CN116867783A - 吡啶衍生物及其在医药上的应用 - Google Patents
吡啶衍生物及其在医药上的应用 Download PDFInfo
- Publication number
- CN116867783A CN116867783A CN202280015677.5A CN202280015677A CN116867783A CN 116867783 A CN116867783 A CN 116867783A CN 202280015677 A CN202280015677 A CN 202280015677A CN 116867783 A CN116867783 A CN 116867783A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- methyl
- piperazin
- picolinamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title abstract description 8
- 150000003222 pyridines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- -1 oxacyclopentyl Chemical group 0.000 claims description 175
- 125000000217 alkyl group Chemical group 0.000 claims description 103
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 65
- 125000003545 alkoxy group Chemical group 0.000 claims description 50
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 46
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000003566 oxetanyl group Chemical group 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 93
- 239000007787 solid Substances 0.000 description 92
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 56
- 238000010189 synthetic method Methods 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 37
- 125000000623 heterocyclic group Chemical group 0.000 description 26
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 24
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 21
- 229940125904 compound 1 Drugs 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 12
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 11
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 10
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 125000003003 spiro group Chemical group 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229940125846 compound 25 Drugs 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- KOMUTQSYZSDLNS-OAHLLOKOSA-N CC(C)(C)OC(N(CC1)CCN1C(C=CC(C(N[C@H]1COCC1)=O)=C1)=C1F)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C(C=CC(C(N[C@H]1COCC1)=O)=C1)=C1F)=O KOMUTQSYZSDLNS-OAHLLOKOSA-N 0.000 description 4
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 4
- ZBNUPHNJTXPEHX-UHFFFAOYSA-N CCC1=CC2=NC=C(CN(CC3)CCN3C3=CC=C(C(N(C4)CC4O)=O)N=C3)C=C2NC1=O Chemical compound CCC1=CC2=NC=C(CN(CC3)CCN3C3=CC=C(C(N(C4)CC4O)=O)N=C3)C=C2NC1=O ZBNUPHNJTXPEHX-UHFFFAOYSA-N 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940125810 compound 20 Drugs 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000004452 carbocyclyl group Chemical group 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 3
- 101150042537 dld1 gene Proteins 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 2
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 2
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CJLZUKCACMUYFP-GOSISDBHSA-N 2-[(5R)-4-[2-[3-(3-methylbutanoyloxy)phenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound CC(C)CC(=O)OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 CJLZUKCACMUYFP-GOSISDBHSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- ODNOCMWPHQLWOR-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C(C=C1)=C(C)N=C1C(O)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C(C=C1)=C(C)N=C1C(O)=O)=O ODNOCMWPHQLWOR-UHFFFAOYSA-N 0.000 description 2
- NALYZMPWKAFEPP-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C(C=CC(C(O)=O)=N1)=C1Cl)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C(C=CC(C(O)=O)=N1)=C1Cl)=O NALYZMPWKAFEPP-UHFFFAOYSA-N 0.000 description 2
- UIFRZKJSGQCAKE-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N(C2)CC2O)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N(C2)CC2O)=O)N=C1)=O UIFRZKJSGQCAKE-UHFFFAOYSA-N 0.000 description 2
- MRPNLLCKSACIDP-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2(C)COCC2)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2(C)COCC2)=O)N=C1)=O MRPNLLCKSACIDP-UHFFFAOYSA-N 0.000 description 2
- OTLCYXKHHSGHFN-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2(C)COCC2)=O)N=C1C)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2(C)COCC2)=O)N=C1C)=O OTLCYXKHHSGHFN-UHFFFAOYSA-N 0.000 description 2
- NOHGCDVRPSHJTH-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2CCOCC2)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2CCOCC2)=O)N=C1)=O NOHGCDVRPSHJTH-UHFFFAOYSA-N 0.000 description 2
- GIGXAUGUHYXOSW-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCC(C)(C)O)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCC(C)(C)O)=O)N=C1)=O GIGXAUGUHYXOSW-UHFFFAOYSA-N 0.000 description 2
- DMPPRDWCUSCRCL-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCCO)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCCO)=O)N=C1)=O DMPPRDWCUSCRCL-UHFFFAOYSA-N 0.000 description 2
- ADAOIRJWNJKRME-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCCOC)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NCCOC)=O)N=C1)=O ADAOIRJWNJKRME-UHFFFAOYSA-N 0.000 description 2
- AVBCGMYPLFYASY-AWEZNQCLSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N[C@@H]2COCC2)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N[C@@H]2COCC2)=O)N=C1)=O AVBCGMYPLFYASY-AWEZNQCLSA-N 0.000 description 2
- NXBHSOWZWTVWSS-UHFFFAOYSA-N CC(CNC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O)O Chemical compound CC(CNC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O)O NXBHSOWZWTVWSS-UHFFFAOYSA-N 0.000 description 2
- SZVDJEJQOCWOIE-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=C(C)N=C2C(NC2(C)COCC2)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=C(C)N=C2C(NC2(C)COCC2)=O)=C2)=C2NC1=O SZVDJEJQOCWOIE-UHFFFAOYSA-N 0.000 description 2
- MXWNHKPWHVUGDI-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=C(C)N=C2C(NC2C3C2COC3)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=C(C)N=C2C(NC2C3C2COC3)=O)=C2)=C2NC1=O MXWNHKPWHVUGDI-UHFFFAOYSA-N 0.000 description 2
- ZOFSSELLIQGNBA-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NC2C3OCCC23)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NC2C3OCCC23)=O)=C2)=C2NC1=O ZOFSSELLIQGNBA-UHFFFAOYSA-N 0.000 description 2
- ANFXMCYPGNTPKI-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NC2CCOCC2)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NC2CCOCC2)=O)=C2)=C2NC1=O ANFXMCYPGNTPKI-UHFFFAOYSA-N 0.000 description 2
- ZWHCQFAPVIBLAO-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCC(C)O)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCC(C)O)=O)=C2)=C2NC1=O ZWHCQFAPVIBLAO-UHFFFAOYSA-N 0.000 description 2
- NWRQBUCURGZFRI-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCCOC)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCCOC)=O)=C2)=C2NC1=O NWRQBUCURGZFRI-UHFFFAOYSA-N 0.000 description 2
- CVVTUMGHERTSHN-INIZCTEOSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(N[C@@H](C)CO)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(N[C@@H](C)CO)=O)=C2)=C2NC1=O CVVTUMGHERTSHN-INIZCTEOSA-N 0.000 description 2
- RNNJQZWIYGWVLZ-GOTSBHOMSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(N[C@@H](COC2)[C@H]2O)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(N[C@@H](COC2)[C@H]2O)=O)=C2)=C2NC1=O RNNJQZWIYGWVLZ-GOTSBHOMSA-N 0.000 description 2
- NUPADQGIFWZZIK-GOSISDBHSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=CC(C(N[C@H]2COCC2)=O)=N2)=C2Cl)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=CC(C(N[C@H]2COCC2)=O)=N2)=C2Cl)=C2)=C2NC1=O NUPADQGIFWZZIK-GOSISDBHSA-N 0.000 description 2
- NXBHSOWZWTVWSS-ZDUSSCGKSA-N C[C@@H](CNC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O)O Chemical compound C[C@@H](CNC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O)O NXBHSOWZWTVWSS-ZDUSSCGKSA-N 0.000 description 2
- ZLSPSSLGCARWBC-ZDUSSCGKSA-N C[C@@H](CO)NC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O Chemical compound C[C@@H](CO)NC(C(N=C1)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O)=O ZLSPSSLGCARWBC-ZDUSSCGKSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SCOKGRQGXYYMMX-UHFFFAOYSA-N OC(C1)CN1C(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound OC(C1)CN1C(C(C=C1)=NC=C1N1CCNCC1)=O SCOKGRQGXYYMMX-UHFFFAOYSA-N 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ODHIACQHCVHASC-ADIFKSSRSA-N [2H]C([2H])(C1=CC(NC(C(CC)=C2)=O)=C2N=C1)N(CC1)CCN1C(C=C1)=CN=C1C(N[C@H]1COCC1)=O Chemical compound [2H]C([2H])(C1=CC(NC(C(CC)=C2)=O)=C2N=C1)N(CC1)CCN1C(C=C1)=CN=C1C(N[C@H]1COCC1)=O ODHIACQHCVHASC-ADIFKSSRSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 125000003725 azepanyl group Chemical group 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000005883 dithianyl group Chemical group 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- IZHGDXUQVBDEBG-UHFFFAOYSA-N methyl 5-bromo-6-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C(C)=N1 IZHGDXUQVBDEBG-UHFFFAOYSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- 230000005731 poly ADP ribosylation Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- IYCKIXVQZXUKMF-UHFFFAOYSA-N tert-butyl 4-(6-methoxycarbonyl-2-methylpyridin-3-yl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(OC)=O)N=C1C)=O IYCKIXVQZXUKMF-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- MIPHRQMEIYLZFZ-SCSAIBSYSA-N (3r)-oxolan-3-amine Chemical compound N[C@@H]1CCOC1 MIPHRQMEIYLZFZ-SCSAIBSYSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- RXNPEQZHMGFNAY-GEALJGNFSA-N (5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN([C@H]4[C@@H]3C4)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl RXNPEQZHMGFNAY-GEALJGNFSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- FJZNNKJZHQFMCK-LRDDRELGSA-N 1-[(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea Chemical compound C1(=CC(=CC(=C1[C@H]1[C@@H](C(=O)NC1)NC(=O)NC1=CC=CC=C1)F)OC)F FJZNNKJZHQFMCK-LRDDRELGSA-N 0.000 description 1
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 1
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 1
- YRTFLDFDKPFNCJ-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-2-oxo-4-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCN1CCCC1 YRTFLDFDKPFNCJ-UHFFFAOYSA-N 0.000 description 1
- ZFNNBIMQDHBELV-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-cyclohexylpropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCC1CCCCC1 ZFNNBIMQDHBELV-UHFFFAOYSA-N 0.000 description 1
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CODBZFJPKJDNDT-UHFFFAOYSA-N 2-[[5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl]amino]-9-(trifluoromethyl)-5,7-dihydropyrimido[5,4-d][1]benzazepine-6-thione Chemical compound CN(C)CCCC1=CN=C(C)C(NC=2N=C3C4=CC=C(C=C4NC(=S)CC3=CN=2)C(F)(F)F)=C1 CODBZFJPKJDNDT-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 1
- HCLQARMRCPEALF-DNQXCXABSA-N 3-[[(2r)-2-[(1r)-2-[[1-(1-benzothiophen-2-yl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]pyrrolidin-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1[C@H](O)CNC(C)(CC=2SC3=CC=CC=C3C=2)C)CCN1CC1=CC=CC(C#N)=C1 HCLQARMRCPEALF-DNQXCXABSA-N 0.000 description 1
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 1
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 1
- TWJHRMWXOKRJFQ-UHFFFAOYSA-N 5-bromo-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide Chemical compound CC(C)(O)CNC(=O)C1=CC=C(Br)C=N1 TWJHRMWXOKRJFQ-UHFFFAOYSA-N 0.000 description 1
- HLYSKRZBSSQQBG-LURJTMIESA-N 5-bromo-N-[(2S)-1-hydroxypropan-2-yl]pyridine-2-carboxamide Chemical compound OC[C@H](C)NC(=O)C1=CC=C(Br)C=N1 HLYSKRZBSSQQBG-LURJTMIESA-N 0.000 description 1
- FFWMNAFOKQYOPG-UHFFFAOYSA-N 5-bromo-n-(2-hydroxyethyl)pyridine-2-carboxamide Chemical compound OCCNC(=O)C1=CC=C(Br)C=N1 FFWMNAFOKQYOPG-UHFFFAOYSA-N 0.000 description 1
- RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 description 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- IICHXTUYKXHOCR-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2C3C2COC3)=O)N=C1C)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2C3C2COC3)=O)N=C1C)=O IICHXTUYKXHOCR-UHFFFAOYSA-N 0.000 description 1
- IKESBNTYCMRXSB-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2C3OCCC23)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(NC2C3OCCC23)=O)N=C1)=O IKESBNTYCMRXSB-UHFFFAOYSA-N 0.000 description 1
- CSDISNCZMBUVPC-HOTGVXAUSA-N CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N[C@@H](COC2)[C@H]2O)=O)N=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C1=CC=C(C(N[C@@H](COC2)[C@H]2O)=O)N=C1)=O CSDISNCZMBUVPC-HOTGVXAUSA-N 0.000 description 1
- AOYZSTIINJWOPT-UHFFFAOYSA-N CC(C)(CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O Chemical compound CC(C)(CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O AOYZSTIINJWOPT-UHFFFAOYSA-N 0.000 description 1
- AZAQJJWSWNZKNN-UHFFFAOYSA-N CC(CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O Chemical compound CC(CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O AZAQJJWSWNZKNN-UHFFFAOYSA-N 0.000 description 1
- WUFDHBACGFBXGG-UHFFFAOYSA-N CC(N=C(C=C1)C(NC2C3C2COC3)=O)=C1N1CCNCC1 Chemical compound CC(N=C(C=C1)C(NC2C3C2COC3)=O)=C1N1CCNCC1 WUFDHBACGFBXGG-UHFFFAOYSA-N 0.000 description 1
- TYDVDGKICDFKSZ-UHFFFAOYSA-N CC1(COCC1)NC(C(C=C1)=NC(C)=C1N1CCNCC1)=O Chemical compound CC1(COCC1)NC(C(C=C1)=NC(C)=C1N1CCNCC1)=O TYDVDGKICDFKSZ-UHFFFAOYSA-N 0.000 description 1
- VQHAOHQCHQXUAO-UHFFFAOYSA-N CC1(COCC1)NC(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound CC1(COCC1)NC(C(C=C1)=NC=C1N1CCNCC1)=O VQHAOHQCHQXUAO-UHFFFAOYSA-N 0.000 description 1
- XQMZQELUQYLDNQ-UHFFFAOYSA-N CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCCO)=O)=C2)=C2NC1=O Chemical compound CCC1=CC(N=CC(CN(CC2)CCN2C(C=C2)=CN=C2C(NCCO)=O)=C2)=C2NC1=O XQMZQELUQYLDNQ-UHFFFAOYSA-N 0.000 description 1
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 1
- IZNYQRAGVQHKPU-UHFFFAOYSA-N COCCNC(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound COCCNC(C(C=C1)=NC=C1N1CCNCC1)=O IZNYQRAGVQHKPU-UHFFFAOYSA-N 0.000 description 1
- AZAQJJWSWNZKNN-JTQLQIEISA-N C[C@@H](CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O Chemical compound C[C@@H](CNC(C(C=C1)=NC=C1N1CCNCC1)=O)O AZAQJJWSWNZKNN-JTQLQIEISA-N 0.000 description 1
- GFDGJCCQDSBCNS-JTQLQIEISA-N C[C@@H](CO)NC(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound C[C@@H](CO)NC(C(C=C1)=NC=C1N1CCNCC1)=O GFDGJCCQDSBCNS-JTQLQIEISA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 101100407084 Caenorhabditis elegans parp-2 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- WHUOGYRCECNTGK-LBPRGKRZSA-N O=C(C(C=C1)=CC(F)=C1N1CCNCC1)N[C@@H]1COCC1 Chemical compound O=C(C(C=C1)=CC(F)=C1N1CCNCC1)N[C@@H]1COCC1 WHUOGYRCECNTGK-LBPRGKRZSA-N 0.000 description 1
- WHUOGYRCECNTGK-GFCCVEGCSA-N O=C(C(C=C1)=CC(F)=C1N1CCNCC1)N[C@H]1COCC1 Chemical compound O=C(C(C=C1)=CC(F)=C1N1CCNCC1)N[C@H]1COCC1 WHUOGYRCECNTGK-GFCCVEGCSA-N 0.000 description 1
- WBUTVTPUVUGXQU-SNVBAGLBSA-N O=C(C(C=C1)=NC(Cl)=C1N1CCNCC1)N[C@H]1COCC1 Chemical compound O=C(C(C=C1)=NC(Cl)=C1N1CCNCC1)N[C@H]1COCC1 WBUTVTPUVUGXQU-SNVBAGLBSA-N 0.000 description 1
- VILNUXIGSLKRSY-UHFFFAOYSA-N O=C(C(C=C1)=NC=C1Br)NC1C2OCCC12 Chemical compound O=C(C(C=C1)=NC=C1Br)NC1C2OCCC12 VILNUXIGSLKRSY-UHFFFAOYSA-N 0.000 description 1
- ASGPKRLDAFMFEC-QMMMGPOBSA-N O=C(C(C=C1)=NC=C1Br)N[C@@H]1COCC1 Chemical compound O=C(C(C=C1)=NC=C1Br)N[C@@H]1COCC1 ASGPKRLDAFMFEC-QMMMGPOBSA-N 0.000 description 1
- MRXGNMZZIBNBGZ-UHFFFAOYSA-N O=C(C(C=C1)=NC=C1N1CCNCC1)NC1C2OCCC12 Chemical compound O=C(C(C=C1)=NC=C1N1CCNCC1)NC1C2OCCC12 MRXGNMZZIBNBGZ-UHFFFAOYSA-N 0.000 description 1
- OHVFHSNYSBYUQS-UHFFFAOYSA-N O=C(C(C=C1)=NC=C1N1CCNCC1)NC1CCCCC1 Chemical compound O=C(C(C=C1)=NC=C1N1CCNCC1)NC1CCCCC1 OHVFHSNYSBYUQS-UHFFFAOYSA-N 0.000 description 1
- DEWTZVKUKNZKSA-UHFFFAOYSA-N OCCNC(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound OCCNC(C(C=C1)=NC=C1N1CCNCC1)=O DEWTZVKUKNZKSA-UHFFFAOYSA-N 0.000 description 1
- DZEXJMLKUWMQPW-IUCAKERBSA-N O[C@@H](COC1)[C@H]1NC(C(C=C1)=NC=C1Br)=O Chemical compound O[C@@H](COC1)[C@H]1NC(C(C=C1)=NC=C1Br)=O DZEXJMLKUWMQPW-IUCAKERBSA-N 0.000 description 1
- WXGOAKPEFLMWEM-STQMWFEESA-N O[C@@H](COC1)[C@H]1NC(C(C=C1)=NC=C1N1CCNCC1)=O Chemical compound O[C@@H](COC1)[C@H]1NC(C(C=C1)=NC=C1N1CCNCC1)=O WXGOAKPEFLMWEM-STQMWFEESA-N 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Chemical class 0.000 description 1
- KZVWEOXAPZXAFB-BQFCYCMXSA-N Temocaprilat Chemical compound C([C@H](N[C@H]1CS[C@@H](CN(C1=O)CC(=O)O)C=1SC=CC=1)C(O)=O)CC1=CC=CC=C1 KZVWEOXAPZXAFB-BQFCYCMXSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 1
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 1
- LXECYAKMMDYOIC-BFWBPSQCSA-N [2H]C([2H])(C1=CN=C(C=C(CC)C(N2)=O)C2=C1)Br Chemical compound [2H]C([2H])(C1=CN=C(C=C(CC)C(N2)=O)C2=C1)Br LXECYAKMMDYOIC-BFWBPSQCSA-N 0.000 description 1
- UOIXDDFYALJITC-NCYHJHSESA-N [2H]C([2H])(C1=CN=C(C=C(CC)C(N2)=O)C2=C1)O Chemical compound [2H]C([2H])(C1=CN=C(C=C(CC)C(N2)=O)C2=C1)O UOIXDDFYALJITC-NCYHJHSESA-N 0.000 description 1
- IZTDWPKQBPEJHU-FIBGUPNXSA-N [2H]C([2H])([2H])C(N=C(C=C1)C(OC)=O)=C1F Chemical compound [2H]C([2H])([2H])C(N=C(C=C1)C(OC)=O)=C1F IZTDWPKQBPEJHU-FIBGUPNXSA-N 0.000 description 1
- IYCKIXVQZXUKMF-FIBGUPNXSA-N [2H]C([2H])([2H])C1=NC(C(OC)=O)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O Chemical compound [2H]C([2H])([2H])C1=NC(C(OC)=O)=CC=C1N(CC1)CCN1C(OC(C)(C)C)=O IYCKIXVQZXUKMF-FIBGUPNXSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- AJRQIXBBIDPNGK-BVSLBCMMSA-N benzyl n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(=O)OCC1=CC=CC=C1 AJRQIXBBIDPNGK-BVSLBCMMSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Chemical class 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- YKEGUYTXACKXKS-IRXDYDNUSA-N tert-butyl (1s,5s)-3-[5-methyl-6-(2-methylpyridin-3-yl)oxypyrimidin-4-yl]oxy-8-azabicyclo[3.2.1]octane-8-carboxylate Chemical compound CC1=NC=CC=C1OC1=NC=NC(OC2C[C@@H]3CC[C@H](N3C(=O)OC(C)(C)C)C2)=C1C YKEGUYTXACKXKS-IRXDYDNUSA-N 0.000 description 1
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/499—Spiro-condensed pyrazines or piperazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
式(I)的化合物及其在医药上的应用,该化合物可用于治疗肿瘤
Description
本申请涉及吡啶衍生物及其在医药上的应用。
PARP(ploy(ADP-ribose)polymerases)是一类聚ADP-核糖聚合酶,催化多种蛋白聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation),该过程在DNA损伤修复、转录调控、染色质重组和重塑等许多细胞过程中发挥重要作用。目前,虽然有多个PARP1/PARP2抑制剂成功上市,但在临床上无论单独用药还是联用用药,仍然普遍存在血液、胃肠道等副作用,导致临床应用受到限制。因此,开发更安全有效的PARP抑制剂依然是临床亟需解决的问题。一系列研究表明,与PARP1/PARP2抑制剂相比,高选择性PARP1抑制剂具有更好的疗效和更低的毒性,有望减少目前临床上PARP类药物的潜在风险,拓宽临床应用范围,提高患者的生活质量。
发明内容
本申请的目的之一是提供吡啶衍生物或者其药物可接受的盐或立体异构体以及包含上述化合物的药物组合物,以及其在医药上的应用。
本申请的一个或多个实施方式提供式(I)的化合物或者其药物可接受的盐或立体异构体:
其中
R
1为C
1-6烷基;
L为-NH-、-CO-或-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地为H或C
1-6烷基,所述C
1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代;
R
3为H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或C
3-8杂环烷基;所述C
3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或C
3-8杂环烷基任选地被1个或多个选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或C
3-8杂环烷基的取代基取代;
R
2为C
1-4烷基、C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或C
3-8杂环烷基;所述C
3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基和C
3-8杂环烷基的取代基取代;当R
2为C
1-4烷基时,所述C
1-4烷基被1个或多个选自羟基和C
1-6烷氧基的取代基取代;
n为1或2;
m为0、1、2或3。
在一个或多个实施方式中,所述式(I)的化合物被1个或多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。
在一个或多个实施方式中,所述C
3-8杂环烷基包含1、2、3或4个选自N、O和S的杂原子。
在一个或多个实施方式中,所述化合物具有式(II)的结构:
其中
R
1为C
1-6烷基;
L为-NH-、-CO-或-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地为H或C
1-6烷基,所述C
1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代;
R
2为C
1-4烷基、C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或C
3-8杂环烷基;所述C
3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基和C
3-8杂环烷基的取代基取代;当R
2为C
1-4烷基时,所述C
1-4烷基被1个或多个选自羟基和C
1-6烷氧基的取代基取代;
n为1或2。
在一个或多个实施方式中,所述式(II)的化合物被1个或者多个氘取代。
在一个或多个实施方式中,所述式(I)的化合物被1个或多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。
在一个或多个实施方式中,所述R
1为乙基。
在一个或多个实施方式中,L为-CH
2-或-CD
2-。
在一个或多个实施方式中,R
3为H、-CH
3、-CD
3、-OCH
3或-Cl。
在一个或多个实施方式中,R
2为环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基;所述环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基任选地被一个或多个选自甲基、甲氧基和羟基的取代基取代。
在一个或多个实施方式中,所述化合物为:
在一个或多个实施方式中,上述化合物被1个或者多个(例如1、2、3、4、5、6、7、8、9或10个)氘取代。
在一个或多个实施方式中,卤素为F、Cl或Br。
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含:
(1)本申请的上述化合物或者其药物可接受的盐或立体异构体;
(2)任选的一种或多种其他活性成分;以及
(3)药物可接受的载体和/或赋形剂。
本申请的一个或多个实施方式提供通式(I’)所示的化合物或者其立体异构体:
其中:
R
1选自C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
A为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子;
R
2选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子;所述的C
1-6烷基、C
1-6烷氧基、C
3- 8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
n为1或者2。
本申请的一个或多个实施方式提供通式(I”)所示的化合物或者其立体异构体:
其中:
R
1选自H、卤素、C
2-6烯基或者C
2-6炔基,所述的C
2-6烯基或者C
2-6炔基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
A为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子;
R
2选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子,所述的C
1-6烷基、C
1-6烷氧基、C
3- 8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
n为1或者2。
本申请的一个或多个实施方式提供通式(I”’)所示的化合物或者其立体异构体:
其中:
R
1选自C
1-6烷基;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
A为7至12元杂环,所述的7至12元杂环选自7至12元单环、7至12元螺环、7至12元并环或者7至12元桥环,所述的7至12元杂环可以包含1至4个选自N、O或S的杂原子;
R
2选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子,所述的C
1-6烷基、C
1-6烷氧基、C
3- 8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
n为1或者2。
本申请的一个或多个实施方式提供通式(II’)所示的化合物或者其立体异构体:
其中:
R
1选自C
1-6烷基;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
X
1、X
2各自独立地选自CR
X或者N;
R
X选自H、羟基、氰基或者C
1-6烷基;
当X
1、X
2均为N时,R
a选自羟基、氰基、=O或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;
当X
1、X
2有一个为CR
X时,R
a选自H、羟基、氰基、=O或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;
R
2选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子,所述的C
1-6烷基、C
1-6烷氧基、C
3- 8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
m为1、2或者3;
n为1或者2。
本申请的一个或多个实施方式提供通式(III’)所示的化合物或者其立体异构体:
其中:
R
1选自C
1-6烷基;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
R
3选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基;所述的C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
R
2选自C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子;所述的C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
n为1或者2。
m为0、1、2或者3
本申请的一个或多个实施方式提供通式(III”)所示的化合物或者其立体异构体:
其中:
R
1选自C
1-6烷基;
L选自-NH-、-CO-或者-(CR
L1R
L2)
n-;
R
L1、R
L2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
R
2选自C
5-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述的C
3-8杂环烷基可以包含1至4个选自N、O或S的杂原子;所述的C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
n为1或者2。
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物在制备抗肿瘤或抗癌药物中的用途。
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物,其用作药物。
本申请的一个或多个实施方式提供本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物,其用于治疗/预防癌症的方法。
本申请的一个或多个实施方式提供治疗/预防肿瘤或癌症的方法,其包括将本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物用于有此需要的对象。
本申请的一个或多个实施方式提供抑制PARP1和/或PARP2的方法,其包括将本申请的上述化合物或者其药物可接受的盐或立体异构体或上述药物组合物用于有此需要的对象。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基,更优选2至8个碳原子的炔基,进一 步优选2至6个碳原子的炔基。非限制性实例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子,优选5至8元杂芳基,杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上,杂芳基可以是桥环或者螺环,非限制性实例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时,其定义与上文“芳基”的定义相同;当为非芳香环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,可以是桥环或者螺环,非限制性实例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以 任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基,其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时,可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1、2、3或4个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时,可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C
1-6烷基氨基、=O、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-NR
q4R
q5、=NR
q6、-C(=O)OC
1-6烷基、-OC(=O)C
1-6烷基、-C(=O)NR
q4R
q5、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-C(=O)OC
6-10芳基、-OC(=O)C
6-10芳基、-OC(=O)C
5-10杂芳基、-C(=O)OC
5-10杂芳基、-OC(=O)C
3-8杂环烷基、-C(=O)OC
3-8杂环烷基、-OC(=O)C
3-8环烷基、-C(=O)OC
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
2-6烯基或者-NHC(=O)C
2-6炔基的取代基所取代,且其中所述的取代基C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8杂环烷基或者-NHC(=O)C
3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、-NR
q4R
q5或者=O的取代基所取代;R
q1选自C
1-6烷基、C
1-6烷氧基或者C
6-10芳基;R
q2、R
q3选自H或者C
1-6烷基;其中,R
q4、R
q5选自H、C
1-6烷基、-NH(C=NR
q1)NR
q2R
q3、-S(=O)
2NR
q2R
q3、-C(=O)R
q1或者-C(=O)NR
q2R
q3,其中所述的C
1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、C
6-10芳基、C
5-10杂芳基、C
3-8环烷基或者C
3-8杂环烷基的取代基所取代;或者R
q4与R
q5及N原子形成一个3至8元杂环,所述杂环可以含有1个或者多个选自N、O或者S的杂原子。
卤素包括F、Cl、Br和I。
“药物可接受的盐”或者“其药物可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药物可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药物可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特 性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10
- 6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400和Bruker Avance 300核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS);
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物1
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide
第一步
4-(6-((1R,3R)-3-羟基环丁基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯1c
tert-butyl 4-(6-(((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
将5-溴-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物1a(1.2g,4.43mmol)、(S)-2-甲基哌嗪-1-羧酸叔丁酯化合物1b(823mg,4.43mmol)溶解于甲苯(15mL)中,加入醋酸钯(购自华捷明生物科技,95.6mg,0.43mmol)、1,1'-联萘-2,2'-双二苯膦(购自成都爱斯特化学技术有限公司,265.2mg,0.43mmol),将反应体系置换氮气,将反应体系置于120℃油浴锅中反应4h,加入水(20mL)淬灭反应,乙酸乙酯(3×30mL)萃取,收集有机相,旋干,柱层析分析(PE:EA=2:1),得到化合物1c(白色固体,1.3g,产率78%)。
1H NMR(400MHz,DMSO-d
6)δ8.56(d,1H),8.28(d,1H),7.82(d,1H),7.41(dd,1H),4.99(d,1H),4.48(q,1H),4.28(q,1H),3.47(t,4H),3.31(dd,4H),2.36-2.26(m,2H),2.12(ddd,2H),1.42(s,9H)。
LC-MS m/z(ESI)=377.46[M+1]。
第二步
N-((1R,3R)-3-羟基环丁基)-5-(哌嗪-1-基)吡啶酰胺1d
N-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
将化合物1c溶解于盐酸-1,4二氧六环溶液(购自安耐吉化学,4M,15mL)中,室温下搅拌反应8h,过滤反应液并收集滤饼,得到化合物1d(白色固体,1.1g,产率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1R,3R)-3-羟基环丁基)吡啶酰胺化合物1
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide
将化合物1d(35.9mg,0.13mmol)和化合物1e(36.7mg,0.13mmol)溶解于乙腈(5mL)中,加入N,N-二异丙基乙胺(购自上海麦克林生化科技有限公司,84mg,1.5mmol),70℃下反应3h,旋干反应液,粗品经柱层析分离(MeOH:DCM=1:60到1:15),得到化合物1(白色固体,36mg,产率62%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.53(d,1H),8.40(d,1H),8.27(d,1H),7.81(d,1H),7.75(s,1H),7.63(d,1H),7.39(dd,1H),5.00(d,1H),4.47(q,1H),4.28(d,1H),3.65(s,2H),3.33(s,4H),2.59-2.52(m,6H),2.30(ddd,2H),2.11(ddt,2H),1.18(t,3H)。
LC-MS m/z(ESI)=463.55[M+1]。
实施例2
(R)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯化合物2
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
第一步
(R)-5-溴-N-(四氢呋喃-3-基)吡啶酰胺2b
(R)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
将化合物2a(2g,9.9mmol)溶解在二氯甲烷(20mL)中,在冰水浴下,滴加入(R)-四氢呋喃-3-胺,HATU(3.5g,14.8mmol)三乙胺(2ml)溶液,室温下反应90分钟,反应完减压浓缩过柱纯化得到化合物2b(黄色固体,1.9g,产率80%)。
LC-MS m/z(ESI)=270.10[M+1]。
第二步
(R)-4-(6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯2c
tert-butyl(R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物2c(白色固体,2.5g,产率89%)。
1H NMR(400MHz,DMSO-d
6)δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H)。
LC-MS m/z(ESI)=377.21[M+1]。
第三步
(R)-3-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺2d
(R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1d的合成方法,得到化合物2d(白色固体,1.6g,产率83%)。
LC-MS m/z(ESI)=277.16[M+1]。
第四步
(R)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯化合物2
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
参考化合物1的合成方法,得到化合物2(白色固体,19mg,产率42%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H)。
LC-MS m/z(ESI)=463.24[M+1]。
实施例3
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基) 吡啶酰胺化合物3
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
第一步
(S)-5-溴-N-(四氢呋喃-3-基)吡啶酰胺3a
(S)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法,得到化合物3a(黄色固体,1.7g,产率77%)。
LC-MS m/z(ESI)=270.10[M+1]。
第二步
(S)-4-(6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯3b
tert-butyl(S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物3b(白色固体,1.1g,产率82%)。
1H NMR(400MHz,DMSO-d
6)δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H)。
LC-MS m/z(ESI)=377.21[M+1]。
第三步
(S)-3-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺3c
(S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1d的合成方法,得到化合物3c(白色固体,1.2g,产率82%)。
LC-MS m/z(ESI)=277.16[M+1]。
第四步
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物3
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物3(白色固体,19mg,产率42%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,2H),1.18(t,3H)。
LC-MS m/z(ESI)=463.24[M+1]。
实施例4
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)吡啶酰胺化合物4
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
第一步
4-(6-((2-甲氧基乙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯4b
tert-butyl 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物4b(白色固体,1.7g,产率67%)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
N-(2-甲氧基乙基)-5-(哌嗪-1-基)吡啶酰胺4c
N-(2-methoxyethyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物4c(白色固体,1.4g,产率89%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)吡啶酰胺化合物4
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
参考化合物1的合成方法,得到化合物4(白色固体,41mg,产率67%)。
1H NMR(400MHz,DMSO-d
6)δ11.21(s,1H),8.68(s,1H),8.62(s,1H),8.39(d,J1H),8.35(s,1H),7.89(d,1H),7.81(d,1H),7.50(s,1H),4.56(s,2H),4.10(d,2H),3.62-3.54(m,4H),3.27-3.14(m,2H),3.26(s,3H),3.14(d,2H),2.57(s,4H),1.20(d,3H)。
LC-MS m/z(ESI)=451.54[M+1]。
实施例5
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物5
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
第一步
4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯5a
tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物5a(白色固体,1.2g,产率67%)。
1H NMR(400MHz,DMSO-d
6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt,1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺5b
N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物5b(白色固体,910mg,产率96%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
6-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物5
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2- hydroxypropyl)picolinamide
参考化合物1的合成方法,得到化合物5(白色固体,60mg,产率68%)。
LC-MS m/z(ESI)=451.54[M+1]。
实施例6
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟乙基)吡啶酰胺化合物6
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide
第一步
5-溴-N-(2-羟乙基)吡啶酰胺6a
5-bromo-N-(2-hydroxyethyl)picolinamide
参考化合物2b的合成方法,得到化合物6a(黄色固体,1.7g,产率77%)。
LC-MS m/z(ESI)=244.98[M+1]。
第二步
4-(6-((2-羟乙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯6b
tert-butyl 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物6b(白色固体,1.9g,产率86%)。
1H NMR(400MHz,DMSO-d
6)δ8.30(d,1H),7.68(d,1H),7.49-7.12(m,2H),5.25(s,1H),3.12(dd,6H),2.75-2.52(m,6H),1.50(s,9H)。
LC-MS m/z(ESI)=351.20[M+1]。
第三步
N-(2-羟乙基)-5-(哌嗪-1-基)吡啶酰胺6c
N-(2-hydroxyethyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物6c(白色固体,1.2g,产率81%)
LC-MS m/z(ESI)=250.14[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟乙基)吡啶酰胺化合物6
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-
hydroxyethyl)picolinamide
将化合物1e(21.3mg,0.08mmol)、化合物6c(22.0mg,0.09mmol)、N,N-二异丙基乙胺(51.6mg,0.4mmol)溶解在乙腈(4mL)中,80℃下反应4h,反应液减压浓缩,经制备色谱得到化合物6(白色固体,16mg,产率46%)。
1H NMR(400MHz,DMSO-d
6)δ11.85(s,1H),8.49-8.31(m,2H),8.27(d,1H),7.83(d,1H),7.75(q,1H),7.62(d,1H),7.44-7.32(m,1H),4.82(t,1H),3.64(s,2H),3.49(q,2H),3.33(dd,6H),2.54(td,6H),1.17(t,3H)。
LC-MS m/z(ESI)=437.22[M+1]。
实施例7
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1s,3s)-3-羟基环丁基)吡啶酰胺化合物7
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide
第一步
4-(6-((1s,3s)-3-羟基环丁基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯7b
tert-butyl 4-(6-(((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物7b(白色固体,1.1g,产率76%)。
LC-MS m/z(ESI)=377.46[M+1]。
第二步
N-((1s,3s)-3-羟基环丁基)-5-(哌嗪-1-基)吡啶酰胺7c
N-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物7c(白色固体,0.9g,产率92%)。
LC-MS m/z(ESI)=277.16[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((1s,3s)-3-羟基环丁基)吡啶酰胺化合物7
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide
参考化合物1的合成方法,得到化合物7(白色固体,41mg,产率59%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.39(d,2H),8.27(d,1H),7.83-7.73(m,2H),7.62(s,1H),7.39(dd,1H),5.03(d,1H),3.94-3.78(m,2H),3.65(s,2H),3.34-3.31(m,4H),2.56-2.53(m,6H),2.50-2.44(m,2H),1.98-1.85(m,2H),1.18(t,3H)。
LC-MS m/z(ESI)=463.24[M+1]。
实施例8
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟基-2-甲基丙基)吡啶酰胺化合物8
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxy-2-methylpropyl)picolinamide
第一步
5-溴-N-(2-羟基-2-甲基丙基)吡啶酰胺8a
5-bromo-N-(2-hydroxy-2-methylpropyl)picolinamide
参考化合物2b的合成方法,得到化合物8a(黄色固体,1.4g,产率71%)。
LC-MS m/z(ESI)=274.13[M+1]。
第二步
4-(6-((2-羟基-2-甲基丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯8b
tert-butyl 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物8b(白色固体,1.1g,产率92%)。
LC-MS m/z(ESI)=379.47[M+1]。
第三步
N-(2-羟基-2-甲基丙基)-5-(哌嗪-1-基)吡啶酰胺8c
N-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物8c(白色固体,920mg,产率89%)
LC-MS m/z(ESI)=279.3[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-2-羟基-2-甲基丙基)吡啶酰胺化合物8
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-
hydroxy-2-methylpropyl)picolinamide
参考化合物6的合成方法,得到化合物8(白色固体,27mg,产率53%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.40(d,1H),8.31(d,1H),8.20(t,1H),7.84(d,1H),7.75(s,1H),7.63(d,1H),7.41(dd,1H),4.70(s,1H),3.65(s,2H),3.35(s,4H),3.23(d,2H),2.59-2.52(m,6H),1.18(t,3H),1.08(s,6H)。
LC-MS m/z(ESI)=465.5[M+1]。
实施例9
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物9
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide
第一步
(S)-5-溴-N-(1-羟基丙烷-2-基)吡啶酰胺9a
(S)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物2b的合成方法,得到化合物9a(黄色固体,1.3g,产率76%)。
LC-MS m/z(ESI)=259.00[M+1]。
第二步
(S)-4-(6-((1-羟基丙烷-2-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯9b
tert-butyl(S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1- carboxylate
参考化合物1c的合成方法,得到化合物9b(白色固体,1.2g,产率91%)。
LC-MS m/z(ESI)=365.21[M+1]。
第三步
(S)-N-(1-羟基丙烷-2-基)-5-(哌嗪-1-基)吡啶酰胺9c
(S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物9c(白色固体,860mg,产率88%)
LC-MS m/z(ESI)=279.3[M+1]。
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99(dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H)。
第四步
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物9
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物6的合成方法,得到化合物9(白色固体,23mg,产率54%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H)。
LC-MS m/z(ESI)=465.5[M+1]。
实施例10
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物10
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide
第一步
(R)-5-溴-N-(1-羟基丙烷-2-基)吡啶酰胺10a
(R)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物2b的合成方法,得到化合物10a(黄色固体,1.4g,产率76%)。
LC-MS m/z(ESI)=259.00[M+1]。
第二步
(R)-4-(6-((1-羟基丙烷-2-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯10b
tert-butyl(R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物10b(白色固体,1.1g,产率90%)。
LC-MS m/z(ESI)=365.21[M+1]。
第三步
(R)-N-(1-羟基丙烷-2-基)-5-(哌嗪-1-基)吡啶酰胺10c
(R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物10c(白色固体,840mg,产率83%)
LC-MS m/z(ESI)=279.3[M+1]。
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99(dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H)。
第四步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(1-羟基丙烷-2-基)吡啶酰胺化合物10
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide
参考化合物6的合成方法,得到化合物10(白色固体,27mg,产率62%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7.38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H)。
LC-MS m/z(ESI)=465.5[M+1]。
实施例11
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物11
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
第一步
(R)-4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯11b
tert-butyl(R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物11b(白色固体,1.1g,产率81%)。
1H NMR(400MHz,DMSO-d
6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt,1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
(R)-N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺11c
(R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物11c(白色固体,902mg,产率92%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物11
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
参考化合物1的合成方法,得到化合物11(白色固体,42mg,产率72%)。
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.35-8.24(m,2H),7.84(d,1H),7.75(s,1H),7.63(d,1H),7.40(dd,1H),4.85(d,1H),3.75(p,1H),3.65(s,2H),3.33(s,4H),3.32-3.27(m,1H),3.13(dt,1H),2.59-2.52(m,6H),1.18(t,3H),1.04(d,3H)。
LC-MS m/z(ESI)=451.54[M+1]。
实施例12
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物12
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
第一步
(S)-4-(6-((2-羟丙基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯12b
tert-butyl(S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物12b(白色固体,1.3g,产率84%)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
(S)-N-(2-羟丙基)-5-(哌嗪-1-基)吡啶酰胺12c
(S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物12c(白色固体,1.1g,产率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
(S)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟丙基)吡啶酰胺化合物12
(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide
参考化合物1的合成方法,得到化合物12(白色固体,37mg,产率76%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.40(d,1H),8.35-8.20(m,2H),7.84(d,1H),7.75(d,1H),7.62(d,1H),7.40(dd,1H),4.84(d,1H),3.75(ddd,1H),3.65(s,2H),3.33(d,4H),3.32-3.28(m,1H),3.13(ddd,1H),2.61-2.51(m,6H),1.18(t,3H),1.04(d,3H)。
LC-MS m/z(ESI)=451.54[M+1]。
实施例13
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢-2H-吡喃-4-基)吡啶甲酰胺化合物13
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide
第一步
4-(6-((四氢-2H-吡喃-4-基)氨基甲酰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯13b
tert-butyl 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物13b(白色固体,1.1g,产率82%)。
LC-MS m/z(ESI)=389.25[M+1]。
第二步
N-环己基-5-(哌嗪-1-基)吡啶甲酰胺13c
N-cyclohexyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物13c(白色固体,1.0g,产率91%)。
LC-MS m/z(ESI)=288.20[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢-2H-吡喃-4-基)吡啶甲酰胺化合物13
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide
参考化合物1的合成方法,得到化合物13(白色固体,32mg,产率74%)。
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.68(s,1H),8.33(s,2H),7.93-7.78(m,3H),7.48(d,1H),4.52(s,2H),4.12-3.92(m,3H),3.91-3.82(m,2H),3.63-3.56(m,2H),3.34-3.17(m,4H),3.15-3.08(m,2H),2.59-2.54(m,2H),1.75-1.58(m,4H),1.19(t,3H)。
LC-MS m/z(ESI)=477.25[M+1]。
实施例14
3-乙基-7-((4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-基)甲基)-1,5-萘啶-2(1H)-酮化合物14
3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one
第一步
4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯14b
tert-butyl 4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物14b(白色固体,1.1g,产率87%)。
1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),7.79(d,1H),7.38(dd,1H),5.66(d,1H),4.72(dd,1H),4.54–4.37(m,1H),4.30–4.11(m,2H),3.74(dd,1H),3.45(d,4H),3.31(d,4H),1.42(s,9H)。
LC-MS m/z(ESI)=363.43[M+1]。
第二步
(3-羟基氮杂环丁烷-1-基)(5-(哌嗪-1-基)吡啶-2-基)甲酮14c
(3-hydroxyazetidin-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone
参考化合物1d的合成方法,得到化合物14c(白色固体,1.1g,产率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
3-乙基-7-((4-(6-(3-羟基氮杂环丁烷-1-羰基)吡啶-3-基)哌嗪-1-基)甲基)-1,5-萘啶-2(1H)-酮化合物14
3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one
参考化合物1的合成方法,得到化合物14(白色固体,37mg,产率76%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.40(d,1H),8.27(d,1H),7.78(d,1H),7.75(d,1H),7.62(d,1H),7.36(dd,1H),5.67(d,1H),4.76–4.65(m,1H),4.46(tdd,1H),4.32–4.14(m,2H),3.81–3.68(m,1H),3.64(s,2H),3.33(d,4H),2.54(qd,6H),1.18(t,3H)。
LC-MS m/z(ESI)=449.53[M+1]。
实施例15
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N- (四氢呋喃-3-基)吡啶酰胺化合物15
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
第一步
(R)-4-(2-甲基-6-((四氢呋喃-3-基)氨基甲酰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯15b
tert-butyl(R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物15b(白色固体,1.3g,产率84%)。
LC-MS m/z(ESI)=391.23[M+1]。
第二步
(R)-6-甲基-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺15c
(R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法,得到化合物15c(白色固体,1.1mg,产率89%)。
LC-MS m/z(ESI)=291.17[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(四氢呋喃-3-基)吡啶酰胺化合物15
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物15(白色固体,26mg,产率77%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.50(s,3H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。
LC-MS m/z(ESI)=477.25[M+1]。
实施例16
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲氧基-N-(四氢呋喃-3-基)吡啶酰胺化合物16
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide
第一步
叔丁基(R)-4-(4-甲氧基-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯16b
tert-butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物16b(黄色固体,1.2g,产率79%)。
LC-MS m/z(ESI)=407.48[M+1]。
第二步
(R)-4-甲氧基-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺16c
(R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法,得到化合物16c(白色固体,920mg,产率86%)。
LC-MS m/z(ESI)=307.37[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲氧基-N-(四氢呋喃-3-基)吡啶酰胺化合物16
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物化合物1的合成方法,得到化合物化合物16(白色固体,56mg,产率76%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.40(d,1H),8.12(d,1H),7.75(s,1H),7.62(d,1H),7.55(d,1H),7.25(d,1H),4.52–4.40(m,1H),3.99(s,3H),3.86(qd,2H),3.71(td,1H),3.64(s,2H),3.60(dd,1H),3.10(s,4H),2.54(t,6H),2.17(dtd,1H),2.02–1.84(m,1H),1.18(t,3H)。
LC-MS m/z(ESI)=493.58[M+1]。
实施例17
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-(甲基-d
3)-N-(四氢呋喃-3-基)吡啶酰胺化合物17
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d
3)-N-(tetrahydrofuran-3-yl)picolinamide
第一步
5-氟-6-(甲基-d
3)吡啶甲酸甲酯17b
methyl 5-fluoro-6-(methyl-d
3)picolinate
取100mL反应瓶干燥,抽换N
2,N
2条件下加入6-溴-5-氟吡啶甲酸甲酯(17a,10mmol)、甲基硼酸-d
3(11mmol)、Pd(dppf)Cl
2(0.5mmol)、K
2CO
3(20mmol)和1,4-二氧六环(50mL),100℃搅拌反应12小时。反应完成后过滤收集滤液,旋蒸除去溶剂,柱层析分离得到化合物17b(无色油状物,产率70%)。
LC-MS m/z(ESI)=173.2[M+1]。
第二步
4-(6-(甲氧羰基)-2-(甲基-d
3)吡啶-3-基)哌嗪-1-羧酸叔丁酯17c
tert-butyl 4-(6-(methoxycarbonyl)-2-(methyl-d
3)pyridin-3-yl)piperazine-1-carboxylate
取50mL反应瓶干燥,抽换N
2,N
2条件下加入17b(5mmol)、K
2CO
3(15mmol)、哌嗪-1-羧酸叔丁酯(10mmol)和20mL DMF,120℃搅拌反应12小时。反应完成后加入100mL水,EA萃取3次,合并有机相Na
2SO
4干燥,旋蒸除去溶剂,组层析分离得到化合物17c(白色固体,产率63%)。
LC-MS m/z(ESI)=339.2[M+1]。
第三步
叔丁基(R)-4-(2-(甲基-d
3)-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯17d
tert-butyl(R)-4-(2-(methyl-d
3)-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物17c(黄色固体,1.2g,产率80%)。
LC-MS m/z(ESI)=394.2[M+1]。
第四步
(R)-6-(甲基-d
3)-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺17e
(R)-6-(methyl-d
3)-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1d的合成方法,得到化合物17e(黄色固体,1.2g,产率80%)。
LC-MS m/z(ESI)=294.2[M+1]。
第五步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-(甲基-d
3)-N-(四氢呋喃-3-基)吡啶酰胺
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d
3)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物17(黄色固体,17g,产率39%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。
LC-MS m/z(ESI)=480.3[M+1]。
实施例18
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d
2)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物18
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d
2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
第一步
3-乙基-7-(羟甲基-d
2)-1,5-萘啶-2(1H)-酮18b
3-ethyl-7-(hydroxymethyl-d
2)-1,5-naphthyridin-2(1H)-one
将化合物18a(2.7g,9mmol)溶于四氢呋喃(10mL),在冰水浴下缓慢滴加四氘锂铝的四氢呋喃溶液(购自安耐吉化学,18mL,18mmol),滴加完搅拌10min,加入乙酸乙酯(5mL),减压浓缩柱层析得到得到18b(白色固体,1.2g,产率63%)。
LC-MS m/z(ESI)=207.2[M+1]。
第二步
7-(溴甲基-d
2)-3-乙基-1,5-萘啶-2(1H)-酮18c
7-(bromomethyl-d
2)-3-ethyl-1,5-naphthyridin-2(1H)-one
将化合物18b(430mg,2mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司,2183mg,4mmol)溶于二氯甲烷(5mL),在冰水浴下加入四溴化碳(购自安耐吉化学,1.3g,4mmol)的二氯甲烷(2mL)溶液,反应0.5h,反应液减压浓缩后经柱层析得到18c(白色固体,450mg,产率80%)。
LC-MS m/z(ESI)=269.1[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d
2)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物18
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d
2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物18(白色固体,46mg,产率49%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H)。
LC-MS m/z(ESI)=465.3[M+1]。
实施例19
(R)-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基-d
2)哌嗪-1-基)-6-(甲基-d
3)-N-(四氢呋喃-3-基)吡啶酰胺化合物19
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d
2)piperazin-1-yl)-6-(methyl-d
3)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物19(白色固体,28mg,产率41%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3.70(m,1H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H)。
LC-MS m/z(ESI)=482.3[M+1]。
实施例20
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)-6-甲基吡啶酰胺化合物20
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide
第一步
5-溴-6-甲基吡啶甲酸甲酯20b
methyl 5-bromo-6-methylpicolinate
将20a(2g,9.26mmol)溶解于甲醇(20mL),然后在冰水浴下缓慢滴加二氯亚砜(20mL),滴加完将反应瓶置于油浴80℃回流2小时。反应完成后减压浓缩,用饱和碳酸钠溶液调节pH到中性,乙酸乙酯(50mL×3)萃取,合并有机相,干燥,过滤,减压浓缩得到20b(黄色固体,2g,产率94%)。
1H NMR(400MHz,DMSO-d6)δ8.20(d,1H),7.78(d,1H),3.86(s,3H),2.62(s,3H)。
LC-MS m/z(ESI)=229.90[M+1]。
第二步
4-(6-(甲氧羰基)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯20c
tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
将20b(2g,8.70mmol)、哌嗪-1-羧酸叔丁酯(1.78g,9.56mmol)、RuPhos Pd G3(364mg,0.44mmol)、碳酸铯(11g,34.8mmol)溶解于二氧六环(40mL)在110℃下回流4小时。反应完成后加入水(50mL),乙酸乙酯(50mL*3)萃取,合并有机相,干燥,过滤,减压浓缩后使用硅胶(200-300目)柱层析(DCM:EA=3-1)分离,得到20c(白色固体,2.2g,产率75%)。
LC-MS m/z(ESI)=336.20[M+1]。
第三步
5-(4-(叔丁氧羰基)哌嗪-1-基)-6-甲基吡啶甲酸20d
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid
将20c(2.2g,6.5mmol)溶解于(四氢呋喃:甲醇:水=1:1:1,20mL)中,加入氢氧化锂(0.78g,32.7mmol),在常温下过夜反应。反应完成后减压浓缩有机相,乙酸乙酯(10mL*2)萃取,收集水相用1M盐酸调节pH至2-3,搅拌30分钟,析出大量固体,过滤,收集滤饼。烘干后得到20d(黄色固体,2g,产率95%)。
LC-MS m/z(ESI)=322.20[M+1]。
第四步
4-(6-((3S,4R)-4-羟基四氢呋喃-3-基)氨甲酰)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯20e
tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法,得到化合物20e(白色固体,150mg,产率95%)。
1H NMR(400MHz,DMSO-d6)δ8.31(d,1H),7.82(d,1H),7.50(d,1H),4.25(p,1H),4.22-4.17(m,1H),3.95(ddd,2H),3.64(dd,1H),3.50-3.48(m,4H),3.13-3.07(m,2H),2.89-2.87(m,4H),2.52(s,3H),1.42(s,9H)。
LC-MS m/z(ESI)=407.20[M+1]。
第五步
N-((3S,4R)-4-羟基四氢呋喃-3-基)-6-甲基-5-(哌嗪-1-基)吡啶酰胺20f
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物20f(白色固体,110mg,产率97%)。
LC-MS m/z(ESI)=307.20[M+1]。
第六步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)-6-甲基吡啶酰胺化合物20
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide
参考化合物6的合成方法,合成分离得到化合物20(白色固体,40mg,产率46%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.41(s,1H),8.29(d,1H),7.81(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),5.34(d,1H),4.25–4.22(m,1H),4.21–4.16(m,1H), 3.94(ddd,2H),3.67(s,2H),3.63(dd,1H),3.51(dd,1H),2.96–2.93(m,4H),2.64–2.51(m,9H),1.18(t,3H)。
LC-MS m/z(ESI)=493.20[M+1]。
实施例21
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物21
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide
第一步
4-(2-甲基-6-((3-甲基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯21a
tert-butyl 4-(2-methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法,得到化合物21a(白色固体,140mg,产率90%)。
1H NMR(400MHz,DMSO-d
6)δ8.23(s,1H),7.80(d,1H),7.50(d,1H),3.96(d,1H),3.84–3.77(m,2H),3.63(d,1H),3.80–3.48(m,4H),2.88–2.86(m,4H),2.52(s,3H),2.40(dt,1H),1.95(dt,1H),1.47(s,3H),1.42(s,9H)。
LC-MS m/z(ESI)=405.20[M+1]。
第二步
6-甲基-N-(3-甲基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺21b
6-methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物21b(白色固体,100mg,产率95%)。
LC-MS m/z(ESI)=305.20[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物21
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide
参考化合物6的合成方法,合成分离得到化合物21(白色固体,35mg,产率40%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.41(s,1H),8.21(s,1H),7.79(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),3.96(d,1H),3.85–3.76(m,2H),3.67(s,2H),3.62(d,1H),2.96–2.93(m,4H),2.65–2.51(m,9H),2.43–2.35(m,1H),2.01–1.90(m,1H),1.47(s,3H),1.18(t,3H)。
LC-MS m/z(ESI)=491.30[M+1]。
实施例22
N-(3-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基吡啶酰胺化合物22
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamide
第一步
4-(6-((3-噁唑环[3.1.0]己烷-6-基)氨甲酰)-2-甲基吡啶-3-基)哌嗪-1-羧酸叔丁酯22a
tert-butyl 4-(6-((3-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
参考化合物2b的合成方法,得到化合物22a(白色固体,110mg,产率81%)。
1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),7.78(d,1H),7.49(d,1H),3.86(s,1H),3.84(s,1H),3.63(s,1H),3.62(s,1H),3.49–2.40(m,4H),2.93–2.84(m,4H),2.60–2.58(m,1H),2.52(s,3H),1.98–1.97(m,2H),1.42(s,9H)。
LC-MS m/z(ESI)=403.20[M+1]。
第二步
N-(3-氧杂环[3.1.0]己烷-6-基)-6-甲基-5-(哌嗪-1-基)吡啶酰胺22b
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物22b(白色固体,80mg,产率96%)。
LC-MS m/z(ESI)=303.20[M+1]。
第三步
N-(3-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基吡啶酰胺化合物22
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamide
参考化合物6的合成方法,合成分离得到化合物22(白色固体,30mg,产率42%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.44(d,1H),8.41(s,1H),7.78(d,1H),7.75(s,1H),7.62(s,1H),7.48(d,1H),3.85(d,2H),3.67(s,2H),3.62(d,2H),2.94–2.91(m,4H),2.61–2.53(m,7H),2.48(s,3H),1.97–1.96(m,2H),1.18(t,3H)。
LC-MS m/z(ESI)=489.20[M+1]。
实施例23
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物23
(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
第一步
5-(4-(叔丁氧羰基)哌嗪-1-基)-6-氯吡啶甲酸23b
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid
参考1c的合成方法,得到23b(白色固体,700mg,产率68%)。
LC-MS m/z(ESI)=342.1[M+1]。
第二步
叔丁基(R)-4-(2-氯-6-((四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸酯23c
tert-butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考2b的合成方法,得到23c(白色固体,340mg,产率53%)。
LC-MS m/z(ESI)=411.2[M+1]。
第三步
(R)-6-氯-5-(哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺23d
(R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考1d的合成方法,得到23d(白色固体,170mg,产率67%)。
LC-MS m/z(ESI)=311.2[M+1]。
第四步
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物23
(R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
参考化合物1的合成方法,得到化合物23(白色固体,23mg,产率55%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,2H),7.93(d,1H),7.74(s,1H),7.69–7.55(m,2H),4.45(dt,1H),3.83(ddd,2H),3.74–3.55(m,4H),3.49(t,2H),3.10(t,2H),2.65–2.54(m,6H),2.15(tq,1H),1.93(ddd,1H),1.17(t,3H)。
LC-MS m/z(ESI)=497.2[M+1]。
实施例24
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物24
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide
第一步
5-溴-N-(3-甲基四氢呋喃-3-基)吡啶酰胺24a
5-bromo-N-(3-methyltetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法,得到化合物24a(黄色固体,1.4g,产率71%)。
LC-MS m/z(ESI)=286.14[M+1]。
第二步
4-(6-((3-甲基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯24b
tert-butyl 4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物24b(白色固体,1.1g,产率92%)。
LC-MS m/z(ESI)=390.48[M+1]。
第三步
N-(3-甲基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺24c
N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物24c(白色固体,920mg,产率89%)
LC-MS m/z(ESI)=291.37[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(3-甲基四氢呋喃-3-基)吡啶酰胺化合物24
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide
参考化合物6的合成方法,得到化合物24(白色固体,27mg,产率53%)。
LC-MS m/z(ESI)=477.58[M+1]。
实施例25
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺化合物25
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide
第一步
N-(2-噁唑环[3.1.0]正己烷-6-基)-5-溴哌啶酰胺25a
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-bromopicolinamide
参考化合物2b的合成方法,得到化合物25a(黄色固体,1.1g,产率74%)。
LC-MS m/z(ESI)=284.13[M+1]。
第二步
4-(6-((2-噁唑环[3.1.0]己烷-6-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯25b
tert-butyl 4-(6-((2-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物25b(白色固体,900mg,产率91%)。
LC-MS m/z(ESI)=389.47[M+1]。
第三步
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(哌嗪-1-基)吡啶酰胺25c
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物25c(白色固体,670mg,产率81%)
LC-MS m/z(ESI)=289.35[M+1]。
第四步
N-(2-噁唑环[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺化合物25
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide
参考化合物6的合成方法,得到化合物25(白色固体,27mg,产率53%)。
LC-MS m/z(ESI)=475.57[M+1]。
实施例26
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)吡啶酰胺化合物26
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide
第一步
5-溴-N-((3S,4R)-4-羟基四氢呋喃-3-基)吡啶酰胺26a
5-bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide
参考化合物2b的合成方法,得到化合物26a(黄色固体,1.1g,产率76%)。
LC-MS m/z(ESI)=288.11[M+1]。
第二步
4-(6-((3S,4R)-4-羟基四氢呋喃-3-基)氨甲酰)吡啶-3-基)哌嗪-1-羧酸叔丁酯26b
tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
参考化合物1c的合成方法,得到化合物26b(白色固体,900mg,产率92%)。
LC-MS m/z(ESI)=393.46[M+1]。
第三步
N-((3S,4R)-4-羟基四氢呋喃-3-基)-5-(哌嗪-1-基)吡啶酰胺26c
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
参考化合物1d的合成方法,得到化合物26c(白色固体,640mg,产率89%)
LC-MS m/z(ESI)=293.46[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)吡啶酰胺化合物26
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide
参考化合物6的合成方法,得到化合物26(白色固体,46mg,产率42%)。
LC-MS m/z(ESI)=479.55[M+1]。
实施例27
(R)-5-(4-((7-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)吡啶酰胺化合物27
(R)-5-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
27a根据专利WO2021013735的中间体14的合成方法,使用三乙基2-膦酰基丙酯替代三乙基2-丁基丙烯酯制备得到,LCMS m/s=253.10[M+1]。
按照化合物1的方法,制备得到化合物27(白色固体,31mg,产率:74%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(d,1H),8.40(d,1H),7.83(d,1H),7.85-7.76(m,2H),7.32(d,1H),7.18(d,1H),4.48-4.36(m,1H),3.87-3.79(m,2H),3.75–3.63(m,3H),3.56(dd,1H),3.06(s,4H),2.58(s,4H),2.13(d,3H),2.09(d,1H),1.94–1.85(m,1H)。
LCMS m/s=449.53[M+1]。
生物评价
1.PARP1、PARP2活性抑制试验
通过PARP1化学发光分析(Chemiluminescent assay,购买自BPS Bioscience公司,货号:80551)、PARP2化学发光分析(Chemiluminescent assay,购买自BPS Bioscience公司,货号:80552)分别检测化合物对PARP1、PARP2的抑制活性。利用化学发光对结果进行定量,具体实验方案如下:
(1)使用1×组蛋白混合物(histone mixture,50μL/孔)对96孔板进行过夜包被;
(2)弃包被液;每孔加入封闭缓冲液3(Blocking buffer 3)(200μL),室温孵育90min;
(3)弃封闭液,PBST洗2遍;加25μL主混合物(含2.5μL 10×PARP buffer、2.5μL10×PARP Assay mixture、5μL活化DNA、15μL ddH2O)、5μL抑制剂(抑制剂初始浓度为10μM,按1:5倍比稀释8个浓度)、20μL酶(2ng/μL);室温孵育1小时;
(4)弃液体,PBST洗2遍;加入链霉亲和素(Streptavidin)-HRP封闭缓冲液3(Blocking buffer 3,稀释50倍)50μL;室温孵育30min;
(5)弃液体,PBST洗3遍;加入100μL ELISA ECL Substrate A/B混合(各50μL);
(6)酶标仪检测结果,利用GraphPad Prism 8进行IC
50的计算。
结果表明,本发明化合物对PARP1具有显著的抑制活性,且相对于PARP2具备良好的选择性。
2.PARP1/PARP2捕获(trapping)试验:
2.1 PARP1捕获(trapping)试验:
(1)用缓冲液制备4×PARP1(购买自BPS Bioscience公司,货号:80501)和Mab anti GST-Tb(购买自cisbio公司,货号:61GSTTLA)混合液,向384孔板(购买自Greiner公司,货号:784075)中加入该混合液4μL/孔;
(2)用缓冲液制备4×DSB DNA probe-1(购买自Generay),向384孔板中加入4μL/孔;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM,按1:5倍比稀释10个浓度),室温孵育1h;
(4)用缓冲液制备4×NAD(购买自Sigma公司,货号:10127965001),向384孔板中加入4μL/孔,室温孵育10min;
(5)结果采用TR-FRET检测,利用GraphPad 5.0拟合曲线,并进行IC50的计算。
2.2 PARP2捕获(trapping)试验:
(1)用缓冲液制备4×PARP2(购买自BPS Bioscience公司,货号:80502)和Mab anti GST-Tb(购买自cisbio公司,货号:61GSTTLA)混合液,向384孔板(购买自G reiner公司,货号:784075)中加入该混合液4μL/孔;
(2)用缓冲液制备4×PARP2probe2(购买自Generay公司),向384孔板中加入4μL/孔;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM,按1:5倍比稀释10个浓度),室温孵育45min;
(4)用缓冲液制备4×NAD(购买自Sigma公司,货号:10127965001),向384孔板中 加入4μL/孔,室温孵育10min;
(5)结果采用TR-FRET检测,利用GraphPad 5.0拟合曲线,并进行IC50的计算。
注:对照例1为J.Med.Chem(2021),64(19),14498–14512的化合物25,其按照化合物25的制备方法得到。
结果表明,本发明化合物对PARP1捕获(trapping)具有显著抑制活性,且相对于PARP2捕获(trapping)具有良好的选择性。
3.DLD1 BRCA2-/-细胞增殖抑制实验
用1640(10%FBS,1%PS)培养基培养DLD-1 BRCA2(-/-)细胞(购买自Horizon Discovery Ltd.公司),培养条件为37℃,5%CO
2。当细胞生长至对数生长期时,重悬细胞,并用1640培养基稀释至15000个/mL。使用Echo移液器向384孔白板(PerkinElmer)中每孔加入40nL待测化合物(终浓度分别为10μM、2μM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、0.00512nM);每个浓度梯度做2个重复,设置对照组1(加入0.1%DMSO)和对照组2(空白培养基)。随后384孔白板(PerkinElmer)每孔加入40μL(600个)细胞悬液(对照组2不加细胞)。
将上述384孔板置于CO
2培养箱(37℃,5%CO
2)中继续培养7天,取出384孔板,室温放置30分钟。每孔加入20μL Celltiter Glo检测液,震板机震荡2分钟,室温放置30分钟。用酶标仪(PerkinElmer;EnVision)测定化学发光值。
用GraphPad Prism 8.0进行曲线拟合并计算IC
50。酶标仪检测结果,利用GraphPad Prism 8进行IC
50的计算。
化合物编号 | DLD1 BRCA2-/-细胞IC 50(nM) |
化合物1 | 11.61 |
化合物2 | 9.84 |
化合物3 | 5.49 |
化合物4 | 5.38 |
化合物6 | 11.00 |
化合物7 | 10.98 |
结果表明,本发明化合物对DLD1 BRCA2-/-细胞增殖具有明显抑制作用。
4.MDA-MB-436细胞增殖抑制实验
用DMEM培养基(10%FBS,1%PS)培养MDA-MB-436细胞(供应商ATCC),培养条件为37℃,5%CO
2。当细胞生长至对数生长期时,用DMEM培养基重悬并稀释细胞至1500个/ml。在384孔板中以每孔40μL加入待测化合物(终浓度分别为10000nM,2000nM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM,0.00512nM);每个浓度梯度做2个重复,设置对照组1(加入0.1%DMSO)和对照组2(空白培养基)。随后向384孔板中加入40μL细胞悬液(对照组2不加细胞)。
将上述384孔板置于培养箱(37℃,5%CO
2)中连续培养7天,然后取出384孔板,在室温放置30min。每孔加入30μL Celltiter Glo assay kit检测液,用震板机震荡3min,在室温放置30min。用酶标仪(PerkinElmer;EnVision)测定化学发光值。
检测结果用GraphPad Prism 8进行曲线拟合并计算IC
50。
化合物编号 | MDA-MB-436细胞IC 50(nM) |
对照例2 | >10000 |
化合物1 | 28.95 |
化合物2 | 10.51 |
化合物3 | 16.41 |
化合物4 | 8.02 |
化合物5 | 19.07 |
化合物6 | 9.81 |
化合物7 | 18.33 |
化合物9 | 35.67 |
化合物11 | 10.68 |
化合物12 | 15.75 |
化合物13 | 37.30 |
化合物15 | 1.83 |
化合物20 | 6.86 |
化合物22 | 39.97 |
化合物23 | 44.83 |
化合物25 | 2.01 |
注:对照例2为专利WO200905337的化合物62,其按照化合物62的制备方法得到。
结果表明,本发明化合物对MDA-MB-436细胞增殖具有明显抑制作用。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (10)
- 式(I)的化合物或者其药物可接受的盐或立体异构体:其中R 1为C 1-6烷基;L为-NH-、-CO-或-(CR L1R L2) n-;R L1、R L2各自独立地为H或C 1-6烷基,所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代;R 3为H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基;所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基任选地被1个或多个选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基的取代基取代;R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基;所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 3-8杂环烷基的取代基取代;当R 2为C 1-4烷基时,所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代;n为1或2;m为0、1、2或3;任选地,所述式(I)的化合物被1个或多个氘取代。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中所述化合物具有式(II)的结构:其中R 1为C 1-6烷基;L为-NH-、-CO-或-(CR L1R L2) n-;R L1、R L2各自独立地为H或C 1-6烷基,所述C 1-6烷基任选地被1个或多个选自卤素、羟基和氰基的取代基取代;R 2为C 1-4烷基、C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基;所述C 3-8杂环烷基包含1-4个选自N、O和S的杂原子;所述C 5-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地被1个或多个选自卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基、 C 3-8环烷基和C 3-8杂环烷基的取代基取代;当R 2为C 1-4烷基时,所述C 1-4烷基被1个或多个选自羟基和C 1-6烷氧基的取代基取代;n为1或2;任选地,所述式(II)的化合物被1个或者多个氘取代。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中所述R 1为乙基。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中L为-CH 2-或-CD 2-。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中R 3为H、-CH 3、-CD 3、-OCH 3或-Cl。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中R 2为环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基;所述环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、甲基、乙基或丙基任选地被一个或多个选自甲基、甲氧基和羟基的取代基取代。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,其中所述卤素为F、Cl或Br。
- 根据权利要求1所述的化合物或者其药物可接受的盐或立体异构体,所述化合物为:所述化合物任选地被1个或者多个氘取代。
- 药物组合物,所述药物组合物包含:(1)权利要求1至8中任一项所述的化合物或者其药物可接受的盐或立体异构体;(2)任选的一种或多种其他活性成分;以及(3)药物可接受的载体和/或赋形剂。
- 权利要求1至8中任一项所述的化合物或者其药物可接受的盐或立体异构体或 权利要求9所述的药物组合物在制备抗肿瘤药物中的用途。
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110440527 | 2021-04-23 | ||
CN2021104405276 | 2021-04-23 | ||
CN202111374283 | 2021-11-19 | ||
CN2021113742832 | 2021-11-19 | ||
CN2021115436776 | 2021-12-17 | ||
CN202111543677 | 2021-12-17 | ||
CN202210034040 | 2022-01-14 | ||
CN2022100340402 | 2022-01-14 | ||
CN2022101209930 | 2022-02-10 | ||
CN202210120993 | 2022-02-10 | ||
PCT/CN2022/087966 WO2022222964A1 (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116867783A true CN116867783A (zh) | 2023-10-10 |
Family
ID=83667865
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280015678.XA Pending CN116867784A (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
CN202210420208.3A Active CN115232121B (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
CN202280015677.5A Pending CN116867783A (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280015678.XA Pending CN116867784A (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
CN202210420208.3A Active CN115232121B (zh) | 2021-04-23 | 2022-04-20 | 吡啶衍生物及其在医药上的应用 |
Country Status (3)
Country | Link |
---|---|
CN (3) | CN116867784A (zh) |
TW (2) | TWI827016B (zh) |
WO (2) | WO2022222964A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202309025A (zh) | 2021-04-19 | 2023-03-01 | 美商辛瑟拉股份有限公司 | Parp1抑制劑及其用途 |
WO2023046158A1 (zh) * | 2021-09-26 | 2023-03-30 | 张文燕 | 氮杂喹啉酮类化合物及其医药用途 |
WO2023056039A1 (en) | 2021-10-01 | 2023-04-06 | Xinthera, Inc. | Azetidine and pyrrolidine parp1 inhibitors and uses thereof |
WO2023141290A1 (en) | 2022-01-21 | 2023-07-27 | Xinthera, Inc. | Parp1 inhibitors and uses thereof |
TW202400596A (zh) | 2022-04-28 | 2024-01-01 | 美商辛瑟拉股份有限公司 | 三環parp1抑制劑及其用途 |
WO2024067691A1 (zh) * | 2022-09-30 | 2024-04-04 | 中国医药研究开发中心有限公司 | 含氮杂环类化合物及其医药用途 |
CN117946074A (zh) * | 2022-10-20 | 2024-04-30 | 上海海和药物研究开发股份有限公司 | 具有parp1抑制活性的化合物及其用途 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20060285A1 (es) * | 2004-03-30 | 2006-05-08 | Aventis Pharma Inc | Piridonas sustituidas como inhibidores de pol(adp-ribosa)-polimerasa (parp) |
US8404713B2 (en) * | 2007-10-26 | 2013-03-26 | Janssen Pharmaceutica Nv | Quinolinone derivatives as PARP inhibitors |
CN102952118B (zh) * | 2011-08-17 | 2016-03-23 | 上海迪诺医药科技有限公司 | 聚(adp-核糖)聚合酶抑制剂、制备方法及其用途 |
PE20181144A1 (es) * | 2015-08-17 | 2018-07-17 | Lupin Ltd | Derivados de heteroarilo como inhibidores de parp |
WO2017042634A2 (en) * | 2015-09-10 | 2017-03-16 | Del Mar Pharmaceuticals | Use of dianhydrogalactitol or derivatives and analogs thereof for treatment of non-small-cell lung carcinoma, glioblastoma, and ovarian carcinoma by induction of dna damage and stalling of cell cycle |
CN110272419A (zh) * | 2018-03-14 | 2019-09-24 | 上海艾力斯医药科技有限公司 | 二氢吡啶并酞嗪酮衍生物、其制备方法及应用 |
US11325906B2 (en) * | 2019-07-19 | 2022-05-10 | Astrazeneca Ab | Chemical compounds |
TW202304911A (zh) * | 2021-04-23 | 2023-02-01 | 大陸商南京明德新藥研發有限公司 | 吡啶醯胺類化合物 |
CN115677688A (zh) * | 2021-07-23 | 2023-02-03 | 南京明德新药研发有限公司 | 1,5-萘啶酮类化合物 |
-
2022
- 2022-04-20 CN CN202280015678.XA patent/CN116867784A/zh active Pending
- 2022-04-20 WO PCT/CN2022/087966 patent/WO2022222964A1/zh active Application Filing
- 2022-04-20 WO PCT/CN2022/087968 patent/WO2022222965A1/zh active Application Filing
- 2022-04-20 CN CN202210420208.3A patent/CN115232121B/zh active Active
- 2022-04-20 CN CN202280015677.5A patent/CN116867783A/zh active Pending
- 2022-04-22 TW TW111115534A patent/TWI827016B/zh active
- 2022-04-22 TW TW111115535A patent/TWI827017B/zh active
Also Published As
Publication number | Publication date |
---|---|
WO2022222964A1 (zh) | 2022-10-27 |
TWI827017B (zh) | 2023-12-21 |
WO2022222965A1 (zh) | 2022-10-27 |
TWI827016B (zh) | 2023-12-21 |
TW202300149A (zh) | 2023-01-01 |
CN116867784A (zh) | 2023-10-10 |
TW202241894A (zh) | 2022-11-01 |
CN115232121A (zh) | 2022-10-25 |
CN115232121B (zh) | 2023-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN116867783A (zh) | 吡啶衍生物及其在医药上的应用 | |
JP7373992B2 (ja) | 過剰増殖性疾患の治療のための置換ピラゾール化合物およびそれらの使用方法 | |
JP5030229B2 (ja) | プロテインキナーゼのインヒビターとして有用なピラゾロ[1,5−a]ピリミジン | |
JP5969054B2 (ja) | Smacミメチックスとしての6−アルキニルピリジン | |
CN116710433A (zh) | 一种选择性parp1抑制剂及其应用 | |
WO2012080284A2 (en) | Substituted 6,6-fused nitrogenous heterocyclic compounds and uses thereof | |
CN114555593A (zh) | 作为parg抑制剂的4-取代的吲哚和吲唑磺酰胺衍生物 | |
JP5863058B2 (ja) | 1H−イミダゾ[4,5−c]キノリン | |
CN101687852A (zh) | 可用作激酶抑制剂的噻唑类和吡唑类化合物 | |
EP2991977A1 (en) | C-linked heterocycloalkyl substituted pyrimidines and their uses | |
CN101679378A (zh) | 用作激酶抑制剂的噻唑和吡唑 | |
EP2991978A1 (en) | Biheteroaryl compounds and uses thereof | |
AU2016261031A1 (en) | Substituted quinoxaline derivatives | |
JP2008519059A5 (zh) | ||
TW201609731A (zh) | 三唑并吡 | |
CA3134261A1 (en) | 6-(isooxazolidin-2-yl)-n-phenylpyrimidin-4-amine derivatives as inhibitors of epidermal growth factor receptors | |
CN101679387A (zh) | 可用作激酶抑制剂的氨基嘧啶类化合物 | |
CN118055933A (zh) | 选择性parp1抑制剂及其应用 | |
CA3117319A1 (en) | Fused bicyclic heterocycles as thereapeutic agents | |
CN115960109B (zh) | 稠环类shp2磷酸酶抑制剂的制备及其应用 | |
WO2024104244A1 (zh) | 草酸酰胺化合物、包含其的药物组合物及其制备方法和用途 | |
CN116693501A (zh) | 一种喹唑啉酮衍生物及其在医药上的应用 | |
CN117126140A (zh) | 具有蛋白激酶抑制活性的杂环化合物、包含其的药物组合物及其制备方法和用途 | |
CN114369083A (zh) | 杂环类化合物、包含其的药物组合物、其制备方法及其用途 | |
CN118047793A (zh) | 一种吡啶衍生物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |