WO2024050825A1 - Compounds as mlkl inhibitors - Google Patents
Compounds as mlkl inhibitors Download PDFInfo
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- WO2024050825A1 WO2024050825A1 PCT/CN2022/118169 CN2022118169W WO2024050825A1 WO 2024050825 A1 WO2024050825 A1 WO 2024050825A1 CN 2022118169 W CN2022118169 W CN 2022118169W WO 2024050825 A1 WO2024050825 A1 WO 2024050825A1
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- compound
- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 206
- 239000003112 inhibitor Substances 0.000 title claims abstract description 23
- 101100237799 Mus musculus Mlkl gene Proteins 0.000 title 1
- 102100030177 Mixed lineage kinase domain-like protein Human genes 0.000 claims abstract description 77
- 229940002612 prodrug Drugs 0.000 claims abstract description 31
- 239000000651 prodrug Substances 0.000 claims abstract description 31
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 nitro, hydroxyl Chemical group 0.000 claims description 235
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
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- 208000035475 disorder Diseases 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- YDSSNARSCZZMIP-UHFFFAOYSA-N n-(3-iodophenyl)benzamide Chemical compound IC1=CC=CC(NC(=O)C=2C=CC=CC=2)=C1 YDSSNARSCZZMIP-UHFFFAOYSA-N 0.000 description 1
- DNJPYUJXYQJJGT-UHFFFAOYSA-N n-(4-iodo-2-methylphenyl)benzamide Chemical compound CC1=CC(I)=CC=C1NC(=O)C1=CC=CC=C1 DNJPYUJXYQJJGT-UHFFFAOYSA-N 0.000 description 1
- HIYTZWYUNKXHKB-UHFFFAOYSA-N n-(4-iodophenyl)-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)NC1=CC=C(I)C=C1 HIYTZWYUNKXHKB-UHFFFAOYSA-N 0.000 description 1
- LEHOFTFWXOAAPS-UHFFFAOYSA-N n-(4-iodophenyl)-2-phenylacetamide Chemical compound C1=CC(I)=CC=C1NC(=O)CC1=CC=CC=C1 LEHOFTFWXOAAPS-UHFFFAOYSA-N 0.000 description 1
- AWWUBUIKOGZKQP-UHFFFAOYSA-N n-(4-iodophenyl)-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NC=2C=CC(I)=CC=2)=C1 AWWUBUIKOGZKQP-UHFFFAOYSA-N 0.000 description 1
- STPGMGRARZZPSI-UHFFFAOYSA-N n-(4-iodophenyl)-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2C=CC(I)=CC=2)=C1 STPGMGRARZZPSI-UHFFFAOYSA-N 0.000 description 1
- IZGODJUUNOBUQV-UHFFFAOYSA-N n-(4-iodophenyl)-3-phenylpropanamide Chemical compound C1=CC(I)=CC=C1NC(=O)CCC1=CC=CC=C1 IZGODJUUNOBUQV-UHFFFAOYSA-N 0.000 description 1
- RKYRTYUWYQIOBL-UHFFFAOYSA-N n-(4-iodophenyl)-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(I)C=C1 RKYRTYUWYQIOBL-UHFFFAOYSA-N 0.000 description 1
- MOEBVDPNOPDLGV-UHFFFAOYSA-N n-(4-iodophenyl)-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(I)C=C1 MOEBVDPNOPDLGV-UHFFFAOYSA-N 0.000 description 1
- SIULLDWIXYYVCU-UHFFFAOYSA-N n-(4-iodophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(I)C=C1 SIULLDWIXYYVCU-UHFFFAOYSA-N 0.000 description 1
- CKKGAPLFCABOSW-UHFFFAOYSA-N n-(4-iodophenyl)benzamide Chemical compound C1=CC(I)=CC=C1NC(=O)C1=CC=CC=C1 CKKGAPLFCABOSW-UHFFFAOYSA-N 0.000 description 1
- BZKUVUJNAPRNKA-UHFFFAOYSA-N n-(4-iodophenyl)cyclohexanecarboxamide Chemical compound C1=CC(I)=CC=C1NC(=O)C1CCCCC1 BZKUVUJNAPRNKA-UHFFFAOYSA-N 0.000 description 1
- OWRJMRAKRDWZHS-UHFFFAOYSA-N n-(4-iodophenyl)cyclopropanecarboxamide Chemical compound C1=CC(I)=CC=C1NC(=O)C1CC1 OWRJMRAKRDWZHS-UHFFFAOYSA-N 0.000 description 1
- SZULKQKLXQZPCZ-UHFFFAOYSA-N n-(4-iodophenyl)furan-2-carboxamide Chemical compound C1=CC(I)=CC=C1NC(=O)C1=CC=CO1 SZULKQKLXQZPCZ-UHFFFAOYSA-N 0.000 description 1
- QGXGZMVBVHCJPM-UHFFFAOYSA-N n-(4-iodophenyl)piperidine-1-carboxamide Chemical compound C1=CC(I)=CC=C1NC(=O)N1CCCCC1 QGXGZMVBVHCJPM-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- XRLJKIYWSQACLG-UHFFFAOYSA-N n-benzyl-4-iodoaniline Chemical compound C1=CC(I)=CC=C1NCC1=CC=CC=C1 XRLJKIYWSQACLG-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- MKJZRZRIEWBTMN-UHFFFAOYSA-N prop-2-ynoyl chloride Chemical compound ClC(=O)C#C MKJZRZRIEWBTMN-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010379 pull-down assay Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 230000006010 pyroptosis Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000001590 sural nerve Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- AVZDGFRDSOPFCR-UHFFFAOYSA-N tert-butyl-(3-iodophenoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(I)=C1 AVZDGFRDSOPFCR-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
Definitions
- the present invention relates to the technical field of medicine, and in particular, to a substituted cyclic compound, a pharmaceutical composition and an application thereof in preparation of MLKL inhibitors.
- necroptosis involves in normal organ development, tissue homeostasis, inflammation, inflammation, and disease pathogenesis.
- necroptosis One of the most well-studied is necroptosis.
- receptor-interacting kinase1 RIP1
- RIP3 receptor-interacting kinase3
- MLKL be phosphorylated by RIP3 and form oligomers, which then translocate to the cell membrane to form pores, triggering cell membrane rupture and damage-associated molecular patterns (DAMP) release (Cancer Biol Ther 2016, 17 (9) , 899-910. ) .
- DAMP damage-associated molecular patterns
- the MLKL-mediated disorder is a pathology associated with cell death or necroptosis or physiological abnormalities, such as ischemia-reperfusion damage, neurodegeneration, multiple sclerosis, diabetic neuropathy, atherosclerosis, tumor, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation, including inflammatory diseases such as sepsis, acute pancreatitis, chronic obstructive pulmonary disease, psoriasis, inflammatory bowel disease, acute colitis and allergic colitis, etc.
- ischemia-reperfusion damage such as ischemia-reperfusion damage, neurodegeneration, multiple sclerosis, diabetic neuropathy, atherosclerosis, tumor, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation, including inflammatory diseases such as sepsis, acute pancreatitis, chronic obstructive
- necroptosis participates in several tissue damage and pro-inflammatory diseases, including acute colitis, chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease, multiple sclerosis, atherosclerosis, allergic colitis, neurodegenerative diseases, systemic inflammatory response syndrome, and psoriasis, etc (Semin Cell Dev Biol 2014, 35, 14-23. ) . Therefore, MLKL, become potential targets for the treatment of necroptosis-related diseases.
- COPD chronic obstructive pulmonary disease
- MLKL is also defined as a druggable target for developing agents to prevent or treat diabetic neuropathy.
- necroptosis can also be triggered independently of the RIPK1-RIPK3-MLKL pathway, for example in ZBP1/RIP3/MLKL-mediated heatstroke (Science 2022, 376 (6593) , 609-615) , making MLKL an attractive target for drug development.
- the present disclosure provides a substituted cyclic compound having a novel structure, which is used as a selective inhibitor for MLKL and has the advantages of high activity, good selectivity, etc.
- the present disclosure provides a compound of Formula (I) , or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof,
- U 2 and U 4 are each independently CH or N;
- L 1 is -CH 2 -or -NR L1 -, wherein R L1 is hydrogen or C 1-6 alkyl;
- R 1 is -Y 1 -R 5 ;
- R 5 is selected from hydrogen, halogen, cyano, -NR a R b , -CHR c R d , C 3-6 cycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R 51 ;
- R 2 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, -NR a R b , or hydroxyl substituted or unsubstituted C 5-8 monocyclic aryl;
- L 1 , L 2 , R 1 , R 2 form together a C 3-6 heterocycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
- R 4 is selected from hydrogen
- Ring A and Ring B are each independently C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
- Ring C and Ring D are each independently selected from C 3-6 cycloalkyl, C 3-6 hetercycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
- R 51 is selected from halogen, cyano, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy or C 5-8 monocyclic aryl;
- R a and R b are each independently hydrogen or C 1-6 alkyl
- R c and R d are each independently C 5-8 monocyclic aryl.
- U 1 and U 3 are CH 2 , U 2 and U 4 are CH; or,
- U 3 is CH 2
- U 2 and U 4 are CH.
- L 1 is selected from -NH 2 , -CH 2 -, -NH-or -N-C 1-3 alkyl-.
- L 1 is selected from -NH 2 , -CH 2 -, -NH-or -N (CH 3 ) -.
- L 1 is selected from -NH-.
- L 3 is selected from -CH 2 C ⁇ C-.
- R 1 is -Y 1 -R 5 ;
- R 5 is selected from hydrogen, halogen, C 3-6 cycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R 51 ;
- R 51 is selected from halogen, cyano, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 5-8 monocyclic aryl;
- R a and R b are each independently hydrogen or C 1-6 alkyl.
- R 1 is selected from hydrogen, -CN,
- R 1 is selected from
- R 2 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy.
- R 2 is selected from hydrogen, chlorine, methyl or methoxy.
- R 2 is selected from hydrogen, halogen, methyl, methoxy, ethoxy, oxo, -SCH 3 , -N (CH 3 ) 2 or hydroxyphenyl.
- R 3 is selected from C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl.
- R 3 is selected from methyl, ethyl, propyl or
- ring A is selected from phenyl, pyridyl, or pyrimidinyl.
- Ring A and Ring D are each independently selected from phenyl or pyridyl.
- R a and R b are each independently hydrogen or C 1-6 alkyl.
- R 4 is selected from hydrogen, cyclopropyl,
- R 4 is selected from hydrogen
- the compound of Formula (I) is a compound of Formula (II) :
- the compound of Formula (I) is a compound of Formula (III) :
- R 1 , R 2 and R 3 are as defined in Formula (I) .
- the compound of Formula (III) is a compound of Formula (IIIa) , a compound of Formula (IIIb) or a compound of Formula (IIIc) :
- R 1 , R 2 , R 3 and R 4 are as defined in Formula (I) .
- the compound of Formula (III) is a compound of Formula (IIIa’) , a compound of Formula (IIIb’) or a compound of Formula (IIIc’) :
- R 1 and R 3 are as defined in Formula (I) .
- the compound of Formula (III) is a compound of Formula (IIIa”) or a compound of Formula (IIIb”) :
- R 1 and R 4 are as defined in Formula (I) .
- the present disclosure provides a preparation method of the above compound, which is selected from the following synthesis routes:
- R 1 , R 2 , L 2 is defined as above.
- R 4 is defined as above.
- R 3 is defined as above.
- the present disclosure provides a pharmaceutical composition, comprising the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof and pharmaceutically acceptable carrier.
- the present disclosure provides use of the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or the pharmaceutical composition as described above in preparing a drug for preventing and/or treating an MLKL-mediated disorder, disease or condition.
- the MLKL-mediated disorder, disease or condition are selected from tissue damage or pro-inflammatory diseases;
- the MLKL-mediated disorder, disease or condition are selected from, chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease, acute pancreatitis, multiple sclerosis, atherosclerosis, allergic colitis, neurodegenerative diseases, ischemia-reperfusion damage, diabetic neuropathy, cancer, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation, systemic inflammatory response syndrome or psoriasis.
- COPD chronic obstructive pulmonary disease
- the present disclosure provides use of the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or the pharmaceutical composition as described above in preparing MLKL inhibitors.
- the MLKL-mediated disorder, disease or condition are selected from inflammatory diseases, ischemia-reperfusion injury, neurodegenerative disease, cancer, acute injury of kidney, blinding eye disease, liver disease or cardiovascular disease.
- the inflammatory diseases are selected from inflammatory bowel disease, acute pancreatitis, sepsis, acute colitis and allergic colitis.
- the neurodegenerative disease are selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal injury, multiple sclerosis and stroke.
- the cancer are selected from breast carcinoma, colon carcinoma, esophageal carcinoma and carcinoma of the pancreas.
- the blinding eye disease are selected from age-related macular degeneration and retinitis pigmentosa.
- the liver disease is alcoholic liver disease.
- the cardiovascular disease is atherosclerosis.
- the present disclosure provides a method to treat a subject having an MLKL disorder, which comprises administering to the subject a compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or a pharmaceutical composition as described above.
- FIG. 1 shows the results of tests for specificity.
- FIG. 2 shows Compounds 144 and 148 covalently bind with sulfhydryl group of GSH.
- FIG. 3 shows Compounds 144 and 148 covalently bind Cys86 of human MLKL.
- (3A) Compounds 144 and 148 do not inhibit necroptosis induced in mouse MEF cells. MEF cells were seeded in 96-well plates, and after TSZ induction for 24h, the cell viability was measured based on ATP levels.
- (3B) The b-/y-ion spectra from LC-MS/MS analysis of the 144-modified Cys86 containing human MLKL peptide.
- (3D) Compounds 144 and 148 covalently binds Cys86 of MLKL.
- FIG. 4 shows Compounds 144 and 148 inhibit the translocation of MLKL to cell membranes.
- (4A) Compounds 144 and 148 partially inhibit MLKL oligomerization.
- (4B) Compounds 144 and 148 inhibited the translocation of MLKL from the cytoplasm to the cell membrane.
- (4C) The effects of different compounds on the cellular localization of p-MLKL. HT-29 cells were treated as indicated for 8 h.
- treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
- “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
- “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
- “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
- the term “subject” refers to an animal.
- the animal is a mammal.
- a subject also refers to for example, primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
- the subject is a human.
- the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
- solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
- solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid, ethanolamine or a combination thereof.
- DMSO dimethylsulfoxide
- hydrate refers to the complex where the solvent molecule is water.
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc. As used herein, the symbol “-” or “*” in a substituent in each group represents a bond for linking to other group or structure.
- the term “pharmaceutically acceptable” refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art.
- the term “prodrug” refers to a compound that is transformed in vivo into a compound. Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
- the term “optionally substituted” means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
- the number, placement and selection of substituents is understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus 'oxo' would not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom would not have three hydroxy or amino substituents.
- substituted refers to the replacement of one or more hydrogen radicals in a given structure or radical with a specified substituent. Unless otherwise indicated, a substituent may substitute at any substitutable position of a radical. When more than one positions of a given structure can be substituted with one or more specified substituents, the substituents may be either the same or different at each position.
- halogen may be fluorine, chlorine, bromine or iodine.
- C 1-3 alkyl refers to straight chain or branched alkyl having 1-3 carbon atoms, such as methyl, ethyl, propyl, isopropyl.
- propyl represents n-propyl
- alkoxy refers to a group having an -O-alkyl structure, where the alkyl is as defined above.
- C 1-3 alkoxy refers to alkoxy having 1 to 3 carbon atoms. Specific examples of alkoxy include but are not limited to methoxy, ethoxy, n-propoxy.
- halogen refers to fluorine, chlorine, bromine, and iodine.
- cycloalkyl can be used interchangeably, which refers to saturated monocyclic or polycyclic fused cyclohydrocarbyl.
- C 3-6 cycloalkyl refers to cycloalkyl having 3 to 6 carbon atoms.
- aryl refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
- aryl groups include phenyl, naphthyl, anthracenyl.
- heteroaryl refers to a monocyclic or bicyclic aryl ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 5 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5-membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6-membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms.
- heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted, the heteroaryl is attached to its pendant group at any
- the terms “8-to 10-membered bicyclic heteroaryl ” which refers to fused bicyclic heteroaryl having 8 to 10 ring atoms with 1, 2 or 3 ring atoms being heteroatoms.
- the fused bicyclic heteroaryl may either a bicyclic group formed by a monoaryl ring (e.g., phenyl) fused with a monoheteroaryl ring (preferably a 5-or 6-membered monoheteroaryl ring) , or a bicyclic group formed by a monoaryl ring fused with a monoheteroaryl ring (preferably a 5-or 6-membered monoheteroaryl ring) .
- MLKL Mixed Lineage Kinase Domain-Like protein
- TNF ⁇ tumor necrosis factor alpha
- RCD regulated cell death
- Cpd compound
- RHIM receptor-interacting protein
- COPD chronic obstructive pulmonary disease
- NSA Necrosulfonamide
- MDFs mouse dermal fibroblasts
- GSH glutathione
- EGFR epidermal growth factor receptor
- MEF mouse embryonic fibroblast
- HATU 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
- GAPDH Glyceraldehyde-3-phosphate dehydrogenase
- the system was equipped with a Waters C 18 5 ⁇ m SunFire separation column (150 mm ⁇ 4.6 mm) , equilibrated with UPLC grade water (solvent A) and UPLC grade acetonitrile (solvent B) with a flow rate of 0.3 mL/min. Thin-layer chromatography was carried out using HS-GF 254 silica plates; chromatographic purification was carried out using silica gel (Qingdao Ocean Chemical Silicone Factory) . All of the tested compounds were determined to be ⁇ 95%pure by UPLC.
- 6-chloro-3-methylpyrimidine-2, 4 (1H, 3H) -dione (15.0 g, 93.4 mmol) was dissolved in concentrated sulfuric acid (45 mL) cooled in water bath that the internal temperature did not exceed 40°C.
- Concentrated nitric acid (15 mL) was added to this mixture dropwise meanwhile maintaining the temperature below 45°C with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 60 min then dumped into 300 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. A yellow solid of I-6 was obtained (12.2 g, 64.2%) .
- Ethenesulfonic acid chloride (75.9 mg, 0.6 mmol) was added to a solution of I-13 (125 mg, 0.6 mmol) and TEA (121 mg, 1.2 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Trifluoromethanesulfonic acid (1.34mL, 15.1 mmol) was added to a solution of I-16 (1.06 g, 5.36 mmol) in TFA (13.4 mL) at 0°C under a nitrogen atmosphere and the mixture was stirred at RT for 10 min until the completion of the reaction.
- I-17 (530 mg, 3.78 mmol) was dissolved in concentrated sulfuric acid (3 mL) cooled in water bath that the internal temperature did not exceed 40°C.
- concentrated nitric acid (1 mL) was added dropwise meanwhile maintaining the temperature below 45°C with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour then dumped into 20 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. A yellow solid of I-18 was obtained (456 mg, 64.3 %) .
- Ethenesulfonic acid chloride (26.6 mg, 0.21 mmol) was added to a solution of I-20 (40 mg, 0.21 mmol) and TEA (42.5 mg, 0.42 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- the I-7 (2.1 g, 12 mmol) was dissolved in dried DMF (100 mL) in a three-necked flask with magnetic stirring.
- the 3- (p-tolyl) propanoic acid (1.97 g, 12 mmol) and HATU (5.93 g, 15.6 mmol) were added and the mixture was cooled to 0 °C.
- DIPEA 3.1 g, 24 mmol
- the reaction was quenched with saturated ammonium chloride solutionand extracted with CH 2 Cl 2 .
- the organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated.
- Acetyl chloride (71.4 mg, 0.91 mmol) was added to a solution of 3-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Benzoyl chloride (128 mg, 0.91 mmol) was added to a solution of 3-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Acetyl chloride (71.4 mg, 0.91 mmol) was added to a solution of 4-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Benzoyl chloride (128 mg, 0.91 mmol) was added to a solution of 4-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- N, O-Bis (trimethylsilyl) acetamide (BSA, 12.2 g, 60 mmol) and chloromethyl ethyl ether (3.1 g, 32.7 mmol) were added to a solution of 6-chloropyrimidine-2, 4 (1H, 3H) -dione (4.0 g, 27.3 mmol) in DCM (100 mL) at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 6 hours. After completion of the reaction, the mixture was diluted with saturated ammonium chloride solution (50 mL) and extracted with DCM (20 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- I-27a 500 mg, 2.15 mmol was dissolved in concentrated sulfuric acid (6 mL) cooled in water bath that the internal temperature did not exceed 40°C.
- concentrated nitric acid (2 mL) was added dropwise meanwhile maintaining the temperature below 45°C with ice-bath.
- I-27b 400 mg, 1.62 mmol was dissolved in concentrated sulfuric acid (4.2 mL) cooled in water bath that the internal temperature did not exceed 40°C.
- concentrated nitric acid 1.4 mL was added dropwise meanwhile maintaining the temperature below 45°C with ice-bath.
- I-27c (176 mg, 0.62 mmol) was dissolved in concentrated sulfuric acid (3 mL) cooled in water bath that the internal temperature did not exceed 40°C.
- concentrated nitric acid (1 mL) was added dropwise meanwhile maintaining the temperature below 45°C with ice-bath.
- the I-29a (200 mg, 1.06 mmol) was dissolved in dried DMF (15 mL) in a three-necked flask with magnetic stirring.
- the 3- (p-tolyl) propanoic acid (173 mg, 1.06 mmol) and HATU (521 mg, 1.37 mmol) were added and the mixture was cooled to 0 °C.
- DIPEA (273 mg, 2.11 mmol) was added dropwise and the mixture was stirred for 5 hours at RT.
- the reaction was quenched with saturated ammonium chloride solution and extracted with CH 2 Cl 2 .
- the organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated.
- the I-29b (150 mg, 0.74 mmol) was dissolved in dried DMF (15 mL) in a three-necked flask with magnetic stirring.
- the 3- (p-tolyl) propanoic acid (122 mg, 0.74 mmol) and HATU (366 mg, 0.96 mmol) were added and the mixture was cooled to 0 °C.
- DIPEA (192 mg, 1.48 mmol) was added dropwise and the mixture was stirred for 5 hours at RT.
- the reaction was quenched with saturated ammonium chloride solution and extracted with CH 2 Cl 2 .
- the organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated.
- the I-29c (42 mg, 0.17 mmol) was dissolved in dried DMF (5 mL) in a three-necked flask with magnetic stirring.
- the 3- (p-tolyl) propanoic acid 28 mg, 0.17 mmol
- HATU 86 mg, 0.22 mmol
- DIPEA 44 mg, 0.34 mmol
- the reaction was quenched with saturated ammonium chloride solution and extracted with CH 2 Cl 2 .
- the organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated.
- acyl chlorides (Y1–Y21, 0.69 mmol) was added to a solution of 4-iodoaniline (100 mg, 0.46 mmol) and TEA (69.8 mg, 0.69 mmol) in dry DCM (10 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (8 mL) , then the mixture was extracted with DCM (4 mL ⁇ 3) , and the organic layer was washed with brine and dried over Na 2 SO 4 .
- Benzoyl chloride (121 mg, 0.86 mmol) was added to a solution of 4-iodo-2-methylaniline (200 mg, 0.86 mmol) and TEA (174 mg, 1.72 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Benzoyl chloride (114 mg, 0.81 mmol) was added to a solution of 2-ethyl-4-iodoaniline (200 mg, 0.81 mmol) and TEA (164 mg, 1.62 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Tetrahydro-2H-pyran-4-carbonyl chloride 120 mg, 0.81 mmol was added to a solution of 2-ethyl-4-iodoaniline (200 mg, 0.81 mmol) and TEA (164 mg, 1.62 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Benzoyl chloride (239 mg, 1.7 mmol) was added to a solution of 2-amino-5-iodophenol (200 mg, 0.85 mmol) and TEA (172 mg, 1.7 mmol) in DCM (10 mL) dropwise at 0°C under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- the I-41 (65 mg, 0.22 mmol) was dissolved in dried DMF (6 mL) in a three-necked flask with magnetic stirring.
- the aniline (21 mg, 0.22 mmol) and HATU (103 mg, 0.26 mmol) were added and the mixture was cooled to 0 °C.
- DIPEA (57 mg, 0.44 mmol) was added dropwise and the mixture was stirred for 5 hours at RT.
- the reaction was quenched with saturated ammonium chloride solution and extracted with CH 2 Cl 2 .
- the organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated.
- Example 1 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 1) .
- Example 2 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 2) .
- Example 3 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 3) .
- Example 4 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 4) .
- Ethenesulfonic acid chloride (43.4 mg, 0.36 mmol) was added to a solution of I-11 (100 mg, 0.24 mmol) and TEA (36.4 mg, 0.36 mmol) in dry DCM (6 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (5 mL) , then the mixture was extracted with DCM (3 mL ⁇ 3) , and the organic layer was washed with brine and dried over Na 2 SO 4 . The solvent was filtered, concentrated under reduced pressure and the residue was directly dissolved in THF (8 mL) .
- Example 5 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -6-methoxy-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 5) .
- Pd(Pph 3 ) 4 (10.8 mg, 0.009 mmol) and CuI (3.6 mg, 0.018 mmol) were added to a solution containing I-14a (48 mg, 0.184 mmol) , 3-iodophenol (48.4 mg, 0.22 mmol) and N, N-diisopropylethylamine (51.6 mg, 0.4 mmol) in DMF (8 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50°C for 4 hours in an oil bath. After completion, the mixture was diluted with water (20 mL) , extracted with EA (5 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Example 6 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3, 6-dimethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 6) .
- Example 7 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -6-methoxy-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 7) .
- Pd (Pph 3 ) 4 (13.3 mg, 0.012 mmol) and CuI (4.4 mg, 0.023 mmol) were added to a solution containing I-14b (69 mg, 0.23 mmol) , 3-iodophenol (62 mg, 0.28 mmol) and N, N-diisopropylethylamine (66 mg, 0.51 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50°Cfor 4 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Example 8 N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3, 6-dimethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 8) .
- Example 10 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) propiolamide (Compound 10) .
- Example 11 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) but-2-ynamide (Compound 11) .
- Example 12 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acetamide (Compound 12) .
- Example 13 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) propionamide (Compound 13) .
- Example 14 2-chloro-N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acetamide (Compound 14) .
- Example 15 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) butyramide (Compound 15) .
- Example 16 ethyl (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate (Compound 16) .
- Example 17 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3, 3-dimethylbutanamide (Compound 17) .
- Example 18 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2, 2-dimethylbutanamide (Compound 18) .
- Example 19 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2-methylbutanamide (Compound 19) .
- Example 20 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) pentanamide (Compound 20) .
- Example 21 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (2-methoxyethoxy) acetamide (Compound 21) .
- Example 22 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) octanamide (Compound 22) .
- Example 23 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclopropanecarboxamide (Compound 23) .
- Example 24 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclobutanecarboxamide (Compound 24) .
- Example 25 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclopentanecarboxamide (Compound 25) .
- Example 26 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) benzamide (Compound 26) .
- Example 27 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2-phenylacetamide (Compound 27) .
- Example 28 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3-phenylpropanamide (Compound 28) .
- Example 29 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -4-phenylbutanamide (Compound 29) .
- Example 30 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cinnamamide (Compound 30) .
- Example 31 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (2-fluorophenyl) acetamide (Compound 31) .
- Example 32 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (3-fluorophenyl) acetamide (Compound 32) .
- Example 33 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-fluorophenyl) acetamide (Compound 33) .
- Example 34 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-methoxyphenyl) acetamide (Compound 34) .
- Example 35 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-chlorophenyl) acetamide (Compound 35) .
- Example 36 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (pyridin-3-yl) propanamide (Compound 36) .
- Example 37 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3, 3-diphenylpropanamide (Compound 37) .
- Example 38 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (2-fluorophenyl) propanamide (Compound 38) .
- Example 39 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3-fluorophenyl) propanamide (Compound 39) .
- Example 40 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-fluorophenyl) propanamide (Compound 40) .
- Example 41 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-chlorophenyl) propanamide (Compound 41) .
- Example 42 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3-chlorophenyl) propanamide (Compound 42) .
- Example 43 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 43) .
- Example 44 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (m-tolyl) propanamide (Compound 44) .
- Example 45 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-ethylphenyl) propanamide (Compound 45) .
- Example 46 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-isopropylphenyl) propanamide (Compound 46) .
- Example 47 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-cyanophenyl) propanamide (Compound 47) .
- Example 48 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-methoxyphenyl) propanamide (Compound 48) .
- Example 49 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4- (trifluoromethyl) phenyl) propanamide (Compound 49) .
- Example 50 N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3, 4-difluorophenyl) propanamide (Compound 50) .
- Example 51 N- (6-chloro-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 51) .
- R are the groups corresponding to the R 4 part of compound 52–75, 79-150 in Formula (I) .
- Example 52 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3-phenylprop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 52) .
- Example 53 N- (6-chloro-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 53) .
- Example 54 N- (6-chloro-1- (3- (2-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 54) .
- Example 55 N- (6-chloro-1- (3- (3-methoxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 55) .
- Example 56 N- (6-chloro-1- (3- (4-methoxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 56) .
- Example 57 N- (6-chloro-1- (3- (3, 5-dihydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 57) .
- Example 58 N- (6-chloro-1- (3- (3, 4-dihydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 58) .
- Example 59 N- (1- (3- (benzo [d] [1, 3] dioxol-5-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 59) .
- Example 60 N- (6-chloro-1- (3- (3- (hydroxymethyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 60) .
- Example 61 N- (6-chloro-1- (3- (4- (hydroxymethyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 61) .
- Example 62 N- (6-chloro-1- (3- (3-fluoro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 62) .
- Example 63 N- (6-chloro-1- (3- (2-fluoro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 63) .
- Example 64 N- (6-chloro-1- (3- (3-chloro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 64) .
- Example 65 N- (6-chloro-1- (3- (2-chloro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 65) .
- Example 66 N- (6-chloro-1- (3- (4-chloro-3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 66) .
- Example 67 N- (6-chloro-1- (3- (4-hydroxy-3-methylphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 67) .
- Example 68 N- (6-chloro-1- (3- (3-hydroxy-4-methylphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 68) .
- Example 69 N- (1- (3- (3-aminophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 69) .
- Example 70 N- (1- (3- (3-acetamidophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 70) .
- Example 71 N- (3- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 71) .
- Example 72 N- (1- (3- (4-aminophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 72) .
- Example 73 N- (1- (3- (4-acetamidophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 73) .
- Example 74 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 74) .
- Example 75 N- (1- (3- (4- (benzylamino) phenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 75) .
- Example 76 N- (6-chloro-3-ethyl-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 76) .
- Example 77 N- (6-chloro-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-3-propyl-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 77) .
- Pd (Pph 3 ) 4 (7.5 mg, 0.007 mmol) and CuI (2.5 mg, 0.013 mmol) were added to a solution containing I-31b (50 mg, 0.13 mmol) , 4-iodophenol (34.1 mg, 0.155 mmol) and N, N-diisopropylethylamine (37 mg, 0.235 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50°Cfor 6 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Example 78 N- (6-chloro-3- (cyclopentylmethyl) -1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 78) .
- Pd (Pph 3 ) 4 (9 mg, 0.0075 mmol) and CuI (2.85 mg, 0.015 mmol) were added to a solution containing I-31c (60 mg, 0.15 mmol) , 4-iodophenol (60 mg, 0.18 mmol) and N, N-diisopropylethylamine (43 mg, 0.33 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50°Cfor 6 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL ⁇ 3) , the organic layer was washed with brine and dried over Na 2 SO 4 .
- Example 79 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- (2-phenylacetamido) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 79) .
- Example 80 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- (3-phenylpropanamido) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 80) .
- Example 81 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cinnamamide (Compound 81) .
- Example 82 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cyclopropanecarboxamide (Compound 82) .
- Example 83 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) tetrahydro-2H-pyran-4-carboxamide (Compound 83) .
- Example 84 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cyclohexanecarboxamide (Compound 84) .
- Example 85 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) piperidine-1-carboxamide (Compound 85) .
- Example 86 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) furan-2-carboxamide (Compound 86) .
- Example 87 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-methoxybenzamide (Compound 87) .
- Example 88 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-fluorobenzamide (Compound 88) .
- Example 89 3-chloro-N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 89) .
- Example 90 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-methylbenzamide (Compound 90) .
- Example 91 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-cyanobenzamide (Compound 91) .
- Example 92 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-methoxybenzamide (Compound 92) .
- Example 93 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-fluorobenzamide (Compound 93) .
- Example 94 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-methylbenzamide (Compound 94) .
- Example 95 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-cyanobenzamide (Compound 95) .
- Example 96 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-methoxybenzamide (Compound 96) .
- Example 97 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-fluorobenzamide (Compound 97) .
- Example 98 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-cyanobenzamide (Compound 98) .
- Example 99 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-hydroxybenzamide (Compound 99) .
- Example 100 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-methylphenyl) benzamide (Compound 100) .
- Example 101 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-methylphenyl) cyclopropanecarboxamide (Compound 101) .
- Example 102 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) benzamide (Compound 102) .
- Example 103 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) cyclopropanecarboxamide (Compound 103) .
- Example 104 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) tetrahydro-2H-pyran-4-carboxamide (Compound 104) .
- Example 105 N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-hydroxyphenyl) benzamide (Compound 105) .
- Example 106 N- (1- (3- (1H-indol-6-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 106) .
- Example 107 N- (1- (3- (1H-indol-5-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 107) .
- Example 108 N- (6-chloro-3-methyl-1- (3- (1-methyl-1H-indol-5-yl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 108) .
- Example 109 N- (6-chloro-1- (3- (2, 3-dioxoindolin-5-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 109) .
- Example 110 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 110) .
- Example 111 methyl 5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -1H-indole-2-carboxylate (Compound 111) .
- Example 112 5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -N-phenyl-1H-indole-2-carboxamide (Compound 112) .
- Example 113 N- (6-chloro-1- (3- (2-hydroxyquinolin-6-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 113) .
- Example 114 N- (6-chloro-1- (3- (1-ethyl-2-oxo-1, 2-dihydroquinolin-6-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 114) .
- Example 115 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 115) .
- Example 116 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 116) .
- Example 117 N- (6-chloro-3-methyl-1- (3- (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 117) .
- Example 118 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxochroman-6-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 118) .
- Example 119 methyl 3- (5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-hydroxyphenyl) propanoate (Compound 119) .
- Example 120 methyl 3- (3- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) propanoate (Compound 120) .
- Example 121 N- (1- (3- (4-acetylphenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 121) .
- Example 122 N- (1- (3- (3-acetylphenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 122) .
- Example 123 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (2-oxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 123) .
- Example 124 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- ( (2-oxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 124) .
- Example 125 N- (6-chloro-1- (3- (3- ( (2, 6-dioxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 125) .
- Example 126 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (3-oxomorpholino) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 126) .
- Example 127 N- (6-chloro-1- (3- (3- ( (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 127) .
- Example 128 methyl 2- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) acetate (Compound 128) .
- Example 129 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 129) .
- Example 130 N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 130) .
- Example 131 N- (6-chloro-3-methyl-1- (3- (3- ( (3-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 131) .
- Example 132 N- (6-chloro-1- (3- (3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 132) .
- Example 133 N– (6-chloro-1- (3- (3- ( (3-fluoro-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 133) .
- Example 134 N- (6-chloro-3-methyl-1- (3- (3- ( (4-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 134) .
- Example 135 N- (6-chloro-1- (3- (3- ( (4-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 135) .
- Example 136 N- (6-chloro-1- (3- (3- ( (4-chloro-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 136) .
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Abstract
A substituted cyclic compound as represented by formula (I) and having a selective inhibitory effect on MLKL, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, a pharmaceutical composition containing the compound and an application thereof in preparation of MLKL inhibitors.
Description
The present invention relates to the technical field of medicine, and in particular, to a substituted cyclic compound, a pharmaceutical composition and an application thereof in preparation of MLKL inhibitors.
Programmed cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, involves in normal organ development, tissue homeostasis, inflammation, inflammation, and disease pathogenesis. One of the most well-studied is necroptosis. After necroptosis induction, receptor-interacting kinase1 (RIP1) is phosphorylated and interacts with downstream receptor-interacting kinase3 (RIP3) to form an amyloid structure named necrosome, as a platform for recruiting mixed lineage kinase domain-like protein (MLKL) . As the executor of necroptosis, MLKL be phosphorylated by RIP3 and form oligomers, which then translocate to the cell membrane to form pores, triggering cell membrane rupture and damage-associated molecular patterns (DAMP) release (Cancer Biol Ther 2016, 17 (9) , 899-910. ) .
The MLKL-mediated disorder is a pathology associated with cell death or necroptosis or physiological abnormalities, such as ischemia-reperfusion damage, neurodegeneration, multiple sclerosis, diabetic neuropathy, atherosclerosis, tumor, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation, including inflammatory diseases such as sepsis, acute pancreatitis, chronic obstructive pulmonary disease, psoriasis, inflammatory bowel disease, acute colitis and allergic colitis, etc. Recent studies have established that necroptosis participates in several tissue damage and pro-inflammatory diseases, including acute colitis, chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease, multiple sclerosis, atherosclerosis, allergic colitis, neurodegenerative diseases, systemic inflammatory response syndrome, and psoriasis, etc (Semin Cell Dev Biol 2014, 35, 14-23. ) . Therefore, MLKL, become potential targets for the treatment of necroptosis-related diseases.
In addition, recent studies have shown that activa tion of MLKL plays an important role in the decompaction of the myelin sheaths of sural nerves in human diabetic neuropathy patients. Small molecule inhibitor targeting MLKL blocked myelin breakdown and prevented the reduction of nerve transmission velocity in model mice. Therefore MLKL is also defined as a druggable target for developing agents to prevent or treat diabetic neuropathy. (Proc Natl Acad Sci 2022, 119 (14) e2121552119. )
In some pathological processes, necroptosis can also be triggered independently of the RIPK1-RIPK3-MLKL pathway, for example in ZBP1/RIP3/MLKL-mediated heatstroke (Science 2022, 376 (6593) , 609-615) , making MLKL an attractive target for drug development.
Until now, the development of MLKL inhibitors is limited. High-affinity inhibitors selectively binding to the pseudokinase domain failed to inhibit MLKL function and necroptosis. GW806742X which targets the pseudokinase domain of MLKL has been found to have off-target activity against other kinases, including VEGFR2, RIP1 and RIP3. So it is possible to conclude that the prevention of necroptosis as mediated by GW806742X relies on the off-target effect. The only two reported covalent MLKL inhibitors, Necrosulfonamide (NSA) and TC13172 (Chem Commun (Camb) 2017, 53 (26) , 3637-3640. ) , covalently bind the Cys86 residue in the N-terminal of human MLKL, preventing MLKL oligomerization and translocation to the cell membrane. The narrow structure-activity relationship (SAR) profile and moderate potency of NSA have limited its development as a drug. Inhibitor TC13172 has high chemical activity with nucleophilic reagents, may cause high off-target effects. Non-covalent MLKL binders have recently been reported, however, its lower affinity (KD=50μM) needs improvement, and its ability to inhibit necroptosis at the cellular level need to be further explored. Because of the small number of MLKL inhibitors at this stage and their many shortcomings, there is a need to develop new MLKL inhibitors.
SUMMARY OF THE INVENTION
The present disclosure provides a substituted cyclic compound having a novel structure, which is used as a selective inhibitor for MLKL and has the advantages of high activity, good selectivity, etc.
In one aspect, the present disclosure provides a compound of Formula (I) , or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof,
wherein,
U
1 and U
3 are each independently CH
2 or C=O;
U
2 and U
4 are each independently CH or N;
L
1 is -CH
2-or -NR
L1-, wherein R
L1 is hydrogen or C
1-6 alkyl;
L
2 and L
3 are each independently selected from a bond, - (CH
2)
m1-, - (CH
2)
m1C (=O) -, - (CH
2)
m1CH=CH-, - (CH
2)
m1C≡C-or -NH (CH
2)
m1C≡C-, wherein m1 is an integer selected from 0 to 3;
R
1 is -Y
1-R
5;
Y
1 is selected from -C
1-6 alkyl-, -C (=O) -, -S (=O)
2-, -C (=O) C
1-10 alkyl-, -C (=O) C
1-6 alkoxy-, -C (=O) CR
a=CHR
b, -C (=O) C≡CR
b, -S (=O)
2CR
a=CHR
b-or -C (=O) (CH
2-O-CH
2)
m2-, wherein m2 is an integer selected from 0 to 3;
R
5 is selected from hydrogen, halogen, cyano, -NR
aR
b, -CHR
cR
d, C
3-6 cycloalkyl, C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R
51;
R
2 is selected from hydrogen, halogen, C
1-6 alkyl, C
1-6 alkoxy, -S-C
1-6 alkyl, -NR
aR
b, or hydroxyl substituted or unsubstituted C
5-8 monocyclic aryl;
R
3 is selected from C
1-6 alkyl, C
1-6 alkyl cyano, C
1-6 alkyl-C
3-6 cycloalkyl or -NHC (=O) CR
a=CHR
b;
or, L
1, L
2, R
1, R
2 form together a C
3-6 heterocycloalkyl, C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
Ring A and Ring B are each independently C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
Ring C and Ring D are each independently selected from C
3-6 cycloalkyl, C
3-6 hetercycloalkyl, C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl;
Y
2 is selected form a bond, -CH
2-, -NH-, -OCH
2-, -CH
2O-, -NHCH
2-, -NHC (=O) -or -C (=O) NH-;
R
41, R
42 and R
43 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, oxo, acyl, halogen substituted or unsubstituted C
1-6 alkyl, C
1-6 alkoxy, -NR
aR
b, C
1-6 alkyl-OH, -OC (=O) -C
1-6 alkyl, -OC (=O) CR
a=CHR
b, -C
1-6 alkoxy-OH, -C (=O) -C
1-6 alkyl, -C (=O) -C
1-6 alkoxy, -C (=O) NH-C
1-6 alkyl, -NHC (=O) -C
1-6 alkoxy, -NHC (=O) CR
a=CHR
b, -NR
aC (=O) CR
a=CHR
b, -CH
2C (=O) -C
1-6 alkoxy, -C
1-6 alkyl-C (=O) -C
1-6 alkyl or -C
1-6 alkyl-C (=O) -C
1-6 alkoxy;
R
51 is selected from halogen, cyano, halogen substituted or unsubstituted C
1-6 alkyl, C
1-6 alkoxy or C
5-8 monocyclic aryl;
R
a and R
b are each independently hydrogen or C
1-6 alkyl;
R
c and R
d are each independently C
5-8 monocyclic aryl.
In an embodiment of the present disclosure, U
1 and U
3 are C=O, U
2 and U
4 are N; or,
U
1 and U
3 are CH
2, U
2 and U
4 are CH; or,
U
1 is C=O, U
3 is CH
2, U
2 and U
4 are CH.
In an embodiment of the present disclosure, L
1 is selected from -NH
2, -CH
2-, -NH-or -N-C
1-3 alkyl-.
Preferably, L
1 is selected from -NH
2, -CH
2-, -NH-or -N (CH
3) -.
Preferably, L
1 is selected from -NH-.
In an embodiment of the present disclosure, L
3 is selected from a bond, -CH
2C≡C-, -CH
2-or -CH
2CH=CH.
Preferably, L
3 is selected from -CH
2C≡C-.
In an embodiment of the present disclosure, R
1 is -Y
1-R
5;
Y
1 is selected from -C (=O) -, -C (=O) C
1-10 alkyl-, -C (=O) C
1-6 alkoxy-, -C (=O) CR
a=CHR
b, -C (=O) C≡CR
b, -S (=O)
2CR
a=CHR
b-or -C (=O) (CH
2-O-CH
2)
m2-, wherein m2 is an integer selected from 0 to 3;
R
5 is selected from hydrogen, halogen, C
3-6 cycloalkyl, C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C
5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R
51;
R
51 is selected from halogen, cyano, halogen substituted or unsubstituted C
1-6 alkyl, C
1-6 alkoxy, C
5-8 monocyclic aryl;
R
a and R
b are each independently hydrogen or C
1-6 alkyl.
In an embodiment of the present disclosure, R
2 is selected from hydrogen, halogen, C
1-6 alkyl or C
1-6 alkoxy.
Preferably, R
2 is selected from hydrogen, chlorine, methyl or methoxy.
In an embodiment of the present disclosure, R
2 is selected from hydrogen, halogen, methyl, methoxy, ethoxy, oxo, -SCH
3, -N (CH
3)
2 or hydroxyphenyl.
In an embodiment of the present disclosure, R
3 is selected from C
1-6 alkyl or C
1-6 alkyl-C
3-6 cycloalkyl.
In an embodiment of the present disclosure, R
3 is selected from methyl, ethyl, propyl, ethyl cyano, NHC (=O) CH=CH-or
In an embodiment of the present disclosure, with regard to
ring A is selected from phenyl, pyridyl, or pyrimidinyl.
In an embodiment of the present disclosure, with regard to
Ring A and Ring D are each independently selected from phenyl or pyridyl.
Preferably, Y
2 is selected from a bound, -NHCH
2-, -NHC (=O) -, -CH
2-, -C (=O) NH-, -NH-, -OCH
2-or CH
2O-.
Preferably, Y
2 is -NHC (=O) -or -CH
2-.
In an embodiment of the present disclosure, wherein R
41, R
42 and R
43 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, oxo, acyl, halogen substituted or unsubstituted C
1-6 alkyl, C
1-6 alkoxy, -NR
aR
b, C
1-6 alkyl-OH, -OC (=O) -C
1-6 alkyl, -OC (=O) CH=CH
2, -C
1-6 alkoxy-OH, -C (=O) -C
1-6 alkyl, -C (=O) -C
1-6 alkoxy, -C (=O) NH-C
1-6 alkyl, -NHC (=O) -C
1-6 alkoxy, -NHC (=O) CH=CH
2, -NR
aC (=O) CH=CH
2, -CH
2C (=O) -C
1-6 alkoxy, -C
1-6 alkyl-C (=O) -C
1-6 alkyl or -C
1-6 alkyl-C (=O) -C
1-6 alkoxy;
R
a and R
b are each independently hydrogen or C
1-6 alkyl.
Preferably, R
41, R
42 and R
43 are each independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxyl, methyl, ethyl, methoxy, CF
3, -CH
2OH, -NHC (=O) CH
3, -C (=O) CH
3, -C (=O) OCH
3 or -CH
2CH
2C (=O) OCH
3.
In an embodiment of the present disclosure, the compound of Formula (I) is a compound of Formula (II) :
wherein U
1, U
2, U
3, U
4, R
1, R
2, R
3, R
4, L
1 and L
2 are as defined in Formula (I) .
In an embodiment of the present disclosure, the compound of Formula (I) is a compound of Formula (III) :
wherein R
1, R
2 and R
3 are as defined in Formula (I) .
In an embodiment of the present disclosure, the compound of Formula (III) is a compound of Formula (IIIa) , a compound of Formula (IIIb) or a compound of Formula (IIIc) :
wherein R
1, R
2, R
3 and R
4 are as defined in Formula (I) .
In an embodiment of the present disclosure, the compound of Formula (III) is a compound of Formula (IIIa’) , a compound of Formula (IIIb’) or a compound of Formula (IIIc’) :
wherein R
1 and R
3 are as defined in Formula (I) .
In an embodiment of the present disclosure, the compound of Formula (III) is a compound of Formula (IIIa”) or a compound of Formula (IIIb”) :
wherein R
1 and R
4 are as defined in Formula (I) .
A compound selected from:
In another aspect, the present disclosure provides a preparation method of the above compound, which is selected from the following synthesis routes:
Route 1:
Wherein R
1, R
2, L
2 is defined as above.
Route 2:
Route 3:
Wherein R
4 is defined as above.
Route 4:
Wherein R
3 is defined as above.
In another aspect, the present disclosure provides a pharmaceutical composition, comprising the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof and pharmaceutically acceptable carrier.
In another aspect, the present disclosure provides use of the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or the pharmaceutical composition as described above in preparing a drug for preventing and/or treating an MLKL-mediated disorder, disease or condition.
Preferably, the MLKL-mediated disorder, disease or condition are selected from tissue damage or pro-inflammatory diseases;
preferably, the MLKL-mediated disorder, disease or condition are selected from, chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease, acute pancreatitis, multiple sclerosis, atherosclerosis, allergic colitis, neurodegenerative diseases, ischemia-reperfusion damage, diabetic neuropathy, cancer, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation, systemic inflammatory response syndrome or psoriasis.
In another aspect, the present disclosure provides use of the compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or the pharmaceutical composition as described above in preparing MLKL inhibitors.
In an embodiment of the present disclosure, the MLKL-mediated disorder, disease or condition are selected from inflammatory diseases, ischemia-reperfusion injury, neurodegenerative disease, cancer, acute injury of kidney, blinding eye disease, liver disease or cardiovascular disease.
Preferably, the inflammatory diseases are selected from inflammatory bowel disease, acute pancreatitis, sepsis, acute colitis and allergic colitis.
Preferably, the neurodegenerative disease are selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal injury, multiple sclerosis and stroke.
Preferably, the cancer are selected from breast carcinoma, colon carcinoma, esophageal carcinoma and carcinoma of the pancreas.
Preferably, the blinding eye disease are selected from age-related macular degeneration and retinitis pigmentosa.
Preferably, the liver disease is alcoholic liver disease.
Preferably, the cardiovascular disease is atherosclerosis.
In another aspect, the present disclosure provides a method to treat a subject having an MLKL disorder, which comprises administering to the subject a compound as described above, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or a pharmaceutical composition as described above.
FIG. 1 shows the results of tests for specificity. (1A) MLKL phosphorylation assays; (1B-1E) apoptosis and ferroptosis assays.
FIG. 2 shows Compounds 144 and 148 covalently bind with sulfhydryl group of GSH. (2A) The chemical mechanism of covalent binding between 144 and GSH. (2B) The reaction rate curve of TC13172, 144 and 148 with GSH. (2C) The EC
50 of the wash/no-wash cell assays for 144.
FIG. 3 shows Compounds 144 and 148 covalently bind Cys86 of human MLKL. (3A) Compounds 144 and 148 do not inhibit necroptosis induced in mouse MEF cells. MEF cells were seeded in 96-well plates, and after TSZ induction for 24h, the cell viability was measured based on ATP levels. (3B) The b-/y-ion spectra from LC-MS/MS analysis of the 144-modified Cys86 containing human MLKL peptide. (3C) Schema of the general procedure for ABPP. (3D) Compounds 144 and 148 covalently binds Cys86 of MLKL.
FIG. 4 shows Compounds 144 and 148 inhibit the translocation of MLKL to cell membranes. (4A) Compounds 144 and 148 partially inhibit MLKL oligomerization. (4B) Compounds 144 and 148 inhibited the translocation of MLKL from the cytoplasm to the cell membrane. (4C) The effects of different compounds on the cellular localization of p-MLKL. HT-29 cells were treated as indicated for 8 h. (4D) Inhibitors inhibit the transfer of oligomerized MLKL to the cell membrane.
DETAILED DESCRIPTION OF EMBODIMENTS
I. Definitions
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as” ) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
As used herein, the term “a, ” “an, ” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
As used herein, the term “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both. In yet another embodiment, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, the term “subject" refers to an animal. In certain aspects, the animal is a mammal. A subject also refers to for example, primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a human.
As used herein, the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term “comprise” or “comprising” is an open expression, it means comprising the contents disclosed herein, but don’t exclude other contents.
As used herein, the terms “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid, ethanolamine or a combination thereof. The term “hydrate” refers to the complex where the solvent molecule is water.
As used herein, the term “stereisomer” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc. As used herein, the symbol “-” or “*” in a substituent in each group represents a bond for linking to other group or structure.
As used herein, the term “pharmaceutically acceptable” refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. As used herein, the term “prodrug” refers to a compound that is transformed in vivo into a compound. Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
As used herein, the term “optionally substituted” means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter. The number, placement and selection of substituents is understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus 'oxo' would not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom would not have three hydroxy or amino substituents.
As used herein, the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure or radical with a specified substituent. Unless otherwise indicated, a substituent may substitute at any substitutable position of a radical. When more than one positions of a given structure can be substituted with one or more specified substituents, the substituents may be either the same or different at each position.
As used herein, the term “halogen” may be fluorine, chlorine, bromine or iodine.
As used herein, the term “C
1-3 alkyl” refers to straight chain or branched alkyl having 1-3 carbon atoms, such as methyl, ethyl, propyl, isopropyl.
As used herein, the term “propyl” represents n-propyl.
As used herein, the term “alkoxy” refers to a group having an -O-alkyl structure, where the alkyl is as defined above. The term “C
1-3 alkoxy” refers to alkoxy having 1 to 3 carbon atoms. Specific examples of alkoxy include but are not limited to methoxy, ethoxy, n-propoxy.
As used herein, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.
As used herein, the terms “cycloalkyl” can be used interchangeably, which refers to saturated monocyclic or polycyclic fused cyclohydrocarbyl. The term “C
3-6 cycloalkyl” refers to cycloalkyl having 3 to 6 carbon atoms.
As used herein, the term “aryl, ” unless otherwise stated, ” refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Examples of aryl groups include phenyl, naphthyl, anthracenyl.
As used herein, the term “heteroaryl” refers to a monocyclic or bicyclic aryl ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 5 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5-membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6-membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the 6-membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
As used herein, the terms “8-to 10-membered bicyclic heteroaryl ” which refers to fused bicyclic heteroaryl having 8 to 10 ring atoms with 1, 2 or 3 ring atoms being heteroatoms. The fused bicyclic heteroaryl may either a bicyclic group formed by a monoaryl ring (e.g., phenyl) fused with a monoheteroaryl ring (preferably a 5-or 6-membered monoheteroaryl ring) , or a bicyclic group formed by a monoaryl ring fused with a monoheteroaryl ring (preferably a 5-or 6-membered monoheteroaryl ring) .
Abbreviations:
Cpd, compound;
MLKL, Mixed Lineage Kinase Domain-Like protein;
SAR, structure-activity relationship;
TNFα, tumor necrosis factor alpha;
Smac, second mitochondrial-derived activator of caspases;
z-VAD-FMK, Z-Val-Ala-Asp- (OMe) -fluoromethyl ketone;
RCD, regulated cell death; Cpd, compound;
RIP1, receptor-interacting protein 1;
RIP3, receptor-interacting protein 3;
RHIM, receptor-interacting protein (RIP) homotypic interaction motif;
DAMP, damage-associated molecular patterns;
COPD, chronic obstructive pulmonary disease;
NSA, Necrosulfonamide; MDFs, mouse dermal fibroblasts;
GSH, glutathione;
T
1/2, half-life;
Cys, Cysteine;
PK, pharmacokinetic;
EGFR, epidermal growth factor receptor;
EC
50, half maximal effective concentration;
DPBS, Dulbecco’s phosphate buffered saline;
p-MLKL, phosphorylated MLKL;
MEF, mouse embryonic fibroblast;
ABPP, activity-based proteome profiling;
RT, room temperature;
BSA, N, O-Bis (trimethylsilyl) acetamide;
TBAF, tetrabutylammonium fluoride;
HATU, 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate;
GAPDH, Glyceraldehyde-3-phosphate dehydrogenase.
II. EXAMPLES
Materials
All chemical reagents were used as supplied by J&K, Sigma-Aldrich, and Alfa Aesar Chemicals. The reagents and solvents for reactions were reagent-grade and used without further purification. Reactions sensitive to water and air rigorously followed water-free and oxygen-free reaction procedures, wherein reagents were added with an injection syringe.
1H NMR spectra were recorded on a Varian 400 MHz spectrometer at ambient temperature with CDCl
3 as the solvent unless otherwise stated.
13C NMR spectra were recorded on a Varian 100 MHz spectrometer (with complete proton decoupling) at ambient temperature with DMSO as the solvent unless otherwise stated. Data for
1H NMR are reported as follows: chemical shift, multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, m = multiplet) , integration, and coupling constants. High-resolution mass spectra were obtained using Agilent Technolodies 6540 UHD Accurate-Mass Q-TOF LC/MS. All of the synthesized compounds were analyzed by UPLC/MS on a Waters Auto Purification LC/MS system (3100 mass detector, 2545 binary gradient module, 2767 sample manager, and 2998 photodiode array (PDA) detector) . The system was equipped with a Waters C
18 5μm SunFire separation column (150 mm × 4.6 mm) , equilibrated with UPLC grade water (solvent A) and UPLC grade acetonitrile (solvent B) with a flow rate of 0.3 mL/min. Thin-layer chromatography was carried out using HS-GF 254 silica plates; chromatographic purification was carried out using silica gel (Qingdao Ocean Chemical Silicone Factory) . All of the tested compounds were determined to be ≥95%pure by UPLC.
Synthesis Procedure for Chemical Intermediates
Intermediate I-1
: tert-butyl (3-iodophenoxy) dimethylsilane.
A mixture of 3-iodophenol (3.00 g, 13.60 mmol) and imidazole (1.48 g, 21.76 mmol) were stirred in DCM (20 mL) under nitrogen atmosphere. A solution of TBDMSCl (3.07 g, 20.4 mmol) in DCM (5 mL) was added dropwise at RT over 3 min and the mixture was stirred for 12 h. The mixture was diluted with water (100 mL) , extracted with DCM (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE) to give intermediate I-1 (3.16 g, 71.8%) as a colorless oil.
1H NMR (400 MHz, CDCl
3) : δ 7.30 (ddd, J = 8.0, 1.6, 0.8 Hz, 1H) , 7.24 (t, J = 2.0 Hz, 1H) , 6.95 (t, J = 8.0 Hz, 1H) , 6.81 (ddd, J = 8.4, 2.4, 0.8 Hz, 1H) , 0.99 (s, 9H) , 0.22 (s, 6H) . UPLC-MS (ESI) [M-C
2H
6]
+: calcd for C
10H
13IOSi, 303.98; found, 304.25. UPLC purity 95%.
Intermediate I-2: 3-methyl-5-nitro-1- (prop-2-yn-1-yl) pyrimidine-2, 4 (1H, 3H) -dione.
3-Bromoprop-1-yne (416 mg, 3.50 mmol) and K
2CO
3 (524 mg, 3.79 mmol) were added to a solution of 3-methyl-5-nitropyrimidine-2, 4 (1H, 3H) -dione (500 mg, 2.92 mmol) in DMF (10 mL) sequentially. The mixture was stirred for 12 h under nitrogen atmosphere until its completion monitored by TLC. The mixture was diluted with water (50 mL) , extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-2 (410 mg, 67.1%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 9.04 (s, 1H) , 4.75 (d, J = 2.6 Hz, 1H) , 3.42 (s, 1H) , 2.74 (t, J = 2.6 Hz, 1H) . UPLC-MS (ESI) [M+H]
+: calcd for C
8H
8N
3O
4, 210.05; found, 210.01. UPLC purity 94%.
Intermediate I-3: 1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -3-methyl-5-nitropyrimidine-2, 4 (1H, 3H) -dione.
Pd (Pph
3)
4 (38.1 mg, 0.033 mmol) and CuI (12.4 mg, 0.065 mmol) were added to a solution containing I-2 (135 mg, 0.65 mmol) , I-1 (257 mg, 0.77 mmol) and N, N-diisopropylethylamine (200 mg, 1.55 mmol) in DMF (10mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 55℃ for 3 h in an oil bath. After completion of the reaction, the mixture was diluted with water (50 mL) , extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=4: 1) to give intermediate I-3 (206 mg, 76.8%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 9.14 (s, 1H) , 7.21 (t, J = 8.0 Hz, 1H) , 7.08 (dt, J = 8.0, 1.2 Hz, 1H) , 6.95–6.93 (m, 1H) , 6.89 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H) , 4.95 (s, 2H) , 3.44 (s, 2H) , 0.98 (s, 9H) , 0.20 (s, 6H) . UPLC-MS (ESI) [M+H]
+: calcd for C
20H
26N
3O
5Si, 416.16; found, 416.36. UPLC purity 94%.
Intermediate I-4: 5-amino-1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione.
Fe (112 mg, 2 mmol) and NH
4Cl (214 mg, 4 mmol) were added to a solution of I-3 (206 mg, 0.5 mmol) in EtOH (95%, 10 mL) , and the mixture was refluxed for 2 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-4 (150 mg, 78.5%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 7.16 (dt, J = 8.0, 1.6 Hz, 1H) , 7.03 (d, J = 7.6 Hz, 1H) , 6.96 (s, 1H) , 6.90 (m, 1H) , 6.82 (d, J = 8.0 Hz, 1H) , 4.76 (s, 2H) , 3.40 (s, 3H) , 0.97 (s, 9H) , 0.18 (s, 6H) . UPLC-MS (ESI) [M+H]
+: calcd for C
20H
28N
3O
3Si, 386.19; found, 386.40. UPLC purity 95%.
Intermediate I-5a: N- (1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide.
Acryloyl chloride (14.1 mg, 0.156 mmol) was added to a solution of I-4 (60 mg, 0.156 mmol) and TEA (31.6 mg, 0.312 mmol) in DCM (5 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (3 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-5a (42 mg, 61.8%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 8.91 (s, 1H) , 7.88 (s, 1H) , 7.16 (t, J = 8.0 Hz, 1H) , 7.07 (dt, J = 7.6, 1.2 Hz, 1H) , 6.96–6.93 (m, 1H) , 6.82 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H) , 6.40 (dd, J = 16.8, 1.6 Hz, 1H) , 6.27 (dd, J = 16.9, 10.0 Hz, 1H) , 5.78 (dd, J = 10.0, 1.5 Hz, 1H) , 4.82 (s, 2H) , 3.44 (s, 3H) , 0.97 (s, 9H) , 0.19 (s, 6H) . UPLC-MS (ESI) [M+H]
+: calcd for C
23H
30N
3O
4Si, 440.20; found, 440.41. UPLC purity 95%.
Intermediate I-5b: N- (1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide
Ethenesulfonic acid chloride was added to a solution of I-4 (60 mg, 0.156 mmol) and TEA (31.6 mg, 0.312 mmol) in DCM (5 mL) (19.7 mg, 0.156 mmol) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (3 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure to give the intermediate I-5b (65 mg, crude) and the compound was used for the next step directly without further purification. UPLC-MS (ESI) [M+H]
+: calcd for C
23H
30N
3O
4Si C
22H
30N
3O
5SSi, 476.17; found, 476.40. UPLC purity 96%.
Intermediate I-6: 6-chloro-3-methyl-5-nitropyrimidine-2, 4 (1H, 3H) -dione.
In a three-necked bottle, 6-chloro-3-methylpyrimidine-2, 4 (1H, 3H) -dione (15.0 g, 93.4 mmol) was dissolved in concentrated sulfuric acid (45 mL) cooled in water bath that the internal temperature did not exceed 40℃. Concentrated nitric acid (15 mL) was added to this mixture dropwise meanwhile maintaining the temperature below 45℃ with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 60 min then dumped into 300 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. A yellow solid of I-6 was obtained (12.2 g, 64.2%) .
1H NMR (400 MHz, DMSO) : δ 10.10 (s, 1H) , 3.11 (s, 3H) . UPLC-MS (ESI) [M-H]
-: calcd for C
5H
3ClN
3O
4, 203.98.00; found, 204.20. UPLC purity 95%.
Intermediate I-7: 5-amino-6-chloro-3-methylpyrimidine-2, 4 (1H, 3H) -dione.
Fe (4.34 g, 77.8 mmol) and NH
4Cl (8.33 g, 155.7 mmol) were added to a solution of I-6 (4 g, 19.5 mmol) in EtOH (95%, 50 mL) , and the mixture was stirred at 80℃ for 4 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (DCM/MeOH=40: 1) to give intermediate I-7 (1.8 g, 52.9%) as a brown solid.
1H NMR (400 MHz, DMSO) δ 11.56 (s, 1H) , 4.25 (s, 2H) , 3.14 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
5H
6ClN
3O
2, 176.02; found, 176.21. UPLC purity 96%.
Intermediate I-8: tert-butyl (6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate.
(Boc)
2O (1.91 g, 8.77 mmol) and TEA (968 mg, 9.57 mmol) were added to a solution of I-7 (1.4 g, 7.98 mmol) in CH
3CN (60 mL) , and the mixture was stirred at 45℃ for 7 h. After completion of the reaction, the solvent was removed directly under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA = 2: 1) to give intermediate I-8 (1.8 g, 81.8%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 10.23 (s, 1H) , 6.01 (s, 1H) , 3.34 (s, 3H) , 1.48 (s, 9H) . UPLC-MS (ESI) [M-C
4H
8]
+: calcd for C
6H
6ClN
3O
4, 219.58; found, 220.12. UPLC purity 97%.
Intermediate I-9: tert-butyl (6-chloro-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate.
3-Bromoprop-1-yne (920 mg, 7.80 mmol) and K
2CO
3 (884 mg, 6.40 mmol) were added to a solution of I-8 (1.68 g, 6.10 mmol) in DMF (30 mL) sequentially. The mixture was stirred for 12 h under nitrogen atmosphere until its completion monitored by TLC. The mixture was diluted with water (100 mL) , extracted with EA (20 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-9 (1.41 g, 73.8%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.89 (s, 1H) , 4.88 (s, 2H) , 3.38 (s, 3H) , 1.48 (s, 9H) . UPLC-MS (ESI) [M-C
4H
8]
+: calcd for C
9H
8ClN
3O
4, 257.63; found, 258.09. UPLC purity 95%.
Intermediate I-10: tert-butyl (1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate.
Pd (Pph
3)
4 (74 mg, 0.064 mmol) and CuI (25 mg, 0.13 mmol) were added to a solution containing I-9 (400 mg, 1.27 mmol) , I-1 (510 mg, 1.53 mmol) and N, N-diisopropylethylamine (390 mg, 3.0 mmol) in DMF (15 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃ for 4 hours in an oil bath. After completion of the reaction, the mixture was diluted with water (60 mL) , extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-10 (502 mg, 60.5%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.15 (t, J = 7.9 Hz, 1H) , 7.03 (dd, J = 7.6, 1.2 Hz, 1H) , 6.90–6.89 (m, 1H) , 6.83–6.79 (m, 1H) , 5.88 (s, 1H) , 5.09 (s, 2H) , 3.40 (s, 3H) , 1.49 (s, 9H) , 0.97 (s, 9H) , 0.18 (s, 6H) . UPLC-MS (ESI) [M-C
4H
8]
+: calcd for C
21H
26ClN
3O
5Si, 463.99; found, 464.30. UPLC purity 95%.
Intermediate I-11: 5-amino-1- (3- (3- ( (tert-butyldimethylsilyl) oxy) phenyl) prop-2-yn-1-yl) -6-chloro-3-methylpyrimidine-2, 4 (1H, 3H) -dione.
TFA (7 mL) was added to a solution of I-10 (360 mg, 0.7 mmol) in DCM (16 mL) dropwise at 0℃ over 3 min under a nitrogen atmosphere and the reaction was stirred for 4 hours in an ice bath. After completion of the reaction, the pH value was adjusted to 8 with a saturated solution of sodium bicarbonate, the mixture was extracted with DCM (10 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-11 (198 mg, 68.3%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 7.14 (t, J = 7.9 Hz, 1H) , 7.02 (d, J = 7.6 Hz, 1H) , 6.89 (s, 1H) , 6.81 (dd, J = 8.0, 2.4 Hz, 1H) , 5.05 (s, 2H) , 3.42 (s, 3H) , 0.97 (s, 9H) , 0.18 (s, 6H) . UPLC-MS (ESI) [M+H]
+: calcd for C
20H
27ClN
3O
3Si, 420.15; found, 420.36. UPLC purity 95%.
Intermediate I-12: tert-butyl (6-methoxy-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate.
MeONa (127 mg, 2.35mmol) was added to a solution of I-9 (738 mg, 2.35 mmol) in MeOH (20 mL, the mixture was stirred for 12 h. After completion of the reaction, the mixture was diluted with saturated ammonium chloride solution (30 mL) and extracted with EA (12 mL×3) . The organic layer was washed with brine, dried over Na
2SO
4, removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-12 (423 mg, 59.6%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.64 (s, 1H) , 4.69 (d, J = 2.4 Hz, 2H) , 4.20 (s, 3H) , 3.34 (s, 3H) , 2.25 (t, J = 2.4 Hz, 1H) , 1.48 (s, 9H) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
20N
3O
5, 310.14; found, 310.33. UPLC purity 96%.
Intermediate I-13: 5-amino-6-methoxy-3-methyl-1- (prop-2-yn-1-yl) pyrimidine-2, 4 (1H, 3H) -dione.
TFA (9.6 mL) was added to a solution of I-12 (400 mg, 1.29 mmol) in DCM (24 mL) dropwise at 0℃ over 3 min under a nitrogen atmosphere and the reaction was stirred for 4 hours in an ice bath. After completion of the reaction, the pH value was adjusted to 8 with a saturated solution of sodium bicarbonate, the mixture was extracted with DCM (12 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-13 (141 mg, 52.3%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 4.67 (d, J = 2.4 Hz, 2H) , 4.10 (s, 3H) , 3.38 (s, 3H) , 2.84 (s, 2H) , 2.29 (t, J = 2.4 Hz, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
9H
12N
3O
3, 210.09; found, 210.22. UPLC purity 95%.
Intermediate I-14a: N- (6-methoxy-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide.
Acryloyl chloride (43.2 mg, 0.478 mmol) was added to a solution of I-13 (100 mg, 0.478 mmol) and TEA (96.7 mg, 0.956 mmol) in DCM (8 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-14a (61 mg, 48.8%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.07 (s, 1H) , 6.43 (dd, J = 17.0, 1.3 Hz, 1H) , 6.32 (dd, J = 17.0, 10.1 Hz, 1H) , 5.80 (dd, J = 10.1, 1.5 Hz, 1H) , 4.73 (d, J = 2.5 Hz, 2H) , 4.09 (s, 3H) , 3.35 (s, 3H) , 2.27 (t, J = 2.4 Hz, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
12H
14N
3O
4, 264.10; found, 264.26. UPLC purity 97%.
Intermediate I-14b: N- (6-methoxy-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide.
Ethenesulfonic acid chloride (75.9 mg, 0.6 mmol) was added to a solution of I-13 (125 mg, 0.6 mmol) and TEA (121 mg, 1.2 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-14b (71 mg, 39.9%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 6.61 (dd, J = 16.5, 9.9 Hz, 1H) , 6.18 (d, J = 16.5 Hz, 1H) , 6.07 (s, 1H) , 5.92 (d, J = 9.9 Hz, 1H) , 4.70 (d, J = 2.3 Hz, 2H) , 4.45 (s, 3H) , 3.32 (s, 3H) , 2.26 (t, J = 2.3 Hz, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
11H
14N
3O
5S, 300.07; found, 300.29. UPLC purity 96%.
Intermediate I-15: 1- (ethoxymethyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione.
BSA (N, O-Bis (trimethylsilyl) acetamide, 805 mg, 3.96 mmol) and chloromethyl ethyl ether (181 mg, 1.91 mmol) were added to a solution of 6-methylpyrimidine-2, 4 (1H, 3H) -dione (200 mg, 1.59 mmol) in DCM (15 mL) at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 6 hours. After completion of the reaction, the mixture was diluted with saturated ammonium chloride solution (30 mL) and extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-15 (180 mg, 61.6%) as a white solid.
1H NMR(400 MHz, CDCl
3) : δ 9.80 (s, 1H) , 5.57 (s, 1H) , 5.29 (s, 2H) , 3.61 (q, J = 7.0 Hz, 2H) , 2.34 (s, 3H) , 1.19 (t, J = 7.0 Hz, 3H) . UPLC-MS (ESI) [M+H] + calcd for C
8H
13N
2O
3, 185.09; found, 185.19. UPLC purity 96%.
Intermediate I-16: 1- (ethoxymethyl) -3, 6-dimethylpyrimidine-2, 4 (1H, 3H) -dione.
K
2CO
3 (78.8 mg, 0.57 mmol) and MeI (92.5 mg, 0.652 mmol) were added to a solution of I-15 (100 mg, 0.543 mmol) in DMF (6 mL) sequentially at 0℃ under a nitrogen atmosphere and the mixture was stirred at RT for 2 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-16 (100 mg, 92.5%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.62 (s, 1H) , 5.32 (s, 2H) , 3.61 (q, J = 7.0 Hz, 2H) , 3.31 (s, 3H) , 2.32 (s, 3H) , 1.19 (t, J = 7.0 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
9H
15N
2O
3, 199.11; found, 199.22. UPLC purity 98%.
Intermediate I-17: 3, 6-dimethylpyrimidine-2, 4 (1H, 3H) -dione.
Trifluoromethanesulfonic acid (1.34mL, 15.1 mmol) was added to a solution of I-16 (1.06 g, 5.36 mmol) in TFA (13.4 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred at RT for 10 min until the completion of the reaction. The mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=40: 1) to give intermediate I-17 (530 mg, 74.9 %) as a white solid.
1H NMR(400 MHz, CDCl
3) : δ 9.90 (s, 1H) , 5.59 (s, 1H) , 3.31 (s, 3H) , 2.17 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
6H
9N
2O
2, 141.07; found, 141.14. UPLC purity 97%.
Intermediate I-18: 3, 6-dimethyl-5-nitropyrimidine-2, 4 (1H, 3H) -dione.
In a three-necked bottle, I-17 (530 mg, 3.78 mmol) was dissolved in concentrated sulfuric acid (3 mL) cooled in water bath that the internal temperature did not exceed 40℃. To this mixture concentrated nitric acid (1 mL) was added dropwise meanwhile maintaining the temperature below 45℃ with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour then dumped into 20 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. A yellow solid of I-18 was obtained (456 mg, 64.3 %) .
1H NMR (400 MHz, CDCl
3) : δ 8.93 (s, 1H) , 3.38 (s, 3H) , 2.45 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
6H
8N
3O
4, 186.05; found, 186.15. UPLC purity 96%.
Intermediate I-19: 3, 6-dimethyl-5-nitro-1- (prop-2-yn-1-yl) pyrimidine-2, 4 (1H, 3H) -dione.
3-Bromoprop-1-yne (381 mg, 3.2 mmol) and K
2CO
3 (374 mg, 2.71 mmol) was added to a solution of I-18 (456 mg, 2.46 mmol) in DMF (18 mL) sequentially. The mixture was stirred for 12 h under nitrogen atmosphere until its completion monitored by TLC. The mixture was diluted with water (60 mL) , extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-19 (340 mg, 62.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 4.78 (d, J = 2.4 Hz, 2H) , 3.41 (s, 3H) , 2.56 (s, 3H) , 2.44 (t, J = 2.5 Hz, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
9H
10N
3O
4, 224.07; found, 224.40. UPLC purity 95%.
Intermediate I-20: 5-amino-3, 6-dimethyl-1- (prop-2-yn-1-yl) pyrimidine-2, 4 (1H, 3H) -dione.
Fe (331 mg, 5.92 mmol) and NH
4Cl (633 mg, 11.84 mmol) were added to a solution of I-19 (330 mg, 1.48 mmol) in EtOH (95%, 30 mL) , and the mixture was refluxed for 2 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-20 (192 mg, 67.4%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 4.70 (s, 2H) , 3.40 (s, 3H) , 2.35 (s, 3H) , 2.31 (s, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
9H
12N
3O
2, 194.09; found, 194.21. UPLC purity 96%.
Intermediate I-21a: N- (3, 6-dimethyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide. Acryloyl chloride (24.4 mg, 0.27 mmol) was added to a solution of I-20 (52 mg, 0.27 mmol) and TEA (55 mg, 0.54 mmol) in DCM (8 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=40: 1) to give intermediate I-21a (60 mg, 90.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : 8.05 (s, 1H) , 6.42 –6.21 (m, 2H) , 5.71 (d, J = 9.2 Hz, 1H) , 4.71 (s, 2H) , 3.35 (s, 3H) , 2.35 (s, 3H) , 2.02 (s, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
12H
14N
3O
3, 248.10; found, 248.24. UPLC purity 97%.
Intermediate I-21b: N- (3, 6-dimethyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide.
Ethenesulfonic acid chloride (26.6 mg, 0.21 mmol) was added to a solution of I-20 (40 mg, 0.21 mmol) and TEA (42.5 mg, 0.42 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 30 min. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-21b (40 mg, 68.2%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 6.59 (dd, J = 16.5, 9.9 Hz, 1H) , 6.20 (s, 1H) , 6.14 (d, J = 16.5 Hz, 1H) , 5.90 (d, J = 9.9 Hz, 1H) , 4.71 (d, J = 2.4 Hz, 2H) , 3.34 (s, 3H) , 2.62 (s, 3H) , 2.37 (t, J = 2.5 Hz, 1H) . UPLC-MS (ESI) [M+H]
+ calcd for C
11H
14N
3O
4S, 284.07; found, 284.18. UPLC purity 95%.
Intermediate I-22: N- (6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
The I-7 (2.1 g, 12 mmol) was dissolved in dried DMF (100 mL) in a three-necked flask with magnetic stirring. The 3- (p-tolyl) propanoic acid (1.97 g, 12 mmol) and HATU (5.93 g, 15.6 mmol) were added and the mixture was cooled to 0 ℃. Then, DIPEA (3.1 g, 24 mmol) was added dropwise and the mixture was stirred for 5 hours at RT. The reaction was quenched with saturated ammonium chloride solutionand extracted with CH
2Cl
2. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=40: 1) to afford I-22 (2.7 g, 71%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 12.47 (s, 1H) , 9.18 (s, 1H) , 7.13 (d, J = 7.9 Hz, 2H) , 7.08 (d, J = 7.9 Hz, 2H) , 3.13 (s, 3H) , 2.81 (t, J = 7.9 Hz, 2H) , 2.53–2.51 (m, 2H) , 2.25 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
15H
17ClN
3O
3, 322.10; found, 322.29. UPLC purity 96%.
Intermediate I-23a: N- (3-iodophenyl) acetamide.
Acetyl chloride (71.4 mg, 0.91 mmol) was added to a solution of 3-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-23a (151 mg, 63.4%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.90 (s, 1H) , 7.51–7.38 (m, 2H) , 7.17 (s, 1H) , 7.07–7.01 (m, 1H) , 2.17 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
8H
9INO, 261.97; found, 262.05. UPLC purity 97%.
Intermediate I-23b: N- (3-iodophenyl) benzamide.
Benzoyl chloride (128 mg, 0.91 mmol) was added to a solution of 3-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-23b (215 mg, 73.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 8.06 (t, J = 1.6 Hz, 1H) , 7.85 (d, J = 7.2 Hz, 2H) , 7.79 (s, 1H) , 7.65–7.61 (m, 1H) , 7.56 (d, J = 6.9 Hz, 1H) , 7.52–7.46 (m, 3H) , 7.09 (t, J = 8.0 Hz, 1H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
11INO, 323.99; found, 324.09. UPLC purity 96%.
Intermediate I-24a: N- (4-iodophenyl) acetamide.
Acetyl chloride (71.4 mg, 0.91 mmol) was added to a solution of 4-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-24a (126 mg, 52.9%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.60 (d, J = 8.7 Hz, 2H) , 7.28 (d, J = 8.7 Hz, 2H) , 2.16 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
8H
9INO, 261.97; found, 262.46. UPLC purity 95%.
Intermediate I-24b: N- (4-iodophenyl) benzamide.
Benzoyl chloride (128 mg, 0.91 mmol) was added to a solution of 4-iodoaniline (200 mg, 0.91 mmol) and TEA (184 mg, 1.82 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-24b (196 mg, 66.7%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.88–7.84 (m, 2H) , 7.77 (s, 1H) , 7.68 (d, J = 8.9 Hz, 2H) , 7.56 (dt, J = 2.7, 1.9 Hz, 1H) , 7.53–7.48 (m, 2H) , 7.44 (d, J = 8.9 Hz, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
11INO, 323.99; found, 324.09. UPLC purity 97%.
Intermediate I-25: N-benzyl-4-iodoaniline.
L-proline (14 mg, 0.12 mmol) and CuI (11.4 mg, 0.06 mmol) were added to a solution containing 1, 4-diiodobenzene (200 mg, 0.61 mmol) , benzylamine (66 mg, 0.61 mmol) and K
2CO
3 (168 mg, 1.22 mmol) in DMF (5 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 40℃ for 3 hours. After completion of the reaction, the mixture was diluted with water (30 mL) , extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=20: 1) to give intermediate I-25 (51 mg, 27.3%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 7.45–7.41 (m, 2H) , 7.40–7.29 (m, 5H) , 6.47–6.36 (m, 2H) , 4.31 (s, 2H) , 4.14 (s, 1H) . UPLC-MS (ESI) [M+H]
+: UPLC-MS (ESI) [M+H]
+: calcd for C
13H
13IN, 310.01; found, 310.10. UPLC purity 95%.
Intermediate I-26: 6-chloro-1- (ethoxymethyl) pyrimidine-2, 4 (1H, 3H) -dione.
N, O-Bis (trimethylsilyl) acetamide (BSA, 12.2 g, 60 mmol) and chloromethyl ethyl ether (3.1 g, 32.7 mmol) were added to a solution of 6-chloropyrimidine-2, 4 (1H, 3H) -dione (4.0 g, 27.3 mmol) in DCM (100 mL) at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 6 hours. After completion of the reaction, the mixture was diluted with saturated ammonium chloride solution (50 mL) and extracted with DCM (20 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-26 (3.1 g, 43.2%) as a white solid.
1H NMR(400 MHz, CDCl
3) : δ 9.15 (s, 1H) , 5.92 (s, 1H) , 5.46 (s, 2H) , 3.66 (q, J = 7.0 Hz, 2H) , 1.22 (t, J = 7.0 Hz, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
7H
10ClN
2O
3, 205.04; found, 205.16. UPLC purity 96%.
Intermediate I-27a: 6-chloro-1- (ethoxymethyl) -3-ethylpyrimidine-2, 4 (1H, 3H) -dione.
Iodoethane (915 mg, 5.87 mmol) was added to a solution of I-26 (1.0 g, 4.89 mmol) and K
2CO
3 (709 mg, 5.13 mmol) in DMF (20 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred at RT for 12 hours. After completion, the mixture was diluted with water (100 mL) and extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=10: 1) to give intermediate I-27a (900 mg, 79.6%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.93 (s, 1H) , 5.48 (s, 2H) , 3.98 (q, J = 7.1 Hz, 2H) , 3.66 (q, J = 7.0 Hz, 2H) , 1.23 (t, J = 7.0 Hz, 3H) , 1.22 (t, J = 7.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
9H
14ClN
2O
3, 233.07; found, 233.16. UPLC purity 97%.
Intermediate I-27b: 6-chloro-1- (ethoxymethyl) -3-propylpyrimidine-2, 4 (1H, 3H) -dione.
1-Iodopropane (998 mg, 5.87 mmol) was added to a solution of I-26 (1.0 g, 4.89 mmol) and K
2CO
3 (709 mg, 5.13 mmol) in DMF (20 mL) was added at 0℃ under a nitrogen atmosphere and the mixture was stirred at RT for 12 hours. After completion, the mixture was diluted with water (100 mL) and extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=10: 1) to give intermediate I-27b (810 mg, 66.9%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.93 (s, 1H) , 5.48 (s, 2H) , 3.94–3.80 (m, 2H) , 3.66 (q, J = 7.0 Hz, 2H) , 1.71–1.56 (m, 2H) , 1.23 (t, J = 7.0 Hz, 3H) , 0.94 (t, J = 7.5 Hz, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
10H
16ClN
2O
3, 247.08; found, 247.19. UPLC purity 95%.
Intermediate I-27c: 6-chloro-3- (cyclopentylmethyl) -1- (ethoxymethyl) pyrimidine-2, 4 (1H, 3H) -dione.
Iodomethylcyclopentane (1.23 g, 5.87 mmol) was added to a solution of I-26 (1.0 g, 4.89 mmol) and K
2CO
3 (709 mg, 5.13 mmol) in DMF (20 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred at RT for 12 hours. After completion, the mixture was diluted with water (100 mL) and extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=10: 1) to give intermediate I-27c (251 mg, 17.9%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 5.93 (s, 1H) , 5.49 (s, 2H) , 3.89 (d, J = 7.6 Hz, 2H) , 3.65 (q, J = 7.0 Hz, 2H) , 2.39–2.26 (m, 1H) , 1.72–1.63 (m, 4H) , 1.33–1.26 (m, 4H) , 1.23 (t, J = 7.0 Hz, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
20ClN
2O
3, 287.12; found, 287.23. UPLC purity 96%.
Intermediate I-28a: 6-chloro-3-ethyl-5-nitropyrimidine-2, 4 (1H, 3H) -dione.
In a three-necked bottle, I-27a (500 mg, 2.15 mmol) was dissolved in concentrated sulfuric acid (6 mL) cooled in water bath that the internal temperature did not exceed 40℃. To this mixture concentrated nitric acid (2 mL) was added dropwise meanwhile maintaining the temperature below 45℃ with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour then dumped into 10 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. The residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-28a (310 mg, 65.7%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 10.58 (s, 1H) , 4.04 (q, J = 7.1 Hz, 2H) , 1.28 (t, J = 7.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
6H
7ClN
3O
4, 220.01; found, 220.12. UPLC purity 96%.
Intermediate I-28b: 6-chloro-5-nitro-3-propylpyrimidine-2, 4 (1H, 3H) -dione.
In a three-necked bottle, I-27b (400 mg, 1.62 mmol) was dissolved in concentrated sulfuric acid (4.2 mL) cooled in water bath that the internal temperature did not exceed 40℃. To this mixture concentrated nitric acid (1.4 mL) was added dropwise meanwhile maintaining the temperature below 45℃ with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour then dumped into 10 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. The residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-28b (327 mg, 86.3%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 10.40 (s, 1H) , 3.96–3.90 (m, 2H) , 1.76–1.63 (m, 2H) , 0.97 (t, J = 7.5 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
7H
9ClN
3O
4, 234.03; found, 234.11. UPLC purity 95%.
Intermediate I-28c: 6-chloro-3- (cyclopentylmethyl) -5-nitropyrimidine-2, 4 (1H, 3H) -dione.
In a three-necked bottle, I-27c (176 mg, 0.62 mmol) was dissolved in concentrated sulfuric acid (3 mL) cooled in water bath that the internal temperature did not exceed 40℃. To this mixture concentrated nitric acid (1 mL) was added dropwise meanwhile maintaining the temperature below 45℃ with ice-bath. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour then dumped into 10 mL of crushed ice. After stirring for 10 min the solid was collected by filtering and washed with cold water then dried in vacuo. The residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-28c (121 mg, 72%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 10.31 (s, 1H) , 3.93 (d, J = 7.1 Hz, 2H) , 2.48–2.25 (m, 1H) , 1.76–1.64 (m, 4H) , 1.59–1.52 (m, 2H) , 1.35–1.26 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
10H
13ClN
3O
4, 274.06; found, 274.15. UPLC purity 95%.
Intermediate I-29a: 5-amino-6-chloro-3-ethylpyrimidine-2, 4 (1H, 3H) -dione.
Fe (306 mg, 5.48 mmol) and NH
4Cl (586 mg, 10.96 mmol) were added to a solution of I-28a (300 mg, 1.37 mmol) in EtOH (95%, 20 mL) , and the mixture was refluxed for 2 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-29a (200 mg, 77.2%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 9.74 (s, 1H) , 4.02 (q, J = 7.0 Hz, 2H) , 3.59 (s, 2H) , 1.25 (t, J = 7.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
6H
9ClN
3O
2, 190.04; found, 190.11. UPLC purity 96%.
Intermediate I-29b: 5-amino-6-chloro-3-propylpyrimidine-2, 4 (1H, 3H) -dione.
Fe (313 mg, 5.6 mmol) and NH
4Cl (599 mg, 11.2 mmol) were added to a solution of I-28b (327 mg, 1.4 mmol) in EtOH (95%, 20 mL) , and the mixture was refluxed for 2 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-29b (160 mg, 56.1%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 10.76 (s, 1H) , 3.96–3.89 (m, 2H) , 3.60 (s, 2H) , 1.76–1.61 (m, 2H) , 0.95 (t, J = 7.4 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
10H
15ClN
3O
2, 204.05; found, 204.10. UPLC purity 96%.
Intermediate I-29c: 5-amino-6-chloro-3- (cyclopentylmethyl) pyrimidine-2, 4 (1H, 3H) -dione.
Fe (95.5 mg, 1.76 mmol) and NH
4Cl (188 mg, 3.52 mmol) were added to a solution of I-28c (120 mg, 0.44 mmol) in EtOH (95%, 10 mL) , and the mixture was refluxed for 2 h. Then the reaction was filtered through a pad of celite and eluted with EtOH. The filtration solution were evaporated in vacuo and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-29c (42 mg, 39.6%) as a brown solid.
1H NMR (400 MHz, CDCl
3) : δ 10.30 (s, 1H) , 3.92 (d, J = 7.5 Hz, 2H) , 3.61 (s, 2H) , 2.45–2.30 (m, 1H) , 1.76–1.66 (m, 4H) , 1.58–1.51 (m, 2H) , 1.34–1.25 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
10H
15ClN
3O
2, 244.09; found, 244.14. UPLC purity 96%.
Intermediate I-30a: N- (6-chloro-3-ethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
The I-29a (200 mg, 1.06 mmol) was dissolved in dried DMF (15 mL) in a three-necked flask with magnetic stirring. The 3- (p-tolyl) propanoic acid (173 mg, 1.06 mmol) and HATU (521 mg, 1.37 mmol) were added and the mixture was cooled to 0 ℃. Then, DIPEA (273 mg, 2.11 mmol) was added dropwise and the mixture was stirred for 5 hours at RT. The reaction was quenched with saturated ammonium chloride solution and extracted with CH
2Cl
2. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=50: 1) to afford I-30a (179 mg, 50.6%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 8.92 (s, 1H) , 7.13 (d, J = 8.1 Hz, 2H) , 7.11 (d, J = 8.1 Hz, 2H) , 6.66 (s, 1H) , 3.96 (q, J = 7.1 Hz, 2H) , 3.03–2.97 (m, 2H) , 2.72–2.63 (m, 2H) , 2.31 (s, 3H) , 1.22 (t, J = 7.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
16H
19ClN
3O
3, 336.11; found, 336.19. UPLC purity 98%.
Intermediate I-30b: N- (6-chloro-2, 4-dioxo-3-propyl-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
The I-29b (150 mg, 0.74 mmol) was dissolved in dried DMF (15 mL) in a three-necked flask with magnetic stirring. The 3- (p-tolyl) propanoic acid (122 mg, 0.74 mmol) and HATU (366 mg, 0.96 mmol) were added and the mixture was cooled to 0 ℃. Then, DIPEA (192 mg, 1.48 mmol) was added dropwise and the mixture was stirred for 5 hours at RT. The reaction was quenched with saturated ammonium chloride solution and extracted with CH
2Cl
2. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1: 1) to afford I-30b (200 mg, 78.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 10.55 (s, 1H) , 7.12 (d, J = 8.2 Hz, 2H) , 7.09 (d, J = 8.1 Hz, 2H) , 6.87 (s, 1H) , 3.87–3.79 (m, 2H) , 3.00 (t, J = 7.6 Hz, 2H) , 2.66 (t, J = 7.6 Hz, 2H) , 2.30 (s, 3H) , 1.67–1.57 (m, 2H) , 0.92 (t, J = 7.4 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
17H
21ClN
3O
3, 350.13; found, 350.24. UPLC purity 97%.
Intermediate I-30c: N- (6-chloro-3- (cyclopentylmethyl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
The I-29c (42 mg, 0.17 mmol) was dissolved in dried DMF (5 mL) in a three-necked flask with magnetic stirring. The 3- (p-tolyl) propanoic acid (28 mg, 0.17 mmol) and HATU (86 mg, 0.22 mmol) were added and the mixture was cooled to 0 ℃. Then, DIPEA (44 mg, 0.34 mmol) was added dropwise and the mixture was stirred for 5 hours at RT. The reaction was quenched with saturated ammonium chloride solution and extracted with CH
2Cl
2. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1: 1) to afford I-30c (54.8 mg, 81.5%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 9.21 (s, 1H) , 7.17–7.04 (m, 4H) , 6.72 (s, 1H) , 3.86 (d, J = 7.6 Hz, 2H) , 2.99 (t, J = 7.9 Hz, 2H) , 2.67 (t, J = 7.9 Hz, 2H) , 2.31 (s, 4H) , 1.73–1.63 (m, 6H) , 1.55–1.47 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
20H
25ClN
3O
3, 390.16; found, 390.26. UPLC purity 95%.
Intermediate I-31a: N- (6-chloro-3-ethyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
To a solution of I-30a (175 mg, 0.52 mmol) and 3-bromoprop-1-yne (82 mg, 0.67 mmol) in dry DMF (10 mL) , K
2CO
3 (76 mg, 0.55 mmol) was added and the mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC) , the mixture was poured into water (20 mL) and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford I-31a (115 mg, 59.2%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.12 (d, J = 8.3 Hz, 2H) , 7.10 (d, J = 8.2 Hz, 2H) , 6.64 (s, 1H) , 4.87 (d, J = 2.5 Hz, 2H) , 4.01 (q, J = 7.1 Hz, 2H) , 3.00 (t, J = 7.7 Hz, 2H) , 2.68 (t, J = 7.8 Hz, 2H) , 2.35 (t, J = 2.5 Hz, 1H) , 2.32 (s, 3H) , 1.23 (t, J = 7.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
19H
21ClN
3O
3, 374.13; found, 374.22. UPLC purity 96%.
Intermediate I-31b: N- (6-chloro-2, 4-dioxo-1- (prop-2-yn-1-yl) -3-propyl-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propenamide.
To a solution of I-30b (200 mg, 0.57 mmol) and 3-bromoprop-1-yne (88 mg, 0.74 mmol) in dry DMF (10 mL) , K
2CO
3 (83 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC) , the mixture was poured into water (20 mL) and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=4: 1) to afford I-31b (153 mg, 69.2%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.14–7.04 (m, 4H) , 4.85 (s, 2H) , 3.90–3.86 (m, 2H) , 2.98 (t, J = 7.5 Hz, 2H) , 2.66 (t, J = 7.5 Hz, 2H) , 2.35 (s, 1H) , 2.31 (s, 3H) , 1.75–1.58 (m, 2H) , 0.92 (t, J = 7.4 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
20H
23ClN
3O
3, 388.14; found, 388.24. UPLC purity 96%.
Intermediate I-31c: N- (6-chloro-3- (cyclopentylmethyl) -2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide.
To a solution of I-30c (27.4 mg, 0.071 mmol) and 3-bromoprop-1-yne (11.1 mg, 0.093 mmol) in dry DMF (5 mL) , K
2CO
3 (10.4 mg, 0.075 mmol) was added and the mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC) , the mixture was poured into water (20 mL) and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford I-31c (20 mg, 66.7%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.14 (s, 1H) , 7.11 (d, J = 8.2 Hz, 2H) , 7.08 (d, J = 7.8 Hz, 2H) , 4.85 (d, J = 2.4 Hz, 2H) , 3.89 (d, J = 7.5 Hz, 2H) , 2.98 (t, J = 7.7 Hz, 2H) , 2.67 (t, J = 7.8 Hz, 2H) , 2.34 (t, J = 2.4 Hz, 1H) , 2.30 (s, 3H) , 2.32–2.24 (m, 1H) , 1.73–1.60 (m, 4H) , 1.54–1.44 (m, 2H) , 1.30–1.20 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
23H
27ClN
3O
3, 428.17; found, 428.26. UPLC purity 96%.
General Synthesis Procedure for Intermediates (I-32a) – (I-32u) .
The corresponding acyl chlorides (Y1–Y21, 0.69 mmol) was added to a solution of 4-iodoaniline (100 mg, 0.46 mmol) and TEA (69.8 mg, 0.69 mmol) in dry DCM (10 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (8 mL) , then the mixture was extracted with DCM (4 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA) to give corresponding intermediates (I-32a) – (I-32u) .
Intermediate I-32a: N- (4-iodophenyl) -2-phenylacetamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y1 (2-phenylacetyl chloride, 107 mg, 0.69 mmol) . White solid (75 mg, 48.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO, 338.00; found, 338.13.
Intermediate I-32b: N- (4-iodophenyl) -3-phenylpropanamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y2 (3-phenylpropanoyl chloride, 116.3 mg, 0.69 mmol) . White solid (86 mg, 53.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
15H
15INO, 352.02; found, 352.19.
Intermediate I-32c: N- (4-iodophenyl) cinnamamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y3 (cinnamoyl chloride, 115 mg, 0.69 mmol) . White solid (89 mg, 55.6%) . UPLC-MS (ESI) [M+H]
+ calcd for C
15H
13INO, 350.00; found, 350.12.
Intermediate I-32d: N- (4-iodophenyl) cyclopropanecarboxamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y4 (cyclopropanecarbonyl chloride, 72.1 mg, 0.69 mmol) . White solid (79 mg, 59.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
10H
11INO, 287.99; found, 288.15.
Intermediate I-32e: N- (4-iodophenyl) tetrahydro-2H-pyran-4-carboxamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y5 (tetrahydro-2H-pyran-4-carbonyl chloride, 102.5 mg, 0.69 mmol) . White solid (83 mg, 54.6%) . UPLC-MS (ESI) [M+H]
+ calcd for C
12H
15INO
2, 332.01; found, 332.13.
Intermediate I-32f: N- (4-iodophenyl) cyclohexanecarboxamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y6 (cyclohexanecarbonyl chloride, 101 mg, 0.69 mmol) . White solid (92 mg, 60.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
17INO
2, 330.04; found, 330.19.
Intermediate I-32g: N- (4-iodophenyl) piperidine-1-carboxamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y7 (piperidine-1-carbonyl chloride, 102 mg, 0.69 mmol) . White solid (63 mg, 41.7%) . UPLC-MS (ESI) [M+H]
+ calcd for C
12H
16IN
2O, 331.03; found, 331.20.
Intermediate I-32h: N- (4-iodophenyl) furan-2-carboxamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y8 (furan-2-carbonyl chloride, 90.1 mg, 0.69 mmol) . White solid (77 mg, 53.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
11H
9INO
2, 313.97; found, 314.18.
Intermediate I-32i: N- (4-iodophenyl) -3-methoxybenzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y9 (3-methoxybenzoyl chloride, 118 mg, 0.69 mmol) . White solid (96 mg, 59.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO
2, 354.00; found, 354.17.
Intermediate I-32j: 3-fluoro-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y10 (3-fluorobenzoyl chloride, 109 mg, 0.69 mmol) . White solid (88 mg, 56.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
10FINO, 341.98; found, 342.13.
Intermediate I-32k: 3-chloro-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y11 (3-chlorobenzoyl chloride, 121 mg, 0.69 mmol) . White solid (95 mg, 58.6%) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
10ClINO, 357.95; found, 358.12.
Intermediate I-32l: N- (4-iodophenyl) -3-methylbenzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y12 (3-methylbenzoyl chloride, 107 mg, 0.69 mmol) . White solid (83 mg, 53.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO, 338.00; found, 338.13.
Intermediate I-32m: 3-cyano-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y13 (3-cyanobenzoyl chloride, 114 mg, 0.69 mmol) . White solid (75 mg, 46.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
10IN
2O, 348.98; found, 349.12.
Intermediate I-32n: N- (4-iodophenyl) -4-methoxybenzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y14 (4-methoxybenzoyl chloride, 118 mg, 0.69 mmol) . White solid (93 mg, 57.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO
2, 354.00; found, 354.17.
Intermediate I-32o: 4-fluoro-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y15 (4-fluorobenzoyl chloride, 109 mg, 0.69 mmol) . White solid (90 mg, 57.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
10FINO, 341.98; found, 342.11.
Intermediate I-32p: N- (4-iodophenyl) -4-methylbenzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y16 (4-methylbenzoyl chloride, 107 mg, 0.69 mmol) . White solid (86 mg, 55.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO, 338.00; found, 338.13.
Intermediate I-32q: 4-cyano-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y17 (4-cyanobenzoyl chloride, 114 mg, 0.69 mmol) . White solid (85 mg, 53.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
10IN
2O, 348.98; found, 349.12.
Intermediate I-32r: N- (4-iodophenyl) -2-methoxybenzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y18 (2-methoxybenzoyl chloride, 118 mg, 0.69 mmol) . White solid (64 mg, 39.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
13INO
2, 354.00; found, 354.17.
Intermediate I-32s: 2-fluoro-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y19 (2-fluorobenzoyl chloride, 109 mg, 0.69 mmol) . White solid (81 mg, 51.6%) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
10FINO, 341.98; found, 342.11.
Intermediate I-32t: 2-cyano-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y20 (2-cyanobenzoyl chloride, 114 mg, 0.69 mmol) . White solid (72 mg, 45.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
14H
10IN
2O, 348.98; found, 349.12.
Intermediate I-32u: 2-hydroxy-N- (4-iodophenyl) benzamide.
Prepared from 4-iodoaniline (100 mg, 0.46 mmol) and Y21 (2-hydroxybenzoyl chloride, 108 mg, 0.69 mmol) . White solid (76 mg, 48.7%) . UPLC-MS (ESI) [M+H] + calcd for C
13H
11INO
2, 339.98; found, 340.11.
Intermediate I-33a: N- (4-iodo-2-methylphenyl) benzamide.
Benzoyl chloride (121 mg, 0.86 mmol) was added to a solution of 4-iodo-2-methylaniline (200 mg, 0.86 mmol) and TEA (174 mg, 1.72 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-33a (176 mg, 60.7%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
14H
13INO, 338.00; found, 338.13. UPLC purity 96%.
Intermediate I-33b: N- (4-iodo-2-methylphenyl) cyclopropanecarboxamide.
Cyclopropanecarbonyl chloride (89.9 mg, 0.86 mmol) was added to a solution of 4-iodo-2-methylaniline (200 mg, 0.86 mmol) and TEA (174 mg, 1.72 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-33b (116 mg, 44.8%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
11H
13INO, 302.00; found, 302.15. UPLC purity 97%.
Intermediate I-34a: N- (2-ethyl-4-iodophenyl) benzamide.
Benzoyl chloride (114 mg, 0.81 mmol) was added to a solution of 2-ethyl-4-iodoaniline (200 mg, 0.81 mmol) and TEA (164 mg, 1.62 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=4: 1) to give intermediate I-34a (151 mg, 53.2%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
15H
15INO, 352.02; found, 352.19. UPLC purity 96%.
Intermediate I-34b: N- (2-ethyl-4-iodophenyl) cyclopropanecarboxamide.
Cyclopropanecarbonyl chloride (84.7 mg, 0.81 mmol) was added to a solution of 2-ethyl-4-iodoaniline (200 mg, 0.81 mmol) and TEA (164 mg, 1.62 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=4: 1) to give intermediate I-34b (138 mg, 54.1%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
15INO, 316.02; found, 316.18. UPLC purity 98%.
Intermediate I-34c: N- (2-ethyl-4-iodophenyl) tetrahydro-2H-pyran-4-carboxamide.
Tetrahydro-2H-pyran-4-carbonyl chloride (120 mg, 0.81 mmol) was added to a solution of 2-ethyl-4-iodoaniline (200 mg, 0.81 mmol) and TEA (164 mg, 1.62 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-34c (109 mg, 37.4%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
14H
19INO
2, 360.05; found, 360.22. UPLC purity 96%.
Intermediate I-35: 2-benzamido-5-iodophenyl benzoate.
Benzoyl chloride (239 mg, 1.7 mmol) was added to a solution of 2-amino-5-iodophenol (200 mg, 0.85 mmol) and TEA (172 mg, 1.7 mmol) in DCM (10 mL) dropwise at 0℃ under a nitrogen atmosphere. Then the mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) , extracted with DCM (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-35 (215 mg, 57.2%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
20H
15INO
3, 444.01; found, 444.17. UPLC purity 96%.
Intermediate I-36: N- (2-hydroxy-4-iodophenyl) benzamide.
LiOH (22 mg, 0.94 mmol) was added to a solution of I-35 (211 mg, 0.47 mmol) in mixed solvent (THF/MeOH/H
2O =12 mL: 3 mL: 5 mL) and the mixture was stirred at 45℃ for 1 h. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford I-36 (92 mg, 57.9%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
13H
11INO
2, 339.98; found, 340.12. UPLC purity 95%.
Intermediate I-37: 5-iodo-1-methyl-1H-indole.
NaH (60%, 48 mg, 1.2 mmol) was added to a solution of 5-iodo-1H-indole (200 mg, 0.82 mmol) in DMF (8 mL) portionwise at 0℃ under a nitrogen atmosphere, and the mixture was stirred for 15 min. Then iodomethane (170 mg, 1.2 mmol) was added to the mixture, and the mixture was stirred at RT for 2 hour until completion of the reaction. The reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=4: 1) to afford I-37 (136 mg, 64.8%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
9H
9IN, 257.98; found, 258.13. UPLC purity 96%.
Intermediate I-38: 5-iodo-1, 3-dihydro-2H-benzo [d] imidazol-2-one.
A mixture of 4-iodobenzene-1, 2-diamine (150 mg, 0.64 mmol) and 1, 1'-Carbonyldiimidazole (CDI, 125 mg, 0.77 mmol) in THF (15 mL) was stirred at 60℃for 6 hour until completion of the reaction. The reaction was quenched with saturated ammonium chloride solution and extracted with EA (6 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=4: 1) to afford I-38 (101 mg, 60.7%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
7H
6IN
2O, 260.95; found, 261.12. UPLC purity 95%.
Intermediate I-39: methyl 3, 5-diiodo-1H-indole-2-carboxylate.
NaIO
4 (267 mg, 1.25 mmol) and one drop of catalytic amount of concentrated sulfuric acid (98%) were added to a solution of methyl 1H-indole-2-carboxylate (200 mg, 1.14 mmol) in EtOH (15 mL) at RT under a nitrogen atmosphere, and the mixture was refluxed for 4 h. After completion of the reaction, the reaction was quenched with sodium bicarbonate solution and extracted with EA (5 mL×3) . The organic layer was washed with saturated sodium thiosulfate solution and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford I-39 (210 mg, 43.2%) as a brown solid. UPLC-MS (ESI) [M+H]
+: calcd for C
10H
8I
2NO
2, 427.86; found, 427.97. UPLC purity 95%.
Intermediate I-40: methyl 5-iodo-1H-indole-2-carboxylate.
Zn powder (123 mg, 1.88 mmol) and concentrated hydrochloric acid (12 mmol/mL, 0.3 mL) were added to a solution of I-39 (200 mg, 0.47 mmol) in EtOH (15 mL) under a nitrogen atmosphere, and the mixture was stirred at RT for 1 h. After completion of the reaction, the reaction was quenched with sodium bicarbonate solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford I-40 (102 mg, 72.3%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
10H
9INO
2, 301.97; found, 302.12. UPLC purity 96%.
Intermediate I-41: 5-iodo-1H-indole-2-carboxylic acid.
LiOH (12 mg, 0.49 mmol) was added to a solution of I-40 (100 mg, 0.33 mmol) in mixed solvent (EtOH/H
2O =12 mL: 5 mL) , and the mixture was stirred at RT overnight. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1: 1) to afford I-41 (68 mg, 72.6%) as a white solid. UPLC-MS (ESI) [M+H] +: calcd for C
9H
7INO
2, 287.95; found, 288.11. UPLC purity 95%.
Intermediate I-42: 5-iodo-N-phenyl-1H-indole-2-carboxamide.
The I-41 (65 mg, 0.22 mmol) was dissolved in dried DMF (6 mL) in a three-necked flask with magnetic stirring. The aniline (21 mg, 0.22 mmol) and HATU (103 mg, 0.26 mmol) were added and the mixture was cooled to 0 ℃. Then, DIPEA (57 mg, 0.44 mmol) was added dropwise and the mixture was stirred for 5 hours at RT. The reaction was quenched with saturated ammonium chloride solution and extracted with CH
2Cl
2. The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1: 1) to afford I-42 (51.5 mg, 64.7%) as a white solid. UPLC-MS (ESI) [M+H]
+ calcd for C
15H
12IN
2O, 363.00; found, 363.18. UPLC purity 95%.
Intermediate I-43: 1-ethyl-6-iodoquinolin-2 (1H) -one.
NaH (60%, 33 mg, 0.83 mmol) was added to a solution of 6-iodoquinolin-2-ol (150 mg, 0.55 mmol) in DMF (8 mL) portionwise at 0℃ under a nitrogen atmosphere, and the mixture was stirred for 15 min. Then iodoethane (129 mg, 0.83 mmol) was added to the mixture, and the mixture was stirred at RT for 2 hour until completion of the reaction. The reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=3: 1) to afford I-43 (105 mg, 64.1%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
11H
11INO, 299.99; found, 300.12. UPLC purity 96%.
Intermediate I-44: 6-iodo-3, 4-dihydroquinolin-2 (1H) -one.
3, 4-Dihydroquinolin-2 (1H) -one (200 mg, 1.36mmol) was added to a solution of iodine monochloride (1M in AcOH, 1.77 mL) , and the mixture was stirred at 80℃ for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (15 mL) , then the mixture was extracted with EA (5 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-44 (168 mg, 45.4%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 8.47 (s, 1H) , 7.48–7.45 (m, 2H) , 6.56 (d, J = 8.1 Hz, 1H) , 2.95–2.91 (m, 2H) , 2.63–2.60 (m, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
9H
9INO, 273.97; found, 274.15. UPLC purity 97%.
Intermediate I-45: 6-iodo-1-methyl-3, 4-dihydroquinolin-2 (1H) -one.
NaH (60%, 16 mg, 0.4 mmol) was added to a solution of I-44 (100 mg, 0.37 mmol) in DMF (5 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then MeI (62.5 mg, 0.44 mmol) was added and the mixture was stirred at RT for 2 h. After completion of the reaction, the mixture was diluted with water (15 mL) and extracted with EA (15 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=5: 1) to give intermediate I-45 (82 mg, 78.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.55 (dd, J = 8.8, 2.0 Hz, 1H) , 7.49–7.46 (m, 1H) , 6.73 (d, J = 8.4 Hz, 1H) , 3.32 (s, 3H) , 2.94–2.80 (m, 2H) , 2.71–2.54 (m, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
10H
11INO, 287.99; found, 288.19. UPLC purity 98%.
Intermediate I-46: 7-iodo-2H-benzo [b] [1, 4] oxazin-3 (4H) -one.
K
2CO
3 (119 mg, 0.86 mmol) was added to a solution of 2-amino-5-iodophenol (100 mg, 0.43 mmol) and 2-chloroacetyl chloride (49 mg, 0.43 mmol) in CH
3CN (20 mL) portionwise at RT under a nitrogen atmosphere, and the mixture was refluxed for 3 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1: 1) to afford I-46 (62 mg, 52.5%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
8H
7INO
2, 275.95; found, 276.12. UPLC purity 96%.
Intermediate I-47: 6-iodochroman-2-one.
Chroman-2-one (200 mg, 1.35 mmol) was added to a solution of iodine monochloride (1M in AcOH, 1.75 mL) , and the mixture was stirred at 80℃ for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (15 mL) , then the mixture was extracted with EA (5 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=8: 1) to give intermediate I-47 (182 mg, 49.3%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.56 (dd, J = 8.4, 2.1 Hz, 1H) , 7.54–7.53 (m, 1H) , 6.82 (d, J = 8.4 Hz, 1H) , 3.02–2.93 (m, 2H) , 2.78 (m, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
9H
8IO
2, 274.96; found, 275.07. UPLC purity 95%.
Intermediate I-48: methyl 3- (2-hydroxy-5-iodophenyl) propanoate.
LiOH (10.5 mg, 0.43 mmol) was added to a solution of I-47 (100 mg, 0.36 mmol) in mixed solvent (MeOH/H
2O =12 mL: 5 mL) , and the mixture was stirred at RT for 30 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=3: 1) to afford I-48 (59 mg, 53.6%) as a white solid. UPLC-MS (ESI) [M+H] +: calcd for C
10H
12IO
3, 306.98; found, 307.13. UPLC purity 95%.
Intermediate I-49: methyl 3- (3-iodophenyl) propanoate.
SOCl
2 (3 mL) was added to a solution of 3- (3-iodophenyl) propanoic acid (100 mg, 0.36 mmol) in MeOH (12 mL) , and the mixture was stirred at 60℃ for 12 h. After completion of the reaction, most of the solvent is removed from the mixture by rotary evaporation under reduced pressure. Then the residue was resolved in EA (10 mL) , and the organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10: 1) to afford I-49 (55 mg, 52.9%) as a white solid. UPLC-MS (ESI) [M+H] +: calcd for C
10H
12IO
2, 290.99; found, 291.11. UPLC purity 97%.
Intermediate I-50a: 1- (3-iodobenzyl) piperidin-2-one.
NaH (60%, 27 mg, 0.67 mmol) was added to a solution of piperidin-2-one (66.4 mg, 0.67 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (200 mg, 0.67 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-50a (133 mg, 63.1%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
15INO, 316.02; found, 316.15. UPLC purity 95%.
Intermediate I-50b: 1- (3-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 27 mg, 0.67 mmol) was added to a solution of pyridin-2 (1H) -one (63.7 mg, 0.67 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (200 mg, 0.67 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-50b (162 mg, 77.5%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.64–7.62 (m, 2H) , 7.33 (ddd, J = 8.8, 6.6, 2.0 Hz, 1H) , 7.29–7.23 (m, 2H) , 7.07 (t, J = 8.0 Hz, 1H) , 6.62 (d, J = 9.2 Hz, 1H) , 6.17 (t, J = 6.8 Hz, 1H) , 5.08 (s, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
12H
11INO, 311.99; found, 312.21. UPLC purity 94%.
Intermediate I-51a: 1- (4-iodobenzyl) piperidin-2-one.
NaH (60%, 28 mg, 0.68 mmol) was added to a solution of piperidin-2-one (67.4 mg, 0.68 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -4-iodobenzene (202 mg, 0.68 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-51a (143 mg, 67.9%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
15INO, 316.02; found, 316.14. UPLC purity 97%.
Intermediate I-51b: 1- (4-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 28 mg, 0.68 mmol) was added to a solution of pyridin-2 (1H) -one (64 mg, 0.68 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -4-iodobenzene (202 mg, 0.68 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-51b (143 mg, 67.9%) as a gray solid.
1H NMR (400 MHz, CDCl
3) : δ 7.66–7.64 (m, 2H) , 7.34–7.31 (m, 1H) , 7.27–7.22 (m, 1H) , 7.06–7.03 (m, 2H) , 6.61 (d, J = 9.2 Hz, 1H) , 6.18–6.13 (m, 1H) , 5.07 (s, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
12H
11INO, 311.99; found, 312.21. UPLC purity 96%.
Intermediate I-52: 1- (3-iodobenzyl) piperidine-2, 6-dione.
NaH (60%, 28 mg, 0.68 mmol) was added to a solution of piperidine-2, 6-dione (77 mg, 0.68 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (202 mg, 0.68 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-52 (122 mg, 54.7%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
13INO
2, 330.00; found, 330.13. UPLC purity 96%.
Intermediate I-53: 4- (3-iodobenzyl) morpholin-3-one.
NaH (60%, 28 mg, 0.68 mmol) was added to a solution of morpholin-3-one (68.8 mg, 0.68 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (202 mg, 0.68 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-53 (137 mg, 63.4%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
11H
13INO
2, 318.00; found, 318.14. UPLC purity 95%.
Intermediate I-54: 6-chloro-1- (3-iodobenzyl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione.
NaH (60%, 28 mg, 0.68 mmol) was added to a solution of 6-chloro-1- (3-iodobenzyl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione (109 mg, 0.68 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (202 mg, 0.68 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-54 (103 mg, 40.2%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
11ClIN
2O
2, 376.96; found, 377.10. UPLC purity 97%.
Intermediate I-55a: 1- (3-iodobenzyl) -3-methylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 3-methylpyridin-2 (1H) -one (110 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-55a (218 mg, 66.5%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.64–7.61 (m, 2H) , 7.28–7.26 (m, 1H) , 7.20 (d, J = 6.7 Hz, 1H) , 7.15 (d, J = 6.8 Hz, 1H) , 7.06 (t, J = 7.8 Hz, 1H) , 6.10 (dt, J = 6.8, 1.6 Hz, 1H) , 5.08 (s, 2H) , 2.17 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
13INO, 326.00; found, 326.23. UPLC purity 97%.
Intermediate I-55b: 1- (3-iodobenzyl) -3-methoxypyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 3-methoxypyridin-2 (1H) -one (126 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55b (266 mg, 77.1%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.65–7.61 (m, 2H) , 7.29 (d, J = 6.8 Hz, 1H) , 7.06 (td, J = 8.0, 1.2 Hz, 1H) , 6.87 (dt, J = 6.8, 1.6 Hz, 1H) , 6.60 (d, J = 7.2 Hz, 1H) , 6.11 (td, J = 7.6, 1.6 Hz, 1H) , 5.11 (s, 2H) , 3.82 (d, J = 1.1 Hz, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
13INO
2, 342.00; found, 342.25. UPLC purity 95%.
Intermediate I-55c: 3-fluoro-1- (3-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 3-fluoropyridin-2 (1H) -one (114 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55c (239 mg, 71.9%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
10FINO, 329.98; found, 330.13. UPLC purity 95%.
Intermediate I-55d: 1- (3-iodobenzyl) -4-methylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 4-methylpyridin-2 (1H) -one (110 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55d (226 mg, 68.7%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.66–7.58 (m, 2H) , 7.28–7.24 (m, 1H) , 7.12 (d, J = 7.0 Hz, 1H) , 7.06 (t, J = 8.0 Hz, 1H) , 6.43 (s, 1H) , 6.02 (dd, J = 7.0, 1.9 Hz, 1H) , 5.04 (s, 2H) , 2.18 (d, J = 0.9 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
13INO, 326.00; found, 326.13. UPLC purity 96%.
Intermediate I-55e: 1- (3-iodobenzyl) -4-methoxypyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 4-methoxypyridin-2 (1H) -one (126 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55e (245 mg, 71.2%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.63–7.61 (m, 2H) , 7.24 (d, J = 7.7 Hz, 1H) , 7.10 (d, J = 7.5 Hz, 1H) , 7.06 (t, J = 7.7 Hz, 1H) , 5.96 (d, J = 2.7 Hz, 1H) , 5.92 (dd, J = 7.6, 2.7 Hz, 1H) , 5.02 (s, 2H) , 3.77 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
13INO
2, 342.00; found, 342.11. UPLC purity 95%.
Intermediate I-55f: 4-chloro-1- (3-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 4-chloropyridin-2 (1H) -one (131 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-55f (198 mg, 56.7%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
10ClINO, 345.95; found, 346.10. UPLC purity 95%.
Intermediate I-55g: 1- (3-iodobenzyl) -5-methylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 5-methylpyridin-2 (1H) -one (110 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55g (215 mg, 65.5%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.66–7.61 (m, 2H) , 7.28–7.26 (m, 1H) , 7.20 (dd, J = 9.2, 2.5 Hz, 1H) , 7.07 (t, J = 8.0 Hz, 1H) , 7.00 (s, 1H) , 6.58 (d, J = 9.2 Hz, 1H) , 5.05 (s, 2H) , 2.05 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
13INO, 326.00; found, 326.12. UPLC purity 96%.
Intermediate I-55h: 1- (3-iodobenzyl) -6-methylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 6-methylpyridin-2 (1H) -one (110 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-55h (153 mg, 46.6%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.59 (d, J = 7.6 Hz, 1H) , 7.50 (s, 1H) , 7.32–7.26 (m, 1H) , 7.13–7.08 (m, 1H) , 7.04 (t, J = 7.7 Hz, 1H) , 6.58 (t, J = 9.1 Hz, 1H) , 6.06 (t, J = 5.8 Hz, 1H) , 5.29 (s, 2H) , 2.26 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
13H
13INO, 326.00; found, 326.12. UPLC purity 95%.
Intermediate I-55i: 1- (3-iodobenzyl) -3, 4-dimethylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 3, 4-dimethylpyridin-2 (1H) -one (124 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-55i (247 mg, 72.2%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
14H
15INO, 340.02; found, 340.15. UPLC purity 96%.
Intermediate I-55j: 5-chloro-1- (3-iodobenzyl) -3-methylpyridin-2 (1H) -one.
NaH (60%, 40 mg, 1.01 mmol) was added to a solution of 5-chloro-3-methylpyridin-2 (1H) -one (145 mg, 1.01 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then 1- (bromomethyl) -3-iodobenzene (300 mg, 1.01 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-55j (230 mg, 63.4%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
13H
12ClINO, 359.97; found, 360.12. UPLC purity 95%.
Intermediate I-56a: (2-fluoro-5-iodophenyl) methanol.
A solution of borane (1M in THF, 5.64 mL) was added to a solution of 2-fluoro-5-iodobenzoic acid (600 mg, 2.26 mmol) in THF (15 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at 70℃ for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with MeOH (5 mL) at 0℃. Then the pH value was adjusted to 5 with a solution of HCl (2M) , the mixture was extracted with EA (5 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-56a (335 mg, 58.9%) as a white solid.
1H NMR (400 MHz, CDCl
3) : 7.77 (ddt, J = 6.8, 2.3, 0.7 Hz, 1H) , 7.57 (ddd, J = 8.6, 4.9, 2.3 Hz, 1H) , 6.82 (dd, J = 9.8, 8.6 Hz, 1H) , 4.72 (s, 2H) , 1.76 (s, 1H) . UPLC-MS (ESI) [M+H]
+: calcd for C
7H
7FIO, 252.95; found, 235.03. UPLC purity 95%.
Intermediate I-56b: (2-chloro-5-iodophenyl) methanol.
A solution of borane (1M in THF, 5.6 mL) was added to a solution of 2-chloro-5-iodobenzoic acid (600 mg, 2.24 mmol) in THF (15 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at 70℃ for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with MeOH (5 mL) at 0℃. Then the pH value was adjusted to 5 with a solution of HCl (2M) , the mixture was extracted with EA (5 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-56b (298 mg, 49.5%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.84 (d, J = 2.2 Hz, 1H) , 7.55 (dd, J = 8.3, 2.2 Hz, 1H) , 7.08 (d, J = 8.3 Hz, 1H) , 4.74 (s, 2H) , 1.90 (s, 1H) . UPLC-MS (ESI) [M-OH]
+: calcd for C
7H
5ClI, 250.91; found, 251.00. UPLC purity 96%.
Intermediate I-57a: 2-fluoro-5-iodobenzyl 4-methylbenzenesulfonate.
NaH (60%, 93 mg, 2.32 mmol) was added to a solution of I-56a (390 mg, 1.55 mmol) in dry THF (18 mL) at 0 ℃ and the mixture was stirred for 30 min keeping the temperature below 10 ℃. Then the TosCl (442 mg, 2.32 mmol) was added and the reaction was warmed to 45 ℃ in an oil bath. The reaction was stirred at 45 ℃ for 6 hours, then the mixture was quenched with saturated ammonium chloride solution and extracted with EA (10 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10: 1) to afford I-57a (246 mg, 39.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.78 (d, J = 8.3 Hz, 2H) , 7.59 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H) , 7.53 (dd, J = 6.7, 2.1 Hz, 1H) , 7.34 (d, J = 8.1 Hz, 2H) , 6.77 (t, J = 9.1 Hz, 1H) , 5.06 (s, 2H) , 2.45 (s, 3H) . UPLC-MS (ESI) [M-C
7H
7O
3S]
+: calcd for C
7H
5FI, 234.94; found, 235.03. UPLC purity 96%.
Intermediate I-57b: 2-chloro-5-iodobenzyl 4-methylbenzenesulfonate.
NaH (60%, 104 mg, 2.6 mmol) was added to a solution of I-56b (465 mg, 1.73 mmol) in dry THF (25 mL) at 0 ℃ and the mixture was stirred for 30 min keeping the temperature below 10 ℃. Then the TosCl (495 mg, 2.6 mmol) was added and the reaction was warmed to 45 ℃ in an oil bath. The reaction was stirred at 45 ℃ for 6 hours, then the mixture was quenched with saturated ammonium chloride solution and extracted with EA (15 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10: 1) to afford I-57b (415 mg, 56.6%) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.80 (d, J = 8.3 Hz, 2H) , 7.60 (d, J = 2.1 Hz, 1H) , 7.55 (dd, J = 8.4, 2.1 Hz, 1H) , 7.34 (d, J = 8.0 Hz, 2H) , 7.04 (d, J = 8.4 Hz, 1H) , 5.09 (s, 2H) , 2.45 (s, 3H) . UPLC-MS (ESI) [M-C
7H
7O
3S]
+: calcd for C
7H
5ClI, 250.91; found, 250.96. UPLC purity 95%.
Intermediate I-58a: 1- (2-fluoro-5-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 22 mg, 0.54 mmol) was added to a solution of pyridin-2 (1H) -one (52 mg, 0.54 mmol) in DMF (10 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-57a (220 mg, 0.54 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-58a (105 mg, 59.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.72 (dd, J = 6.9, 2.3 Hz, 1H) , 7.57 (ddd, J = 8.6, 4.9, 2.3 Hz, 1H) , 7.37–7.29 (m, 2H) , 6.83 (dd, J = 9.7, 8.7 Hz, 1H) , 6.62–6.56 (m, 1H) , 6.18 (td, J = 6.7, 1.4 Hz, 1H) , 5.09 (s, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
12H
10FINO, 329.98; found, 330.11. UPLC purity 95%.
Intermediate I-58b: 1- (2-chloro-5-iodobenzyl) pyridin-2 (1H) -one.
NaH (60%, 24 mg, 0.6 mmol) was added to a solution of pyridin-2 (1H) -one (57 mg, 0.6 mmol) in DMF (10 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-57b (250 mg, 0.6 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-58b (125 mg, 61.21%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.52 (dd, J = 8.4, 2.1 Hz, 1H) , 7.48 (d, J = 2.0 Hz, 1H) , 7.34 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H) , 7.28 (dd, J = 6.8, 1.5 Hz, 1H) , 7.09 (d, J = 8.4 Hz, 1H) , 6.60 (d, J = 9.1 Hz, 1H) , 6.17 (td, J = 6.7, 1.3 Hz, 1H) , 5.16 (s, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
12H
10ClINO, 345.95; found, 346.04. UPLC purity 95%.
Intermediate I-58c: 1- (2-fluoro-5-iodobenzyl) -3-methoxypyridin-2 (1H) -one.
NaH (60%, 22 mg, 0.54 mmol) was added to a solution of 3-methoxypyridin-2 (1H) -one (68 mg, 0.54 mmol) in DMF (12 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-57a (220 mg, 0.54 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-58c (131 mg, 67.5%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.74 (dd, J = 6.9, 2.2 Hz, 1H) , 7.54 (ddd, J = 8.5, 4.9, 2.3 Hz, 1H) , 6.96 (dt, J = 7.0, 1.4 Hz, 1H) , 6.80 (dd, J = 9.6, 8.7 Hz, 1H) , 6.57 (dd, J = 7.4, 1.5 Hz, 1H) , 6.09 (t, J = 7.2 Hz, 1H) , 5.12 (s, 2H) , 3.79 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
12FINO
2, 359.99; found, 360.07. UPLC purity 96%.
Intermediate I-58d: 1- (2-chloro-5-iodobenzyl) -3-methoxypyridin-2 (1H) -one.
NaH (60%, 24 mg, 0.6 mmol) was added to a solution of 3-methoxypyridin-2 (1H) -one (75 mg, 0.6 mmol) in DMF (10 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-57b (250 mg, 0.6 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-58d (130 mg, 58.5%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) : δ 7.58–7.53 (m, 2H) , 7.11 (d, J = 8.3 Hz, 1H) , 6.94 (dd, J = 7.0, 1.7 Hz, 1H) , 6.63 (dd, J = 7.4, 1.6 Hz, 1H) , 6.16 (t, J = 6.9 Hz, 1H) , 5.24 (s, 2H) , 3.84 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
12ClINO
2, 375.96; found, 376.04 . UPLC purity 95%.
Intermediate I-59: 4-iodo-2- ( (tosyloxy) methyl) phenyl 4-methylbenzenesulfonate.
NaH (60%, 416 mg, 10.4 mmol) was added to a solution of 2- (hydroxymethyl) -4-iodophenol (1.0 g, 4 mmol) in dry THF (35 mL) at 0 ℃ and the mixture was stirred for 30 min keeping the temperature below 10 ℃. Then the TosCl (1.68 g, 8.8 mmol) was added and the reaction was warmed to 45 ℃ in an oil bath. The reaction was stirred at 45 ℃ for 6 hours, then the mixture was quenched with saturated ammonium chloride solution and extracted with EA (10 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=20: 1) to afford I-59 (1.2 g, 54.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.75 (d, J = 8.4 Hz, 2H) , 7.70 (d, J = 8.4 Hz, 2H) , 7.58–7.55 (m, 2H) , 7.36–7.34 (m, 4H) , 6.80 (d, J = 8.4 Hz, 1H) , 4.84 (s, 2H) , 2.49 (s, 3H) , 2.47 (s, 3H) . UPLC-MS (ESI) [M-C
7H
7O
3S]
+: calcd for C
14H
12IO
3S, 386.96; found, 387.20. UPLC purity 96%.
Intermediate I-60a: 4-iodo-2- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl-4-methylbenzenesulfonate.
NaH (60%, 22 mg, 0.67 mmol) was added to a solution of pyridin-2 (1H) -one (51.4 mg, 0.54 mmol) in DMF (10 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-59 (300 mg, 0.54 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (10 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=3: 1) to give intermediate I-60a (180 mg, 69.7%) as a white oil.
1H NMR (400 MHz, CDCl
3) : δ 7.81–7.74 (m, 2H) , 7.60 (d, J = 2.4 Hz, 1H) , 7.53 (dd, J = 8.4, 2.2 Hz, 1H) , 7.38 (d, J = 8.0 Hz, 2H) , 7.35–7.31 (m, 1H) , 7.31–7.27 (m, 1H) , 6.70 (d, J = 8.4 Hz, 1H) , 6.58 (d, J = 9.2 Hz, 1H) , 6.16 (dt, J = 6.8, 1.2 Hz, 1H) , 4.98 (s, 2H) , 2.49 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
19H
17INO
4S, 481.99; found, 482.20. UPLC purity 97%.
Intermediate I-60b: 4-iodo-2- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl-4-methylbenzenesulfonate.
NaH (60%, 36 mg, 0.9 mmol) was added to a solution of 3-methoxypyridin-2 (1H) -one (113 mg, 0.9 mmol) in DMF (15 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then I-59 (500 mg, 0.9 mmol) was added and the mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with water (45 mL) and extracted with EA (12 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-60b (320 mg, 70.0%) as a white oil.
1H NMR (400 MHz, CDCl
3) : δ 7.76 (d, J = 8.4 Hz, 2H) , 7.62 (d, J = 2.2 Hz, 1H) , 7.51 (dd, J = 8.6, 2.2 Hz, 1H) , 7.37 (d, J = 8.1 Hz, 2H) , 6.90 (dd, J = 7.0, 2.0 Hz, 1H) , 6.71 (d, J = 8.8 Hz, 1H) , 6.58 (dd, J = 7.2, 1.4 Hz, 1H) , 6.09 (t, J = 7.2 Hz, 1H) , 4.98 (s, 2H) , 3.81 (s, 3H) , 2.48 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
20H
19INO
5S, 512.00; found, 512.27. UPLC purity 95%.
Intermediate I-61a: 1- (2-hydroxy-5-iodobenzyl) pyridin-2 (1H) -one.
To a solution of I-60a (480 mg, 0.99 mmol) in mixed solvent (THF/MeOH/H
2O =12 mL: 3 mL: 5 mL) was added LiOH (24 mg, 0.99 mmol) and the mixture was stirred at 45℃ for 1 h. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=4: 1) to afford I-61a (230 mg, 70.6%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 10.31 (s, 1H) , 7.79 (dd, J = 6.8, 2.0 Hz, 1H) , 7.50–7.42 (m, 2H) , 7.35 (d, J = 2.0 Hz, 1H) , 6.68 (d, J = 8.4 Hz, 1H) , 6.45 (d, J = 8.8 Hz, 1H) , 6.30 (td, J = 6.8, 1.3 Hz, 1H) , 4.96 (s, 2H) . UPLC-MS (ESI) [M+H]
+: calcd for C
12H
11INO
2, 327.98; found, 328.18. UPLC purity 97%.
Intermediate I-61b: 1- (2-hydroxy-5-iodobenzyl) -3-methoxypyridin-2 (1H) -one.
LiOH (11.3 mg, 0.47 mmol) was added to a solution of I-60b (200 mg, 0.39mmol) in mixed solvent (THF/MeOH/H
2O =8 mL: 2 mL: 3 mL) and the mixture was stirred at 45℃ for 1 h. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (5 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=3: 1) to afford I-61b (82.5 mg, 59.1%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 10.28 (s, 1H) , 7.55–7.48 (m, 2H) , 7.15 (d, J = 7.2 Hz, 1H) , 6.74 (d, J = 8.0 Hz, 2H) , 6.34 (t, J = 7.2 Hz, 1H) , 5.01 (s, 2H) , 3.83 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
13INO
3, 357.99; found, 358.28. UPLC purity 95%.
Intermediate I-62a: 1- (5-iodo-2-methoxybenzyl) pyridin-2 (1H) -one.
NaH (60%, 4.2 mg, 0.104 mmol) was added to a solution of I-61a (35 mg, 0.104 mmol) in DMF (5 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then MeI (14.8 mg, 0.104 mmol) was added and the mixture was stirred at RT for 2 hours. After completion of the reaction, the mixture was diluted with water (15 mL) and extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-62a (29 mg, 79.7%) as a yellow solid.
1H NMR (400 MHz, DMSO) : δ 7.66 (dd, J = 6.8, 2.0 Hz, 1H) , 7.58 (dd, J = 8.4, 2.2 Hz, 1H) , 7.43 (ddd, J = 8.8, 6.4, 2.0 Hz, 1H) , 7.14 (d, J = 2.0 Hz, 1H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.38 (d, J = 8.8 Hz, 1H) , 6.23 (td, J = 6.8, 1.1 Hz, 1H) , 4.95 (s, 2H) , 3.79 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C
13H
13INO
2, 342.00; found, 342.22. UPLC purity 95%.
Intermediate I-62b: 1- (5-iodo-2-methoxybenzyl) -3-methoxypyridin-2 (1H) -one.
NaH (60%, 6 mg, 0.14 mmol) was added to a solution of I-61b (50 mg, 0.14 mmol) in DMF (5 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then MeI (20 mg, 0.14 mmol) was added and the mixture was stirred at RT for 2 hours. After completion of the reaction, the mixture was diluted with water (15 mL) and extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give intermediate I-62b (33 mg, 63.5%) as a yellow solid.
1H NMR (400 MHz, CDCl3) : δ 7.58–7.53 (m, 2H) , 6.98 (d, J = 7.2 Hz, 1H) , 6.64 (d, J = 8.4 Hz, 1H) , 6.58 (d, J = 7.2 Hz, 1H) , 6.07 (t, J = 7.2 Hz, 1H) , 5.11 (s, 2H) , 3.83 (s, 3H) , 3.81 (s, 3H) . UPLC-MS (ESI) [M+H]
+: calcd for C14H15INO3, 372.01; found, 372.31. UPLC purity 95%.
Intermediate I-63a: 4-iodo-1-methylpyridin-2 (1H) -one.
NaH (60%, 20 mg, 0.45 mmol) was added to a solution of 4-iodopyridin-2 (1H) -one (100 mg, 0.45 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then MeI (64 mg, 0.45 mmol) was added and the mixture was stirred at RT for 2 hours. After completion of the reaction, the mixture was diluted with water (15 mL) and extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-63a (60 mg, 57.1%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
6H
7INO, 235.96; found, 236.10. UPLC purity 96%.
Intermediate I-63b: 1-benzyl-4-iodopyridin-2 (1H) -one.
NaH (60%, 20 mg, 0.45 mmol) was added to a solution of 4-iodopyridin-2 (1H) -one (100 mg, 0.45 mmol) in DMF (8 mL) at 0℃ under a nitrogen atmosphere and the mixture was stirred for 5 min in an ice bath. Then benzyl iodide (98.1 mg, 0.45 mmol) was added and the mixture was stirred at RT for 2 hours. After completion of the reaction, the mixture was diluted with water (15 mL) and extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give intermediate I-63b (72 mg, 51.4%) as a white solid. UPLC-MS (ESI) [M+H]
+: calcd for C
12H
11INO, 311.99; found, 312.12. UPLC purity 96%.
Synthesis Procedure for Compounds 1–150.
Example 1: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 1) .
A solution of TBAF (1M in THF, 0.091 mL) was added to a solution of I-5a (40 mg, 0.091 mmol) in THF (3 mL) dropwise, and the mixture was stirred at RT for 10 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (2 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=50: 1) to afford compound 1 (18.2 mg, 62.3%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.70 (s, 1H) , 9.60 (s, 1H) , 8.76 (s, 1H) , 7.18 (td, J = 7.6, 0.8 Hz, 1H) , 6.88 (dt, J = 7.6, 1.2 Hz, 1H) , 6.83–6.79 (m, 2H) , 6.74 (dd, J = 17.0, 10.2 Hz, 1H) , 6.21 (dd, J = 17.0, 2.0 Hz, 1H) , 5.71 (dd, J = 10.2, 2.1 Hz, 1H) , 4.89 (s, 2H) , 3.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 163.70, 159.21, 157.33, 149.08, 131.11, 130.46, 129.91, 127.00, 122.38, 122.31, 117.98, 116.58, 113.62, 84.80, 83.19, 38.77, 28.16. HRMS (ESI) [M+H]
+: calcd for C
17H
16N
3O
4, 326.1136; found, 326.1134.
Example 2: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 2) .
A solution of TBAF (1M in THF, 0.15 mL) was added to a solution of I-5b (65 mg, crude) in THF (3 mL) dropwise, and the mixture was stirred at RT for 10 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (2 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=30: 1) to afford compound 2 (18.2 mg) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.74 (s, 1H) , 9.24 (s, 1H) , 7.96 (s, 1H) , 7.21–7.15 (m, 1H) , 6.86 (d, J = 7.6 Hz, 1H) , 6.80–6.73 (m, 3H) , 6.03 (d, J = 16.5 Hz, 1H) , 5.94 (d, J = 9.9 Hz, 1H) , 4.86 (s, 2H) , 3.20 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 160.60, 157.36, 149.84, 140.40, 136.99, 129.95, 125.88, 122.33, 122.28, 117.95, 116.62, 110.21, 84.72, 83.17, 38.89, 28.18. HRMS (ESI) [M-H]
-: calcd for C
16H
14N
3O
5S, 360.0654; found, 360.0659.
Example 3: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 3) .
Acryloyl chloride (32.6 mg, 0.36 mmol) was added to a solution of I-11 (100 mg, 0.24 mmol) and TEA (36.4 mg, 0.36 mmol) in dry DCM (6 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (5 mL) , then the mixture was extracted with DCM (3 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was filtered, concentrated under reduced pressure and the residue was directly dissolved in THF (8 mL) . A solution of TBAF (1M in THF, 0.24 mL) was added to the mixture dropwise and the mixture was stirred at RT for 10 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (3 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=40: 1) to give corresponding compound 3 (35 mg, 40.7%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.73 (s, 1H) , 9.61 (s, 1H) , 7.17 (dd, J = 8.8, 7.7 Hz, 1H) , 6.86 (d, J = 7.6 Hz, 1H) , 6.83–6.75 (m, 2H) , 6.43 (dd, J = 17.1, 10.2 Hz, 1H) , 6.22 (dd, J = 17.1, 1.8 Hz, 1H) , 5.76 (dd, J = 10.2, 1.8 Hz, 1H) , 5.08 (s, 2H) , 3.23 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 163.92, 158.75, 157.36, 149.39, 143.16, 130.62, 129.94, 127.53, 122.41, 122.22, 118.04, 116.69, 110.51, 83.89, 83.04, 37.61, 28.71. HRMS (ESI) [M+H]
+: calcd for C
17H
15ClN
3O
4, 360.0746; found, 360.0743.
Example 4: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 4) .
Ethenesulfonic acid chloride (43.4 mg, 0.36 mmol) was added to a solution of I-11 (100 mg, 0.24 mmol) and TEA (36.4 mg, 0.36 mmol) in dry DCM (6 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (5 mL) , then the mixture was extracted with DCM (3 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was filtered, concentrated under reduced pressure and the residue was directly dissolved in THF (8 mL) . A solution of TBAF (1M in THF, 0.24 mL) was added to the mixture dropwise and the mixture was stirred at RT for 10 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (3 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=30: 1) to give corresponding compound 4 as a white solid (42 mg, 45.1%) .
1H NMR (400 MHz, DMSO) : δ 9.72 (s, 1H) , 9.39 (s, 1H) , 7.17 (t, J = 7.7 Hz, 1H) , 6.87–6.78 (m, 4H) , 6.05 (d, J = 16.6 Hz, 1H) , 5.93 (d, J = 9.9 Hz, 1H) , 5.07 (s, 2H) , 3.21 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 159.46, 157.34, 149.17, 146.77, 138.51, 129.96, 124.78, 122.41, 122.20, 118.00, 116.68, 109.71, 83.92, 82.95, 37.98, 28.79. HRMS (ESI) [M+H]
+: calcd for C
16H
15ClN
3O
5S, 396.0421; found, 396.0413.
Example 5: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -6-methoxy-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 5) .
Pd(Pph
3)
4 (10.8 mg, 0.009 mmol) and CuI (3.6 mg, 0.018 mmol) were added to a solution containing I-14a (48 mg, 0.184 mmol) , 3-iodophenol (48.4 mg, 0.22 mmol) and N, N-diisopropylethylamine (51.6 mg, 0.4 mmol) in DMF (8 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃ for 4 hours in an oil bath. After completion, the mixture was diluted with water (20 mL) , extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=30: 1) to give the compound 5 (31 mg, 47.8%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.72 (s, 1H) , 9.23 (s, 1H) , 7.17–7.12 (m, 1H) , 6.85 (d, J = 6.9 Hz, 1H) , 6.84–6.79 (m, 2H) , 6.44 (dd, J = 16.8, 10.4 Hz, 1H) , 6.21 (d, J = 16.8 Hz, 1H) , 5.75 (d, J = 9.9 Hz, 1H) , 4.85 (s, 2H) , 4.02 (s, 3H) , 3.19 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 165.26, 160.97, 157.60, 157.34, 149.29, 130.84, 129.89, 127.16, 122.41, 122.34, 118.00, 116.47, 95.77, 83.99, 82.60, 61.73, 32.96, 28.26. HRMS (ESI) [M+H]
+: calcd for C
18H
18N
3O
5, 356.1246; found, 356.1240 .
Example 6: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3, 6-dimethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acrylamide (Compound 6) .
Pd (Pph
3)
4 (13.9 mg, 0.012 mmol) and CuI (4.6 mg, 0.024 mmol) were added to a solution containing I-21a (60 mg, 0.24 mmol) , 3-iodophenol (63.8 mg, 0.29 mmol) and N, N-diisopropylethylamine (68.5 mg, 0.53 mmol) in DMF (15 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃ for 4 hours in an oil bath. After completion of the reaction, the mixture was diluted with water (35 mL) , extracted with EA (8 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=40: 1) to give the compound 6 (36.3 mg, 44.1%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.74 (s, 1H) , 9.35 (s, 1H) , 7.17 (dd, J = 8.9, 7.6 Hz, 1H) , 6.88–6.84 (m, 1H) , 6.82–6.79 (m, 2H) , 6.45 (dd, J = 17.1, 10.2 Hz, 1H) , 6.19 (dd, J = 17.1, 2.0 Hz, 1H) , 5.73 (dd, J = 10.2, 2.0 Hz, 1H) , 5.01 (s, 2H) , 3.22 (s, 3H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 164.23, 159.63, 157.35, 150.45, 148.73, 130.98, 129.92, 126.94, 122.38, 122.24, 118.01, 116.60, 109.48, 83.66, 83.63, 35.37, 28.24, 15.24. HRMS (ESI) [M+H]
+: calcd for C
18H
18N
3O
4, 340.1297; found, 340.1291.
Example 7: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -6-methoxy-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 7) .
Pd (Pph
3)
4 (13.3 mg, 0.012 mmol) and CuI (4.4 mg, 0.023 mmol) were added to a solution containing I-14b (69 mg, 0.23 mmol) , 3-iodophenol (62 mg, 0.28 mmol) and N, N-diisopropylethylamine (66 mg, 0.51 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃for 4 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=20: 1) to give the compound 7 (39.2 mg, 43.3%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.68 (s, 1H) , 8.91 (s, 1H) , 7.16 (t, J = 7.6 Hz, 1H) , 6.84 (d, J = 6.7 Hz, 1H) , 6.81–6.74 (m, 3H) , 6.02 (d, J = 16.5 Hz, 1H) , 5.93 (d, J = 9.9 Hz, 1H) , 4.84 (s, 2H) , 4.28 (s, 3H) , 3.18 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 161.83, 159.70, 157.31, 149.09, 140.20, 137.96, 129.91, 124.97, 122.37, 117.99, 116.47, 94.58, 83.87, 82.60, 62.73, 33.14, 28.33. HRMS (ESI) [M+H]
+: calcd for C
17H
18N
3O
6S, 392.0916; found, 392.0909.
Example 8: N- (1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3, 6-dimethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) ethenesulfonamide (Compound 8) .
Pd (Pph
3)
4 (8.1 mg, 0.007 mmol) and CuI (2.7 mg, 0.014 mmol) were added to a solution containing I-21b (40 mg, 0.14 mmol) , 3-iodophenol (37.4 mg, 0.17 mmol) and N, N-diisopropylethylamine (40.1 mg, 0.31 mmol) in DMF (6 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃ for 4 hours in an oil bath. After completion of the reaction, the mixture was diluted with water (30 mL) , extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=30: 1) to give the compound 8 (23.9 mg, 45.2%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.00 (s, 1H) , 7.17 (t, J = 8.2 Hz, 1H) , 6.85 (d, J = 7.6 Hz, 1H) , 6.83–6.68 (m, 3H) , 5.99 (d, J = 16.5 Hz, 1H) , 5.91 (d, J = 9.9 Hz, 1H) , 5.00 (s, 2H) , 3.20 (s, 3H) , 2.55 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 160.16, 157.34, 153.11, 150.22, 137.82, 129.93, 124.97, 122.37, 122.20, 117.98, 116.61, 108.61, 83.69, 83.48, 35.64, 28.33, 15.88. HRMS (ESI) [M+H]
+: calcd for C
17H
18N
3O
5S, 376.0967; found, 376.0962.
General Synthesis Procedure for Compounds 9–50.
The corresponding acyl chlorides (X1–X42, 0.36 mmol) was added to a solution of I-11 (100 mg, 0.24 mmol) and TEA (36.4 mg, 0.36 mmol) in dry DCM (6 mL) at 0℃ under a nitrogen atmosphere, and the mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC) , the mixture was quenched with a saturated solution of sodium bicarbonate (5 mL) , then the mixture was extracted with DCM (3 mL×3) , and the organic layer was washed with brine and dried over Na
2SO
4. The solvent was filtered, concentrated under reduced pressure and the residue was directly dissolved in THF (8 mL) . A solution of TBAF (1M in THF, 0.24 mL) was added to the mixture dropwise and the mixture was stirred at RT for 10 min. Then the reaction was quenched with saturated ammonium chloride solution and extracted with EA (3 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH) to give corresponding compounds 9–50.
Example 9: (E) -N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) but-2-enamide (Compound 9) .
Prepared from I-11 (100 mg, 0.24 mmol) and X1 ( (E) -but-2-enoyl chloride, 37.6 mg, 0.36 mmol) . White solid (36 mg, 40.1%) .
1H NMR (400 MHz, DMSO) : δ 9.72 (s, 1H) , 9.61 (s, 1H) , 7.19–7.16 (m, 1H) , 6.89–6.85 (m, 1H) , 6.82–6.78 (m, 2H) , 6.85 (dq, J = 15.2, 6.8 Hz, 1H) , 6.18 (dq, J = 15.2, 1.6 Hz, 1H) , 5.08 (s, 2H) , 3.23 (s, 3H) , 1.87 (dd, J = 6.8, 1.6 Hz,3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
18H
17ClN
3O
4, 374.09; found, 374.21.
Example 10: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) propiolamide (Compound 10) .
Prepared from I-11 (100 mg, 0.24 mmol) and X2 (propioloyl chloride, 31.9 mg, 0.36 mmol) . White solid (32 mg, 37.3%) .
1H NMR (400 MHz, DMSO) : δ 9.81 (s, 1H) , 9.70 (s, 1H) , 7.23–7.18 (m, 1H) , 6.95–6.90 (m, 1H) , 6.89–6.81 (m, 2H) , 5.11 (s, 2H) , 4.05 (s, 1H) , 3.25 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
17H
13ClN
3O
4, 358.06; found, 358.19.
Example 11: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) but-2-ynamide (Compound 11) .
Prepared from I-11 (100 mg, 0.24 mmol) and X3 (but-2-ynoyl chloride, 36.9 mg, 0.36 mmol) . White solid (35 mg, 39.2%) .
1H NMR (400 MHz, DMSO) : δ 9.79 (s, 1H) , 9.71 (s, 1H) , 7.22–7.16 (m, 1H) , 6.94–6.91 (m, 1H) , 6.88–6.82 (m, 2H) , 5.08 (s, 2H) , 3.23 (s, 3H) , 2.03 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
18H
15ClN
3O
4, 372.08; found, 372.18.
Example 12: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acetamide (Compound 12) .
Prepared from I-11 (100 mg, 0.24 mmol) and X4 (acetyl chloride, 28.3 mg, 0.36 mmol) . White solid (40 mg, 47.9%) .
1H NMR (400 MHz, DMSO) : δ 9.74 (s, 1H) , 9.30 (s, 1H) , 7.18–7.15 (m, 1H) , 6.89–6.85 (m, 1H) , 6.82–6.77 (m, 2H) , 5.08 (s, 2H) , 3.22 (s, 3H) , 2.13 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
16H
15ClN
3O
4, 348.08; found, 348.20.
Example 13: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) propionamide (Compound 13) .
Prepared from I-11 (100 mg, 0.24 mmol) and X5 (propionyl chloride, 33.3 mg, 0.36 mmol) . White solid (33 mg, 37.9%) .
1H NMR (400 MHz, DMSO) : δ 9.75 (s, 1H) , 9.29 (s, 1H) , 7.19–7.14 (m, 1H) , 6.88–6.84 (m, 1H) , 6.82–6.78 (m, 2H) , 5.07 (s, 2H) , 3.22 (s, 3H) , 2.28 (q, J = 7.6 Hz, 2H) , 1.06 (t, J = 7.6 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 172.63, 158.83, 157.35, 149.38, 143.08, 129.89, 122.34, 122.18, 118.01, 116.65, 110.81, 83.80, 83.03, 37.54, 28.63, 28.25, 9.72. HRMS (ESI) [M+H]
+: calcd for C
17H
17ClN
3O
4, 362.0902; found, 362.0898.
Example 14: 2-chloro-N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) acetamide (Compound 14) .
Prepared from I-11 (100 mg, 0.24 mmol) and X6 (2-chloroacetyl chloride, 40.7 mg, 0.36 mmol) . White solid (35 mg, 38.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
16H
14Cl
2N
3O
4, 382.04; found, 382.19.
Example 15: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) butyramide (Compound 15) .
Prepared from I-11 (100 mg, 0.24 mmol) and X7 (butyryl chloride, 38.4 mg, 0.36 mmol) . White solid (36 mg, 39.9%) .
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.22 (s, 1H) , 7.17 (t, J = 7.6, 1H) , 6.88–6.83 (m, 1H) , 6.83–6.78 (m, 2H) , 5.08 (s, 2H) , 3.28 (s, 3H) , 2.28 (q, J = 7.7 Hz, 2H) , 1.64–1.61 (m, 2H) , 0.96 (t, J = 7.7 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
18H
19ClN
3O
4, 376.11; found, 376.21.
Example 16: ethyl (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) carbamate (Compound 16) .
Prepared from I-11 (100 mg, 0.24 mmol) and X8 (ethyl carbonochloridate, 39.1 mg, 0.36 mmol) . White solid (41 mg, 45.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
17H
17ClN
3O
5, 378.09; found, 378.19.
Example 17: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3, 3-dimethylbutanamide (Compound 17) .
Prepared from I-11 (100 mg, 0.24 mmol) and X9 (3, 3-dimethylbutanoyl chloride, 48.4 mg, 0.36 mmol) . White solid (35 mg, 36.4%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.20 (s, 1H) , 7.17 (td, J = 7.6, 0.9 Hz, 1H) , 6.85 (dt, J = 7.6, 0.9 Hz, 1H) , 6.82–6.77 (m, 2H) , 5.07 (s, 2H) , 3.22 (s, 3H) , 2.14 (s, 2H) , 1.03 (s, 9H) .
13C NMR (100 MHz, DMSO) : δ 170.39, 158.72, 157.31, 149.40, 142.97, 129.91, 122.38, 122.21, 118.00, 116.63, 110.99, 83.79, 83.07, 48.37, 37.55, 30.79, 29.72, 28.64. HRMS (ESI) [M+H]
+: calcd for C
20H
23ClN
3O
4, 404.1372; found, 404.1369.
Example 18: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2, 2-dimethylbutanamide (Compound 18) .
Prepared from I-11 (100 mg, 0.24 mmol) and X10 (2, 2-dimethylbutanoyl chloride, 48.4 mg, 0.36 mmol) . White solid (39 mg, 40.6%) .
1H NMR (400 MHz, DMSO) : δ 9.68 (s, 1H) , 8.81 (s, 1H) , 7.17 (t, J = 7.8 Hz, 1H) , 6.85 (d, J = 8.0 Hz, 1H) , 6.82–6.79 (m, 2H) , 5.08 (s, 2H) , 3.23 (d, J = 0.4 Hz, 3H) , 1.59 (q, J = 7.4 Hz, 2H) , 1.13 (s, 6H) , 0.86 (t, J = 7.4 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 176.48, 158.67, 157.31, 149.40, 143.29, 129.90, 122.36, 122.17, 117.99, 116.63, 111.30, 83.79, 83.02, 42.22, 37.50, 32.93, 28.59, 24.87, 9.07. HRMS (ESI) [M+H]
+: calcd for C
20H
23ClN
3O
4, 404.1372; found, 404.1371.
Example 19: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2-methylbutanamide (Compound 19) .
Prepared from I-11 (100 mg, 0.24 mmol) and X11 (2-methylbutanoyl chloride, 43.4 mg, 0.36 mmol) . White solid (42 mg, 45.1%) .
1H NMR (400 MHz, DMSO) : δ 9.74 (s, 1H) , 9.26 (s, 1H) , 7.16 (dd, J = 9.2, 7.6 Hz, 1H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.80 (m, 2H) , 5.07 (s, 2H) , 3.23 (s, 3H) , 2.44–2.36 (m, 1H) , 1.61–1.54 (m, 1H) , 1.41–1.34 (m, 1H) , 1.06 (d, J = 6.8 Hz, 3H) , 0.90 (t, J = 7.4 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 175.46, 158.87, 157.41, 149.48, 143.18, 129.99, 122.46, 122.27, 118.08, 116.73, 110.89, 83.88, 83.09, 48.70, 41.19, 28.69, 26.89, 17.54, 11.83. HRMS (ESI) [M+H]
+: calcd for C
19H
21ClN
3O
4, 390.1215; found, 390.1214.
Example 20: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) pentanamide (Compound 20) .
Prepared from I-11 (100 mg, 0.24 mmol) and X12 (pentanoyl chloride, 43.4 mg, 0.36 mmol) . White solid (30 mg, 32.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
19H
21ClN
3O
4, 390.12; found, 390.23.
Example 21: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (2-methoxyethoxy) acetamide (Compound 21) .
Prepared from I-11 (100 mg, 0.24 mmol) and X13 (2- (2-methoxyethoxy) acetyl chloride, 54.9 mg, 0.36 mmol) . White solid (35 mg, 34.6%) .
1H NMR (400 MHz, DMSO) : δ 9.76 (s, 1H) , 9.17 (s, 1H) , 7.16 (dd, J = 8.8, 7.7 Hz, 1H) , 6.86–6.80 (m, 3H) , 5.08 (s, 2H) , 4.07 (s, 2H) , 3.67–3.65 (m, 2H) , 3.53–3.51 (m, 2H) , 3.27 (s, 3H) , 3.23 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 169.25, 158.59, 157.38, 149.36, 143.37, 129.91, 122.36, 122.17, 118.03, 116.69, 110.20, 83.90, 82.98, 71.06, 70.11, 69.83, 58.15, 37.60, 28.68. HRMS (ESI) [M+H]
+: calcd for C
19H
21ClN
3O
6, 422.1114; found, 422.1113.
Example 22: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) octanamide (Compound 22) .
Prepared from I-11 (100 mg, 0.24 mmol) and X14 (octanoyl chloride, 58.5 mg, 0.36 mmol) . White solid (42 mg, 40.8%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.28 (s, 1H) , 7.17 (td, J = 7.8, 0.8 Hz, 1H) , 6.87–6.83 (m, 1H) , 6.82–6.78 (m, 2H) , 5.07 (s, 2H) , 3.22 (s, 3H) , 2.25 (t, J = 7.4 Hz, 2H) , 1.59–1.52 (m, 2H) , 1.31–1.26 (m, 8H) , 0.86 (t, J = 6.8 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.86, 158.78, 157.30, 149.36, 143.00, 129.88, 122.35, 122.19, 117.98, 116.61, 110.83, 83.77, 83.04, 37.53, 35.03, 31.20, 28.62, 28.50, 28.46, 25.20, 22.08, 13.97. HRMS (ESI) [M+H]
+: calcd for C
22H
27ClN
3O
4, 432.1685; found, 432.1684.
Example 23: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclopropanecarboxamide (Compound 23) .
Prepared from I-11 (100 mg, 0.24 mmol) and X15 (cyclopropanecarbonyl chloride, 37.6 mg, 0.36 mmol) . White solid (34 mg, 37.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
18H
17ClN
3O
4, 374.09; found, 374.20.
Example 24: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclobutanecarboxamide (Compound 24) .
Prepared from I-11 (100 mg, 0.24 mmol) and X16 (cyclobutanecarbonyl chloride, 42.7 mg, 0.36 mmol) . White solid (39 mg, 41.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
19H
19ClN
3O
4, 388.11; found, 388.20.
Example 25: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cyclopentanecarboxamide (Compound 25) .
Prepared from I-11 (100 mg, 0.24 mmol) and X17 (cyclopentanecarbonyl chloride, 47.7 mg, 0.36 mmol) . White solid (40 mg, 41.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
20H
21ClN
3O
4, 402.12; found, 402.21.
Example 26: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) benzamide (Compound 26) .
Prepared from I-11 (100 mg, 0.24 mmol) and X18 (benzoyl chloride, 50.6 mg, 0.36 mmol) . White solid (31 mg, 31.6%) .
1H NMR (400 MHz, DMSO) : δ 9.86 (s, 1H) , 9.70 (s, 1H) , 7.96 (d, J = 7.2 Hz, 2H) , 7.63–7.58 (m, 1H) , 7.55–7.51 (m, 2H) , 7.18 (dd, J = 8.9, 7.6 Hz, 1H) , 6.88–6.85 (m, 1H) , 6.83–6.79 (m, 2H) , 5.12 (s, 2H) , 3.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 165.82, 158.78, 157.34, 149.42, 143.75, 133.21, 132.06, 129.96, 128.48, 127.77, 122.41, 122.20, 118.02, 116.68, 110.91, 83.88, 83.03, 37.64, 28.73. HRMS (ESI) [M+H]
+: calcd for C
21H
17ClN
3O
4, 410.0907; found, 410.0902.
Example 27: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2-phenylacetamide (Compound 27) .
Prepared from I-11 (100 mg, 0.24 mmol) and X19 (2-phenylacetyl chloride, 55.7 mg, 0.36 mmol) . White solid (44 mg, 43.1%) .
1H NMR (400 MHz, DMSO) : δ 9.67 (s, 1H) , 9.61 (s, 1H) , 7.35–7.29 (m, 4H) , 7.26–7.22 (m, 1H) , 7.16 (td, J = 7.7, 0.8 Hz, 1H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.77 (m, 2H) , 5.06 (s, 2H) , 3.63 (s, 2H) , 3.22 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 169.69, 158.75, 157.30, 149.34, 143.11, 135.73, 129.89, 129.07, 128.23, 126.46, 122.36, 122.18, 117.97, 116.61, 110.66, 83.79, 83.00, 41.77, 37.54, 28.64. HRMS (ESI) [M+H]
+: calcd for C
22H
19ClN
3O
4, 424.1064; found, 424.1056.
Example 28: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3-phenylpropanamide (Compound 28) .
Prepared from I-11 (100 mg, 0.24 mmol) and X20 (3-phenylpropanoyl chloride, 60.7 mg, 0.36 mmol) . White solid (55 mg, 52.9%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.38 (s, 1H) , 7.30–7.25 (m, 4H) , 7.21–7.15 (m, 2H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.78 (m, 2H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.88 (t, J = 7.6 Hz, 2H) , 2.58 (t, J = 7.6 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 171.45, 159.20, 157.72, 149.76, 143.47, 141.41, 130.31, 128.70, 126.36, 122.77, 122.60, 118.39, 117.03, 111.10, 84.20, 83.44, 37.94, 37.00, 31.28, 29.04. HRMS (ESI) [M+H]
+: calcd for C
23H
21ClN
3O
4, 438.1215; found, 438.1217.
Example 29: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -4-phenylbutanamide (Compound 29) .
Prepared from I-11 (100 mg, 0.24 mmol) and X21 (4-phenylbutanoyl chloride, 65.7 mg, 0.36 mmol) . White solid (48 mg, 44.4%) .
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.34 (s, 1H) , 7.31–7.25 (m, 2H) , 7.22–7.15 (m, 4H) , 6.86 (dt, J = 8.0, 0.9 Hz, 1H) , 6.83–6.81 (m, 2H) , 5.07 (s, 2H) , 3.22 (s, 3H) , 2.63 (t, J = 7.2 Hz, 2H) , 2.30 (t, J = 7.2 Hz, 2H) , 1.92–1.85 (m, 2H) .
13C NMR (100 MHz, DMSO) : δ 171.71, 158.84, 157.36, 149.39, 143.11, 141.77, 129.92, 128.43, 128.34, 125.81, 122.42, 122.25, 118.04, 116.66, 110.87, 83.86, 83.06, 37.57, 34.52, 28.66, 27.14. HRMS (ESI) [M+H]
+: calcd for C
24H
23ClN
3O
4, 452.1372; found, 452.1371.
Example 30: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) cinnamamide (Compound 30) .
Prepared from I-11 (100 mg, 0.24 mmol) and X22 (cinnamoyl chloride, 59.9 mg, 0.36 mmol) . White solid (36 mg, 34.6%) .
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.60 (s, 1H) , 7.65–7.60 (m, 2H) , 7.55 (d, J = 15.9 Hz, 1H) , 7.47–7.39 (m, 3H) , 7.21–7.13 (m, 1H) , 6.89–6.78 (m, 4H) , 5.09 (s, 2H) , 3.24 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 164.25, 158.82, 157.34, 149.39, 143.12, 140.82, 134.54, 129.94, 129.07, 127.80, 122.39, 122.22, 120.79, 118.01, 116.66, 110.67, 109.58, 83.85, 83.06, 37.63, 28.72. HRMS (ESI) [M+H]
+: calcd for C
23H
19ClN
3O
4, 436.1064; found, 436.1058.
Example 31: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (2-fluorophenyl) acetamide (Compound 31) .
Prepared from I-11 (100 mg, 0.24 mmol) and X23 (2- (2-fluorophenyl) acetyl chloride, 62.1 mg, 0.36 mmol) . White solid (38 mg, 35.9%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.65 (s, 1H) , 7.42 (td, J = 7.6, 1.5 Hz, 1H) , 7.34–7.28 (m, 1H) , 7.20–7.13 (m, 3H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.76 (m, 2H) , 5.07 (s, 2H) , 3.69 (s, 2H) , 3.23 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 168.76, 160.58 (d, J = 244.2 Hz) , 158.73, 157.33, 149.36, 143.16, 131.79 (d, J = 3.8 Hz) , 129.92, 128.80 (d, J = 8.2 Hz) , 124.22 (d, J = 3.8 Hz) , 122.71 (d, J = 15.2 Hz) , 122.37, 122.18, 117.99, 116.65, 115.02 (d, J = 21.0 Hz) , 110.63, 83.81, 83.01, 37.58, 34.85, 28.67. HRMS (ESI) [M+H]
+: calcd for C
22H
18ClFN
3O
4, 442.0969; found, 442.0962.
Example 32: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (3-fluorophenyl) acetamide (Compound 32) .
Prepared from I-11 (100 mg, 0.24 mmol) and X24 (2- (3-fluorophenyl) acetyl chloride, 62.1 mg, 0.36 mmol) . White solid (40 mg, 37.7%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.66 (s, 1H) , 7.39–7.34 (m, 1H) , 7.18–7.16 (m, 3H) , 7.08 (t, J = 8.7 Hz, 1H) , 6.85 (dd, J = 7.6, 1.6 Hz, 1H) , 6.81–6.79 (m, 2H) , 5.06 (s, 2H) , 3.67 (s, 2H) , 3.23 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 169.25, 162.06 (d, J = 243.6 Hz) , 158.75, 157.33, 149.36, 143.16, 138.48 (d, J = 7.8 Hz) , 130.11 (d, J = 8.5 Hz) , 129.92, 125.27 (d, J = 1.9 Hz) , 122.38, 122.19, 117.99, 116.65, 115.84 (d, J = 21.8 Hz) , 113.35 (d, J = 21.1 Hz) , 110.57, 83.82, 83.00, 41.34, 37.58, 28.68. HRMS (ESI) [M+H]
+: calcd for C
22H
18ClFN
3O
4, 442.0969; found, 442.0962.
Example 33: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-fluorophenyl) acetamide (Compound 33) .
Prepared from I-11 (100 mg, 0.24 mmol) and X25 (2- (4-fluorophenyl) acetyl chloride, 62.1 mg, 0.36 mmol) . White solid (46 mg, 43.4%) .
1H NMR (400 MHz, DMSO) : δ 9.69 (s, 1H) , 9.62 (s, 1H) , 7.36 (dd, J = 8.5, 5.7 Hz, 2H) , 7.19–7.10 (m, 3H) , 6.84 (d, J = 7.6 Hz, 1H) , 6.82–6.74 (m, 2H) , 5.06 (s, 2H) , 3.62 (s, 2H) , 3.22 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 169.67, 161.08 (d, J = 241.7 Hz) , 158.76, 157.33, 149.37, 143.16, 131.89, 130.92 (d, J = 8.1 Hz) , 129.92, 122.38, 122.18, 117.99, 116.65, 114.99 (d, J = 20.8 Hz) , 110.61, 83.80, 83.01, 40.84, 29.06, 28.67. HRMS (ESI) [M+H]
+: calcd for C
22H
18ClFN
3O
4, 442.0969; found, 442.0965.
Example 34: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-methoxyphenyl) acetamide (Compound 34) .
Prepared from I-11 (100 mg, 0.24 mmol) and X26 (2- (4-methoxyphenyl) acetyl chloride, 66.4 mg, 0.36 mmol) . White solid (45 mg, 41.3%) .
1H NMR (400 MHz, DMSO) : δ 9.68 (s, 1H) , 9.53 (s, 1H) , 7.24 (d, J = 8.4 Hz, 2H) , 7.16 (t, J = 7.7 Hz, 1H) , 6.88 (d, J = 8.4 Hz, 2H) , 6.84 (d, J = 7.7 Hz, 1H) , 6.82–6.72 (m, 2H) , 5.06 (s, 2H) , 3.73 (s, 3H) , 3.55 (s, 2H) , 3.22 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 170.02, 158.76, 157.94, 157.31, 149.34, 143.08, 130.07, 129.90, 127.61, 122.36, 122.18, 117.98, 116.62, 113.66, 110.71, 83.78, 83.00, 55.01, 40.91, 37.53, 28.64. HRMS (ESI) [M+H]
+: calcd for C
23H
21ClN
3O
5, 454.1169; found, 454.1161.
Example 35: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -2- (4-chlorophenyl) acetamide (Compound 35) .
Prepared from I-11 (100 mg, 0.24 mmol) and X27 (2- (4-chlorophenyl) acetyl chloride, 68.1 mg, 0.36 mmol) . White solid (39 mg, 35.5%) .
1H NMR (400 MHz, DMSO) : δ 9.65 (s, 1H) , 9.59 (s, 1H) , 7.35 (d, J = 8.3 Hz, 2H) , 7.31 (d, J = 8.2 Hz, 2H) , 7.13 (t, J = 7.6 Hz, 1H) , 6.82–6.75 (m, 3H) , 5.02 (s, 2H) , 3.60 (s, 2H) , 3.18 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 169.36, 158.71, 157.30, 149.33, 143.13, 134.74, 130.94, 129.88, 128.18, 122.34, 122.16, 117.97, 116.61, 110.55, 109.57, 83.79, 82.98, 40.97, 37.53, 28.64. HRMS (ESI) [M+H]
+: calcd for C
22H
18Cl
2N
3O
4, 458.0674; found, 458.0669.
Example 36: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (pyridin-3-yl) propanamide (Compound 36) .
Prepared from I-11 (100 mg, 0.24 mmol) and X28 (3- (pyridin-3-yl) propanoyl chloride, 61.1 mg, 0.36 mmol) . Brown solid (40 mg, 37.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
22H
20ClN
4O
4, 439.12; found, 439.23.
Example 37: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3, 3-diphenylpropanamide (Compound 37) .
Prepared from I-11 (100 mg, 0.24 mmol) and X29 (3, 3-diphenylpropanoyl chloride, 87.9 mg, 0.36 mmol) . White solid (51 mg, 41.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
29H
25ClN
3O
4, 514.15; found, 514.24.
Example 38: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (2-fluorophenyl) propanamide (Compound 38) .
Prepared from I-11 (100 mg, 0.24 mmol) and X30 (3- (2-fluorophenyl) propanoyl chloride, 67.2 mg, 0.36 mmol) . White solid (50 mg, 45.9%) .
1H NMR (400 MHz, DMSO) : δ 9.77 (s, 1H) , 9.44 (s, 1H) , 7.35 (t, J = 7.2 Hz, 1H) , 7.28–7.23 (m, 1H) , 7.19–7.11 (m, 3H) , 6.86–6.81 (m, 3H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.90 (t, J = 7.7 Hz, 2H) , 2.60 (t, J = 7.7 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 171.17, 160.92 (d, J = 241.9 Hz) , 159.17, 157.78, 149.77, 143.49, 131.19 (d, J = 4.9 Hz) , 130.29, 128.55 (d, J = 8.2 Hz) , 127.89 (d, J = 15.4 Hz) , 124.78 (d, J = 3.0 Hz) , 122.75, 122.59, 118.42, 117.07, 115.47 (d, J = 21.5 Hz) , 111.07, 84.24, 83.41, 37.96, 35.36, 29.05, 24.48. HRMS (ESI) [M+H]
+: calcd for C
23H
20ClFN
3O
4, 456.1121; found, 456.1120.
Example 39: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3-fluorophenyl) propanamide (Compound 39) .
Prepared from I-11 (100 mg, 0.24 mmol) and X31 (3- (3-fluorophenyl) propanoyl chloride, 67.2 mg, 0.36 mmol) . White solid (46 mg, 42.2%) .
1H NMR (400 MHz, DMSO) : δ 9.77 (s, 1H) , 9.42 (s, 1H) , 7.34–7.29 (m, 1H) , 7.19–7.15 (m, 1H) , 7.11–7.07 (m, 2H) , 7.00 (td, J = 8.0, 1.2 Hz, 1H) , 6.86–6.80 (m, 3H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.91 (t, J = 7.6 Hz, 2H) , 2.61 (t, J = 7.6 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 170.91, 162.22 (d, J = 241.5 Hz) , 158.77, 157.37, 149.37, 143.97 (d, J = 7.6 Hz) , 143.05, 130.12 (d, J = 8.4 Hz) , 129.89, 124.51, 122.35, 122.19, 118.01, 116.66, 115.07 (d, J = 20.6 Hz) , 112.74 (d, J = 20.1 Hz) , 110.68, 83.83, 83.01, 37.55, 36.13, 30.47, 28.65. HRMS (ESI) [M+H]
+: calcd for C
23H
20ClFN
3O
4, 456.1121; found, 456.1123.
Example 40: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-fluorophenyl) propanamide (Compound 40) .
Prepared from I-11 (100 mg, 0.24 mmol) and X32 (3- (4-fluorophenyl) propanoyl chloride, 67.2 mg, 0.36 mmol) . White solid (38 mg, 34.9%) .
1H NMR (400 MHz, DMSO) : δ 9.70 (s, 1H) , 9.38 (s, 1H) , 7.31–7.27 (m, 2H) , 7.17 (td, J = 7.8, 0.8 Hz, 1H) , 7.12–7.06 (m, 2H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.77 (m, 2H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.87 (t, J = 7.6 Hz, 2H) , 2.57 (t, J = 7.6 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 171.38, 161.15 (d, J = 240.3 Hz) , 159.20, 157.73, 149.77, 143.47, 137.53, 130.52 (d, J = 7.9 Hz) , 130.33, 122.79, 122.62, 118.40, 117.05, 115.35 (d, J =20.9 Hz) , 111.08, 84.21, 83.45, 37.95, 37.04, 30.41, 29.06. HRMS (ESI) [M+H]
+: calcd for C
23H
20ClFN
3O
4, 456.1121; found, 456.1121.
Example 41: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-chlorophenyl) propanamide (Compound 41) .
Prepared from I-11 (100 mg, 0.24 mmol) and X33 (3- (4-chlorophenyl) propanoyl chloride, 73.1 mg, 0.36 mmol) . White solid (43 mg, 38.1%) .
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.38 (s, 1H) , 7.33 (d, J = 8.5 Hz, 2H) , 7.28 (d, J = 8.5 Hz, 2H) , 7.17 (td, J = 7.6, 1.0 Hz, 1H) , 6.85 (dt, J = 7.6, 0.8 Hz, 1H) , 6.82–6.78 (m, 2H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.88 (t, J = 7.6 Hz, 2H) , 2.58 (t, J = 7.6 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 170.90, 158.79, 157.33, 149.37, 143.07, 140.03, 130.59, 130.25, 129.92, 128.20, 122.39, 122.21, 118.00, 116.65, 110.66, 83.82, 83.04, 37.55, 36.32, 30.13, 28.66. HRMS (ESI) [M+H]
+: calcd for C
23H
20Cl
2N
3O
4, 472.0826; found, 472.0827.
Example 42: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3-chlorophenyl) propanamide (Compound 42) .
Prepared from I-11 (100 mg, 0.24 mmol) and X34 (3- (3-chlorophenyl) propanoyl chloride, 73.1 mg, 0.36 mmol) . White solid (48 mg, 42.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
23H
20Cl
2N
3O
4, 472.08; found, 472.19.
Example 43: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 43) .
Prepared from I-11 (100 mg, 0.24 mmol) and X35 (3- (p-tolyl) propanoyl chloride, 65.7 mg, 0.36 mmol) . White solid (60 mg, 55.6%) .
1H NMR (400 MHz, DMSO) : δ 9.87 (s, 1H) , 9.44 (s, 1H) , 7.18–7.07 (m, 5H) , 6.86–6.82 (m, 3H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.55 (t, J = 7.7 Hz, 2H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.59, 159.19, 157.86, 149.78, 143.47, 138.33, 135.24, 130.25, 129.28, 128.56, 122.69, 122.55, 118.45, 117.10, 111.17, 84.27, 83.40, 37.96, 37.18, 30.93, 29.05, 21.06. HRMS (ESI) [M+H]
+: calcd for C
24H
23ClN
3O
4, 452.1372; found, 452.1371.
Example 44: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (m-tolyl) propanamide (Compound 44) .
Prepared from I-11 (100 mg, 0.24 mmol) and X36 (3- (m-tolyl) propanoyl chloride, 65.7 mg, 0.36 mmol) . White solid (52 mg, 47.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
23ClN
3O
4, 452.14; found, 452.23.
Example 45: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-ethylphenyl) propanamide (Compound 45) .
Prepared from I-11 (100 mg, 0.24 mmol) and X37 (3- (4-ethylphenyl) propanoyl chloride, 70.8 mg, 0.36 mmol) . White solid (47 mg, 42.3%) .
1H NMR (400 MHz, DMSO) : δ 9.71 (s, 1H) , 9.37 (s, 1H) , 7.19–7.15 (m, 3H) , 7.11 (d, J = 8.1 Hz, 2H) , 6.85 (dt, J = 7.6, 1.2 Hz, 1H) , 6.82–6.78 (m, 2H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.84 (t, J = 7.6 Hz, 2H) , 2.58–2.52 (m, 4H) , 1.15 (t, J = 7.6 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.57, 159.21, 157.78, 149.77, 143.48, 141.71, 138.58, 130.28, 128.63, 128.09, 122.75, 122.60, 118.42, 117.05, 111.14, 84.24, 83.42, 37.95, 37.15, 30.96, 29.05, 28.23, 16.20. HRMS (ESI) [M+H]
+: calcd for C
25H
25ClN
3O
4, 466.1528; found, 466.1529.
Example 46: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-isopropylphenyl) propanamide (Compound 46) .
Prepared from I-11 (100 mg, 0.24 mmol) and X38 (3- (4-isopropylphenyl) propanoyl chloride, 75.9 mg, 0.36 mmol) . White solid (50 mg, 43.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
26H
27ClN
3O
4, 480.17; found, 480.26.
Example 47: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-cyanophenyl) propanamide (Compound 47) .
Prepared from I-11 (100 mg, 0.24 mmol) and X39 (3- (4-cyanophenyl) propanoyl chloride, 69.7 mg, 0.36 mmol) . White solid (39 mg, 35.5%) .
1H NMR (400 MHz, DMSO) : δ 9.94 (s, 1H) , 9.53 (s, 1H) , 7.75 (d, J = 8.1 Hz, 2H) , 7.48 (d, J = 8.1 Hz, 2H) , 7.15 (t, J = 7.8 Hz, 1H) , 6.87–6.827 (m, 3H) , 5.05 (s, 2H) , 3.21 (s, 3H) , 2.97 (t, J = 7.5 Hz, 2H) , 2.63 (t, J = 7.5 Hz, 2H) .
13C NMR (100 MHz, DMSO) : δ 170.66, 158.75, 157.31, 149.35, 147.11, 143.04, 132.20, 129.90, 129.51, 122.36, 122.19, 119.02, 117.97, 116.61, 110.59, 108.85, 83.79, 83.02, 37.53, 35.70, 30.78, 28.65. HRMS (ESI) [M+H]
+: calcd for C
24H
20ClN
4O
4, 463.1168; found, 463.1165.
Example 48: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4-methoxyphenyl) propanamide (Compound 48) .
Prepared from I-11 (100 mg, 0.24 mmol) and X40 (3- (4-methoxyphenyl) propanoyl chloride, 71.5 mg, 0.36 mmol) . White solid (53 mg, 47.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
23ClN
3O
5, 468.13; found, 468.25.
Example 49: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (4- (trifluoromethyl) phenyl) propanamide (Compound 49) .
Prepared from I-11 (100 mg, 0.24 mmol) and X41 (3- (4- (trifluoromethyl) phenyl) propanoyl chloride, 85.2 mg, 0.36 mmol) . White solid (57 mg, 47.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
20ClF
3N
3O
4, 506.11; found, 506.22.
Example 50: N- (6-chloro-1- (3- (3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (3, 4-difluorophenyl) propanamide (Compound 50) .
Prepared from I-11 (100 mg, 0.24 mmol) and X42 (3- (3, 4-difluorophenyl) propanoyl chloride, 73.7 mg, 0.36 mmol) . White solid (49 mg, 43.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
23H
19ClF
2N
3O
4, 474.10; found, 474.21.
Example 51: N- (6-chloro-3-methyl-2, 4-dioxo-1- (prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 51) .
K
2CO
3 (691 mg, 5 mmol) was added to a solution of I-22 (1.53 g, 4.76 mmol) and 3-bromoprop-1-yne (738 mg, 6.2 mmol) in dry DMF (30 mL) , and the mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC) , the mixture was poured into water (200 mL) and extracted with EA (50 mL×3) . The organic layer was washed with brine and dried over Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2: 1) to afford compound 51 (1.1 g, 64%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.11 (q, J = 8.0 Hz, 4H) , 6.78 (s, 1H) , 4.87 (s, 2H) , 3.36 (s, 3H) , 2.99 (t, J = 7.6 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.35 (m, 1H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 158.78, 149.26, 142.99, 137.91, 134.86, 128.87, 128.15, 110.70, 77.92, 75.67, 36.81, 36.76, 30.50, 28.61, 20.66. HRMS (ESI) [M+H]
+: calcd for C
18H
19ClN
3O
3, 360.1115; found, 360.1109.
General Synthesis Procedure for Compounds 52–75, 79-150
Wherein R are the groups corresponding to the R
4 part of compound 52–75, 79-150 in Formula (I) .
Pd (Pph
3)
4 (8.1 mg, 0.007 mmol) and CuI (2.7 mg, 0.014 mmol) were added to a solution containing compound 51 (50 mg, 0.14 mmol) , N, N-diisopropylethylamine (41.4 mg, 0.32 mmol) and the corresponding chemical intermediates (0.167 mmol) in DMF (8 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 60℃ for 4 hours in an oil bath. After completion of the reaction, the mixture was diluted with water (20 mL) , extracted with EA (5 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH or PE/EA) to give the corresponding compounds 52-75
, 79-150.
Example 52: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3-phenylprop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 52) .
Prepared from compound 51 (50 mg, 0.14 mmol) and iodobenzene (34.1 mg, 0.167 mmol) . White solid (28 mg, 45.9%) .
1H NMR (400 MHz, DMSO) : δ 9.38 (s, 1H) , 7.47–7.37 (m, 5H) , 7.14 (d, J = 7.9 Hz, 2H) , 7.08 (d, J = 7.9 Hz, 2H) , 5.09 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.55 (t, J = 7.8 Hz, 2H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 158.81, 149.38, 143.07, 137.91, 134.86, 131.62, 129.17, 128.88, 128.77, 128.16, 121.36, 110.74, 83.70, 37.57, 36.77, 30.50, 28.66, 20.65. HRMS (ESI) [M+H]
+: calcd for C
24H
23ClN
3O
3, 436.1428; found, 436.1422.
Example 53: N- (6-chloro-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 53) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodophenol (36.7 mg, 0.167 mmol) . White solid (32 mg, 50.8%) .
1H NMR (400 MHz, DMSO) : δ 9.94 (s, 1H) , 9.38 (s, 1H) , 7.27 (d, J = 8.4 Hz, 2H) , 7.14 (d, J = 7.6 Hz, 2H) , 7.08 (d, J = 8.0 Hz, 2H) , 6.76 (d, J = 8.4 Hz, 2H) , 5.04 (s, 2H) , 3.22 (s, 3H) , 2.85 (t, J = 7.7 Hz, 2H) , 2.57 (t, J = 7.7 Hz, 2H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.19, 158.83, 158.28, 149.39, 143.19, 137.92, 134.88, 133.35, 128.90, 128.18, 115.73, 111.49, 110.67, 84.28, 81.46, 37.71, 36.78, 30.51, 28.66, 20.67. HRMS (ESI) [M+H]
+: calcd for C
24H
23ClN
3O
4, 452.1372; found, 452.1373.
Example 54: N- (6-chloro-1- (3- (2-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 54) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 2-iodophenol (36.7 mg, 0.167 mmol) . White solid (29 mg, 45.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
23ClN
3O
4, 452.14; found, 452.23.
Example 55: N- (6-chloro-1- (3- (3-methoxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 55) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 3-iodoanisole (39.1 mg, 0.167 mmol) . White solid (23 mg, 35.4%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
25ClN
3O
4, 466.15; found, 466.23.
Example 56: N- (6-chloro-1- (3- (4-methoxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 56) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodoanisole (39.1 mg, 0.167 mmol) . White solid (36 mg, 55.4%) .
1H NMR (400 MHz, CDCl
3) : δ 7.36 (d, J = 8.9 Hz, 2H) , 7.13 (d, J = 7.8 Hz, 2H) , 7.09 (d, J = 8.0 Hz, 2H) , 7.01 (s, 1H) , 6.81 (d, J = 8.9 Hz, 2H) , 5.07 (s, 2H) , 3.79 (s, 3H) , 3.36 (s, 3H) , 2.99 (t, J = 7.7 Hz, 2H) , 2.68 (t, J = 7.7 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.57, 160.14, 159.20, 149.78, 143.52, 138.32, 135.24, 133.65, 129.27, 128.56, 114.76, 113.64, 111.12, 84.19, 82.55, 55.69, 38.06, 37.17, 30.91, 29.04, 21.06. HRMS (ESI) [M+H]
+: calcd for C
25H
25ClN
3O
4, 466.1528; found, 466.1528.
Example 57: N- (6-chloro-1- (3- (3, 5-dihydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 57) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 5-iodoresorcinol (39.4 mg, 0.167 mmol) . White solid (30 mg, 45.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
23ClN
3O
5, 468.13; found, 468.24.
Example 58: N- (6-chloro-1- (3- (3, 4-dihydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 58) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodobenzene-1, 2-diol (39.4 mg, 0.167 mmol) . White solid (32 mg, 48.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
23ClN
3O
5, 468.13; found, 468.24.
Example 59: N- (1- (3- (benzo [d] [1, 3] dioxol-5-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 59) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 5-iodobenzo [d] [1, 3] dioxole (41.4 mg, 0.167 mmol) . White solid (39 mg, 58.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
23ClN
3O
5, 480.13; found, 480.22.
Example 60: N- (6-chloro-1- (3- (3- (hydroxymethyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 60) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 3-iodobenzyl alcohol (39.1 mg, 0.167 mmol) . White solid (35 mg, 53.7%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
25ClN
3O
4, 466.15; found, 466.23.
Example 61: N- (6-chloro-1- (3- (4- (hydroxymethyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 61) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodobenzyl alcohol (39.1 mg, 0.167 mmol) . White solid (29 mg, 44.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
25ClN
3O
4, 466.15; found, 466.23.
Example 62: N- (6-chloro-1- (3- (3-fluoro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 62) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 2-fluoro-4-iodophenol (39.7 mg, 0.167 mmol) . White solid (31 mg, 47.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
22ClFN
3O
4, 470.13; found, 470.21.
Example 63: N- (6-chloro-1- (3- (2-fluoro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 63) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 3-fluoro-4-iodophenol (39.7 mg, 0.167 mmol) . White solid (27 mg, 41.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
22ClFN
3O
4, 470.13; found, 470.22.
Example 64: N- (6-chloro-1- (3- (3-chloro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 64) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 2-chloro-4-iodophenol (42.5 mg, 0.167 mmol) . White solid (32 mg, 46.9%) .
1H NMR (400 MHz, DMSO) : δ 10.74 (s, 1H) , 9.36 (s, 1H) , 7.41 (d, J = 2.0 Hz, 1H) , 7.23 (dd, J = 8.4, 2.0 Hz, 1H) , 7.14–7.07 (m, 4H) , 6.94 (d, J = 8.4 Hz, 1H) , 5.04 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.56–2.52 (m, 2H) , 2.26 (s, 3H) .
UPLC-MS (ESI) [M+H]
+ calcd for C
24H
22Cl
2N
3O
4, 486.10; found, 486.21.
Example 65: N- (6-chloro-1- (3- (2-chloro-4-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 65) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 3-chloro-4-iodophenol (42.5 mg, 0.167 mmol) . White solid (30 mg, 44.1%) .
1H NMR (400 MHz, DMSO) : δ 10.41 (s, 1H) , 9.35 (s, 1H) , 7.37 (d, J = 8.6 Hz, 1H) , 7.11 (dd, J = 21.6, 8.0 Hz, 4H) , 6.89 (d, J = 2.4 Hz, 1H) , 6.73 (dd, J = 8.5, 2.4 Hz, 1H) , 5.09 (s, 2H) , 3.22 (s, 3H) , 2.87–2.77 (m, 2H) , 2.54 (m, 2H) , 2.26 (s, 3H) .
UPLC-MS (ESI) [M+H]
+ calcd for C
24H
22Cl
2N
3O
4, 486.10; found, 486.21.
Example 66: N- (6-chloro-1- (3- (4-chloro-3-hydroxyphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 66) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 2-chloro-5-iodophenol (42.5 mg, 0.167 mmol) . White solid (32 mg, 46.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
22Cl
2N
3O
4, 486.10; found, 486.21.
Example 67: N- (6-chloro-1- (3- (4-hydroxy-3-methylphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 67) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodo-2-methylphenol (39.1 mg, 0.167 mmol) . White solid (36 mg, 55.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
25ClN
3O
4, 466.15; found, 466.23.
Example 68: N- (6-chloro-1- (3- (3-hydroxy-4-methylphenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 68) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 5-iodo-2-methylphenol (39.1 mg, 0.167 mmol) . White solid (28 mg, 42.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
25ClN
3O
4, 466.15; found, 466.23.
Example 69: N- (1- (3- (3-aminophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 69) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 3-iodoaniline (36.6 mg, 0.167 mmol) . Brown solid (26 mg, 41.2%) .
1H NMR (400 MHz, DMSO) : δ 9.38 (s, 1H) , 7.14 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 8.0 Hz, 2H) , 6.99 (t, J = 7.8 Hz, 1H) , 6.65–6.50 (m, 3H) , 5.25 (s, 2H) , 5.04 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.6 Hz, 2H) , 2.55 (t, J = 7.6 Hz, 2H) , 2.25 (s, 3H) . HRMS (ESI) [M+H]
+: calcd for C
24H
24ClN
4O
3, 451.1537; found, 451.1529.
Example 70: N- (1- (3- (3-acetamidophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 70) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-23a (43.6 mg, 0.167 mmol) . White solid (30 mg, 43.4%) .
1H NMR (400 MHz, DMSO) : δ 10.05 (s, 1H) , 9.38 (s, 1H) , 7.77 (s, 1H) , 7.51 (d, J = 8.1 Hz, 1H) , 7.30 (t, J = 7.9 Hz, 1H) , 7.18–7.00 (m, 5H) , 5.08 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.55 (t, J = 7.7 Hz, 2H) , 2.25 (s, 3H) , 2.04 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.14, 168.61, 158.80, 149.38, 143.02, 139.55, 137.91, 134.85, 129.25, 128.88, 128.15, 126.13, 121.65, 121.59, 119.64, 110.73, 83.61, 83.42, 37.55, 36.78, 30.50, 28.66, 24.06, 20.65. HRMS (ESI) [M+H]
+: calcd for C
26H
26ClN
4O
4, 493.1643; found, 493.1635.
Example 71: N- (3- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 71) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-23b (53.9 mg, 0.167 mmol) . White solid (39 mg, 50.2%) .
1H NMR (400 MHz, DMSO) : δ 10.34 (s, 1H) , 9.39 (s, 1H) , 7.97–7.95 (m, 3H) , 7.81 (d, J = 8.1 Hz, 1H) , 7.57–7.52 (m, 3H) , 7.37 (t, J = 8.0 Hz, 1H) , 7.18 (d, J = 7.7 Hz, 1H) , 7.14 (d, J = 7.9 Hz, 2H) , 7.08 (d, J = 7.9 Hz, 2H) , 5.10 (s, 2H) , 3.23 (s, 3H) , 2.84 (t, J = 7.7 Hz, 2H) , 2.56 (t, J = 7.8 Hz, 2H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.12, 165.71, 158.79, 149.37, 143.01, 139.45, 137.90, 134.83, 134.62. δ 131.77, 129.19, 128.87, 128.45, 128.14, 127.68, 126.69, 123.04, 121.54, 120.95, 110.73, 83.56, 83.51, 37.55, 36.76, 30.49, 28.65, 20.64. HRMS (ESI) [M+H]
+: calcd for C
31H
28ClN
4O
4, 555.1799; found, 555.1795.
Example 72: N- (1- (3- (4-aminophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 72) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 4-iodoaniline (36.6 mg, 0.167 mmol) . Brown solid (18 mg, 28.6%) .
1H NMR (400 MHz, DMSO) : δ 9.35 (s, 1H) , 7.72 (d, J = 9.1 Hz, 2H) , 7.66 (d, J = 9.1 Hz, 2H) , 7.14 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 8.7 Hz, 3H) , 5.01 (s, 2H) , 3.22 (s, 3H) , 2.88–2.79 (m, 2H) , 2.57–2.51 (m, 2H) , 2.26 (s, 3H) . HRMS (ESI) [M+H]
+: calcd for C
24H
24ClN
4O
3, 451.1537; found, 451.1530.
Example 73: N- (1- (3- (4-acetamidophenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 73) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-24a (43.6 mg, 0.167 mmol) . White solid (33 mg, 47.8%) .
1H NMR (400 MHz, DMSO) : δ 10.12 (s, 1H) , 9.37 (s, 1H) , 7.59 (d, J = 8.3 Hz, 2H) , 7.37 (d, J = 8.3 Hz, 2H) , 7.13 (d, J = 7.6 Hz, 2H) , 7.08 (d, J = 7.6 Hz, 2H) , 5.06 (s, 2H) , 3.22 (s, 3H) , 2.83 (t, J = 7.5 Hz, 2H) , 2.55 (t, J = 7.7 Hz, 2H) , 2.25 (s, 3H) , 2.05 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 168.63, 158.80, 149.37, 143.10, 140.03, 137.91, 134.85, 132.35, 128.88, 128.16, 118.74, 115.39, 110.70, 83.82, 82.66, 37.65, 36.77, 30.51, 28.65, 24.12, 20.65. HRMS (ESI) [M+H]
+: calcd for C
26H
26ClN
4O
4, 493.1643; found, 493.1635.
Example 74: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 74) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-24b (53.9 mg, 0.167 mmol) . White solid (34 mg, 44.2%) .
1H NMR (400 MHz, DMSO) : δ 10.43 (s, 1H) , 9.39 (s, 1H) , 7.94 (d, J = 7.1 Hz, 2H) , 7.83 (d, J = 8.7 Hz, 2H) , 7.57–7.51 (m, 3H) , 7.44 (d, J = 8.7 Hz, 2H) , 7.14 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 7.9 Hz, 2H) , 5.08 (s, 2H) , 3.23 (s, 3H) , 2.84 (t, J = 7.7 Hz, 2H) , 2.56 (t, J = 7.8 Hz, 2H) , 2.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.14, 165.78, 158.80, 149.36, 143.09, 139.96, 137.91, 134.84, 134.74, 132.24, 131.76, 128.87, 128.44, 128.15, 127.74, 120.03, 116.05, 110.72, 83.81, 82.93, 37.64, 36.77, 30.51, 28.64, 20.65. HRMS (ESI) [M+H]
+: calcd for C
31H
28ClN
4O
4, 555.1799; found, 555.1792.
Example 75: N- (1- (3- (4- (benzylamino) phenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 75) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-25 (51.6 mg, 0.167 mmol) . White solid (26 mg, 34.3%) .
1H NMR (400 MHz, DMSO) : δ 7.37–7.28 (m, 5H) , 7.26–7.22 (m, 3H) , 7.14 (d, J = 8.1 Hz, 2H) , 7.11 (d, J = 7.2 Hz, 2H) , 6.60 (s, 1H) , 6.52 (d, J = 8.7 Hz, 2H) , 5.07 (s, 2H) , 4.33 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.6 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.32 (s, 3H) . HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
3, 541.2006; found, 541.2002.
Example 76: N- (6-chloro-3-ethyl-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 76) .
Pd (Pph
3)
4 (8.1 mg, 0.007 mmol) and CuI (2.6 mg, 0.013 mmol) were added to a solution containing I-31a (50 mg, 0.14 mmol) , 4-iodophenol (35.5 mg, 0.16 mmol) and N, N-diisopropylethylamine (38.1 mg, 0.295 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃for 6 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=1: 1) to give the compound 76 (30.8 mg, 47.4%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.26 (d, J = 8.7 Hz, 2H) , 7.14 (d, J = 7.9 Hz, 2H) , 7.10 (d, J = 8.1 Hz, 2H) , 6.74 (d, J = 8.7 Hz, 2H) , 6.68 (s, 1H) , 5.82 (s, 1H) , 5.06 (s, 2H) , 4.02 (q, J = 7.1 Hz, 2H) , 3.01 (t, J = 7.8 Hz, 2H) , 2.70 (t, J = 7.8 Hz, 2H) , 2.32 (s, 3H) , 1.24 (t, J = 7.1 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.14, 158.42, 158.29, 148.96, 143.34, 137.91, 134.87, 133.36, 128.89, 128.17, 115.72, 111.47, 110.80, 84.28, 81.47, 37.65, 37.10, 36.80, 30.51, 20.66, 12.53. HRMS (ESI) [M+H]
+: calcd for C
25H
25ClN
3O
4, 466.1534; found, 466.1529.
Example 77: N- (6-chloro-1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-3-propyl-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 77) .
Pd (Pph
3)
4 (7.5 mg, 0.007 mmol) and CuI (2.5 mg, 0.013 mmol) were added to a solution containing I-31b (50 mg, 0.13 mmol) , 4-iodophenol (34.1 mg, 0.155 mmol) and N, N-diisopropylethylamine (37 mg, 0.235 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃for 6 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (DCM/MeOH=40: 1) to give the compound 77 (25.2 mg, 40.4%) as a white solid.
1H NMR (400 MHz, DMSO) : δ 9.95 (s, 1H) , 9.37 (s, 1H) , 7.26 (d, J = 8.7 Hz, 2H) , 7.13 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 8.0 Hz, 2H) , 6.75 (d, J = 8.7 Hz, 2H) , 5.03 (s, 2H) , 3.82–3.76 (m, 2H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.54 (t, J = 7.7 Hz, 2H) , 2.25 (s, 3H) , 1.60–1.51 (m, 2H) , 0.86 (t, J = 7.4 Hz, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.13, 158.63, 158.29, 149.15, 143.32, 137.91, 134.86, 133.34, 128.89, 128.16, 115.71, 111.47, 110.76, 84.28, 81.45, 43.32, 37.71, 36.80, 30.51, 20.66, 20.33, 11.19. HRMS (ESI) [M+H]
+: calcd for C
26H
27ClN
3O
4, 480.1690; found, 480.1683.
Example 78: N- (6-chloro-3- (cyclopentylmethyl) -1- (3- (4-hydroxyphenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 78) .
Pd (Pph
3)
4 (9 mg, 0.0075 mmol) and CuI (2.85 mg, 0.015 mmol) were added to a solution containing I-31c (60 mg, 0.15 mmol) , 4-iodophenol (60 mg, 0.18 mmol) and N, N-diisopropylethylamine (43 mg, 0.33 mmol) in DMF (10 mL) under a nitrogen atmosphere. Then the mixture was replaced with nitrogen three times and stirred at 50℃for 6 hours in an oil bath. After completion, the mixture was diluted with water (25 mL) , extracted with EA (6 mL×3) , the organic layer was washed with brine and dried over Na
2SO
4. The solvent was removed under reduced pressure and the residue was purified with chromatography on silica gel (PE/EA=2: 1) to give the compound 78 (20.6 mg, 26.3%) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.29–7.27 (m, 2H) , 7.13 (d, J = 8.1 Hz, 2H) , 7.10 (d, J = 8.2 Hz, 2H) , 6.74 (d, J = 8.7 Hz, 2H) , 6.67 (s, 1H) , 5.60 (s, 1H) , 5.06 (s, 2H) , 3.92 (d, J = 7.5 Hz, 2H) , 3.01 (t, J = 7.7 Hz, 2H) , 2.69 (t, J = 7.7 Hz, 2H) , 2.32 (s, 3H) , 1.72–1.63 (m, 4H) , 1.56–1.50 (m, 3H) , 1.32–1.25 (m, 2H) .
13C NMR (100 MHz, DMSO) : δ171.07, 158.86, 158.27, 149.38, 143.26, 137.89, 134.83, 133.32, 128.86, 128.14, 115.69, 111.45, 110.74, 84.25, 81.44, 45.82, 37.86, 36.78, 30.49, 30.03, 29.72, 24.32, 20.64. HRMS (ESI) [M+H]
+: calcd for C
29H
31ClN
3O
4, 520.2003; found, 520.2008.
Example 79: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- (2-phenylacetamido) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 79) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32a (56.3 mg, 0.167 mmol) . White solid (31 mg, 38.9%) .
1H NMR (400 MHz, CDCl
3) : δ 7.48–7.44 (m, 2H) , 7.38–7.33 (m, 7H) , 7.18 (s, 1H) , 7.14–7.08 (m, 4H) , 6.71 (s, 1H) , 5.07 (s, 2H) , 3.74 (s, 2H) , 3.37 (s, 3H) , 2.99 (t, J = 8.4 Hz, 2H) , 2.68 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
4, 569.20; found, 569.31.
Example 80: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- (3-phenylpropanamido) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 80) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32b (58.6 mg, 0.167 mmol) . White solid (37 mg, 45.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.40–7.34 (m, 4H) , 7.31–7.28 (m, 2H) , 7.23–7.20 (m, 3H) , 7.14–7.09 (m, 4H) , 6.69 (s, 1H) , 5.07 (s, 2H) , 3.37 (s, 3H) , 3.06–2.98 (m, 4H) , 2.70–2.64 (m, 4H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
33H
32ClN
4O
4, 583.21; found, 583.30.
Example 81: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cinnamamide (Compound 81) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32c (58.3 mg, 0.167 mmol) . White solid (35 mg, 42.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
33H
30ClN
4O
4, 581.20; found, 581.31.
Example 82: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cyclopropanecarboxamide (Compound 82) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32d (47.9 mg, 0.167 mmol) . White solid (31 mg, 42.7%) . UPLC-MS (ESI) [M+H]
+ calcd for C
28H
28ClN
4O
4, 519.18; found, 519.28.
Example 83: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) tetrahydro-2H-pyran-4-carboxamide (Compound 83) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32e (55.3 mg, 0.167 mmol) . White solid (29 mg, 36.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.48 (d, J = 8.4 Hz, 2H) , 7.38 (d, J = 8.4 Hz, 2H) , 7.22 (s, 1H) , 7.14–7.09 (m, 4H) , 6.68 (s, 1H) , 5.08 (s, 2H) , 4.07–4.04 (m, 2H) , 3.48-3.41 (dt, J = 2.4, 11.6 Hz, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.68 (t, J = 8 Hz, 2H) , 2.51-2.44 (m, 1H) , 2.31 (s, 3H) , 1.92–1.81 (m, 4H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
32ClN
4O
5, 563.21; found, 563.33.
Example 84: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) cyclohexanecarboxamide (Compound 84) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32f (54.9 mg, 0.167 mmol) . White solid (37 mg, 47.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
34ClN
4O
4, 561.23; found, 561.31.
Example 85: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) piperidine-1-carboxamide (Compound 85) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32g (55.1 mg, 0.167 mmol) . White solid (25 mg, 31.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
33ClN
5O
4, 562.22; found, 562.32.
Example 86: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) furan-2-carboxamide (Compound 86) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32h (52.3 mg, 0.167 mmol) . White solid (36 mg, 47.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
29H
26ClN
4O
5, 545.16; found, 545.24.
Example 87: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-methoxybenzamide (Compound 87) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32i (58.9 mg, 0.167 mmol) . White solid (45 mg, 54.9%) .
1H NMR (400 MHz, CDCl
3) : δ 7.87 (s, 1H) , 7.63–7.60 (m, 2H) , 7.45–7.42 (m, 3H) , 7.39–7.37 (m, 2H) , 7.14–7.08 (m, 5H) , 6.67 (s, 1H) , 5.09 (s, 2H) , 3.87 (s, 3H) , 3.38 (s, 3H) , 3.00 (t, J = 8.4 Hz, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
5, 585.19; found, 585.27.
Example 88: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-fluorobenzamide (Compound 88) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32j (56.9 mg, 0.167 mmol) . White solid (41 mg, 51.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
27ClFN
4O
4, 573.17; found, 573.25.
Example 89: 3-chloro-N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) benzamide (Compound 89) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32k (59.7 mg, 0.167 mmol) . White solid (44 mg, 53.3%) .
1H NMR (400 MHz, CDCl
3) : δ 8.00 (s, 1H) , 7.85–7.84 (m, 1H) , 7.73 (d, J = 8.0 Hz, 1H) , 7.62–7.60 (m, 2H) , 7.55–7.51 (m, 1H) , 7.44–7.40 (m, 3H) , 7.14–7.09 (m, 4H) , 6.74 (s, 1H) , 5.08 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
27Cl
2N
4O
4, 589.14; found, 589.26.
Example 90: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-methylbenzamide (Compound 90) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32l (47.2 mg, 0.167 mmol) . White solid (35 mg, 43.9%) .
1H NMR (400 MHz, CDCl
3) : δ 8.23 (s, 1H) , 7.66–7.59 (m, 4H) , 7.37 (d, J = 8.4 Hz, 2H) , 7.33–7.32 (m, 2H) , 7.11–7.07 (m, 4H) , 5.03 (s, 2H) , 3.31 (s, 3H) , 2.97 (t, J = 8.0 Hz, 2H) , 2.66 (t, J = 8.0 Hz, 2H) , 2.38 (s, 3H) , 2.30 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
4, 569.20; found, 569.29.
Example 91: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -3-cyanobenzamide (Compound 91) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32m (58.1 mg, 0.167 mmol) . White solid (31 mg, 38.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
27ClN
5O
4, 580.18; found, 580.30.
Example 92: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-methoxybenzamide (Compound 92) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32n (58.9 mg, 0.167 mmol) . White solid (40 mg, 48.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
5, 585.19; found, 585.29.
Example 93: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-fluorobenzamide (Compound 93) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32o (56.9 mg, 0.167 mmol) . White solid (45 mg, 56.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.91–7.86 (m, 3H) , 7.60 (d, J = 8.4 Hz, 2H) , 7.41 (d, J = 8.8 Hz, 2H) , 7.18–7.09 (m, 6H) , 6.71 (s, 1H) , 5.09 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.6 Hz, 2H) , 2.69 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
27ClFN
4O
4, 573.17; found, 573.28.
Example 94: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-methylbenzamide (Compound 94) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32p (56.3 mg, 0.167 mmol) . White solid (42 mg, 52.7%) .
1H NMR (400 MHz, CDCl
3) : δ 7.99 (s, 1H) , 7.75 (d, J = 8.0 Hz, 2H) , 7.61 (d, J = 8.4 Hz, 2H) , 7.41 (d, J = 8.8 Hz, 2H) , 7.27 (d, J = 8.0 Hz, 2H) , 7.14–7.08 (m, 4H) , 6.84 (s, 1H) , 5.08 (s, 2H) , 3.36 (s, 3H) , 2.99 (t, J = 7.6 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.41 (s, 3H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
4, 569.20; found, 569.31.
Example 95: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -4-cyanobenzamide (Compound 95) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32q (58.1 mg, 0.167 mmol) . White solid (39 mg, 47.9%) .
1H NMR (400 MHz, CDCl
3) : δ 9.28 (s, 1H) , 8.15 (d, J = 8 Hz, 2H) , 7.81 (d, J = 8 Hz, 4H) , 7.74–7.70 (m, 2H) , 7.64–7.61 (dt, J = 2.8, 7.6 Hz, 2H) , 7.53 (d, J = 8.8 Hz, 2H) , 7.42 (s, 1H) , 5.20 (s, 2H) , 3.46 (s, 3H) , 3.13 (t, J = 8 Hz, 2H) , 2.83 (t, J = 8 Hz, 2H) , 2.47 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
27ClN
5O
4, 580.18; found, 580.30.
Example 96: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-methoxybenzamide (Compound 96) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32r (58.9 mg, 0.167 mmol) . White solid (46 mg, 48.8%) .
1H NMR (400 MHz, CDCl
3) : δ 9.90 (s, 1H) , 7.65–7.63 (m, 2H) , 7.55–7.46 (m, 2H) , 7.43–7.41 (d, J = 8.8 Hz, 2H) , 7.16–7.09 (m, 4H) , 7.05–7.03 (d, J = 8.4 Hz, 1H) , 6.75 (s, 1H) , 5.10 (s, 2H) , 4.06 (s, 3H) , 3.38 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.69 (t, J = 8 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
5, 585.19; found, 585.31.
Example 97: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-fluorobenzamide (Compound 97) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32s (56.9 mg, 0.167 mmol) . White solid (38 mg, 47.4%) .
1H NMR (400 MHz, CDCl
3) : δ 8.53–8.49 (d, J = 16.4 Hz, 1H) , 8.19–8.14 (m, 1H) , 7.65–7.63 (m, 2H) , 7.55–7.53 (m, 1H) , 7.45–7.43 (m, 2H) , 7.34–7.30 (m, 1H) , 7.21–7.16 (m, 1H) , 7.15–7.09 (m, 4H) , 6.72 (s, 1H) , 5.10 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.69 (t, J = 8 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
27ClFN
4O
4, 573.17; found, 573.29.
Example 98: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-cyanobenzamide (Compound 98) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32t (58.1 mg, 0.167 mmol) . White solid (39 mg, 48%) .
1H NMR (400 MHz, CDCl
3) : δ 7.98–7.93 (m, 2H) , 7.79–7.71 (m, 2H) , 7.61–7.59 (d, J = 8.4 Hz, 2H) , 7.37–7.35 (d, J = 8.4 Hz, 2H) , 7.14–7.09 (m, 4H) , 6.79 (s, 1H) , 5.12 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.69 (t, J = 6.8 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
27ClN
5O
4, 580.18; found, 580.26.
Example 99: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) -2-hydroxybenzamide (Compound 99) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-32u (56.6 mg, 0.167 mmol) . White solid (34 mg, 42.6%) .
1H NMR (400 MHz, CDCl
3) : δ 11.82 (s, 1H) , 8.13 (s, 1H) , 7.62–7.53 (m, 3H) , 7.46–7.43 (m, 3H) , 7.14–7.09 (m, 4H) , 7.03 (d, J = 8.4 Hz, 1H) , 6.91 (t, J = 8 Hz, 1H) , 6.69 (s, 1H) , 5.09 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.68 (t, J = 7.2 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (101 MHz, DMSO) δ 171.57, 166.82, 159.23, 158.38, 149.79, 143.51, 139.48, 138.33, 135.27, 134.09, 132.75, 129.70, 129.30, 128.58, 120.89, 119.57, 118.50, 117.58, 116.88, 111.13, 84.11, 83.54, 38.06, 37.19, 30.92, 29.07, 21.07. UPLC-MS (ESI) [M+H]
+ calcd for C
31H
28ClN
4O
5, 571.17; found, 571.27.
Example 100: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-methylphenyl) benzamide (Compound 100) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-33a (56.3 mg, 0.167 mmol) . White solid (37 mg, 46.4%) .
1H NMR (400 MHz, CDCl
3) : δ 8.02 (d, J = 8 Hz, 1H) , 7.87–7.85 (m, 2H) , 7.78 (s, 1H) , 7.57–7.54 (m, 1H) , 7.51–7.47 (m, 1H) , 7.33–7.31 (m, 2H) , 7.13–7.08 (m, 4H) , 6.97 (s, 1H) , 5.08 (s, 2H) , 3.36 (s, 3H) , 2.99 (t, J = 8 Hz, 2H) , 2.67 (t, J = 8 Hz, 2H) , 2.31 (s, 3H) , 2.29 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
30ClN
4O
4, 569.20; found, 569.29.
Example 101: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-methylphenyl) cyclopropanecarboxamide (Compound 101) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-33b (50.3 mg, 0.167 mmol) . White solid (35 mg, 46.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
29H
30ClN
4O
4, 533.20; found, 533.30.
Example 102: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) benzamide (Compound 102) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-34a (58.6 mg, 0.167 mmol) . White solid (39 mg, 47.8%) .
1H NMR (400 MHz, CDCl
3) : δ 8.08 (s, J = 8.0 Hz, 1H) , 7.87–7.85 (m, 2H) , 7.77 (s, 1H) , 7.58–7.51 (m, 3H) , 7.36–7.33 (m, 2H) , 7.15–7.09 (m, 4H) , 6.70 (s, 1H) , 5.10 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.71–2.62 (m, 4H) , 2.31 (s, 3H) , 1.28 (t, J = 7.6 Hz, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
33H
32ClN
4O
4, 583.21; found, 583.33.
Example 103: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) cyclopropanecarboxamide (Compound 103) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-34b (52.6 mg, 0.167 mmol) . White solid (31 mg, 40.5%) .
1H NMR (400 MHz, CDCl
3) : δ 7.92 (s, 1H) , 7.27–7.26 (m, 3H) , 7.14–7.08 (m, 4H) , 6.83 (s, 1H) , 5.08 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.68 (t, J = 8.0 Hz, 2H) , 2.59 (q, J = 7.6 Hz, 2H) , 2.31 (s, 3H) , 1.75–1.68 (m, 1H) , 1.24 (t, J = 8.0 Hz, 3H) , 1.09–1.08 (m, 2H) , 0.88–0.84 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
32ClN
4O
4, 547.21; found, 547.32.
Example 104: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-ethylphenyl) tetrahydro-2H-pyran-4-carboxamide (Compound 104) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-34c (59.9 mg, 0.167 mmol) . White solid (29 mg, 35.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
36ClN
4O
5, 591.24; found, 591.37.
Example 105: N- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-hydroxyphenyl) benzamide (Compound 105) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-36 (56.6 mg, 0.167 mmol) . White solid (27 mg, 33.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
28ClN
4O
5, 571.17; found, 571.28.
Example 106: N- (1- (3- (1H-indol-6-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 106) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 6-iodo-1H-indole (40.6 mg, 0.167 mmol) . White solid (26 mg, 39.1%) .
1H NMR (400 MHz, DMSO) : δ 11.27 (s, 1H) , 9.38 (s, 1H) , 7.53 (d, J = 8.2 Hz, 1H) , 7.49 (s, 1H) , 7.45 (t, J = 2.6 Hz, 1H) , 7.14 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 8.0 Hz, 2H) , 7.03 (dd, J = 8.2, 1.0 Hz, 1H) , 6.46 (s, 1H) , 5.09 (s, 2H) , 3.23 (s, 3H) , 2.84 (t, J = 7.7 Hz, 2H) , 2.55 (t, J = 7.8 Hz, 2H) , 2.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 158.83, 149.40, 143.22, 137.92, 135.26, 134.86, 128.88, 128.20, 128.16, 127.52, 122.33, 120.34, 115.13, 113.13, 110.67, 101.52, 85.65, 81.44, 37.79, 36.79, 30.51, 28.66, 20.66. HRMS (ESI) [M+H]
+: calcd for C
26H
24ClN
4O
3, 475.1537; found, 475.1531.
Example 107: N- (1- (3- (1H-indol-5-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 107) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 5-iodo-1H-indole (40.6 mg, 0.167 mmol) . White solid (21 mg, 31.6%) .
1H NMR (400 MHz, DMSO) : δ 11.32 (s, 1H) , 9.38 (s, 1H) , 7.67 (d, J = 0.7 Hz, 1H) , 7.43–7.36 (m, 2H) , 7.17–7.09 (m, 3H) , 7.08 (d, J = 7.9 Hz, 2H) , 6.45–6.43 (m, 1H) , 5.08 (s, 2H) , 3.23 (s, 3H) , 2.84 (t, J = 7.7 Hz, 2H) , 2.58–2.53 (m, 2H) , 2.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.16, 158.83, 149.40, 143.25, 137.92, 135.80, 134.85, 128.88, 128.17, 127.51, 126.76, 124.43, 124.24, 111.85, 111.37, 110.67, 101.40, 85.83, 80.59, 37.80, 36.79, 30.52, 28.65, 20.66. HRMS (ESI) [M+H]
+: calcd for C
26H
24ClN
4O
3, 475.1537; found, 475.1530.
Example 108: N- (6-chloro-3-methyl-1- (3- (1-methyl-1H-indol-5-yl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 108) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-37 (42.9 mg, 0.167 mmol) . White solid (33 mg, 48.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
27H
26ClN
4O
3, 489.17; found, 489.29.
Example 109: N- (6-chloro-1- (3- (2, 3-dioxoindolin-5-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 109) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 5-iodoindoline-2, 3-dione (45.6 mg, 0.167 mmol) . White solid (29 mg, 41.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
26H
22ClN
4O
5, 505.13; found, 505.26.
Example 110: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 110) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-38 (43.4 mg, 0.167 mmol) . White solid (24 mg, 34.9%) . UPLC-MS (ESI) [M+H]
+ calcd for C
25H
23ClN
5O
4, 492.14; found, 492.27.
Example 111: methyl 5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -1H-indole-2-carboxylate (Compound 111) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-40 (50.3 mg, 0.167 mmol) . White solid (30 mg, 40.2%) . UPLC-MS (ESI) [M+H]
+ calcd for C
28H
26ClN
4O
5, 533.16; found, 533.29.
Example 112: 5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -N-phenyl-1H-indole-2-carboxamide (Compound 112) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-42 (60.5 mg, 0.167 mmol) . White solid (36 mg, 43.3%) . UPLC-MS (ESI) [M+H]
+ calcd for C
33H
29ClN
5O
4, 594.19; found, 594.33.
Example 113: N- (6-chloro-1- (3- (2-hydroxyquinolin-6-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 113) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 6-iodoquinolin-2-ol (45.3 mg, 0.167 mmol) . White solid (31 mg, 44.1%) . UPLC-MS (ESI) [M+H]
+ calcd for C
27H
24ClN
4O
4, 503.15; found, 503.27.
Example 114: N- (6-chloro-1- (3- (1-ethyl-2-oxo-1, 2-dihydroquinolin-6-yl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 114) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-43 (49.9 mg, 0.167 mmol) . White solid (40 mg, 53.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
29H
28ClN
4O
4, 531.18; found, 531.30.
Example 115: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 115) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-44 (45.6 mg, 0.167 mmol) . White solid (36.8 mg, 52.1%) .
1H NMR (400 MHz, CDCl
3) : δ 8.09 (s, 1H) , 7.26–7.22 (m, 2H) , 7.12 (q, J = 8.1 Hz, 4H) , 6.86 (s, 1H) , 6.69 (d, J = 8.8 Hz, 1H) , 5.09 (s, 2H) , 3.39 (s, 3H) , 3.00 (t, J = 7.7 Hz, 2H) , 2.95–2.91 (m, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.62 (dd, J = 8.4, 6.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.18, 170.23, 158.81, 149.36, 143.13, 139.08, 137.91, 134.87, 131.16, 130.77, 128.89, 128.16, 124.05, 115.20, 114.39, 110.69, 83.97, 82.28, 37.67, 36.76, 30.50, 30.09, 28.66, 24.38, 20.66. HRMS (ESI) [M+H]
+: calcd for C
27H
26ClN
4O
4, 505.1637; found, 505.1637.
Example 116: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 116) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-46 (45.9 mg, 0.167 mmol) . White solid (33 mg, 46.5%) . UPLC-MS (ESI) [M+H]
+ calcd for C
26H
24ClN
4O
5, 507.14; found, 507.28.
Example 117: N- (6-chloro-3-methyl-1- (3- (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 117) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-45 (47.9 mg, 0.167 mmol) . White solid (42.1 mg, 58.1%) .
1H NMR (400 MHz, DMSO) : δ 9.37 (s, 1H) , 7.35–7.31 (m, 2H) , 7.13 (d, J = 7.9 Hz, 2H) , 7.09–7.06 (m, 3H) , 5.07 (s, 2H) , 3.23 (s, 3H) , 3.22 (s, 3H) , 2.86–2.81 (m, 4H) , 2.57–2.52 (m, 4H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 169.36, 158.80, 149.36, 143.09, 140.95, 137.90, 134.85, 130.82, 130.74, 128.87, 128.14, 126.55, 115.04, 114.92, 110.71, 83.61, 82.84, 37.65, 36.75, 30.82, 30.49, 29.06, 28.64, 24.18, 20.64. HRMS (ESI) [M+H]
+: calcd for C
28H
28ClN
4O
4, 519.1794; found, 519.1796.
Example 118: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (2-oxochroman-6-yl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 118) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-47 (45.7 mg, 0.167 mmol) . White solid (36.2 mg, 51.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.34–7.29 (m, 2H) , 7.13 (d, J = 8.2 Hz, 2H) , 7.10 (d, J = 8.1 Hz, 2H) , 6.98 (d, J = 8.3 Hz, 1H) , 6.79 (s, 1H) , 5.09 (s, 2H) , 3.38 (s, 3H) , 3.02–2.94 (m, 4H) , 2.79–2.76 (m, 2H) , 2.69 (t, J = 7.7 Hz, 2H) , 2.31 (s, 3H) . HRMS (ESI) [M-H]
-: calcd for C
27H
23ClN
3O
5, 504.1326 ; found, 504.1332.
Example 119: methyl 3- (5- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) -2-hydroxyphenyl) propanoate (Compound 119) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-48 (51.1 mg, 0.167 mmol) . White solid (28 mg, 37.2%) .
1H NMR (400 MHz, CDCl
3) : δ 7.62 (s, 1H) , 7.19–7.16 (m, 2H) , 7.14–7.09 (m, 4H) , 6.81–6.79 (d, J = 8.8 Hz, 1H) , 6.67 (s, 1H) , 5.06 (s, 2H) , 3.68 (s, 3H) , 3.37 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.83 (t, J = 6.8 Hz, 2H) , 2.71–2.68 (m, 4H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
28H
29ClN
3O
6, 538.17; found, 538.29.
Example 120: methyl 3- (3- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) propanoate (Compound 120) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-49 (48.4 mg, 0.167 mmol) . White solid (34 mg, 41.1%) .
1H NMR (400 MHz, CDCl3) : δ 7.26–7.24 (m, 2H) , 7.21–7.17 (m, 1H) , 7.15–7.13 (m, 1H) , 7.11–7.06 (m, 5H) , 5.06 (s, 2H) , 3.63 (s, 3H) , 3.34 (s, 3H) , 2.97 (t, J = 8.0 Hz, 2H) , 2.88 (t, J = 8.0 Hz, 2H) , 2.66 (t, J = 8.0 Hz, 2H) , 2.58 (t, J = 8.0 Hz, 2H) , 2.28 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
28H
29ClN
3O
5, 522.18; found, 522.30.
Example 121: N- (1- (3- (4-acetylphenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 121) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 1- (4-iodophenyl) ethan-1-one (41.1 mg, 0.167 mmol) . White solid (32 mg, 47.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
26H
25ClN
3O
4, 478.15; found, 478.28.
Example 122: N- (1- (3- (3-acetylphenyl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 122) .
Prepared from compound 51 (50 mg, 0.14 mmol) and 1- (3-iodophenyl) ethan-1-one (41.1 mg, 0.167 mmol) . White solid (36 mg, 53.8%) . UPLC-MS (ESI) [M+H]
+ calcd for C
26H
25ClN
3O
4, 478.15; found, 478.27.
Example 123: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (2-oxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 123) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-50a (52.6 mg, 0.167 mmol) . White solid (29 mg, 37.9%) .
1H NMR (400 MHz, CDCl
3) : δ 7.34–7.32 (m, 2H) , 7.26–7.21 (m, 2H) , 7.14–7.09 (m, 4H) , 6.78 (s, 1H) , 5.09 (s, 2H) , 4.54 (s, 2H) , 3.38 (s, 3H) , 3.17 (t, J = 6.0 Hz, 2H) , 3.00 (t, J = 7.2 Hz, 2H) , 2.69 (t, J = 7.2 Hz, 2H) , 2.46 (t, J = 6.4 Hz, 2H) , 2.31 (s, 3H) , 1.80-1.77 (m, 4H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
32ClN
4O
4, 547.21; found, 547.35.
Example 124: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- ( (2-oxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 124) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-51a (52.6 mg, 0.167 mmol) . White solid (31 mg, 40.5%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38 (d, J = 8.4 Hz, 2H) , 7.18 (d, J = 8.4 Hz, 2H) , 7.14–7.09 (m, 4H) , 6.76 (s, 1H) , 5.09 (s, 2H) , 4.57 (s, 2H) , 3.38 (s, 3H) , 3.16 (t, J = 6.0 Hz, 2H) , 3.00 (t, J = 7.2 Hz, 2H) , 2.69 (t, J = 7.2 Hz, 2H) , 2.46 (t, J = 6.4 Hz, 2H) , 2.31 (s, 3H) , 1.81–1.76 (m, 4H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
32ClN
4O
4, 547.21; found, 547.35.
Example 125: N- (6-chloro-1- (3- (3- ( (2, 6-dioxopiperidin-1-yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 125) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-52 (54.9 mg, 0.167 mmol) . White solid (32 mg, 40.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.42 (s, 1H) , 7.35–7.29 (m, 2H) , 7.23–7.20 (m, 1H) , 7.14–7.09 (m, 4H) , 6.74 (s, 1H) , 5.08 (s, 2H) , 4.89 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.2 Hz, 2H) , 2.70-2.66 (m, 6H) , 2.31 (s, 3H) , 1.95-1.91 (m, 2H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
30ClN
4O
5, 561.19; found, 561.32.
Example 126: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (3-oxomorpholino) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 126) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-53 (52.9 mg, 0.167 mmol) . White solid (28 mg, 36.5%) .
1H NMR (400 MHz, CDCl
3) : δ 7.37–7.34 (m, 2H) , 7.30–7.26 (m, 1H) , 7.24–7.22 (m, 1H) , 7.14–7.10 (m, 4H) , 6.71 (s, 1H) , 5.09 (s, 2H) , 4.58 (s, 2H) , 4.25 (s, 2H) , 3.86–3.83 (m, 2H) , 3.38 (s, 3H) , 3.26 (t, J = 5.2 Hz, 2H) , 3.00 (t, J = 8 Hz, 2H) , 2.69 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (101 MHz, DMSO) δ 171.13, 166.23, 158.80, 149.36, 143.02, 137.90, 137.62, 134.85, 130.95, 130.62, 129.10, 128.87, 128.63, 128.14, 121.58, 110.73, 83.88, 83.46, 67.40, 63.21, 48.09, 45.62, 37.55, 36.76, 30.49, 28.64, 20.64. UPLC-MS (ESI) [M+H]
+ calcd for C
29H
30ClN
4O
5, 549.19; found, 549.31.
Example 127: N- (6-chloro-1- (3- (3- ( (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 127) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-54 (62.9 mg, 0.167 mmol) . White solid (37 mg, 43.5%) .
1H NMR (400 MHz, CDCl3) : δ 7.39–7.36 (m, 2H) , 7.30–7.28 (m, 3H) , 7.12 (q, J = 8.1 Hz, 4H) , 6.68 (s, 1H) , 5.96 (s, 1H) , 5.23 (s, 2H) , 5.10 (s, 2H) , 3.39 (s, 3H) , 3.36 (s, 3H) , 3.01 (t, J = 7.7 Hz, 2H) , 2.69 (t, J = 7.7 Hz, 2H) , 2.32 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
28Cl
2N
5O
5, 608.15; found, 608.31.
Example 128: methyl 2- (4- (3- (6-chloro-3-methyl-2, 4-dioxo-5- (3- (p-tolyl) propanamido) -3, 4-dihydropyrimidin-1 (2H) -yl) prop-1-yn-1-yl) phenyl) acetate (Compound 128) .
Prepared from compound 51 (50 mg, 0.14 mmol) and methyl 2- (4-iodophenyl) acetate (46.1 mg, 0.167 mmol) . White solid (40 mg, 56.3%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38 (d, J = 8.0 Hz, 2H) , 7.21 (d, J = 8.0 Hz, 2H) , 7.14–7.09 (m, 4H) , 6.73 (s, 1H) , 5.09 (s, 2H) , 3.68 (s, 3H) , 3.61 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 7.6 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
27H
27ClN
3O
5, 508.16; found, 508.29.
Example 129: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 129) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-50b (51.9 mg, 0.167 mmol) . White solid (46.9 mg, 60.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38 (m, 1H) , 7.36–7.34 (m, 1H) , 7.33–7.29 (m, 1H) , 7.28–7.27 (m, 2H) , 7.25 (m, 1H) , 7.12 (q, J = 8.1 Hz, 4H) , 6.88 (s, 1H) , 6.62 (d, J = 8.8 Hz, 1H) , 6.17 (td, J = 6.8, 1.2 Hz, 1H) , 5.09 (s, 2H) , 5.08 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.16, 161.41, 158.78, 149.36, 142.99, 140.26, 139.14, 138.08, 137.91, 134.84, 130.89, 130.76, 129.06, 128.87, 128.64, 128.14, 121.51, 119.90, 110.76, 105.73, 83.94, 83.34, 50.77, 37.54, 36.76, 30.50, 28.64, 20.64. HRMS (ESI) [M+H]
+: calcd for C
30H
28ClN
4O
4, 543.1794; found, 543.1796.
Example 130: N- (6-chloro-3-methyl-2, 4-dioxo-1- (3- (4- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 130) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-51b (51.9 mg, 0.167 mmol) . White solid (40.9 mg, 53.9%) .
1H NMR (400 MHz, CDCl
3) : δ 7.41–7.38 (m, 2H) , 7.33 (ddd, J = 8.8, 6.8, 2.2 Hz, 1H) , 7.23–7.21 (m, 3H) , 7.11 (q, J = 8.2 Hz, 4H) , 6.73 (s, 1H) , 6.62–6.60 (m, 1H) , 6.16 (td, J = 6.8, 1.6 Hz, 1H) , 5.12 (s, 2H) , 5.08 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 7.6 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.17, 161.43, 158.81, 149.38, 143.06, 140.32, 139.21, 138.50, 137.91, 134.87, 131.83, 128.89, 128.17, 127.91, 120.45, 119.94, 110.73, 105.73, 83.85, 83.40, 50.95, 37.59, 36.77, 30.51, 28.66, 20.66. HRMS (ESI) [M+H]
+: calcd for C
30H
28ClN
4O
4, 543.1794; found, 543.1796.
Example 131: N- (6-chloro-3-methyl-1- (3- (3- ( (3-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 131) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55a (54.3 mg, 0.167 mmol) . White solid (43.1 mg, 55.3%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38–7.34 (m, 2H) , 7.28–7.26 (m, 2H) , 7.20–7.16 (m, 2H) , 7.14–7.08 (m, 4H) , 6.83 (s, 1H) , 6.08 (t, J = 7.2 Hz, 1H) , 5.09–4.93 (m, 4H) , 3.37–3.34 (m, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.68 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) , 2.16 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.18, 161.88, 158.80, 149.37, 143.01, 138.20, 137.91, 137.16, 136.37, 134.86, 130.97, 130.74, 129.05, 128.88, 128.73, 128.47, 128.16, 121.47, 110.76, 105.29, 83.94, 83.39, 51.06, 37.55, 36.77, 30.51, 28.65, 20.65, 17.01. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
4, 557.1950; found, 557.1953.
Example 132: N- (6-chloro-1- (3- (3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 132) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55b (56.9 mg, 0.167 mmol) . White solid (36.3 mg, 45.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.41 (s, 1H) , 7.34 (dt, J = 7.2, 1.6 Hz, 1H) , 7.30–7.27 (m, 2H) , 7.14–7.09 (m, 4H) , 6.88 (dd, J = 7.2, 1.6 Hz, 1H) , 6.79 (s, 1H) , 6.59 (dd, J = 7.2, 1.6 Hz, 1H) , 6.09 (t, J = 7.2 Hz, 1H) , 5.13 (s, 2H) , 5.07 (s, 2H) , 3.81 (s, 3H) , 3.38 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.16, 158.79, 156.83, 149.39, 149.38, 143.00, 138.11, 137.91, 134.86, 130.85, 130.75, 129.41, 129.06, 128.89, 128.62, 128.16, 121.48, 113.28, 110.74, 104.56, 83.94, 83.34, 55.51, 50.79, 37.54, 36.77, 30.51, 28.66, 20.65. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
5, 573.1899; found, 573.1904.
Example 133: N– (6-chloro-1- (3- (3- ( (3-fluoro-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 133) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55c (54.9 mg, 0.167 mmol) . White solid (39 mg, 49.7%) .
1H NMR (400 MHz, CDCl
3) : δ 7.40–7.36 (m, 2H) , 7.29–7.26 (m, 2H) , 7.14–7.07 (m, 6H) , 6.82 (s, 1H) , 6.11–6.06 (m, 1H) , 5.13 (s, 2H) , 5.08 (s, 2H) , 3.37–3.34 (m, 3H) , 3.02–2.98 (m, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
27ClFN
4O
4, 561.17; found, 561.31.
Example 134: N- (6-chloro-3-methyl-1- (3- (3- ( (4-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 134) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55d (54.3 mg, 0.167 mmol) . White solid (31.8 mg, 40.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.36–7.33 (m, 2H) , 7.27–7.26 (m, 2H) , 7.16–7.08 (m, 5H) , 6.79 (s, 1H) , 6.43 (s, 1H) , 6.03 (dd, J = 7.0, 1.8 Hz, 1H) , 5.08 (s, 2H) , 5.06 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) , 2.17 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.17, 161.31, 158.80, 151.37, 149.37, 143.00, 138.28, 137.93, 134.86, 130.81, 130.71, 129.03, 128.88, 128.58, 128.16, 121.50, 118.17, 110.77, 108.11, 83.92, 83.38, 50.32, 37.55, 36.79, 30.52, 28.65, 20.74, 20.65. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
4, 557.1956; found, 557.1952.
Example 135: N- (6-chloro-1- (3- (3- ( (4-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 135) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55e (56.9 mg, 0.167 mmol) . White solid (34.3 mg, 42.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.36–7.33 (m, 2H) , 7.29–7.26 (m, 2H) , 7.16–7.08 (m, 5H) , 6.81 (s, 1H) , 5.95 (d, J = 2.7 Hz, 1H) , 5.92 (dd, J = 7.5, 2.7 Hz, 1H) , 5.08 (s, 2H) , 5.04 (s, 2H) , 3.77 (s, 3H) , 3.38 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.7 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.17, 167.77, 162.76, 158.81, 149.38, 143.02, 138.98, 138.46, 137.91, 134.87, 130.70, 130.66, 129.04, 128.89, 128.50, 128.16, 121.47, 110.74, 99.97, 96.62, 83.91, 83.38, 55.56, 49.90, 37.56, 36.78, 30.51, 28.66, 20.66. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
5, 573.1905; found, 573.1901.
Example 136: N- (6-chloro-1- (3- (3- ( (4-chloro-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 136) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55f (57.7 mg, 0.167 mmol) . White solid (43 mg, 53.2%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38–7.36 (m, 2H) , 7.31–7.26 (m, 2H) , 7.19 (d, J = 7.6 Hz, 1H) , 7.14–7.09 (m, 4H) , 6.77 (s, 1H) , 6.65–6.64 (m, 1H) , 6.20–6.17 (m, 1H) , 5.08 (s, 2H) , 5.04 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
27Cl
2N
4O
4, 577.14; found, 577.27.
Example 137: N- (6-chloro-3-methyl-1- (3- (3- ( (5-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 137) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55g (54.3 mg, 0.167 mmol) . White solid (35.1 mg, 45.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.37 (s, 1H) , 7.36–7.34 (m, 1H) , 7.28–7.25 (m, 2H) , 7.18 (dd, J = 9.3, 2.5 Hz, 1H) , 7.13 (d, J = 8.1 Hz, 2H) , 7.10 (d, J = 8.0 Hz, 2H) , 7.00 (s, 1H) , 6.86 (s, 1H) , 6.56 (d, J = 9.3 Hz, 1H) , 5.08 (s, 2H) , 5.06 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.7 Hz, 2H) , 2.69 (t, J = 7.7 Hz, 2H) , 2.31 (s, 3H) , 2.04 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.17, 160.67, 158.80, 149.37, 143.01, 142.68, 138.23, 137.92, 136.20, 134.86, 130.87, 130.76, 129.06, 128.88, 128.65, 128.16, 121.50, 119.59, 114.26, 110.77, 83.94, 83.38, 50.66, 37.55, 36.78, 30.52, 28.65, 20.66, 16.48. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
4, 557.1956; found, 557.1949.
Example 138: N- (6-chloro-3-methyl-1- (3- (3- ( (6-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 138) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55h (54.3 mg, 0.167 mmol) . White solid (30.7 mg, 39.4%) .
1H NMR (400 MHz, CDCl
3) : δ 7.31 (dt, J = 7.5, 1.1 Hz, 1H) , 7.29–7.26 (m, 1H) , 7.24 (s, 1H) , 7.22 (s, 1H) , 7.15–7.09 (m, 5H) , 6.76 (s, 1H) , 6.55 (d, J = 9.1 Hz, 1H) , 6.04 (d, J = 6.7 Hz, 1H) , 5.29 (s, 2H) , 5.07 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.68 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) , 2.24 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 162.70, 158.80, 149.36, 147.30, 142.99, 139.76, 137.91, 137.80, 134.85, 130.43, 129.31, 129.19, 128.88, 128.15, 127.12, 121.66, 116.61, 110.76, 106.41, 84.00, 83.35, 45.84, 37.54, 36.78, 30.51, 28.64, 20.65, 20.01. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
4, 557.1956; found, 557.1947.
Example 139: N- (6-chloro-1- (3- (3- ( (3, 4-dimethyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 139) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55i (56.6 mg, 0.167 mmol) . White solid (40 mg, 50.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.36 (m, 1H) , 7.34–7.32 (m, 1H) , 7.26 (m, 1H) , 7.25 (m, 1H) , 7.14–7.08 (m, 4H) , 7.04–7.03 (d, J = 7.2 Hz, 1H) , 6.82 (s, 1H) , 6.01–5.99 (d, J = 7.2 Hz, 1H) , 5.07 (s, 2H) , 5.06 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 8 Hz, 2H) , 2.68 (t, J = 8 Hz, 2H) , 2.31 (s, 3H) , 2.14 (s, 3H) , 2.10 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
32H
32ClN
4O
4, 571.21; found, 571.34.
Example 140: N- (6-chloro-1- (3- (3- ( (5-chloro-3-methyl-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 140) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-55j (60.1 mg, 0.167 mmol) . White solid (36 mg, 43.5%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38–7.35 (m, 2H) , 7.28–7.25 (m, 2H) , 7.18–7.15 (m, 2H) , 7.13–7.07 (m, 4H) , 7.02 (s, 1H) , 5.07 (s, 2H) , 5.04 (s, 2H) , 3.36 (s, 3H) , 2.99 (t, J = 8 Hz, 2H) , 2.68 (t, J = 8 Hz, 2H) , 2.30 (s, 3H) , 2.15 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
31H
29Cl
2N
4O
4, 591.16; found, 591.29.
Example 141: N- (6-chloro-1- (3- (4-fluoro-3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 141) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-58a (54.9 mg, 0.167 mmol) . White solid (48.7 mg, 52.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.54 (dd, J = 7.1, 2.1 Hz, 1H) , 7.38–7.29 (m, 3H) , 7.14 (d, J = 8.2 Hz, 2H) , 7.10 (d, J = 8.2 Hz, 2H) , 7.01 (dd, J = 9.7, 8.6 Hz, 1H) , 6.78 (s, 1H) , 6.58 (d, J = 9.0 Hz, 1H) , 6.18 (td, J = 6.7, 1.3 Hz, 1H) , 5.11 (s, 2H) , 5.05 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.28, 161.44, 160.36 (d, J = 250.6 Hz) , 158.86, 149.43, 143.05, 140.62, 139.45, 137.95, 134.94, 133.36 (d, J = 9.4 Hz) , 128.95, 128.22, 124.80 (d, J = 15.8 Hz) , 119.88, 117.74 (d, J = 3.2 Hz) , 116.35 (d, J = 22.4 Hz) , 110.78, 109.64, 105.85, 83.79, 82.41, 45.96, 37.56, 36.82, 30.55, 28.71, 20.71. HRMS (ESI) [M+H]
+: calcd for C
30H
27ClFN
4O
4, 561.1705; found, 561.1700.
Example 142: N- (6-chloro-1- (3- (4-chloro-3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 142) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-58b (57.7 mg, 0.167 mmol) . White solid (36.9 mg, 45.7%) .
1H NMR (400 MHz, CDCl
3) : δ 7.38–7.35 (m, 1H) , 7.34–7.29 (m, 4H) , 7.13 (d, J = 7.8 Hz, 2H) , 7.10 (d, J = 8.1 Hz, 2H) , 6.91–6.78 (m, 1H) , 6.62 (d, J = 9.5 Hz, 1H) , 6.19 (td, J = 6.7, 1.3 Hz, 1H) , 5.21 (s, 2H) , 5.05 (s, 2H) , 3.37 (s, 3H) , 3.00 (t, J = 7.7 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.14, 161.39, 158.78, 149.36, 142.91, 140.67, 139.42, 137.91, 135.06, 134.86, 133.01, 132.25, 131.29, 130.08, 128.88, 128.16, 120.48, 119.90, 110.76, 105.87, 85.11, 82.26, 49.34, 37.51, 36.77, 30.50, 28.64, 20.66. HRMS (ESI) [M+H]
+: calcd for C
30H
27Cl
2N
4O
4, 577.1409; found, 577.1407.
Example 143: N- (6-chloro-1- (3- (4-methoxy-3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 143) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-62a (56.9 mg, 0.167 mmol) . White solid (38.9 mg, 48.6%) .
1H NMR (400 MHz, DMSO) : δ 9.38 (s, 1H) , 7.68 (d, J = 6.0 Hz, 1H) , 7.45–7.38 (m, 2H) , 7.15–7.07 (m, 4H) , 7.04 (d, J = 8.6 Hz, 1H) , 6.98 (s, 1H) , 6.40 (d, J = 8.8 Hz, 1H) , 6.24 (t, J = 6.0 Hz, 1H) , 5.03 (s, 2H) , 4.98 (s, 2H) , 3.85 (s, 3H) , 3.21 (s, 3H) , 2.83 (t, J = 7.6 Hz, 2H) , 2.55 (t, J = 7.6 Hz, 2H) , 2.25 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.57, 161.88, 159.20, 157.90, 149.78, 143.46, 140.69, 140.01, 138.34, 135.27, 133.21, 132.20, 129.30, 128.58, 125.59, 120.16, 113.40, 111.76, 111.11, 105.81, 83.89, 82.78, 56.21, 47.41, 38.04, 37.19, 30.92, 29.05, 21.07. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
5, 573.1899; found, 573.1901.
Example 144: N- (6-chloro-1- (3- (4-hydroxy-3- ( (2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 144) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-61a (54.6 mg, 0.167 mmol) . White solid (34.9 mg, 44.8%) .
1H NMR (400 MHz, CDCl
3) : δ 10.74 (s, 1H) , 7.59 (d, J = 6.4 Hz, 1H) , 7.47–7.43 (m, 1H) , 7.39 (d, J = 2.0 Hz, 1H) , 7.31 (dd, J = 8.4, 2.0 Hz, 1H) , 7.14–7.06 (m, 4H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.73 (s, 1H) , 6.69–6.67 (m, 1H) , 6.38 (td, J = 6.8, 1.6 Hz, 1H) , 5.07 (s, 2H) , 5.01 (s, 2H) , 3.38 (s, 3H) , 3.00 (t, J = 8.0 Hz, 2H) , 2.69 (t, J = 8.0 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.19, 161.84, 158.80, 156.42, 149.36, 143.10, 140.58, 139.41, 137.92, 134.87, 133.27, 132.90, 128.89, 128.16, 123.59, 119.57, 116.08, 111.65, 110.68, 106.11, 83.88, 81.72, 47.26, 37.68, 36.79, 30.52, 28.64, 20.66. HRMS (ESI) [M+H]
+: calcd for C
30H
28ClN
4O
5, 559.1743; found, 559.1745.
Example 145: N- (6-chloro-1- (3- (4-fluoro-3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 145) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-58c (59.9 mg, 0.167 mmol) . White solid (37.2 mg, 44.9%) .
1H NMR (400 MHz, CDCl
3) : δ 7.59 (dd, J = 7.1, 2.1 Hz, 1H) , 7.33 (ddd, J = 8.3, 5.0, 2.1 Hz, 1H) , 7.14 (d, J = 8.1 Hz, 2H) , 7.10 (d, J = 7.9 Hz, 2H) , 7.02–6.97 (m, 2H) , 6.83 (s, 1H) , 6.58 (dd, J = 7.4, 1.6 Hz, 1H) , 6.11 (t, J = 7.2 Hz, 1H) , 5.15 (s, 2H) , 5.05 (s, 2H) , 3.80 (s, 3H) , 3.38 (s, 3H) , 3.01 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.15, 160.24 (d, J = 249.9 Hz) , 158.78, 156.77, 149.37, 149.29, 142.96, 137.91, 134.86, 133.27 (d, J = 8.9 Hz) , 133.26, 129.62, 128.88, 128.15, 124.81 (d, J = 15.9 Hz) , 117.68 (d, J = 3.3 Hz) , 116.27 (d, J = 22.9 Hz) , 113.40, 110.74, 104.55, 83.74, 82.34, 55.53, 45.72, 37.49, 36.77, 30.50, 28.65, 20.65. HRMS (ESI) [M+H]
+: calcd for C
31H
29ClFN
4O
5, 591.1810; found, 591.1807.
Example 146: N- (6-chloro-1- (3- (4-chloro-3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 146) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-58d (62.7 mg, 0.167 mmol) . White solid (30.6 mg, 36.1%) .
1H NMR (400 MHz, CDCl
3) : δ 7.39 (d, J = 1.8 Hz, 1H) , 7.34–7.27 (m, 2H) , 7.14 (d, J = 8.1 Hz, 2H) , 7.10 (d, J = 8.1 Hz, 2H) , 6.96 (dd, J = 7.0, 1.6 Hz, 1H) , 6.81 (s, 1H) , 6.62 (dd, J = 7.5, 1.6 Hz, 1H) , 6.13 (t, J = 7.2 Hz, 1H) , 5.26 (s, 2H) , 5.05 (s, 2H) , 3.82 (s, 3H) , 3.38 (s, 3H) , 3.00 (t, J = 7.8 Hz, 2H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.14, 158.78, 156.83, 149.36, 149.33, 142.91, 137.91, 135.12, 134.87, 132.97, 132.27, 131.13, 130.08, 129.63, 128.89, 128.16, 120.48, 113.53, 110.75, 104.73, 85.13, 82.25, 55.56, 49.23, 37.51, 36.76, 30.49, 28.65, 20.66. HRMS (ESI) [M+H]
+: calcd for C
31H
29Cl
2N
4O
5, 607.1515; found, 607.1506.
Example 147: N- (6-chloro-1- (3- (4-methoxy-3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 147) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-62b (61.9 mg, 0.167 mmol) . White solid (42.9 mg, 50.9%) .
1H NMR (400 MHz, DMSO) : δ 9.36 (s, 1H) , 7.39 (dd, J = 8.4, 2.0 Hz, 1H) , 7.25 (dd, J = 7.2, 1.6 Hz, 1H) , 7.14 (d, J = 8.0 Hz, 2H) , 7.08 (d, J = 7.9 Hz, 2H) , 7.04 (d, J = 8.8 Hz, 1H) , 6.92 (d, J = 2.0 Hz, 1H) , 6.82 (dd, J = 7.6, 1.6 Hz, 1H) , 6.17 (t, J = 7.2 Hz, 1H) , 5.03 (s, 2H) , 5.00 (s, 2H) , 3.85 (s, 3H) , 3.69 (s, 3H) , 3.21 (s, 3H) , 2.83 (t, J = 7.7 Hz, 2H) , 2.56–2.52 (m, 2H) , 2.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ171.11, 158.77, 157.37, 156.84, 149.35, 149.25, 143.02, 137.91, 134.84, 132.73, 131.42, 129.85, 128.87, 128.14, 125.27, 113.29, 112.96, 111.32, 110.66, 104.19, 83.45, 82.35, 55.79, 55.50, 46.78, 37.60, 36.77, 30.49, 28.63, 20.65. HRMS (ESI) [M+H]
+: calcd for C
32H
32ClN
4O
6, 603.2005; found, 603.2001.
Example 148: N- (6-chloro-1- (3- (4-hydroxy-3- ( (3-methoxy-2-oxopyridin-1 (2H) -yl) methyl) phenyl) prop-2-yn-1-yl) -3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 148) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-61b (59.6 mg, 0.167 mmol) . White solid (31.9 mg, 38.9%) .
1H NMR (400 MHz, DMSO) : δ 10.52 (s, 1H) , 9.37 (s, 1H) , 7.33 (d, J = 5.6 Hz, 1H) , 7.22 (d, J = 8.0 Hz, 1H) , 7.14–7.08 (m, 5H) , 6.85 (d, J = 8.0 Hz, 2H) , 6.21 (t, J = 6.8 Hz, 1H) , 5.02 (s, 2H) , 4.99 (s, 2H) , 3.69 (s, 3H) , 3.21 (s, 3H) , 2.82 (t, J = 6.8 Hz, 2H) , 2.55 (t, J = 7.2 Hz, 2H) , 2.26 (s, 3H) .
13C NMR (100 MHz, DMSO) : δ 171.57, 159.20, 157.44, 156.70, 149.77, 149.59, 143.50, 138.34, 135.27, 133.25, 133.15, 130.10, 129.30, 128.58, 124.12, 116.33, 114.05, 111.98, 111.08, 105.12, 84.29, 82.11, 55.98, 47.34, 38.07, 37.19, 30.93, 29.06, 21.08. HRMS (ESI) [M+H]
+: calcd for C
31H
30ClN
4O
6, 589.1849; found, 589.1852.
Example 149: N- (6-chloro-3-methyl-1- (3- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) prop-2-yn-1-yl) -2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 149) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-63a (39.2 mg, 0.167 mmol) . White solid (23 mg, 30.6%) . UPLC-MS (ESI) [M+H]
+ calcd for C
24H
24ClN
4O
4, 467.15; found, 467.28.
Example 150: N- (1- (3- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) prop-2-yn-1-yl) -6-chloro-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) -3- (p-tolyl) propanamide (Compound 150) .
Prepared from compound 51 (50 mg, 0.14 mmol) and I-63b (51.9 mg, 0.167 mmol) . White solid (28 mg, 36.8%) .
1H NMR (400 MHz, CDCl
3) : δ 7.35–7.29 (m, 3H) , 7.27–7.25 (m, 2H) , 7.18 (d, J = 7.2 Hz, 1H) , 7.14–7.08 (m, 4H) , 6.77 (s, 1H) , 6.68 (d, J = 1.6 Hz, 1H) , 6.11 (dd, J = 1.2, 7.2 Hz, 1H) , 5.10 (s, 2H) , 5.08 (s, 2H) , 3.37 (s, 3H) , 2.99 (t, J = 7.2 Hz, 2H) , 2.68 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) . UPLC-MS (ESI) [M+H]
+ calcd for C
30H
28ClN
4O
4, 543.18; found, 543.30.
Test Examples
In vitro kinase assays
The RIP1 kinase assay was performed in white 384-well plate. The assay buffer contained 25mM HEPES (pH7.2) , 20 mM MgCl
2, 12.5 mM MnCl
2, 5 mM EGTA, 2 mM EDTA, 12.5 mM β-glycerol phosphate and 2 mM DTT. RIPK1 was first incubated with compounds or DMSO control for 15 min, then ATP/MBP substrate mixture was added to initiate the reaction. The RIP3 kinase assay conditions were similar with that of RIP1 assay, except the assay buffer contained 5 mM MgCl
2 instead of 20 mM MgCl
2 and 12.5 mM MnCl
2. After 90 min reaction at room temperature, the ADP-Glo reagent and detection solution were added following the technical manual of ADP-GloTM kinase assay kit (Promega) . The luminescence was measured on PerkinElmer Enspire. All the data were analyzed using GraphPad Prism (GraphPad Software, Inc., San Diego, CA, USA) .
Cell culture
Cell culture: HT-29 cells were cultured in McCoy’s 5A culture medium (Gibco) . HeLa and MEF cells were cultured in Dulbecco’s modified Eagle medium (DMEM) (Gibco) . The medium contained 10%fetal bovine serum (FBS) (Gibco) and 1%Penicillin Streptomycin solution (Gibco) . The cells were cultured at 37 ℃ in an atmosphere of 5%CO
2.
Cell survival assay
Cells were seeded into 96-well plates, 4000 cells per well. After 12h, necroptosis was induced by adding 20 ng/mL TNFα (T) , 100 nM Smac mimetic (S) , and 20 mM z-VAD-FMK (Z) to the well. Identical concentrations of these necrosis-inducing agents were used in subsequent experiments unless otherwise stated. Extrinsic apoptosis was induced by adding 50 ng/mL TNFα (T) plus 100 nM Smac mimetic (S) ; 50 ng/mL TNFα (T) plus 1.25 μg/mL Cycloheximide (CHX) ; Intrinsic apoptosis was induced by 5μM ABT737 plus 2μM S63845; Ferroptosis was induced by 1μM PACMA31 plus 10μM Regorafenib. Cell viability in this and subsequent panels was determined by measuring ATP levels by Cell Titer-Glo assay kit (Promega) according to the manufacturer’s instructions. Luminescence was recorded with a PerkinElmer Enspire plate reader. All the data were analyzed using GraphPad Prism (GraphPad Software, Inc., San Diego, CA, USA) . The curves were fitted using a non-linear regression model.
Western-Blot analysis
Cell pellets were collected and re-suspended with lysis buffer (20 mM Tris-HCl, pH 7.4, 150 mM NaCl, 10%glycerol, 1%Triton X-100, complete protease inhibitor cocktail, phosphatase inhibitor cocktail) . The re-suspended cell pellet was incubated on ice for 30 min and centrifuged at 15000g for 10 min. The supernatants were collected for Western-blot analysis. The antibodies used: MLKL (CST14993) ; p-MLKL (CST91689) ; GAPDH (CST5174) .
Compound wash/no-wash assay.
HT-29 cells were seeded in 96-well plate at a density of 3000 cells/well. After 24h, cells were treated with compound 144 for 5min, 1h or 3h. Then the medium was washed away, the cells were wash with cold sodium phosphate buffer three times and treated with TSZ for 24h. The cells treated with compound 144 without washaway were used as control. The cell survival ratio was determined using the Cell Titer-Glo Luminescent Cell Viability Assay kit (Promega) according to the manufacturer’s instructions.
Immunofluorescence Staining
The MLKL-flag HT-29 cells were seeded in Lab-Tek eight-chambered slides (Thermo) for 12h. After treatment with indicated compounds and TSZ for 6h, the cells were washed with PBS buffer for three times and fixed in freshly prepared 4%PFA for 30min at room temperature followed by three washes in PBS and incubation in PBS containing 0.1%Triton X-100 for 15 min. The cells were then blocked for 30 min in blocking buffer (5%BSA in PBS) . p-MLKL (Abcam187091) were diluted in 5%BSA in PBS and incubated with the cells at 4℃ overnight. The next day, the cells were washed three times with PBS followed by incubation with a fluorescein-conjugated secondary antibody for one hour. The nuclei were stained with Hoechst 33342 for another 15 min. After three washes in PBS, the slides were covered and sealed and were examined. Similar results were obtained in at least three independent experiments. The colocalization was analyzed by the fluorescence intensity quantification using Zeiss LSM software.
Fractionation by Phase Separation
The pellets from treated cells were re-suspended in Triton X-114 lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 2%Triton X-114, and complete protease inhibitor) and incubated on ice for 30 min. The cell lysate was centrifuged at 15,000g at 4℃ for 10 min, and then the supernatant was harvested as the detergent soluble fraction. After warming at 30℃ for 3 min, the detergent soluble fraction was centrifuged at 1500 × g for 5 min at room temperature. The aqueous layer was collected then re-centrifuged at 1500 g for 5 min to remove the contamination from the detergent enriched layer and saved as the aqueous faction (Aq) . The detergent enriched layer was diluted with basal buffer (20 mM HEPES, pH 7.4, 150 mM NaCl) to the same volume of the detergent soluble fraction and re-centrifuged at 1500 g for 5 min. The washed detergent enriched layer was diluted with the basal buffer to the same volume as the aqueous faction and saved as the detergent fraction (Det) .
Pull Down Assay
HT-29 cells were seeded in 10 cm dishes one day before the start of the experiment. Cells were incubated with DMSO, TC13172 (1 μM) , compound 144 (5 μM) or compound 148 (5 μM) for 1 h; the Probe TC13136 (5 μM) was then added and the samples were incubated for an additional 1 h. The cells were collected and lysed in RIPA lysis buffer. Subsequently, cell lysates were incubated for 2 h for the click chemistry reaction after addition of Biotin-N3 (10 μM) , CuSO4 (50 μM) , Tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl] amine (TBTA, 50 μM) , and tris (2-carboxyethyl) phosphine (TCEP, 50 μM) . The proteins were precipitated by adding 5 sample volumes of methanol and centrifuging at 15000g for 5 min. Precipitated protein was washed once with methanol and the pellet was re-suspended in PBS containing 1%SDS. Once dissolved, the samples were diluted 10-fold with PBS to 0.1%SDS. The biotin-modified proteins were then enriched using streptavidin beads; the beads were washed three times with PBS containing 0.1%SDS. The pull-down fraction was eluted in protein loading buffer for 15 min at 95℃, followed by immunoblotting with antibodies against MLKL.
Test Example 1: activities of Compounds 1-150 in TSZ-induced necroptosis model
Necroptosis was induced with TSZ (TNF-α, Smac mimetics and z-VAD-FMK) in HT-29 cell lines for 24h; The EC
50 values of each compound were determined in 2-3 independent assays. The experimental results are shown below in Table 1, where, for EC
50 values, where “++++” indicates an EC
50 ≤ 0.2 μM; “+++” indicates an EC
50 between 0.2 μM and 1 μM; “++” indicates an EC
50 between 1 μM and 10 μM; “+” indicates EC
50 ≥ 10 μM.
Table 1 Biological activity for Compound 1-150
Test Example 2: tests for specificity
In vitro kinase assays
During SAR analysis, the bioactivity of this series of compounds was primarily measured at the cell level. To identify if this series of compounds is targeting to RIP1 or RIP3, highly bioactive inhibitors (EC
50 < 300 nM) was selected to conduct ADP-Glo
TM Kinase Assays in vitro with purified RIP1 and RIP3 kinases (Table 2) . Except for compound 3 (1 μM and 10 μM) and compound 144 (10 μM) which slightly inhibited RIP1, no other compounds exerted obvious effects on RIP1 or RIP3 kinase activity, even at a concentration of 10 μM.
Table 2 Results of Kinase inhibition test for uracil derivatives with RIP1/RIP3 kinase.
aATP and substrate protein are added to the target kinase, the kinase uses the ATP to phosphorylate the substrate protein, and finally the target kinase activity is measured by monitoring the amount of ADP generated by luciferase.
MLKL phosphorylation assays
The phosphorylation status of MLKL can also indicate whether the necroptosis inhibitor targets RIP1/3 or downstream executor MLKL. The RIP1 inhibitor RIPA-56 inhibits the phosphorylation of RIP1 and MLKL. To further confirm if this series of compounds is off-target to RIP1 and RIP3 at the cell level, HT-29 cells were treated with compounds and measured the phosphorylation status of RIP1 and MLKL under TSZ induction. TSZ-treated HT-29 cells were incubated with DMSO, compound 144, compound 148, or RIPA-56 for 8 h. The samples were analyzed by western blotting using antibodies against p-RIP1, RIP1, p-MLKL, MLKL, and GAPDH.
The RIP1 inhibitor RIPA-56 inhibits the phosphorylation of RIP1 and MLKL. Similar to the MLKL inhibitor TC13172, neither compound 144 nor compound 148 affects the phosphorylation status of RIP1 and MLKL (Fig. 1A) , confirming that this series of compounds does not affect RIP1 and RIP3.
The structure of the reference compounds TC13172 and RIPA-56 are:
Other kinds of cell death
The inhibition effect of this series of compounds on other kinds of cell death were measured. The cell death was induced in HeLa cells as indicated for 24 h. 50ng/ml TNFα, 10μM Smac, 5μM ABT737, 2μM S63845, 1μM PACMA31 and 10μM Regorafenib were used. Cell viability was assessed based on ATP levels.
Cell viability results demonstrated that compounds 144 and 148 had no effect on that TNFα plus CHX or TNFα plus Smac induced extrinsic apoptosis, that ABT737 plus S63845 induced intrinsic apoptosis, and that P+R induced ferroptosis (Fig. 1B-E) . Compounds 144 and 148 do not inhibit apoptosis and ferroptosis. This indicates that this series of compounds are specific to necroptosis. Test Example 3: demonstration test
Compounds covalently bind with sulfhydryl group of GSH
To determine whether this series of compounds directly targets MLKL, the covalent behavior of this series of compounds were investigated. Mass spectrometry data indicate that compound 144 is covalently bound to the sulfhydryl group of GSH in vitro through the departure of the chlorine atom at the 6-position of the uracil ring (Fig. 2A) .
The reaction rate with GSH of compounds 144 and 148 were measured, which is more than 150-fold slower than TC13172 (Fig. 2B) . Compared to TC13172, the lower reaction rate of compounds 144 and 148 indicates improved off-target effects.
The necroptosis inhibition activity of compound 144 in wash/no-wash cell assays were also compared (Fig. 2C) .. The EC
50 value of necroptosis inhibition for the washed sample was comparable to that of the non-washed sample, indicating that 144 is a covalent inhibitor of necroptosis.
Compounds covalently bind Cys86 of human MLKL
The necroptosis inhibition effect of compounds 144 and 148 on mouse embryonic fibroblast (MEF) cells were next detected. MEF cells were seeded in 96-well plates, and after TSZ induction for 24h, the cell viability was measured based on ATP levels. The cell viability results (Fig. 3A) showed that RIP1 inhibitor RIPA-56 inhibited TSZ-induced necroptosis in MEF cells. However, neither 144 nor 148 inhibited necroptosis in mouse origin MEF cells. Therefore, this series of compounds could inhibit necroptosis by covalently binding with Cys86 of human MLKL.
To detect if compounds 144 and 148 covalently bind to Cys86 of MLKL directly, recombinant MLKL protein were incubated with compound 144. LC-MS/MS analysis and b-/y-ion spectra showed that compound 144 indeed covalently bound to Cys86 of human MLKL (Fig. 3B) .
Furthermore, based on the activity-based protein profiling (ABPP) method, the previous reported probe TC13136, which targets MLKL, was incubated with HT-29 cell lysates, followed by a click reaction to conjugate TC13136 to a biotin-tag. HT-29 cells were incubated with indicated compounds for 4 h. For the binding competition sampled, cells were pre-incubated with 10μM TC13136 for 2 h; 10μM compounds 144 or 148 was then added and incubated for an additional 2 h. The click reaction (Biotin-C
2H
4-N
3 10 mM, TBTA 10 mM, CuSO
4 50 mM, Sodium ascorbate 50 mM) was carried out with cell lysates for 2 h. The biotin-modified proteins were enriched and analyzed by western blotting using indicated. The biotin-labeled compound–protein complexes were pulled down and analyzed via SDS-PAGE. It can be observed that compounds 144 and 148 efficiently outcompeted TC13136 when binding to MLKL (Fig. 3C-D) . These results establish that Cys-86 of MLKL is rquired for the covalent binding of this series of MLKL inhibitors.
The structure of the reference compound TC13136 is:
Compounds inhibit the translocation of MLKL to cell membranes
As necroptosis executor, phosphorylated MLKL undergoes oligomerization and then migrates from the cytoplasm to the cell membrane, causing membrane rupture and cell death. Compounds 144 and 148 inhibit the oligomerization and translocation of MLKL, thereby preventing cell death. Therefore, the effect of compounds 144 and 148 on MLKL oligomerization and translocation were detected. HT-29 cells was treated with TSZ in the presence of compounds 144 and 148. HT-29 cells were seeded in 6-well plates and TSZ was added combined with indicated inhibitors and MLKL oligomerization was detected after 6h. Both RIPA-56 and TC13172 completely prevented MLKL oligomerization, while compounds 144 and 148 only partially inhibit the formation of MLKL oligomers (Fig. 4A) .
Then, the effects of compounds 144 and 148 on MLKL translocation were evaluated. TSZ-treated HT-29 cells were incubated with RIPA-56, 200 nM TC13172, 500 nM compound 144, 500 nM compound 148 for 8 h. The cell lysates were separated to the soluble and membrane phase. The samples were analyzed by western blotting with MLKL antibodies. GAPDH and Cox4 were used as controls for the soluble and membrane phases, respectively. (Fig. 4B) . Compounds 144 and 148 significantly decreased MLKL levels in the membrane phase, demonstrating that these MLKL inhibitors block the translocation of MLKL to the cell membrane.
Further, immunofluorescence staining in HT-29 cells were performed using an anti-pMLKL antibody. HT-29 cells were treated as indicated for 8 h. The cellular localization of p-MLKL (green) was monitored by immunofluorescence (scale bars, 10 μm) . After TSZ induction, large, bright fluorescent dots (p-MLKL) were present in the plasma membrane (Fig. 4C) . RIPA-56 completely blocked MLKL phosphorylation, and no p-MLKL dots were observed. In contrast, much smaller p-MLKL dots were dispersed in the cytoplasm of cells treated with compound 148. The results demonstrate that, compared with TC13172, compounds 144 and 148 have a much weaker inhibitory effect on MLKL oligomerization but significantly inhibit MLKL membrane translocation, indicating that they have a different action mechanism to MLKL (Fig. 4D) .
Claims (22)
- A compound of Formula (I) , or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof,wherein,U 1 and U 3 are each independently CH 2 or C=O;U 2 and U 4 are each independently CH or N;L 1 is -CH 2-or -NR L1-, wherein R L1 is hydrogen or C 1-6 alkyl;L 2 and L 3 are each independently selected from a bond, - (CH 2) m1-, - (CH 2) m1C (=O) -, - (CH 2) m1CH=CH-, - (CH 2) m1C≡C-or -NH (CH 2) m1C≡C-, wherein m1 is an integer selected from 0 to 3;R 1 is -Y 1-R 5;Y 1 is selected from -C 1-6 alkyl-, -C (=O) -, -S (=O) 2-, -C (=O) C 1-10 alkyl-, -C (=O) C 1-6 alkoxy-, -C (=O) CR a=CHR b, -C (=O) C≡CR b, -S (=O) 2CR a=CHR b-or -C (=O) (CH 2-O-CH 2) m2-, wherein m2 is an integer selected from 0 to 3;R 5 is selected from hydrogen, halogen, cyano, -NR aR b, -CHR cR d, C 3-6 cycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R 51;R2 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, -S-C1-6 alkyl, -NRaRb, or hydroxyl substituted or unsubstituted C5-8 monocyclic aryl;R 3 is selected from C 1-6 alkyl, C 1-6 alkyl cyano, C 1-6 alkyl-C 3-6 cycloalkyl or -NHC (=O) CR a=CHR b;or, L 1, L 2, R 1, R 2 form together a C 3-6 heterocycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;Ring A and Ring B are each independently C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;Ring C and Ring D are each independently selected from C 3-6 cycloalkyl, C 3-6 hetercycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl;Y 2 is selected form a bond, -CH 2-, -NH-, -OCH 2-, -CH 2O-, -NHCH 2-, -NHC (=O) -or -C (=O) NH-;R 41, R 42 and R 43 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, oxo, acyl, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, -NR aR b, C 1-6 alkyl-OH, -OC (=O) -C 1-6 alkyl, -OC (=O) CR a=CHR b, -C 1-6 alkoxy-OH, -C (=O) -C 1-6 alkyl, -C (=O) -C 1-6 alkoxy, -C (=O) NH-C 1-6 alkyl, -NHC (=O) -C 1-6 alkoxy, -NHC (=O) CR a=CHR b, -NR aC (=O) CR a=CHR b, -CH 2C (=O) -C 1-6 alkoxy, -C 1-6 alkyl-C (=O) -C 1-6 alkyl or -C 1-6 alkyl-C (=O) -C 1-6 alkoxy;R 51 is selected from halogen, cyano, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy or C 5-8 monocyclic aryl;R a and R b are each independently hydrogen or C 1-6 alkyl;R c and R d are each independently C 5-8 monocyclic aryl.
- The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein U 1 and U 3 are C=O, U 2 and U 4 are N; or,U 1 and U 3 are CH 2, U 2 and U 4 are CH; or,U 1 is C=O, U 3 is CH 2, U 2 and U 4 are CH.
- The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein L 1 is selected from -NH 2, -CH 2-, -NH-or -N-C 1-3 alkyl-;preferably, L 1 is selected from -NH 2, -CH 2-, -NH-or -N (CH 3) -;preferably, L 1 is selected from -NH-.
- The compound according to any one of claim 1-3, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein L 3 is selected from a bond, -CH 2C≡C-, -CH 2-or -CH 2CH=CH;preferably, L 3 is selected from -CH 2C≡C-.
- The compound according to any one of claim 1-4, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein R 1 is -Y 1-R 5;Y 1 is selected from -C (=O) -, -C (=O) C 1-10 alkyl-, -C (=O) C 1-6 alkoxy-, -C (=O) CR a=CHR b, -C (=O) C≡CR b, -S (=O) 2CR a=CHR b-or -C (=O) (CH 2-O-CH 2) m2-, wherein m2 is an integer selected from 0 to 3;R 5 is selected from hydrogen, halogen, C 3-6 cycloalkyl, C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl, wherein the C 5-8 aryl or 5-to 8-membered monocyclic heteroaryl are optionally substituted by one or more groups selected from R 51;R 51 is selected from halogen, cyano, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy or C 5-8 monocyclic aryl;R a and R b are each independently hydrogen or C 1-6 alkyl.
- The compound according to any one of claim 1-6, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein R 2 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy;preferably, R 2 is selected from hydrogen, chlorine, methyl or methoxy.
- The compound according to any one of claim 1-6, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein R 2 is selected from hydrogen, halogen, methyl, methoxy, ethoxy, oxo, -SCH 3, -N (CH 3) 2 or hydroxyphenyl.
- The compound according to any one of claim 1-12, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, with regard to Ring A and Ring D are each independently selected from phenyl or pyridyl;preferably, Y 2 is selected from a bound, -NHCH 2-, -NHC (=O) -, -CH 2-, -C (=O) NH-, -NH-, -OCH 2-or CH 2O-.preferably, Y 2 is -NHC (=O) -or -CH 2-.
- The compound according to any one of claim 1-13, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein R 41, R 42 and R 43 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, oxo, acyl, halogen substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, -NR aR b, C 1-6 alkyl-OH, -OC (=O) -C 1-6 alkyl, -OC (=O) CH=CH 2, -C 1-6 alkoxy-OH, -C (=O) -C 1-6 alkyl, -C (=O) -C 1-6 alkoxy, -C (=O) NH-C 1-6 alkyl, -NHC (=O) -C 1-6 alkoxy, -NHC (=O) CH=CH 2, -NR aC (=O) CH=CH 2, -CH 2C (=O) -C 1-6 alkoxy, -C 1-6 alkyl-C (=O) -C 1-6 alkyl or -C 1-6 alkyl-C (=O) -C 1-6 alkoxy;R a and R b are each independently hydrogen or C 1-6 alkyl;preferably, R 41, R 42 and R 43 are each independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxyl, methyl, ethyl, methoxy, CF 3, -CH 2OH, -NHC (=O) CH 3, -C (=O) CH 3, -C (=O) OCH 3 or -CH 2CH 2C (=O) OCH 3.
- The compound according to any one of claim 1-15, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, wherein the compound of Formula (I) is a compound of Formula (III) :preferably, the compound of Formula (III) is a compound of Formula (IIIa) ) , a compound of Formula (IIIb) or a compound of Formula (IIIc) :preferably, the compound of Formula (III) is a compound of Formula (IIIa’) , a compound of Formula (IIIb’) or a compound of Formula (IIIc’) :preferably, the compound of Formula (III) is a compound of Formula (IIIa”) or a compound of Formula (IIIb”) :wherein R 1, R 2, R 3 and R 4 are as defined in Formula (I) .
- A pharmaceutical composition, comprising the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof and pharmaceutically acceptable carrier.
- Use of the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof or the pharmaceutical composition according to claim 19 in preparing a drug for preventing and/or treating an MLKL-mediated disorder, disease or condition;preferably, the MLKL-mediated disorder, disease or condition are selected from tissue damage or pro-inflammatory diseases;preferably, the MLKL-mediated disorder, disease or condition are selected from chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease, acute pancreatitis, multiple sclerosis, atherosclerosis, allergic colitis, neurodegenerative diseases, ischemia-reperfusion damage, diabetic neuropathy, cancer, acute kidney injury, liver injury, age-related macular degeneration, retinitis pigmentosa, Gaucher’s disease, heatstrock and inflammation systemic inflammatory response syndromeor psoriasis.
- Use of the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or the pharmaceutical composition according to claim 19 in preparing MLKL inhibitors.
- A method to treat a subject having an MLKL disorder, which comprises administering to the subject a compound of any of claims 1-18, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, or a pharmaceutical composition of claim 19.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005021548A2 (en) * | 2003-08-25 | 2005-03-10 | Adenosine Therapeutics, Llc | Substituted 8-heteroaryl xanthines |
WO2018157800A1 (en) * | 2017-02-28 | 2018-09-07 | National Institute Of Biological Sciences, Beijing | Mlkl inhibitors |
WO2018192416A1 (en) * | 2017-04-17 | 2018-10-25 | National Institute Of Biological Sciences, Beijing | Treating Male Senescence |
US20190381052A1 (en) * | 2017-02-28 | 2019-12-19 | National Institute Of Biological Sciences, Beijing | MLKL Inhibitors |
WO2019242576A1 (en) * | 2018-06-19 | 2019-12-26 | National Institute Of Biological Sciences, Beijing | Treating demyelinating disease |
WO2021031893A1 (en) * | 2019-08-21 | 2021-02-25 | National Institute Of Biological Sciences, Beijing | Prostatitis treatment |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2005021548A2 (en) * | 2003-08-25 | 2005-03-10 | Adenosine Therapeutics, Llc | Substituted 8-heteroaryl xanthines |
WO2018157800A1 (en) * | 2017-02-28 | 2018-09-07 | National Institute Of Biological Sciences, Beijing | Mlkl inhibitors |
CN110573509A (en) * | 2017-02-28 | 2019-12-13 | 北京生命科学研究所 | MLKL inhibitors |
US20190381052A1 (en) * | 2017-02-28 | 2019-12-19 | National Institute Of Biological Sciences, Beijing | MLKL Inhibitors |
WO2018192416A1 (en) * | 2017-04-17 | 2018-10-25 | National Institute Of Biological Sciences, Beijing | Treating Male Senescence |
WO2019242576A1 (en) * | 2018-06-19 | 2019-12-26 | National Institute Of Biological Sciences, Beijing | Treating demyelinating disease |
WO2021031893A1 (en) * | 2019-08-21 | 2021-02-25 | National Institute Of Biological Sciences, Beijing | Prostatitis treatment |
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