H) , 2.61-2.78 (m, 2H) , 2.46-2.56 (m, 5H) , 2.14-2.24 (m, 2H) , 1.58-1.69 (m, 3H) , 1.44-1.49 (m, 4H) , 1.31-1.37 (m, 6H) , 1.24-1.28 (m, 6H) , 1.05 (s, 9H) .
Example 72: Compound 237
Step A: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a solution of tert-butyl 8- [5-fluoro-6- (4-hydroxyphenyl) -3-pyridyl] octanoate (300 mg, 774.22 μmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (182.47 mg, 774.22 μmol) in THF (3 mL) was added 2- (tributyl-phosphanylidene) acetonitrile (747.43 mg, 3.10 mmol) . The mixture was stirred at 80 ℃ for 16 hr under N2 atmosphere. The mixture was concentrated to give crude. The crude was purified by Combi-flash (silica gel, 0~100%MeOH/DCM = 50/1 in DCM) to afford the desired product. LCMS: MS (ESI) m/z 605.3
[M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H) , 7.86 (d, J = 9.2 Hz, 2H) , 7.57-7.67 (m, 1H) , 7.03 (d, J = 9.2 Hz, 2H) , 4.08 (t, J = 6.4 Hz, 2H) , 3.79 (m, 3H) , 2.64 (t, J = 7.2 Hz, 2H) , 2.08-2.20 (m, 4H) , 1.55-1.63 (m, 2H) , 1.43-1.50 (m, 4H) , 1.38 (s, 9H) , 1.20-1.32 (m, 6H) .
Step B: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (740 mg, 1.22 mmol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (422.91 mg, 1.22 mmol, HCl) in dioxane (9 mL) was added Pd2 (dba) 3 (559.88 mg, 611.41 μmol) , SPhos (251.00 mg, 611.41 μmol) and t-BuOK (343.04 mg, 3.06 mmol) . The mixture was stirred at 90 ℃ for 3 hr under N2 atmosphere. The mixture was diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated to give the crude product. The crude was purified by Combi-flash (silica gel, 0~4%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 878.3 [M+H] +.
Step C: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -5-fluoro-3-pyridyl] octanoic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-fluoro-2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (524 mg, 596.75 μmol) was added HCOOH (28.67 mg, 596.75 μmol, 6.5 mL) . The mixture was stirred at 25 ℃ for 1 hr. The mixture was concentrated to afford the desired product. LCMS: MS (ESI) m/z 822.3 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a solution of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] phenyl] -5-fluoro-3-pyridyl] octanoic acid (515.3 mg, 593.66 μmol, FA) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (316.72 mg, 712.39 μmol) in DMF (7.5 mL) was added HOBt (120.33 mg, 890.49 μmol) , EDCI (227.61 mg, 1.19 mmol) and DIEA (306.91 mg, 2.37 mmol, 413.62 μL) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was diluted with H2O (100 mL) . The mixture was filtered and the filtrate was extracted with EtOAc (60 mL × 2) . The combined organic layer was washed with brine (60 mL) , dried over Na2SO4, filtered and concentrated under reduce pressure. The residue
was purified by column chromatography (SiO2, 5%MeOH) to afford the desired product. LCMS: MS (ESI) m/z 1248.6 [M+H] +.
Step E: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (3-fluoro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [3-fluoro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (340 mg, 272.32 μmol) in MeOH (0.9 mL) , THF (0.9 mL) and H2O (0.3 mL) was added LiOH. H2O (68.56 mg, 1.63 mmol) . The mixture was stirred at 25 ℃ for 16 hr. The colorless solution was treated with 1M HCl aq. until pH to 7. The suspension was concentrated to give crude product. The residue was purified by prep-HPLC (column: C18-1150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v) - (ACN-THF2/1) ] ; B%: 20%-60%, 9min) and dried by loyphilization to afford Compound 237. LCMS: MS (ESI) m/z 1234.6 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.32-8.39 (m, 2H) , 8.01 (d, J = 8.0 Hz, 1H) , 7.84 (d, J = 7.6 Hz, 2H) , 7.78 (d, J = 8.8 Hz, 2H) , 7.60-7.68 (m, 2H) , 7.35-7.47 (m, 8H) , 7.02 (d, J = 8.8 Hz, 2H) , 4.91 (t, J = 7.2 Hz, 1H) , 4.84 (m, 2H) , 4.51 (d, J = 9.6 Hz, 1H) , 4.41 (t, J = 8.0 Hz, 1H) , 4.27 (s, 1H) , 4.04 (t, J = 6.4 Hz, 2H) , 3.72 (t, J = 6.0 Hz, 2H) , 3.60 (s, 2H) , 3.19 (t, J = 7.6 Hz, 3H) , 3.02 (t, J = 6.0 Hz, 2H) , 2.62-2.68 (m, 2H) , 2.45 (s, 3H) , 2.25 (dt, J = 14.4, 7.6 Hz, 1H) , 2.09-2.15 (m, 1H) , 2.03 (m, 3H) , 1.78 (m, 1H) , 1.56-1.64 (m, 2H) , 1.48 (m, 2H) , 1.37 (m, 3H) , 1.23-1.31 (m, 6H) , 0.92 (s, 9H) .
Example 73: Compound 178
Step A: tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -3-pyridyl] oct-7-enoate
To a mixture of tert-butyl 8- (6-chloro-3-pyridyl) oct-7-enoate (300 mg, 968 umol) in dioxane (4 mL) and H2O (1 mL) was added K3PO4 (822 mg, 3870 umol) , Pd (dppf) Cl2 (71 mg, 97 umol) and (3-chloro-4-hydroxy-phenyl) boronic acid (175 mg, 1.02 mmol) . The mixture was stirred at 80 ℃ under N2 for 14 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was purified by flash silica gel chromatography (eluent of 0~20%
ethyl acetate/petroleum ether) to afford the desired product. LCMS: MS (ESI) m/z 402.2 [M+H] +.
Step B: tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -3-pyridyl] octanoate
To a mixture of tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -3-pyridyl] oct-7-enoate (350 mg, 870umol) in EtOAc (5 mL) was added Pd/C (50 mg, 10%purity) . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15psi) at 30℃ for 1 h. The mixture was filtered and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 405.3 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.47 (s, 1H) , 8.01 (d, J = 2.0 Hz, 1H) , 7.78 (dd, J = 2.0, 2.4 Hz, 1H) , 7.55-7.58 (m, 2H) , 7.08 (d, J=8.8 Hz, 1H) , 2.63 (t, J=7.6 Hz, 2H) , 2.21 (t, J=7.6 Hz, 2H) , 1.56-1.66 (m, 4H) , 1.45 (s, 9H) , 1.30-1.37 (m, 6H) .
Step C: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] -2-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a mixture of tert-butyl 8- [6- (3-chloro-4-hydroxy-phenyl) -3-pyridyl] octanoate (300 mg, 742 umol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (210 mg, 891 umol) in THF (5 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (896 mg, 3.71 mmol) . The mixture was stirred at 80 ℃ under N2 for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was purified by flash silica gel chromatography (eluent of 0~30%ethyl acetate/petroleum) to afford the desired product. LCMS: MS (ESI) m/z 622.5 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] -2-chloro-phenoxy] propyl] thiazole-4-carboxylate
To a mixture of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] -2-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (370 mg, 595 umol) in dioxane (5 mL) was added N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (216 mg, 624 umol) , SPhos (122 mg, 297 umol) , t-BuOK (166 mg, 1490 umol) and Pd2 (dba) 3 (272 mg, 297 umol) . The mixture was stirred at 90 ℃ under N2 for 3h. The mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was purified by flash silica gel chromatography (eluent of 0~5%MeOH/DCM) to afford the desired product. LCMS: MS (ESI) m/z 894.4 [M+H] +.
Step E: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-chloro-phenyl] -3-pyridyl] octanoic acid
To a mixture of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -2-pyridyl] -2-chloro-phenoxy] propyl] thiazole-4-
carboxylate (220 mg, 186 umol) in HCOOH (2 mL) . The mixture was stirred at 30 ℃ under N2 for 3 h. The mixture was concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 838.2 [M+H] +.
Step F: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a mixture of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -3-chloro-phenyl] -3-pyridyl] octanoic acid (156 mg, 186 umol) in DMF (2 mL) was added (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (99 mg, 223 umol) , HATU (141 mg, 372 umol) and DIEA (96 mg, 744 umol) . The mixture was stirred at 30 ℃ under N2 for 17 h. The mixture was concentrated under reduced pressure to give a residue. The mixture was purified by reversed column (99%MeOH in H2O) to afford the desired product. LCMS: MS (ESI) m/z 1264.3 [M+H] +.
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (2-chloro-4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a mixture of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [2-chloro-4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (60 mg, 47.4 umol) in MeOH (1 mL) , THF (1 mL) and H2O (0.5 mL) was added LiOH. H2O (9.95 mg, 237 umol) . The mixture was stirred at 30 ℃ for 14 h. The mixture was ajusted to pH 1-2 with 2N HCl solution. The mixture was concentrated under reduced pressure to give a residue. The mixture was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 29%-69%, 9min) . The residue was combined and concentrated under reduced pressure then dried through lyophilization to afford Compound 178. LCMS: MS (ESI) m/z 1250.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.46 (s, 1H) , 8.37 (d, J = 7.6 Hz, 1H) , 8.10 (d, J = 2.0 Hz, 1H) , 8.02 (d, J = 8.0 Hz, 1H) , 7.97 (dd, J = 1.6, 2.0 Hz, 1H) , 7.84 (d, J = 8.0 Hz, 1H) , 7.78 (d, J = 8.8 Hz, 2H) , 7.67 (d, J = 7.2 Hz, 2H) , 7.32-7.49 (m, 9H) , 7.19 (d, J = 8.8 Hz, 1H) , 5.09 (brs, 1H) , 4.91 (t, J = 7.2 Hz, 1H) , 4.83 (s, 1H) , 4.51 (d, J = 9.2 Hz, 1H) , 4.41 (t, J = 8.0 Hz, 1H) , 4.27 (s, 1H) , 4.13 (t, J = 6.0 Hz, 1H) , 3.71 (t, J = 5.6 Hz, 2H) , 3.57–3.61 (m, 2H) , 3.22 (t, J = 7.2 Hz, 2H) , 3.02 (t, J = 5.6 Hz, 2H) , 2.60 (t, J = 7.6 Hz, 2H) ,
2.45 (s, 3H) , 2.21-2.29 (m, 1H) , 1.98-2.13 (m, 4H) 1.75–1.82 (m, 1H) , 1.55–1.62 (m, 2H) , 1.43-1.52 (m, 2H) , 1.37 (d, J = 6.8 Hz, 3H) , 1.19-1.32 (m, 7H) , 0.92 (s, 9H) .
Example 74: Compound 238
Step A: tert-butyl 8- [5-chloro-6- (2-chloro-4-hydroxy-phenyl) -3-pyridyl] oct-7-enoate
To a mixture of tert-butyl 8- (5, 6-dichloro-3-pyridyl) oct-7-enoate (300 mg, 0.871 mmol) and 3-chloro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (333 mg, 1.31 mmol) in H2O (0.7 mL) , dioxane (2.8 mL) was added Pd (dppf) Cl2 (95.6 mg, 0.131 mmol) , K3PO4 (740 mg, 3.49
mmol) under N2 and the solution was stirred at 80 ℃ for 16 h. The solution was diluted with water (5 mL) and filtered. The filtrate was extracted with EtOAc (5 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude was purified by Combi-flash (silica gel 12 g, 30 mL/min, 0-30 %ethyl acetate in petroleum ether, 254, 280 nm, UV) to afford the desired product. LCMS: MS (ESI) m/z 436.4 [M+H] +.
Step B: tert-butyl 8- [5-chloro-6- (2-chloro-4-hydroxy-phenyl) -3-pyridyl] octanoate
To a compound of tert-butyl 8- [5-chloro-6- (2-chloro-4-hydroxy-phenyl) -3-pyridyl] oct-7-enoate (240 mg, 0.550 mmol) in EtOAc (10 mL) was added Pd/C (70 mg, 10%purity) under H2 (15 psi) for three times and the mixture was stirred at 20 ℃ for 1 h. The mixture was filtered and washed with EtOAc (15 mL) . The filtrate was concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 439.2 [M+H] +.
Step C: methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate
To a mixture of tert-butyl 8- [5-chloro-6- (2-chloro-4-hydroxy-phenyl) -3-pyridyl] octanoate (262 mg, 0.598 mmol) and methyl 2-chloro-5- (3-hydroxypropyl) thiazole-4-carboxylate (225 mg, 0.955 mmol) in THF (3 mL) was added 2- (tributyl-λ5-phosphanylidene) acetonitrile (730 mg, 3.02 mmol) under N2 and the solution was stirred at 80 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude as brown oil and the crude product was purified by column chromatography (SiO2, ethyl acetate in petroleum ether= 0%to 14%, 254, 280 nm, UV) to afford the desired product. LCMS: MS (ESI) m/z 656.4 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.41 (s, 1H) , 7.64 (s, 1H) , 7.30 (s, 1H) , 6.99-7.04 (m, 1H) , 6.89 (dd, J = 2.4, 8.4 Hz, 1H) , 4.07 (t, J = 6.0 Hz, 2H) , 3.93 (s, 3H) , 3.43 (t, J = 7.6 Hz, 2H) , 2.67 (t, J = 8.4 Hz, 2H) , 2.18-2.25 (m, 4H) , 1.64-1.72 (m, 4H) , 1.45 (s, 9H) , 1.32-1.42 (m, 6H) .
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-chloro-phenoxy] propyl] thiazole-4-carboxylate
To a solution of methyl 5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-chloro-phenoxy] propyl] -2-chloro-thiazole-4-carboxylate (315 mg, 480 umol) and N- (1, 3-benzothiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-8-carboxamide (166 mg, 480 umol, HCl) in dioxane (3 mL) were added Pd2 (dba) 3 (220 mg, 240 umol) , SPhos (99 mg, 241 umol) and t-BuOK (135 mg, 1.20 mmol) under N2. The mixture was stirred at 90 ℃ for 3 h. The mixture was diluted with EtOAc (15 mL) and filtered. The filtrate was concentrated to give crude product. The crude was purified by Combi-flash (silica gel, 0~5%MeOH in DCM) to afford the desired product. LCMS: MS (ESI) m/z 928.3 [M+H] +.
Step E: 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-chloro-phenyl] -5-chloro-3-pyridyl] octanoic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- (8-tert-butoxy-8-oxo-octyl) -3-chloro-2-pyridyl] -3-chloro-phenoxy] propyl] thiazole-4-carboxylate (290 mg, 0.312 mmol) in HCOOH (5 mL) under N2 and the solution was stirred at 25 ℃ for 16 h. The crude was dissolved in DCM (15 mL) and concentrated under reduced pressure to remove residual FA for three times to afford the desired product. LCMS: MS (ESI) m/z 872.4 [M+H] +.
Step F: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-chloro-4- [3-chloro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate
To a mixture of 8- [6- [4- [3- [2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -4-methoxycarbonyl-thiazol-5-yl] propoxy] -2-chloro-phenyl] -5-chloro-3-pyridyl] octanoic acid (272 mg, 0.312 mmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (193 mg, 0.434 mmol) in DMF (3 mL) was added DIEA (161 mg, 1.25 mmol) , HATU (142 mg, 0.373 mmol) under N2 and the solution was stirred at 25℃ for 16 h. The solution was diluted with water (4 mL) and extracted with EtOAc (4 mL x3) . The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO2, methanol : dichloromethane= 0%to 6%, 254, 280 nm, UV) to afford the desired product. LCMS: MS (ESI) m/z 1298.6 [M+H] +.
Step G: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (3-chloro-4- (3-chloro-5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a compound of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [3-chloro-4- [3-chloro-5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] -2-pyridyl] phenoxy] propyl] thiazole-4-carboxylate (95 mg, 73.11 umol) in THF (1 mL) , EtOH (1 mL) , H2O (0.5 mL) was added LiOH. H2O (22 mg, 0.524 mmol) under N2 and the solution was stirred at 25 ℃ for 16 h. The solution was diluted with EtOH (2.0 mL) , acidified with HCl (2 M) until pH~7. The solution was concentrated under reduced pressure to give crude product. The
crude was diluted with MeOH (1.0 mL) , DMF (0.5 mL) and purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 70%-90%, 16 min) . The desired fractions was lyophilized under reduced pressure to afford Compound 238. LCMS: MS (ESI) m/z 1286.4 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.70 (s, 1H) , 8.42 (s, 1H) , 7.86 (d, J = 8.0 Hz, 1H) , 7.66-7.74 (m, 2H) , 7.61 (s, 1H) , 7.48-7.54 (m, 1H) , 7.30-7.44 (m, 8H) , 7.10-7.25 (m, 2H) , 6.93 (d, J = 2.0 Hz, 1H) , 6.82 (d, J = 7.2 Hz, 1H) , 6.31 (d, J = 8.4 Hz, 1H) , 5.07 (t, J = 7.2 Hz, 1H) , 4.94 (m, 2H) , 4.66-4.77 (m, 1H) , 4.58 (d, J = 8.4 Hz, 1H) , 4.47 (s, 1H) , 4.11 (d, J = 10.8 Hz, 1H) , 3.98 (t, J = 6.0 Hz, 2H) , 3.75-3.83 (m, 2H) , 3.58 (d, J = 8.4 Hz, 1H) , 3.30 (t, J = 7.2 Hz, 2H) , 3.05 (t, J = 5.6 Hz, 2H) , 2.58-2.71 (m, 2H) , 2.52 (m, 3H) , 2.21-2.24 (m, 2H) , 2.12-2.15 (m, 2H) , 1.59-1.68 (m, 4H) , 1.44-1.48 (m, 3H) , 1.31-1.35 (m, 4H) , 1.26 (m, 3H) , 1.16-1.21 (m, 2H) , 1.04 (s, 9H) .
Example 75: Compound 239
Step A: (E) -8- (6-chloro-3-pyridyl) non-7-enoic acid
To a solution of 5-bromo-2-chloro-pyridine (2.96 g, 15.36 mmol) and non-8-enoic acid (2 g, 12.80 mmol) in DMF (15 mL) was added Pd (OAc) 2 (229.94 mg, 1.02 mmol) and PPh3 (134.31 mg, 512.09 umol) , Et3N (5.57 g, 55.05 mmol, 7.66 mL) . The mixture was stirred at 110 ℃ for
16 hr under N2. The reaction mixture was quenched by addition water (100 mL) , and then diluted with EtOAc (100 mL) and extracted with EtOAc (300 mL× 3) . The combined organic layers were washed with brine (100 mL × 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (220 gSilica Flash Column, Eluent of 0~50%Ethylacetate/Petroleum ethergradient @100 mL/min) to give compound 3.6 g. The residue was purified by prep-HPLC (column: C18 (250*50mm*10 um) ; mobile phase: [water (FA) -ACN] ; B%: 33%-73%, 9 min) to afford the desired product. LCMS: MS (ESI) m/z 268.1 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.4 Hz, 1H) , 8.22 (d, J = 2.0 Hz, 1H) , 7.59-7.68 (m, 1H) , 7.29 (d, J = 8.4 Hz, 1H) , 5.31 (s, 1H) , 5.17 (d, J = 0.8 Hz, 1H) , 2.47 (t, J = 7.2 Hz, 2H) , 2.31-2.40 (m, 5H) , 2.22 (q, J = 7.2 Hz, 1H) , 1.57-1.68 (m, 4H) , 1.28-1.50 (m, 12H) .
Step B: (2R, 4S) -1- [ (2S) -2- [8- (6-chloro-3-pyridyl) non-8-enoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1R) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of (E) -8- (6-chloro-3-pyridyl) non-7-enoic acid (700 mg, 2.61 mmol, 1 eq) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (1.39 g, 3.14 mmol) in DMF (10 mL) was added EDCI (1.00 g, 5.23 mmol) , TEA (1.32 g, 13.07 mmol, 1.82 mL) and HOBt (529.88 mg, 3.92 mmol) . The mixture was stirred at 25℃ for 5 hr. The reaction mixture was quenched by addition water (20 mL) , and then diluted with EtOAc (50 mL) and extracted with EtOAc (100 mL× 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 694.3 [M+H] +.
Step C: 4-hydroxy-1- [2- [8- [6- (4-hydroxyphenyl) -3-pyridyl] non-8-enoylamino] -3, 3-dimethyl-butanoyl] -N- [1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of (2R, 4S) -1- [ (2S) -2- [8- (6-chloro-3-pyridyl) non-8-enoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1R) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (600.00 mg, 864.15 umol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (475.44 mg, 2.16 mmol) and K3PO4 (733.73 mg, 3.46 mmol) in H2O (2 mL) and THF (8 mL) was bubbled with N2 for 5 minutes. Then the mixture was added [2- (2-aminophenyl) phenyl] palladium (1+) ; bis (1-adamantyl) -butyl-phosphane; methanesulfonate (94.40 mg, 129.62 umol, ) and stirred at 70 ℃ for 1 hr under N2. The mixture was poured into water (8 mL) and extracted with EtOAc (30 mL × 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0~10%
MeOH/DCM gradient @40mL/min) to afford the desired product. LCMS: MS (ESI) m/z 752.3 [M+H] +.
Step D: (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [6- (4-hydroxyphenyl) -3-pyridyl] nonanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
To a solution of 4-hydroxy-1- [2- [8- [6- (4-hydroxyphenyl) -3-pyridyl] non-8-enoylamino] -3, 3-dimethyl-butanoyl] -N- [1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (550 mg, 731.41 umol) in MeOH (5 mL) was added Pd/C (10 mg, 731.41 umol, 10%purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 ℃ for 1 hr . The reaction mixture was filtered via celite pad and concentrated under reduced pressure to afford the desired product. LCMS: MS (ESI) m/z 754.4 [M+H] +.
Step E: methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononan-2-yl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylate
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate (30 mg, 51 umol) and (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [6- (4-hydroxyphenyl) -3-pyridyl] nonanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (38 mg, 51 umol) in DMF (0.8 mL) was added Cs2CO3 (42 mg, 129 umol) . The mixture was stirred at 25 ℃ for 16 h. The mixture was diluted with DCM (5 mL) , and filtered. The filtrate was concentrated to afford the desired product. LCMS: MS (ESI) m/z 1245.8 [M+H] +.
Step F: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononan-2-yl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (9- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononan-2-yl) pyridin-2-yl) phenoxy) propyl) thiazole-4-carboxylate (80 mg, 0.064 mmol) in THF (1 mL) , MeOH (1 mL) and H2O (0.5 mL) was added LiOH. H2O (13.5 mg, 0.32 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h under N2. The mixture was concentrated under reduced pressure to give crude. The resdiue was purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 45%-65%, 16 min) .
It was impure, and then purified by prep-HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (FA) -ACN] ; B%: 53%-73%, 16 min) to afford Compound 239. LCMS: MS (ESI) m/z 1230.5 [M+H] +. 1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H) , 8.48 (s, 1H) , 7.83 (t, J =8.0 Hz, 3H) , 7.59-7.64 (m, 2H) , 7.52-7.57 (m, 2H) , 7.31-7.41 (m, 8H) , 6.89 (d, J =8.0 Hz, 2H) , 6.29-6.38 (m, 1H) , 5.02-5.14 (m, 1H) , 4.89 (s, 2H) , 4.70 (d, J =8.0 Hz, 1H) , 4.58 (d, J =8.0 Hz, 1H) , 4.44-4.53 (m, 1H) , 4.05-4.17 (m, 1H) , 3.93-4.03 (m, 2H) , 3.72-3.80 (m, 2H) , 3.57 (d, J =8.0 Hz, 1H) , 3.29 (t, J =8.0 Hz, 2H) , 2.95-3.03 (m, 2H) , 2.59-2.65 (m, 1H) , 2.51 (s, 4H) , 2.10-2.19 (m, 5H) , 2.05 (s, 1H) , 1.53-1.64 (m, 4H) , 1.46 (d, J =8.0 Hz, 3H) , 1.19-1.31 (m, 11H) , 1.03 (s, 9H) .
Example 76: Compound 187
Step A: ethyl 8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoate
A solution of ethyl 8- (2-chloropyrimidin-5-yl) octanoate (270 mg, 0.948 mmol) and (4-hydroxy-2-methyl-phenyl) boronic acid (216 mg, 1.42 mmol) in dioxane (4 mL) and H2O (1 mL) was added K3PO4 (805 mg, 3.79 mmol) and Pd (dppf) Cl2 (104 mg, 0.142 mmol) at 25 ℃. The mixture was stirred at 80 ℃ for 4 h. The mixture was diluted with H2O (35 mL) and extracted with EtOAc (30 mL *2) . The combined organic were washed with brine (20 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (12.0 gSilica Flash Column, petroleum ether /EtOAc with EtOAc from 0~30%, flow rate = 40 mL/min) to afford the desired product. LCMS: MS (ESI) m/z 357.2 [M+H] +.
Step B: 8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoic acid
To a solution of ethyl 8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoate (280 mg, 0.786 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added LiOH. H2O (165 mg, 3.93 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 2 h. The solvent was quenched with 1M HCl (8 mL) and extracted with EtOAc (35 mL *2) . The combined organic layer were washed with brine (40 mL) , dried over Na2SO4, filtered and the filtrate was concentrater to afford the desired product. LCMS: MS (ESI) m/z 329.0 [M+H] +.
Step C: (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide
A solution of 8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoic acid (327 mg, 0.996 mmol) and (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (531 mg, 1.19 mmol) in DMF (4 mL) was added DIEA (515 mg, 3.98 mmol) , EDCI (382 mg, 1.99 mmol) and HOBt (202 mg, 1.49 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h. The reaction was diluted with aqueous NH4Cl (50 mL) and extracted with EtOAc (35 mL *2) . The combined organic were washed with brine (45 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (12.0 gSilica Flash Column, DCM /MeOH with MeOH from 0 ~ 8%, flow rate = 35 mL/min, 254 nm) to afford the desired product. LCMS: MS (ESI) m/z 755.5 [M+H] +.
Step D: methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate
A solution of (2S, 4R) -4-hydroxy-1- [ (2S) -2- [8- [2- (4-hydroxy-2-methyl-phenyl) pyrimidin-5-yl] octanoylamino] -3, 3-dimethyl-butanoyl] -N- [ (1S) -1- [4- (4-methylthiazol-5-
yl) phenyl] ethyl] pyrrolidine-2-carboxamide (20 mg, 0.0265 mmol) and methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- (3-methylsulfonyloxypropyl) thiazole-4-carboxylate (20.20 mg, 0.0344 mmol) in DMF (1 mL) was added K2CO3 (9.15 mg, 0.0662 mmol) and Cs2CO3 (4.32 mg, 0.0133 mmol) at 25 ℃. The mixture was stirred at 60 ℃ for 16 h. The 15 batches reaction mixture were combined for work-up. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (60 mL *2) . The combined organic layer were washed with brine (40 mL) , dried over Na2SO4, filtrated and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (12.0 gSilica Flash Column, DCM /MeOH with MeOH from 0 ~ 8%, flow rate = 35 mL/min, 254 nm) to afford the desired product. LCMS: MS (ESI) m/z 1245.9 [M+H] +.
Step E: 2- (8- (benzo [d] thiazol-2-ylcarbamoyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -5- (3- (4- (5- (8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) pyrimidin-2-yl) -3-methylphenoxy) propyl) thiazole-4-carboxylic acid
To a solution of methyl 2- [8- (1, 3-benzothiazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinolin-2-yl] -5- [3- [4- [5- [8- [ [ (1S) -1- [ (2S, 4R) -4-hydroxy-2- [ [ (1S) -1- [4- (4-methylthiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2, 2-dimethyl-propyl] amino] -8-oxo-octyl] pyrimidin-2-yl] -3-methyl-phenoxy] propyl] thiazole-4-carboxylate (226 mg, 0.181 mmol) in MeOH (1 mL) and THF (1 mL) , H2O (0.5 mL) was added LiOH. H2O (38.1 mg, 0.907 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 16 h. The colorless solution was treated with 1N HCl aq. until pH to 7. The suspension was concentrated to give crude. The crude was purified by prep-HPLC. Column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; B%: 40%-60%, 9 min. The fraction was concentrated to remove most of the solvent, and the remaining was dried by lyophilization to afford Compound 187. LCMS: MS (ESI) m/z 1231.3 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H) , 8.71 (m, 2H) , 8.37 (d, J =8.0 Hz, 1H) , 7.99 (d, J =8.0 Hz, 1H) , 7.74-7.83 (m, 3H) , 7.68 (d, J =8.0 Hz, 1H) , 7.40-7.45 (m, 4H) , 7.35-7.39 (m, 3H) , 7.30-7.34 (m, 1H) , 6.80-6.85 (m, 2H) , 4.91 (t, J = 7.2 Hz, 1H) , 4.85 (m, 2H) , 4.51 (d, J = 9.6 Hz, 1H) , 4.42 (t, J = 8.0 Hz, 1H) , 4.23-4.30 (m, 1H) , 4.03 (t, J = 5.6 Hz, 2H) , 3.71 (t, J = 5.6 Hz, 2H) , 3.56-3.62 (m, 2H) , 3.19 (t, J = 7.2 Hz, 2H) , 3.00-3.05 (m, 2H) , 2.53-2.64 (m, 2H) , 2.47 (m, 3H) , 2.45 (m, 3H) , 2.16-2.32 (m, 2H) , 2.09-2.15 (m, 1H) , 1.94-2.09 (m, 4H) , 1.71-1.84 (m, 1H) , 1.56-1.67 (m, 2H) , 1.43-1.52 (m, 2H) , 1.36 (d, J = 6.8 Hz, 3H) , 1.29-1.33 (m, 4H) , 1.19-1.26 (m, 2H) , 0.92 (s, 9H) .
II. Biological Evaluation
PROTAC6 (structure shown as below) as disclosed in Chung et al., “Structural Insights into PROTAC-Mediated Degradation of Bcl-xL” ACS Chem. Biol. 2020, 15, 9, 2316-2323 was chosen as reference compound.
Example B1: BCL-XL Degradation Assay
Cell Culture
Human T lymphoblast MOLT-4 (ATCC, CRL1582) were cultured in RPMI 1640 (Gibco, 11875119) media, supplemented with 10%FBS (Gibco, 10099-141) . All cell lines were maintained at 37 ℃ in an atmosphere of 5%CO2.
Protein extraction and Western blotting
Whole cell lysates were prepared using cell Lysis Buffer (CST, 9803) supplemented with Protease inhibitor, phosphatase inhibitor and PMSF solution. The concentration of protein was quantified using a Pierce Bicinchoninic Acid (BCA) Protein Concentration Kit (Solarbio, PC0020) . Equal amounts of protein were loaded for PAGE and transfer samples onto a PVDF membrane using Bio-Rad's Trans blot. The blots were incubated with a primary antibody (anti-BCL-XL, and anti-α-Tubulin) , followed by HRP conjugated to an appropriate secondary antibody.
Cell viability assay
Cell viability was measured using a CellTiter-Glo Assay kit (Promega, G7573) according to the manufacturer’s protocol. MOLT-4 were seeded into 384-well plates and treated with various increasing doses of compound for 72 hours. Cell plates were taken from the incubator and equilibrated withThe plates were read on an Envision 2104 Multi-plate reader using a luminescence detector.
Representative degradation activity and cell viability from exemplary compounds is presented in Table 8.
Table 8:
Note: The “-” indicates not determined.
Table 8
DC50: Concentration of a compound to induce 50%of the target protein.
Dmax: Maximum degradation ratio.
GI50: Concentration of a compound to inhibit 50%of cell growth.
Example B2: In Vivo Pharmacokinetic Determinations
The study was conducted in male CD-1 mice with an age of 6-8 weeks. Animals received a single intravenous injection at the dose of 2.0 mg/kg.
Blood samples were taken from three different mice at certain time points (eg: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, etc) . Blood samples were taken from mice and transferred to EDTA tubes. Blood was centrifuged at 4000 g for 5 minutes in a 4℃ centrifuge to obtain plasma. All plasma samples were stored in a freezer at -75±15℃ prior to analysis.
WinNonlin (PhoenixTM) software was used for pharmacokinetic calculations and the following pharmacokinetic parameters were calculated from the plasma concentration versus time data: T1/2, AUC, Cl, and VDss.
Representative pharmacokinetic parameters for exemplary compounds are presented in Table 9.
Table 9. CD1 mouse PK data
Example 3: In vivo efficacy study of test articles in treatment of MOLT-4 xenograft models in female Balb/c nude mice
Cell Culture: Tumor cells were cultured at 37 ℃ in an atmosphere of 5%CO2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
Animals: Balb/c nude mice, female, 6-8 weeks, weighing approximately 18-22g, mice were purchased from Beijing VR Laboratory Animal Co., LTD. or other certified vendors.
Tumor Cell Inoculation: Each mouse was inoculated subcutaneously at the right flank with tumor cells for tumor development. The animals were randomized and treatment were started when the average tumor volume reaches approximately 150 mm3 for MOLT-4. The test articles administration and the animal numbers in each group are shown in below experimental design table.
Group design
Endpoints: The major endpoint was to see if the tumor growth could be delayed or mice could be cured. Tumor sizes were measured twice per week in two dimensions using a caliper, and the volume were expressed in mm3 using the formula: V = 0.5 a x b2 where a and b are the long and short diameters of the tumor, respectively. The tumor sizes were then used for the calculations of T/C and TGI values.
The T/C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volume of the treated and control groups, respectively, on a given day.
TGI was calculated for each group using the formula: TGI (%) = [1- (Ti-T0) / (Vi-V0) ] ×100; Ti is the average tumor volume of a treatment group on a given day, T0 is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the first day of treatment.
For PD analysis:
Western blotting protocol
Protein Extraction &Protein Quantification
1. Take the snap-frozen tissues out from -80℃ freezer or liquid nitrogen tank.
2. Cut up to about 30-100mg of tissue. Place the tissues in a 2mL microcentrifuge tube, and add 400μL of RIPA Buffer (contains 1%Protease Inhibitor Cocktail and 1%Phosphatase Inhibitor Cocktail 2) .
3. Grind tumors with Tissuelyser at 50Hz for 5min.
4. Keep the tissue lysates on ice for 30min.
5. Centrifuge at 12,000 rpm at 4℃ for 10min; gently transfer the supernatants to a new microcentrifuge tube kept on ice.
6. Measure protein concentrations by PierceTM BCA Protein Assay Kit.
7. According to the result of BCA protein quantification, dilute all samples to the same final concentration (at 4μg/μL) using RIPA buffer plus 4X LDS Sample Buffer and 10X Sample Reducing Agent . Heat the samples at 100℃ for 10min.
8. Proceed to western blotting or keep the denatured samples in the -80℃ refrigerator for long term storage.
Western Blotting
1. Add protein samples to 4-12%Bis-Tris Gel (26-well) , 10 μL per slot.
2. Electrophoresis with MES running buffer, 80 V for 30 min and then 120 V for 90 min.
3. Transfer protein to nitrocellulose membranes with Gel Transfer Device, 20 V, 7 min.
4. Cut the membrane and keep the interest parts, wash the membranes with 5-10 mL 1x TBS, three times for 5 min each.
5. Block the non-specific protein by 5-10 mL Odyssey blocking buffer at room temperature, 1 h.
6. Wash the membrane with 1x TBST five times for 5 min each.
7. Incubate membrane with 5-10 mL freshly prepared primary antibody in Odyssey blocking buffer with 0.1%Tween 20 at 4 ℃, with gentle agitation overnight.
8. Wash the membrane with 5-10 mL 1x TBST five times for 5 min each.
9. These next steps should be operated in the dark. Incubate membrane with 5-10 mL secondary antibodies mixture in Odyssey blocking buffer with 0.1%Tween20 with gentle agitation for 1 h at room temperature.
10. Wash the membrane with 5-10 mL 1x TBST five times for 5 min each.
11. Wash the membrane with 5-10 mL 1x TBS twice for 5 min each.
12. Detect the near-infrared fluorescence signal by Odyssey Clx system.
Quantification of band intensity
Intensity of individual bands were quantified using Image Studio Lite Ver 5.2 software.
Data Analysis
Band intensity of individual bands were obtained for analysis. Protein expression were quantitated in relation to a reference protein, and then the normalized folds of protein expression in each sample were ratios to vehicle group. The normalized data were interpreted by GraphPad Prism.
Representative data from exemplary compounds is presented in Fig 1 and 2.
Example 4: In vivo efficacy study of test articles in treatment of MOLT-4-luc orthotopic models in female Balb/c nude mice
Cell Culture: Tumor cells were cultured at 37 ℃ in an atmosphere of 5%CO2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
Animals: Balb/c nude mice, female, 6-8 weeks, weighing approximately 18-22g, mice were purchased from Beijing VR Laboratory Animal Co., LTD. or other certified vendors.
Tumor Cell Inoculation: Tumor cells were injected intravenously into the tail of each mouse for tumor development. The animals were randomized and treatment were started when the average bioluminescence reaches about 2.50E+06 to 3.00E+06 (photon/second) for MOLT-4-luc. The test articles administration and the animal numbers in each group are shown in below experimental design table.
Group design for each model
Endpoints: The major endpoint was to see the tumor growth and animal survival. The bioluminescence of each animal was measured once per week. The data of bioluminescence were then used for the calculations of T/C (%) values, where T and C were the mean bioluminescence of the treated and control groups, respectively, on a given day. TGI is calculated for each group using the formula: TGI (%) = [1- (Ti-T0) / (Vi-V0) ] ×100, where Ti is the average bioluminescence of a treatment group on a given day, T0 is the average bioluminescence of the treatment group on the first day of treatment, Vi is the average bioluminescence of the vehicle control group on the same day with Ti, and V0 is the average
bioluminescence of the vehicle group on the first day of treatment. 2) The major endpoint is to see the tumor growth and animal survival. All of the mice death or sacrificing were recorded and the survival rate were analysis at the ending.
The bioluminescence of each animal was measured once per week and body weight data were updated twice per week in excel files. Any abnormal findings were reported on real time.
Representative data from exemplary compounds is presented in Fig 3. We use a reported PROTAC DT2216 as a reference compound for comparison (J Hematol Oncol. 2022 Mar 9; 15 (1) : 23. doi: 10.1186/s13045-022-01241-3) .
III. Preparation of Pharmaceutical Dosage Forms
Example C1: Oral capsule
The active ingredient is a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
Example C2: Solution for injection
The active ingredient is a compound of Formula (I-A) , Formula (I-B) , Formula (I-C1) , Formula (I-C2) , Formula (I-D1) , Formula (I-D2) , Formula (I-E1a) , Formula (I-E1b) , Formula (I-E2a) , Formula (I-E2b) , Formula (I-F) , Formula (I-G) , Formula (I-H) , Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.
The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.
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Claims (78)
- A compound, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-A) :
wherein,o is 0, 1, 2 or 3;Y is S or CH=CH;each R1 is independently selected from halogen, nitro, cyano, -OR2, -N (R2) 2, -SR2, -S (O) R2, -S (O) 2R2, -S (O) 2N (R2) 2, -NR2S (O) 2R2, -NR2S (O) 2N (R2) 2, -C (O) R2, -C (O) OR2, -OC (O) R2, -OC (O) OR2, -OC (O) N (R2) 2, -NR2C (O) R2, -NR2C (O) OR2, -NR2C (O) N (R2) 2, -C (O) N (R2) 2, -P (O) (OR2) 2, -P (O) (R2) 2, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkyl wherein 1 to 2 -CH2-units are replaced with N, O, or S provided that two adjacent-CH2-units are not both replaced, optionally substituted C3-12 carbocyclyl, and optionally substituted 3-to 12-membered heterocyclyl;each R2 is each independently hydrogen or optionally substituted C1-6 alkyl; ortwo R2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring;V is a bond, -C≡C-, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted C3-7 cycloalkyl, or an optionally substituted heterocyclyl; oris taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1;L is selected from a) C2-C15 alkylene, b) C2-15 alkylene wherein one or more -CH2-units are replaced with O, provided that two O atoms are not adjacent, and c) -Ak1-Z1-Ak2-Z2-Ak3-*;wherein,Ak1 is selected from - (CR3R4) k-;Ak2 is selected from - (CR3R4) m-;Ak3 is selected from - (CR3R4) n-;each of k, m, and n is 0 to 6;each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl; orR3 and R4 together form an oxo group;Z1 and Z2 are each independently selected from bond, -O-, heterocyclene, and cycloalkylene; wherein at least one of Z1 and Z2 is heterocyclene or cycloalkylene;wherein the point of bonding to U is indicated by the asterisk andU is a recruitment motif selected from a VHL ligand. - The compound of claim 1, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:Y is S.
- The compound of claim 1, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:Y is CH=CH.
- The compound of any one of claims 1-3, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R1 is independently selected from halogen, nitro, cyano, -OR2, -N (R2) 2, -SR2, -S (O) R2, -S (O) 2R2, -S (O) 2N (R2) 2, -NR2S (O) 2R2, -NR2S (O) 2N (R2) 2, -C (O) R2, -C (O) OR2, -OC (O) R2, -OC (O) OR2, -OC (O) N (R2) 2, -NR2C (O) R2, -NR2C (O) OR2, -NR2C (O) N (R2) 2, -C (O) N (R2) 2, -P (O) (OR2) 2, -P (O) (R2) 2, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkyl wherein 1 to 2 -CH2-units are replaced with N, O, or S provided that two adjacent-CH2-units are not both replaced, optionally substituted C3-12 carbocyclyl, and optionally substituted 3-to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, carbocyclyl, and heterocyclyl are independently optionally substituted with one or more Re;each R2 is independently hydrogen or optionally substituted C1-6 alkyl, wherein the alkyl is optionally substituted with one or more Re; ortwo R2 together with the nitrogen atom to which they are attached may form an optionally substituted 3-6 membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more Re;each Re is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; ortwo Re attached to the same atom are taken together to form an oxo.V is a bond.-C≡C-, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted C3-7 cycloalkyl, or optionally substituted heterocyclyl, wherein the heteroaryl, aryl, cycloalkyl, or heterocyclyl are optionally substituted with one or more RV; oris taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1; andeach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; ortwo RV attached to the same atom of a cycloalkyl or heterocyclyl are taken together to form an oxo.
- The compound of any one of claims 1-4, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R1 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-3 alkoxy, halogen, -N (R2) 2, -OR2, and cyano, wherein the alkyl, haloalkyl, and alkoxy are each independently optionally substituted with one or more Re; andeach Re is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; ortwo Re attached to the same atom are taken together to form an oxo.
- The compound of any one of claims 1-5, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R1 is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.
- The compound of any one of claims 1-6, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R1 is independently selected from -F, -Cl, -CH3, -CH2CH3, and -CF3.
- The compound of any one of claims 1-6, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R1 is independently selected from -Cl, -CH3, -CH2CH3, and -CF3.
- The compound of any one of claims 1-8, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:o is 0 or 1.
- The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C4-15 alkylene.
- The compound of any one of claims 1-10, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C4-9 alkylene.
- The compound of any one of claims 1-11, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C5-8 alkylene.
- The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C2-15 alkylene wherein one or more -CH2-units are replaced with O, having the structure – (CH2) x-O– (CH2) y-*, wherein:x is 0 to 10;y is 1 to 10;wherein the point of bonding to the recruitment motif indicated by the asterisk; andwherein the sum of x and y is not more than 14.
- The compound of claim 13, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:x is 0 to 7; andy is 1 to 7.
- The compound of claim 13 or claim 14, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:x is 0 to 6; andy is 1 to 6.
- The compound of any one of claims 1-9, or 11-15, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C2-15 alkylene wherein one or more -CH2-units are replaced with O, having a structure selected from:
- The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C4-15 alkylene wherein one or more -CH2-units are replaced with O, having the structure – (CH2) j-O– (CH2) p-O– (CH2) v-*, wherein:j is 0 to 10;p is 1 to 10;v is 1 to 10;wherein the point of bonding to the recruitment motif indicated by the asterisk; andwherein the sum of j, p, and v is not more than 13.
- The compound of claim 17, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:j is 0 to 4;p is 1 to 5; andv is 1 to 4.
- The compound of claim 17 or claim 18, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:j is 0 to 2;p is 2 to 4; andv is 1 to 3.
- The compound of any one of claims 1-9, or 15-19, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is C4-15 alkylene wherein one or more -CH2-units are replaced with O, having a structure selected from:
- The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
X, X1 and X2 at each instance are independently CH or N;k is 0 to 6;m is 0 to 6;n is 0 to 6; andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of claim 21, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl.
- The compound of any one of claims 1-9, 21 or 22, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
X, X1 and X2 at each instance are independently CH or N;k is 0 to 6;m is 0 to 6;n is 0 to 6; andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of any one of claims 1-9, or 21-23, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
X, X1, and X2 at each instance are independently CH or N;k is 0 to 6;m is 0 to 6;n is 0 to 6; andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of any one of claims 21-24, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:k is 0 to 3;m is 0 to 3; andn is 0 to 2.
- The compound of any one of claims 1-9, or 21-25, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
X1, X2, X3, and X4 at each instance are independently CH or N;k is 0 to 6;m is 0 to 6;n is 0 to 6; andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of claim 27, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:each R3 and R4 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C1-3 alkyl, and C3 cycloalkyl.
- The compound of any one of claims 1-9, 27, or 28, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
X1, X2, X3, and X4 at each instance are independently CH or N;k is 0 to 6;m is 0 to 6;n is 0 to 6; andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of any one of claims 27-29, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:k is 0 or 1;m is 0 or 1; andn is 0 to 2.
- The compound of any one of claims 1-9, or 27-30, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:L is -Ak1-Z1-Ak2-Z2-Ak3-*, having a structure selected from:
andwherein the point of bonding to the VHL ligand is indicated by the asterisk. - The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is a bond.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is an optionally substituted heteroaryl.
- The compound of claim 33, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heteroaryl is pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or pyridazinyl, each of which is optionally substituted with one or more RV; andeach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl.
- The compound of claim 33 or claim 34, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heteroaryl iseach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 33-35, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heteroaryl is andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is an optionally substituted aryl.
- The compound of claim 37, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the aryl is phenyl optionally substituted with one or more RV; andeach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl.
- The compound of claim 37 or claim 38, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the aryl iseach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 37-39, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the aryl isandwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is an optionally substituted C3-7 cycloalkyl.
- The compound of claim 41, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the C3-7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with one or more RV; andeach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two RV attached to the same atom are taken together to form an oxo.
- The compound of claim 41 or claim 42, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the C3-7 cycloalkyl iseach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; or two RV attached to the same atom are taken together to form an oxo; andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 41-43, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the C3-7 cycloalkyl isandwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is an optionally substituted heterocyclyl.
- The compound of claim 45, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heterocyclyl is pyrrolidinyl, piperazinyl, piperidinyl, or morpholino, each of which is optionally substituted with one, or more RV; andeach RV is independently selected from hydrogen halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; ortwo RV attached to the same atom are taken together to form an oxo.
- The compound of claim 45 or claim 46, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heterocyclyl iseach RV is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -S (=O) CH3, -S (=O) 2CH3, -S (=O) 2NH2, -S (=O) 2NHCH3, -S (=O) 2N (CH3) 2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl; ortwo RV attached to the same atom are taken together to form an oxo; andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 45-47, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the heterocyclyl isandwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:V is -C≡C-.
- The compound of any one of claims 1-31, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:is taken together to form a fused bicyclic aryl ring or a fused bicyclic heteroaryl ring, each of which is substituted with o instances of R1.
- The compound of claim 50, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:is taken together to form a fused bicyclic aryl ring substituted with o instances of R1.
- The compound of claim 51, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic aryl ring is a naphthyl substituted with o instances of R1.
- The compound of claim 51 or claim 52, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic aryl ring is andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 51-53, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic aryl ring iswherein the asterisk indicates the point of attachment to L.
- The compound of claim 50, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:is taken together to form a fused bicyclic heteroaryl ring substituted with o instances of R1.
- The compound of claim 55, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic heteroaryl ring is a quinolinyl, an isoquinolinyl, a cinnolinyl, a quinazolinyl, a quinoxalinyl, or an indolyl, each of which is substituted with o instances of R1.
- The compound of claim 55 or claim 56, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic heteroaryl ring is andwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 55-57, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:the fused bicyclic heteroaryl ring isandwherein the asterisk indicates the point of attachment to L.
- The compound of any one of claims 1-58, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:U is selected from
- The compound of any one of claims 1-59, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:U is selected from
- The compound of any one of claims 1-60, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:U is selected from
- The compound of any one of claims 1-61, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:U is
- The compound of any one of claims 1-61 or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:U is
- The compound of claim 1 or claim 4, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the compound has a structure listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7.
- A pharmaceutical composition comprising the compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.
- The compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 65, for use in a method of treatment of the human or animal body.
- The compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 65, for use in a method of treatment of cancer or neoplastic disease.
- Use of the compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
- A method of treating cancer in a patient in need thereof comprising administering to the patient the compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 65.
- A method of treating a disease caused by senescent cells, in a patient in need thereof comprising administering to the patient the compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 65.
- The method of claim 70, wherein the disease caused by senescent cells is an ocular disease.
- The method of claim 71, wherein the ocular disease is age related macular degeneration (AMD) or diabetic macular edema (DME) .
- The compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 65, for use in a method of treatment of a disease caused by senescent cells.
- The compound of claim 73, wherein the disease caused by senescent cells is an ocular disease.
- The compound of claim 74, wherein the ocular disease is age related macular degeneration (AMD) or diabetic macular edema (DME) .
- Use of the compound of any one of claims 1-64, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease caused by senescent cells.
- The use of claim 76, wherein the disease caused by senescent cells is an ocular disease.
- The use of claim 77, wherein the ocular disease is age related macular degeneration (AMD) or diabetic macular edema (DME) .
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