TWI827017B - 吡啶衍生物及其在醫藥上的應用 - Google Patents
吡啶衍生物及其在醫藥上的應用 Download PDFInfo
- Publication number
- TWI827017B TWI827017B TW111115535A TW111115535A TWI827017B TW I827017 B TWI827017 B TW I827017B TW 111115535 A TW111115535 A TW 111115535A TW 111115535 A TW111115535 A TW 111115535A TW I827017 B TWI827017 B TW I827017B
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- Taiwan
- Prior art keywords
- compound
- methyl
- alkyl
- ethyl
- naphthyridin
- Prior art date
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- 239000003814 drug Substances 0.000 title abstract description 7
- 150000003222 pyridines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 52
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- -1 -CD3 Chemical group 0.000 description 99
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 93
- 239000007787 solid Substances 0.000 description 92
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 56
- 238000001308 synthesis method Methods 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 35
- 238000010189 synthetic method Methods 0.000 description 32
- 125000000623 heterocyclic group Chemical group 0.000 description 29
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- 125000004093 cyano group Chemical group *C#N 0.000 description 25
- 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
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 23
- 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
- 238000006243 chemical reaction Methods 0.000 description 18
- 229940125904 compound 1 Drugs 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 13
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 12
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 12
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000003756 stirring Methods 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
- 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 3
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- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-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
- 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 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
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- 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
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- 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
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
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Classifications
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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Abstract
本申請式(I)的化合物及其在醫藥上的應用,該化合物可用於治療腫瘤
Description
本申請涉及吡啶衍生物及其在醫藥上的應用。
PARP(ploy(ADP-ribose)polymerases)是一類聚ADP-核糖聚合酶,催化多種蛋白聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation),該過程在DNA損傷修復、轉錄調控、染色質重組和重塑等許多細胞過程中發揮重要作用。目前,雖然有多個PARP1/PARP2抑制劑成功上市,但在臨床上無論單獨用藥還是聯用用藥,仍然普遍存在血液、胃腸道等副作用,導致臨床應用受到限制。因此,開發更安全有效的PARP抑制劑依然是臨床亟需解決的問題。一系列研究表明,與PARP1/PARP2抑制劑相比,高選擇性PARP1抑制劑具有更好的療效和更低的毒性,有望減少目前臨床上PARP類藥物的潛在風險,拓寬臨床應用範圍,提高患者的生活品質。
本申請的目的之一是提供吡啶衍生物或者其藥物可接受的鹽或立體異構物以及包含上述化合物的藥物組合物,以及其在醫藥上的應用。
其中R1為C1-6烷基;L為-NH-、-CO-或-(CRL1RL2)n-;RL1、RL2各自獨立地為H或C1-6烷基,所述C1-6烷基任選地被1個或多個選自鹵素、羥基和氰基的取代基取代;R3為H、鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或C3-8雜環烷基;所述C3-8雜環烷基包含1-4個選自N、O和S的雜原子;所述C1-6烷基、C1-6烷氧基、C3-8環烷基或C3-8雜環烷基任選地被1個或多個選自H、鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或C3-8雜環烷基的取代基取代;R2為C1-4烷基、C5-6烷基、C1-6烷氧基、C3-8環烷基或C3-8雜環烷基;所述C3-8雜環烷基包含1-4個選自N、O和S的雜原子;所述C5-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地被1個或多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基和C3-8雜環烷基的取代基取代;當R2為C1-4烷基時,所述C1-4烷基被1個或多個選自羥基和C1-6烷氧基的取代基取代;n為1或2;
m為0、1、2或3。
在一個或多個實施方式中,所述式(I)的化合物被1個或多個(例如1、2、3、4、5、6、7、8、9或10個)氘取代。
在一個或多個實施方式中,所述C3-8雜環烷基包含1、2、3或4個選自N、O和S的雜原子。
其中R1為C1-6烷基;L為-NH-、-CO-或-(CRL1RL2)n-;RL1、RL2各自獨立地為H或C1-6烷基,所述C1-6烷基任選地被1個或多個選自鹵素、羥基和氰基的取代基取代;R2為C1-4烷基、C5-6烷基、C1-6烷氧基、C3-8環烷基或C3-8雜環烷基;所述C3-8雜環烷基包含1-4個選自N、O和S的雜原子;所述C5-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地被1個或多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基和C3-8雜環烷基的取代基取代;當R2為C1-4烷基時,所述C1-4烷基被1個或多個選自羥基和C1-6烷氧基的取代基取代;n為1或2。
在一個或多個實施方式中,所述式(II)的化合物被1個或者多個氘取代。
在一個或多個實施方式中,所述式(I)的化合物被1個或多個(例如1、2、3、4、5、6、7、8、9或10個)氘取代。
在一個或多個實施方式中,所述R1為乙基。
在一個或多個實施方式中,L為-CH2-或-CD2-。
在一個或多個實施方式中,R3為H、-CH3、-CD3、-OCH3或-Cl。
在一個或多個實施方式中,R2為環丁基、氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基;所述環丁基、氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基任選地被一個或多個選自甲基、甲氧基和羥基的取代基取代。
在一個或多個實施方式中,上述化合物被1個或者多個(例如1、2、3、4、5、6、7、8、9或10個)氘取代。
在一個或多個實施方式中,鹵素為F、Cl或Br。
本申請的一個或多個實施方式提供藥物組合物,所述藥物組合物包含:(1)本申請的上述化合物或者其藥物可接受的鹽或立體異構物;(2)任選的一種或多種其他活性成分;以及(3)藥物可接受的載體和/或賦形劑。
其中:
R1選自C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子;L選自-NH-、-CO-或者-(CRL1RL2)n-;RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;A為4至12元雜環,所述的4至12元雜環選自4至12元單環、5至12元螺環、4至12元並環或者4至12元橋環,所述的4至12元雜環可以包含1至4個選自N、O或S的雜原子;R2選自H、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子;所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;n為1或者2。
其中:
R1選自H、鹵素、C2-6烯基或者C2-6炔基,所述的C2-6烯基或者C2-6炔基任選地進一步被1個或者多個選自鹵素或者C1-6烷基的取代基取代;L選自-NH-、-CO-或者-(CRL1RL2)n-;RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;A為4至12元雜環,所述的4至12元雜環選自4至12元單環、5至12元螺環、4至12元並環或者4至12元橋環,所述的4至12元雜環可以包含1至4個選自N、O或S的雜原子;R2選自H、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子,所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;n為1或者2。
其中:R1選自C1-6烷基;
L選自-NH-、-CO-或者-(CRL1RL2)n-;RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;A為7至12元雜環,所述的7至12元雜環選自7至12元單環、7至12元螺環、7至12元並環或者7至12元橋環,所述的7至12元雜環可以包含1至4個選自N、O或S的雜原子;R2選自H、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子,所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;n為1或者2。
其中:R1選自C1-6烷基;L選自-NH-、-CO-或者-(CRL1RL2)n-;
RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;X1、X2各自獨立地選自CRX或者N;RX選自H、羥基、氰基或者C1-6烷基;當X1、X2均為N時,Ra選自羥基、氰基、=O或C1-6烷基,所述C1-6烷基任選地進一步被1個或者多個選自羥基、鹵素或者氰基的取代基取代;當X1、X2有一個為CRX時,Ra選自H、羥基、氰基、=O或C1-6烷基,所述C1-6烷基任選地進一步被1個或者多個選自羥基、鹵素或者氰基的取代基取代;R2選自H、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子,所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;m為1、2或者3;n為1或者2。
其中:R1選自C1-6烷基;L選自-NH-、-CO-或者-(CRL1RL2)n-;RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;R3選自H、鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基;所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自H、鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;R2選自C5-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子;所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;n為1或者2。
m為0、1、2或者3
其中:R1選自C1-6烷基;L選自-NH-、-CO-或者-(CRL1RL2)n-;RL1、RL2各自獨立地選自H或C1-6烷基,所述的C1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代;R2選自C5-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基,所述的C3-8雜環烷基可以包含1至4個選自N、O或S的雜原子;所述的C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基或者C3-8雜環烷基的取代基取代;n為1或者2。
本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物在製備抗腫瘤或抗癌藥物中的用途。
本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物,其用作藥物。
本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物,其用於治療/預防癌症的方法。
本申請的一個或多個實施方式提供治療/預防腫瘤或癌症的方法,其包括將本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物用於有此需要的物件。
本申請的一個或多個實施方式提供抑制PARP1和/或PARP2的方法,其包括將本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物用於有此需要的物件。
除非有相反的陳述,在說明書和申請專利範圍中使用的術語具有下述含義。
本發明所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況,及本發明所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選進一步被一個或多個它們對應的同位素所替代,其中碳的同位素包括12C、13C和14C,氫的同位素包括氕(H)、氘(D,又叫重氫)、氚(T,又叫超重氫),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個碳原子的直鏈或支鏈飽和脂肪族烴基,優選為1至8個(例如1、2、3、4、5、6、7、8個)碳原子的烷基,更優選為1至6個碳原子的烷基,進一步優選為1至4個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構物;當烷基被取代基時,可以任選進一步被1個或者多個取代基所取代。
「烷氧基」是指烷基中至少1個碳原子被氧原子取代所形成的基團。非限制性實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。所述的烷基定義與上文所述的「烷基」定義相同。
「烯基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、10個)碳-碳雙鍵,由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基,優選2至12個(例如2、3、4、5、6、7、8、9、10、11、12個)碳原子的烯基,更優選2至8個碳原子的烯基,進一步優選2至6個碳原子的烯基。非限制性實例包括乙烯基、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。所述的烯基可以任選進一步被1個或者多個取代基所取代。
「炔基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、或10個)碳-碳三鍵,由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基,優選2至12個(例如2、3、4、5、6、7、8、9、10、11或12個)碳原子的炔基,更優選2至8個碳原子的炔基,進一步優選2至6個碳原子的炔基。非限制性實例包括乙炔基、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。所述的炔基可以任選進一步被一至多個取代基所取代。
「芳基」是指是指取代的或未取代的芳香環,其可以是5至8元(例如5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系,其可以是橋環或者螺環,非限制性實例包括苯基、萘基。所述的芳基可以任選進一步被1個或者多個取代基所取代。
「雜芳基」是指取代的或未取代的芳香環,其可以是3至8元(例如3、4、5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)
雙環或者10至15元(例如10、11、12、13、14、15元)三環體系,且包含1至6個(例如1、2、3、4、5、6個)選自N、O或S的雜原子,優選5至8元雜芳基,雜芳基的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態。雜芳基可以連接在雜原子或者碳原子上,雜芳基可以是橋環或者螺環,非限制性實例包括環吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、呱啶基苯並咪唑基、苯並吡啶基、吡咯並吡啶基。雜芳基任選進一步被1個或多個取代基所取代。
「碳環基」或「碳環」是指飽和或者不飽和的芳香環或者非芳香環。當為芳香環時,其定義與上文「芳基」的定義相同;當為非芳香環時,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系,可以是橋環或者螺環,非限制性實例包括環丙基、環丁基、環戊基、1-環戊基-1-烯基、1-環戊基-2-烯基、1-環戊基-3-烯基、環己基、1-環己基-2-烯基、1-環己基-3-烯基、環己烯基、環己二烯基、環庚基、環辛基、環壬基、環癸基、環十一烷基、環十二烷基、、、、。所述的「碳環基」或「碳環」任選進一步被1個或者多個取代基所取代。
「雜環基」或「雜環」是指飽和或不飽和的芳香性雜環或者非芳香性雜環,當為芳香性雜環時,其定義與上文「雜芳基」定義相同;當為非芳香性雜環時,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系,且包含1至4個(例如1、2、3、4個)選自N、O或S
的雜原子,優選3至8元雜環基。「雜環基」或「雜環」的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態;「雜環基」或「雜環」可以連接在雜原子或者碳原子上;「雜環基」或「雜環」可以為橋環或者螺環。「雜環基」或「雜環」的非限制性實例包括環氧乙基、環氧丙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、硫雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、氧雜環庚基、硫雜環庚基、氧氮雜卓基、二氮雜卓基、硫氮雜卓基、吡啶基、呱啶基、高呱啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、呱嗪基、高呱嗪基、咪唑基、呱啶基、嗎啉基、硫代嗎啉基、噻噁烷基、1,3-二噻烷基、二氫呋喃基、二噻戊環基、四氫呋喃基、四氫噻吩基、四氫吡喃基、四氫噻喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、2-吡咯啉基、3-吡咯啉基、二氫吲哚基、2H-吡喃基、4H-吡喃基、二氧雜環己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氫噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氫異喹啉基、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚基、氮雜雙環[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代嗎啉基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。所述的「雜環基」或「雜環」可以任選進一步被1個或者多個取代基所取代。
「環烷基」是指飽和的環烴基,其環可以為3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多環體系,環碳原子優選3至10個碳原子,進一步優選3至8個碳原子。「環烷基」非限
制性實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、1,5-環辛二烯基、1,4-環己二烯基和環庚三烯基等。當環烷基被取代時,可以任選進一步被1個或者多個取代基所取代。
「雜環烷基」是指取代的或未取代的飽和非芳香環基,其可以是3至8元(例如3、4、5、6、7、8元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系,且包含1、2、3或4個選自N、O或S的雜原子,優選3至8元雜環基。「雜環烷基」的環中選擇性取代的1、2或3個N、S可被氧化成各種氧化態;「雜環烷基」可以連接在雜原子或者碳原子上;「雜環烷基」可以為橋環或者螺環。「雜環烷基」非限制性實例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、呱啶基、呱叮基、嗎啉基、硫代嗎啉基、1,3-二噻烷基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。
當上文所述的「烷基」、「烷氧基」、「烯基」、「炔基」、「芳基」、「雜芳基」、「碳環基」、「碳環」、「雜環基」、「雜環」、「環烷基」、「雜環烷基」或者「雜環基」被取代時,可以選進一步被0、1、2、3、4、5、6、7、8、9或者10個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8環烷基、C3-8雜環烷基、C6-10芳基、C5-10雜芳基、-C(=O)OC6-10芳基、
-OC(=O)C6-10芳基、-OC(=O)C5-10雜芳基、-C(=O)OC5-10雜芳基、-OC(=O)C3-8雜環烷基、-C(=O)OC3-8雜環烷基、-OC(=O)C3-8環烷基、-C(=O)OC3-8環烷基、-NHC(=O)C3-8雜環烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10雜芳基、-NHC(=O)C3-8環烷基、-NHC(=O)C3-8雜環烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8環烷基、C3-8雜環烷基、C6-10芳基、C5-10雜芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10雜芳基、-NHC(=O)C3-8雜環烷基或者-NHC(=O)C3-8環烷基任選進一步被1至3個選自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1選自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3選自H或者C1-6烷基;其中,Rq4、Rq5選自H、C1-6烷基、-NH(C=NRq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任選進一步被1個或者多個選自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10雜芳基、C3-8環烷基或者C3-8雜環烷基的取代基所取代;或者Rq4與Rq5及N原子形成一個3至8元雜環,所述雜環可以含有1個或者多個選自N、O或者S的雜原子。
鹵素包括F、Cl、Br和I。
「藥物可接受的鹽」或者「其藥物可接受的鹽」是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性,且所述的游離酸通過與無毒的無機鹼或者有機鹼,所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。
「藥物組合物」是指一種或多種本發明所述化合物、其藥物可接受的鹽或前藥和其它化學組分形成的混合物,其中,「其它化學組分」是指藥物可接受的載體、賦形劑和/或一種或多種其它治療劑。
「載體」是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。
「賦形劑」是指加入到藥物組合物中以促進化合物給藥的惰性物質。非限制性實施例包括碳酸鈣、磷酸鈣、糖、澱粉、纖維素衍生物(包括微晶纖維素)、明膠、植物油、聚乙二醇類、稀釋劑、成粒劑、潤滑劑、粘合劑和崩解劑。
「立體異構物」是指由分子中原子在空間上排列方式不同所產生的異構物,包括順反異構物、對映異構物和構象異構物。
「任選」或「任選地」或「選擇性的」或「選擇性地」是指隨後所述的事件或狀況可以但未必發生,該描述包括其中發生該事件或狀況的情況及其中未發生的情況。例如,「選擇性地被烷基取代的雜環基」是指該烷基可以但未必存在,該描述包括其中雜環基被烷基取代的情況,及其中雜環基未被烷基取代的情況。
以下實施例詳細說明本發明的技術方案,但本發明的保護範圍包括但是不限於此。
化合物的結構是通過核磁共振(NMR)或(和)質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用Bruker Avance III 400和Bruker Avance 300核磁儀,測定溶劑為氘代二甲基亞碸(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),內標為四甲基矽烷(TMS);MS的測定用Agilent 6120B(ESI)和Agilent 6120B(APCI);薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板,薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm-0.20mm,薄層層析分離純化產品採用的規格是0.4mm-0.5mm;柱層析一般使用煙臺黃海矽膠200-300目矽膠為載體。
實施例1
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((1R,3R)-3-羥基環丁基)吡啶醯胺 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-羥基環丁基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯1c
tert-butyl-4-(6-(((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
將5-溴-N-((1R,3R)-3-羥基環丁基)吡啶醯胺化合物1a(1.2g,4.43mmol)、(S)-2-甲基呱嗪-1-羧酸叔丁酯化合物1b(823mg,4.43mmol)溶解於甲苯(15mL)中,加入醋酸鈀(購自華捷明生物科技,95.6mg,0.43mmol)、1,1'-聯萘-2,2'-雙二苯膦(購自成都愛斯特化學技術有限公司,265.2mg,0.43mmol),將反應體系置換氮氣,將反應體系置於120℃油浴鍋中反應4h,加入水(20mL)淬滅反應,乙酸乙酯(3×30mL)萃取,收集有機相,旋幹,柱層析分析(PE:EA=2:1),得到化合物1c(白色固體,1.3g,產率78%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.56(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-羥基環丁基)-5-(呱嗪-1-基)吡啶醯胺1d
N-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
將化合物1c溶解於鹽酸-1,4二氧六環溶液(購自安耐吉化學,4M,15mL)中,室溫下攪拌反應8h,過濾反應液並收集濾餅,得到化合物1d(白色固體,1.1g,產率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((1R,3R)-3-羥基環丁基)吡啶醯胺 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
將化合物1d(35.9mg,0.13mmol)和化合物1e(36.7mg,0.13mmol)溶解於乙腈(5mL)中,加入N,N-二異丙基乙胺(購自上海麥克林生化科技有限公司,84mg,1.5mmol),70℃下反應3h,旋幹反應液,粗品經柱層析分離(MeOH:DCM=1:60到1:15),得到化合物1(白色固體,36mg,產率62%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.88(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]。
實施例2
(R)-4-(2-氟-4-((四氫呋喃-3-基)氨甲醯)苯基)呱嗪-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-(四氫呋喃-3-基)吡啶醯胺2b
(R)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
將化合物2a(2g,9.9mmol)溶解在二氯甲烷(20mL)中,在冰水浴下,滴加入(R)-四氫呋喃-3-胺,HATU(3.5g,14.8mmol)三乙胺(2ml)溶液,室溫下反應90分鐘,反應完減壓濃縮過柱純化得到化合物2b(黃色固體,1.9g,產率80%)。
LC-MS m/z(ESI)=270.10[M+1]。
第二步
(R)-4-(6-((四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯2c
tert-butyl(R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物2c(白色固體,2.5g,產率89%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.43-8.34(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-(呱嗪-1-基)-N-(四氫呋喃-3-基)苯甲醯胺2d
(R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
參考化合物1d的合成方法,得到化合物2d(白色固體,1.6g,產率83%)。
LC-MS m/z(ESI)=277.16[M+1]。
第四步
(R)-4-(2-氟-4-((四氫呋喃-3-基)氨甲醯)苯基)呱嗪-1-羧酸叔丁酯化合物2
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuram-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
參考化合物1的合成方法,得到化合物2(白色固體,19mg,產率42%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.86(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]。
實施例3
(S)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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-(四氫呋喃-3-基)吡啶醯胺3a
(S)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide
參考化合物2b的合成方法,得到化合物3a(黃色固體,1.7g,產率77%)。
LC-MS m/z(ESI)=270.10[M+1]。
第二步
(S)-4-(6-((四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯3b
tert-butyl(S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物3b(白色固體,1.1g,產率82%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.43-8.34(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-(呱嗪-1-基)-N-(四氫呋喃-3-基)苯甲醯胺3c
(S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
參考化合物1d的合成方法,得到化合物3c(白色固體,1.2g,產率82%)。
LC-MS m/z(ESI)=277.16[M+1]。
第四步
(S)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物3(白色固體,19mg,產率42%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.86(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]。
實施例4
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-甲氧基乙基)吡啶醯胺 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)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯4b
tert-butyl 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物4b(白色固體,1.7g,產率67%)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
N-(2-甲氧基乙基)-5-(呱嗪-1-基)吡啶醯胺4c
N-(2-methoxyethyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物4c(白色固體,1.4g,產率89%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-甲氧基乙基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物4(白色固體,41mg,產率67%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.21(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]。
實施例5
(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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-羥丙基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯5a
tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物5a(白色固體,1.2g,產率67%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.31(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-羥丙基)-5-(呱嗪-1-基)吡啶醯胺5b
N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物5b(白色固體,910mg,產率96%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物5(白色固體,60mg,產率68%)。
LC-MS m/z(ESI)=451.54[M+1]。
實施例6
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥乙基)吡啶醯胺 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-羥乙基)吡啶醯胺6a
5-bromo-N-(2-hydroxyethyl)picolinamide
參考化合物2b的合成方法,得到化合物6a(黃色固體,1.7g,產率77%)。
LC-MS m/z(ESI)=244.98[M+1]。
第二步
4-(6-((2-羥乙基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯6b
tert-butyl 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物6b(白色固體,1.9g,產率86%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.30(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-羥乙基)-5-(呱嗪-1-基)吡啶醯胺6c
N-(2-hydroxyethyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物6c(白色固體,1.2g,產率81%)
LC-MS m/z(ESI)=250.14[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥乙基)吡啶醯胺 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
將化合物1e(21.3mg,0.08mmol)、化合物6c(22.0mg,0.09mmol)、N,N-二異丙基乙胺(51.6mg,0.4mmol)溶解在乙腈(4mL)中,80℃下反應4h,反應液減壓濃縮,經製備色譜得到化合物6(白色固體,16mg,產率46%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.85(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]。
實施例7
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((1s,3s)-3-羥基環丁基)吡啶醯胺 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-羥基環丁基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯7b
tert-butyl 4-(6-(((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物7b(白色固體,1.1g,產率76%)。
LC-MS m/z(ESI)=377.46[M+1]。
第二步
N-((1s,3s)-3-羥基環丁基)-5-(呱嗪-1-基)吡啶醯胺7c
N-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物7c(白色固體,0.9g,產率92%)。
LC-MS m/z(ESI)=277.16[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((1s,3s)-3-羥基環丁基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物7(白色固體,41mg,產率59%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.87(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]。
實施例8
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥基-2-甲基丙基)吡啶醯胺 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-羥基-2-甲基丙基)吡啶醯胺8a
5-bromo-N-(2-hydroxy-2-methylpropyl)picolinamide
參考化合物2b的合成方法,得到化合物8a(黃色固體,1.4g,產率71%)。
LC-MS m/z(ESI)=274.13[M+1]。
第二步
4-(6-((2-羥基-2-甲基丙基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯8b
tert-butyl 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物8b(白色固體,1.1g,產率92%)。
LC-MS m/z(ESI)=379.47[M+1]。
第三步
N-(2-羥基-2-甲基丙基)-5-(呱嗪-1-基)吡啶醯胺8c
N-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物8c(白色固體,920mg,產率89%)
LC-MS m/z(ESI)=279.3[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-2-羥基-2-甲基丙基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物8(白色固體,27mg,產率53%)。
1H NMR(400MHz,DMSO-d 6)δ 11.88(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]。
實施例9
(S)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(1-羥基丙烷-2-基)吡啶醯胺 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-羥基丙烷-2-基)吡啶醯胺9a
(S)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
參考化合物2b的合成方法,得到化合物9a(黃色固體,1.3g,產率76%)。
LC-MS m/z(ESI)=259.00[M+1]。
第二步
(S)-4-(6-((1-羥基丙烷-2-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯9b
tert-butyl(S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物9b(白色固體,1.2g,產率91%)。
LC-MS m/z(ESI)=365.21[M+1]。
第三步
(S)-N-(1-羥基丙烷-2-基)-5-(呱嗪-1-基)吡啶醯胺9c
(S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物9c(白色固體,860mg,產率88%)
LC-MS m/z(ESI)=279.3[M+1]。
1H NMR(400MHz,DMSO-d 6)δ 9.53(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-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(1-羥基丙烷-2-基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物9(白色固體,23mg,產率54%)。
1H NMR(400MHz,DMSO-d 6)δ 11.87(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]。
實施例10
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(1-羥基丙烷-2-基)吡啶醯胺 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-羥基丙烷-2-基)吡啶醯胺10a
(R)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide
參考化合物2b的合成方法,得到化合物10a(黃色固體,1.4g,產率76%)。
LC-MS m/z(ESI)=259.00[M+1]。
第二步
(R)-4-(6-((1-羥基丙烷-2-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯10b
tert-butyl(R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物10b(白色固體,1.1g,產率90%)。
LC-MS m/z(ESI)=365.21[M+1]。
第三步
(R)-N-(1-羥基丙烷-2-基)-5-(呱嗪-1-基)吡啶醯胺10c
(R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物10c(白色固體,840mg,產率83%)
LC-MS m/z(ESI)=279.3[M+1]。
1H NMR(400MHz,DMSO-d 6)δ 9.53(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-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(1-羥基丙烷-2-基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物10(白色固體,27mg,產率62%)。
1H NMR(400MHz,DMSO-d 6)δ 11.87(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]。
實施例11
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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-羥丙基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯11b
tert-butyl(R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物11b(白色固體,1.1g,產率81%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.31(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-羥丙基)-5-(呱嗪-1-基)吡啶醯胺11c
(R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物11c(白色固體,902mg,產率92%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物11(白色固體,42mg,產率72%)。
1H NMR(400MHz,DMSO-d6)δ 11.88(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]。
實施例12
(S)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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-羥丙基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯12b
tert-butyl(S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物12b(白色固體,1.3g,產率84%)。
LC-MS m/z(ESI)=365.45[M+1]。
第二步
(S)-N-(2-羥丙基)-5-(呱嗪-1-基)吡啶醯胺12c
(S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物12c(白色固體,1.1g,產率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
(S)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(2-羥丙基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物12(白色固體,37mg,產率76%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.87(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]。
實施例13
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫-2H-吡喃-4-基)吡啶甲醯胺 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-((四氫-2H-吡喃-4-基)氨基甲醯基)吡啶-3-基)呱嗪-1-羧酸叔丁酯13b
tert-butyl 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物13b(白色固體,1.1g,產率82%)。
LC-MS m/z(ESI)=389.25[M+1]。
第二步
N-環己基-5-(呱嗪-1-基)吡啶甲醯胺13c
N-cyclohexyl-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物13c(白色固體,1.0g,產率91%)。
LC-MS m/z(ESI)=288.20[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫-2H-吡喃-4-基)吡啶甲醯胺 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
參考化合物1的合成方法,得到化合物13(白色固體,32mg,產率74%)。
1H NMR(400MHz,DMSO-d6)δ 12.21(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]。
實施例14
3-乙基-7-((4-(6-(3-羥基氮雜環丁烷-1-羰基)吡啶-3-基)呱嗪-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-羥基氮雜環丁烷-1-羰基)吡啶-3-基)呱嗪-1-羧酸叔丁酯14b
tert-butyl 4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物14b(白色固體,1.1g,產率87%)。
1H NMR(400MHz,DMSO-d6)δ 8.29(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-羥基氮雜環丁烷-1-基)(5-(呱嗪-1-基)吡啶-2-基)甲酮14c
(3-hydroxyazetidin-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone
參考化合物1d的合成方法,得到化合物14c(白色固體,1.1g,產率94%)。
LC-MS m/z(ESI)=265.33[M+1]。
第三步
3-乙基-7-((4-(6-(3-羥基氮雜環丁烷-1-羰基)吡啶-3-基)呱嗪-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
參考化合物1的合成方法,得到化合物14(白色固體,37mg,產率76%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.87(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]。
實施例15
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基-N-(四氫呋喃-3-基)吡啶醯胺 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-((四氫呋喃-3-基)氨基甲醯基)吡啶-3-基)呱嗪-1-羧酸叔丁酯15b
tert-butyl(R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物15b(白色固體,1.3g,產率84%)。
LC-MS m/z(ESI)=391.23[M+1]。
第二步
(R)-6-甲基-5-(呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺15c
(R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
參考化合物1d的合成方法,得到化合物15c(白色固體,1.1mg,產率89%)。
LC-MS m/z(ESI)=291.17[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基-N-(四氫呋喃-3-基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物15(白色固體,26mg,產率77%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.88(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]。
實施例16
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲氧基-N-(四氫呋喃-3-基)吡啶醯胺 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-((四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸酯16b
tert-butyl (R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物16b(黃色固體,1.2g,產率79%)。
LC-MS m/z(ESI)=407.48[M+1]。
第二步
(R)-4-甲氧基-5-(呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺16c
(R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
參考化合物1d的合成方法,得到化合物16c(白色固體,920mg,產率86%)。
LC-MS m/z(ESI)=307.37[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲氧基-N-(四氫呋喃-3-基)吡啶醯胺 化合物16
(R)-5-(4-((7-ethyl-6-0xo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide
參考化合物化合物1的合成方法,得到化合物化合物16(白色固體,56mg,產率76%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.88(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]。
實施例17
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-(甲基-d 3 )-N-(四氫呋喃-3-基)吡啶醯胺 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反應瓶乾燥,抽換N2,N2條件下加入6-溴-5-氟吡啶甲酸甲酯(17a,10mmol)、甲基硼酸-d 3 (11mmol)、Pd(dppf)Cl2(0.5mmol)、K2CO3(20mmol)和1,4-二氧六環(50mL),100℃攪拌反應12小時。反應完成後過濾收集濾液,旋蒸除去溶劑,柱層析分離得到化合物17b(無色油狀物,產率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)呱嗪-1-羧酸叔丁酯17c
tert-butyl 4-(6-(methoxycarbonyl)-2-(methyl-d 3 )pyridin-3-yl)piperazine-1-carboxylate
取50mL反應瓶乾燥,抽換N2,N2條件下加入17b(5mmol)、K2CO3(15mmol)、呱嗪-1-羧酸叔丁酯(10mmol)和20mL DMF,120℃攪拌反應
12小時。反應完成後加入100mL水,EA萃取3次,合併有機相Na2SO4乾燥,旋蒸除去溶劑,組層析分離得到化合物17c(白色固體,產率63%)。
LC-MS m/z(ESI)=339.2[M+1]。
第三步
叔丁基(R)-4-(2-(甲基-d 3 )-6-((四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸酯17d
tert-butyl(R)-4-(2-(methyl-d 3 )-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物17c(黃色固體,1.2g,產率80%)。
LC-MS m/z(ESI)=394.2[M+1]。
第四步
(R)-6-(甲基-d 3 )-5-(呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺17e
(R)-6-(methyl-d 3 )-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
參考化合物1d的合成方法,得到化合物17e(黃色固體,1.2g,產率80%)。
LC-MS m/z(ESI)=294.2[M+1]。
第五步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-(甲基-d 3 )-N-(四氫呋喃-3-基)吡啶醯胺
(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
參考化合物1的合成方法,得到化合物17(黃色固體,17g,產率39%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.88(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]。
實施例18
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基-d 2 )呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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-(羥甲基-d 2 )-1,5-萘啶-2(1H)-酮18b
3-ethyl-7-(hydroxymethyl-d 2 )-1,5-naphthyridin-2(1H)-one
將化合物18a(2.7g,9mmol)溶於四氫呋喃(10mL),在冰水浴下緩慢滴加四氘鋰鋁的四氫呋喃溶液(購自安耐吉化學,18mL,18mmol),滴加完攪拌10min,加入乙酸乙酯(5mL),減壓濃縮柱層析得到得到18b(白色固體,1.2g,產率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
將化合物18b(430mg,2mmol)和三苯基膦(購自上海阿達瑪斯試劑有限公司,2183mg,4mmol)溶於二氯甲烷(5mL),在冰水浴下加入四溴化碳(購自安耐吉化學,1.3g,4mmol)的二氯甲烷(2mL)溶液,反應0.5h,反應液減壓濃縮後經柱層析得到18c(白色固體,450mg,產率80%)。
LC-MS m/z(ESI)=269.1[M+1]。
第三步
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基-d 2 )呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物18(白色固體,46mg,產率49%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.86(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]。
實施例19
(R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基-d 2 )呱嗪-1-基)-6-(甲基-d 3 )-N-(四氫呋喃-3-基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物19(白色固體,28mg,產率41%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.88(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]。
實施例20
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((3S,4R)-4-羥基四氫呋喃-3-基)-6-甲基吡啶醯胺 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
將20a(2g,9.26mmol)溶解於甲醇(20mL),然後在冰水浴下緩慢滴加二氯亞碸(20mL),滴加完將反應瓶置於油浴80℃回流2小時。反應完成後減壓濃縮,用飽和碳酸鈉溶液調節pH到中性,乙酸乙酯(50mL×3)萃取,合併有機相,乾燥,過濾,減壓濃縮得到20b(黃色固體,2g,產率94%)。
1H NMR(400MHz,DMSO-d6)δ 8.20(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)呱嗪-1-羧酸叔丁酯20c
tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate
將20b(2g,8.70mmol)、呱嗪-1-羧酸叔丁酯(1.78g,9.56mmol)、RuPhos Pd G3(364mg,0.44mmol)、碳酸絕(11g,34.8mmol)溶解於二氧六環(40mL)在110℃下回流4小時。反應完成後加入水(50mL),乙酸乙酯(50mL*3)萃取,合併有機相,乾燥,過濾,減壓濃縮後使用矽膠(200-300目)柱層析(DCM:EA=3-1)分離,得到20c(白色固體,2.2g,產率75%)。
LC-MS m/z(ESI)=336.20[M+1]。
第三步
5-(4-(叔丁氧羰基)呱嗪-1-基)-6-甲基吡啶甲酸20d
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid
將20c(2.2g,6.5mmol)溶解於(四氫呋喃:甲醇:水=1:1:1,20mL)中,加入氫氧化鋰(0.78g,32.7mmol),在常溫下過夜反應。反應完成後減壓濃縮有機相,乙酸乙酯(10mL*2)萃取,收集水相用1M鹽酸調節pH至2-3,攪拌30分鐘,析出大量固體,過濾,收集濾餅。烘乾後得到20d(黃色固體,2g,產率95%)。
LC-MS m/z(ESI)=322.20[M+1]。
第四步
4-(6-((3S,4R)-4-羥基四氫呋喃-3-基)氨甲醯)-2-甲基吡啶-3-基)呱嗪-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
參考化合物2b的合成方法,得到化合物20e(白色固體,150mg,產率95%)。
1H NMR(400MHz,DMSO-d6)δ 8.31(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-羥基四氫呋喃-3-基)-6-甲基-5-(呱嗪-1-基)吡啶醯胺20f
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物20f(白色固體,110mg,產率97%)。
LC-MS m/z(ESI)=307.20[M+1]。
第六步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((3S,4R)-4-羥基四氫呋喃-3-基)-6-甲基吡啶醯胺 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
參考化合物6的合成方法,合成分離得到化合物20(白色固體,40mg,產率46%)。
1H NMR(400MHz,DMSO-d6)δ 11.87(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]。
實施例21
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基-N-(3-甲基四氫呋喃-3-基)吡啶醯胺 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-甲基四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯21a
tert-butyl 4-(2-methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物2b的合成方法,得到化合物21a(白色固體,140mg,產率90%)。
1H NMR(400MHz,DMSO-d 6 )δ 8.23(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
4-甲基-N-(3-甲基四氫呋喃-3-基)-5-(呱嗪-1-基)吡啶醯胺21b
5-methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物21b(白色固體,100mg,產率95%)。
LC-MS m/z(ESI)=305.20[M+1]。
第三步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基-N-(3-甲基四氫呋喃-3-基)吡啶醯胺 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
參考化合物6的合成方法,合成分離得到化合物21(白色固體,35mg,產率40%)。
1H NMR(400MHz,DMSO-d 6 )δ 11.87(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]。
實施例22
N-(3-噁唑環[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基吡啶醯胺 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-噁唑環[3.1.0]己烷-6-基)氨甲醯)-2-甲基吡啶-3-基)呱嗪-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
參考化合物2b的合成方法,得到化合物22a(白色固體,110mg,產率81%)。
1H NMR(400MHz,DMSO-d6)δ 8.45(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),2.932.84(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-氧雜環[3.1.0]己烷-6-基)-6-甲基-5-(呱嗪-1-基)吡啶醯胺22b
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-methyl-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物22b(白色固體,80mg,產率96%)。
LC-MS m/z(ESI)=303.20[M+1]。
第三步
N-(3-噁唑環[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-6-甲基吡啶醯胺 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
參考化合物6的合成方法,合成分離得到化合物22(白色固體,30mg,產率42%)。
1H NMR(400MHz,DMSO-d6)δ 11.87(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]。
實施例23
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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)呱嗪-1-基)-6-氯吡啶甲酸23b
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid
參考1c的合成方法,得到23b(白色固體,700mg,產率68%)。
LC-MS m/z(ESI)=342.1[M+1]。
第二步
叔丁基(R)-4-(2-氯-6-((四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸酯23c
tert-butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考2b的合成方法,得到23c(白色固體,340mg,產率53%)。
LC-MS m/z(ESI)=411.2[M+1]。
第三步
(R)-6-氯-5-(呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺23d
(R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
參考1d的合成方法,得到23d(白色固體,170mg,產率67%)。
LC-MS m/z(ESI)=311.2[M+1]。
第四步
(R)-6-氯-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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
參考化合物1的合成方法,得到化合物23(白色固體,23mg,產率55%)。
1H NMR(400MHz,DMSO-d6)δ 11.87(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]。
實施例24
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(3-甲基四氫呋喃-3-基)吡啶醯胺 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
6-溴-N-(3-甲基四氫呋喃-3-基)吡啶醯胺24a
7-bromo-N-(3-methyltetrahydrofuran-3-yl)picolinamide
參考化合物2b的合成方法,得到化合物24a(黃色固體,1.4g,產率71%)。
LC-MS m/z(ESI)=286.14[M+1]。
第二步
4-(6-((3-甲基四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯24b
tert-butyl
4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物24b(白色固體,1.1g,產率92%)。
LC-MS m/z(ESI)=390.48[M+1]。
第三步
N-(3-甲基四氫呋喃-3-基)-5-(呱嗪-1-基)吡啶醯胺24c
N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物24c(白色固體,920mg,產率89%)
LC-MS m/z(ESI)=291.37[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(3-甲基四氫呋喃-3-基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物24(白色固體,27mg,產率53%)。
LC-MS m/z(ESI)=477.58[M+1]。
實施例25
N-(2-噁唑環[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)吡啶醯胺 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-噁唑環[3.1.0]正己烷-6-基)-5-溴呱啶醯胺25a
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-bromopicolinamide
參考化合物2b的合成方法,得到化合物25a(黃色固體,1.1g,產率74%)。
LC-MS m/z(ESI)=284.13[M+1]。
第二步
4-(6-((2-噁唑環[3.1.0]己烷-6-基)氨甲醯)吡啶-3-基)呱嗪-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
參考化合物1c的合成方法,得到化合物25b(白色固體,900mg,產率91%)。
LC-MS m/z(ESI)=389.47[M+1]。
第三步
N-(2-噁唑環[3.1.0]己烷-6-基)-5-(呱嗪-1-基)吡啶醯胺25c
N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物25c(白色固體,670mg,產率81%)
LC-MS m/z(ESI)=289.35[M+1]。
第四步
N-(2-噁唑環[3.1.0]己烷-6-基)-5-(4-((7-乙基-6-氧基-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物25(白色固體,27mg,產率53%)。
LC-MS m/z(ESI)=475.57[M+1]。
實施例26
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((3S,4R)-4-羥基四氫呋喃-3-基)吡啶醯胺 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
8-溴-N-((3S,4R)-4-羥基四氫呋喃-3-基)吡啶醯胺26a
9-bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide
參考化合物2b的合成方法,得到化合物26a(黃色固體,1.1g,產率76%)。
LC-MS m/z(ESI)=288.11[M+1]。
第二步
4-(6-((3S,4R)-4-羥基四氫呋喃-3-基)氨甲醯)吡啶-3-基)呱嗪-1-羧酸叔丁酯26b
tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
參考化合物1c的合成方法,得到化合物26b(白色固體,900mg,產率92%)。
LC-MS m/z(ESI)=393.46[M+1]。
第三步
N-((3S,4R)-4-羥基四氫呋喃-3-基)-5-(呱嗪-1-基)吡啶醯胺26c
N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide
參考化合物1d的合成方法,得到化合物26c(白色固體,640mg,產率89%)
LC-MS m/z(ESI)=293.46[M+1]。
第四步
5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-((3S,4R)-4-羥基四氫呋喃-3-基)吡啶醯胺 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
參考化合物6的合成方法,得到化合物26(白色固體,46mg,產率42%)。
LC-MS m/z(ESI)=479.55[M+1]。
實施例27
(R)-5-(4-((7-甲基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)呱嗪-1-基)-N-(四氫呋喃-3-基)吡啶醯胺 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根據專利WO2021013735的中間體14的合成方法,使用三乙基2-膦醯基丙酯替代三乙基2-丁基丙烯酯製備得到,LCMS m/s=253.10[M+1]。
按照化合物1的方法,製備得到化合物27(白色固體,31mg,產率:74%)。
1H NMR(400MHz,DMSO-d6)δ 11.87(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]。
生物評價
1.PARP1、PARP2活性抑制試驗
通過PARP1化學發光分析(Chemiluminescent assay,購買自BPS Bioscience公司,貨號:80551)、PARP2化學發光分析(Chemiluminescent assay,
購買自BPS Bioscience公司,貨號:80552)分別偵測化合物對PARP1、PARP2的抑制活性。利用化學發光對結果進行定量,具體實驗方案如下:
(1)使用1×組蛋白混合物(histone mixture,50μL/孔)對96孔板進行過夜包被;
(2)棄包被液;每孔加入封閉緩衝液3(Blocking buffer 3)(200μL),室溫孵育90min;
(3)棄封閉液,PBST洗2遍;加25μL主混合物(含2.5μL 10×PARP buffer、2.5μL 10×PARP Assay mixture、5μL活化DNA、15μL ddH2O)、5μL抑制劑(抑制劑初始濃度為10μM,按1:5倍比稀釋8個濃度)、20μL酶(2ng/μL);室溫孵育1小時;
(4)棄液體,PBST洗2遍;加入鏈黴親和素(Streptavidin)-HRP封閉緩衝液3(Blocking buffer 3,稀釋50倍)50μL;室溫孵育30min;
(5)棄液體,PBST洗3遍;加入100μL ELISA ECL Substrate A/B混合(各50μL);
(6)酶標儀偵測結果,利用GraphPad Prism 8進行IC50的計算。
(7)結果表明,本發明化合物對PARP1具有顯著的抑制活性,且相對於PARP2具備良好的選擇性。
2.PARP1/PARP2捕獲(trapping)試驗:
2.1 PARP1捕獲(trapping)試驗:
(1)用緩衝液製備4×PARP1(購買自BPS Bioscience公司,貨號:80501)和Mab anti GST-Tb(購買自cisbio公司,貨號:61GSTTLA)混合液,向384孔板(購買自Greiner公司,貨號:784075)中加入該混合液4μL/孔;(2)用緩衝液製備4×DSB DNA probe-1(購買自Generay),向384孔板中加入4μL/孔;(3)向384孔板中加入4μL/孔抑制(初始濃度為10μM,按1:5倍比稀釋10個濃度),室溫孵育1h;(4)用緩衝液製備4×NAD(購買自Sigma公司,貨號:10127965001),向384孔板中加入4μL/孔,室溫孵育10min;(5)結果採用TR-FRET偵測,利用GraphPad 5.0擬合曲線,並進行IC50的計算。
2.2 PARP2捕獲(trapping)試驗:
(1)用緩衝液製備4×PARP2(購買自BPS Bioscience公司,貨號:80502)和Mab anti GST-Tb(購買自cisbio公司,貨號:61GSTTLA)混合液,向384孔板(購買自Greiner公司,貨號:784075)中加入該混合液4μL/孔;(2)用緩衝液製備4×PARP2 probe2(購買自Generay公司),向384孔板中加入4μL/孔;(3)向384孔板中加入4μL/孔抑制(初始濃度為10μM,按1:5倍比稀釋10個濃度),室溫孵育45min;(4)用緩衝液製備4×NAD(購買自Sigma公司,貨號:10127965001),向384孔板中加入4μL/孔,室溫孵育10min;
結果採用TR-FRET偵測,利用GraphPad 5.0擬合曲線,並進行IC50的計算。
結果表明,本發明化合物對PARP1捕獲(trapping)具有顯著抑制活性,且相對於PARP2捕獲(trapping)具有良好的選擇性。
1.DLD1 BRCA2-/-細胞增殖抑制實驗
用1640(10% FBS,1% PS)培養基培養DLD-1 BRCA2(-/-)細胞(購買自Horizon Discovery Ltd.公司),培養條件為37℃,5% CO2。當細胞生長至對數生長期時,重懸細胞,並用1640培養基稀釋至15000個/mL。使用Echo移液器向384孔白板(PerkinElmer)中每孔加入40nL待測化合物(終濃度分別為10μM、2μM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、
0.00512nM);每個濃度梯度做2個重複,設置對照組1(加入0.1% DMSO)和對照組2(空白培養基)。隨後384孔白板(PerkinElmer)每孔加入40μL(600個)細胞懸液(對照組2不加細胞)。
將上述384孔板置於CO2培養箱(37℃,5% CO2)中繼續培養7天,取出384孔板,室溫放置30分鐘。每孔加入20μL Celltiter Glo偵測液,震板機震盪2分鐘,室溫放置30分鐘。用酶標儀(PerkinElmer;EnVision)測定化學發光值。
用GraphPad Prism 8.0進行曲線擬合併計算IC50。酶標儀偵測結果,利用GraphPad Prism 8進行IC50的計算。
結果表明,本發明化合物對DLD1 BRCA2-/-細胞增殖具有明顯抑制作用。
4.MDA-MB-436細胞增殖抑制實驗
用DMEM培養基(10% FBS,1% PS)培養MDA-MB-436細胞(供應商ATCC),培養條件為37℃,5% CO2。當細胞生長至對數生長期時,用DMEM
培養基重懸並稀釋細胞至1500個/ml。在384孔板中以每孔40μL加入待測化合物(終濃度分別為10000nM,2000nM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM,0.00512nM);每個濃度梯度做2個重複,設置對照組1(加入0.1%DMSO)和對照組2(空白培養基)。隨後向384孔板中加入40μL細胞懸液(對照組2不加細胞)。
將上述384孔板置於培養箱(37℃,5% CO2)中連續培養7天,然後取出384孔板,在室溫放置30min。每孔加入30μL Celltiter Glo assay kit偵測液,用震板機震盪3min,在室溫放置30min。用酶標儀(PerkinElmer;EnVision)測定化學發光值。
偵測結果用GraphPad Prism 8進行曲線擬合併計算IC50。
結果表明,本發明化合物對MDA-MB-436細胞增殖具有明顯抑制作用。
本發明說明書對具體實施方案進行了詳細描述,本領域技術人員應認識到,上述實施方案是示例性的,不能理解為對本發明的限制,對於本領域技術人員來說,在不脫離本發明原理的前提下,通過對本發明進行若干改進和修飾,這些改進和修飾獲得技術方案也落在本發明的申請專利範圍的保護範圍內。
Claims (10)
- 如請求項1所述的化合物或者其藥物可接受的鹽或立體異構物,其中所述R1為乙基。
- 如請求項1所述的化合物或者其藥物可接受的鹽或立體異構物,其中L為-CH2-或-CD2-。
- 如請求項1所述的化合物或者其藥物可接受的鹽或立體異構物,其中R3為H、-CH3、-CD3、-OCH3或-Cl。
- 如請求項1所述的化合物或者其藥物可接受的鹽或立體異構物,其中R2為環丁基、氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基;所述環丁基、氧雜環戊基、氧雜環己基、氮雜環丁基任選地被一個或多個選自甲基、甲氧基和羥基的取代基取代;所述甲基、乙基或丙基被一個或多個選自羥基的取代基取代。
- 如請求項1所述的化合物或者其藥物可接受的鹽或立體異構物,其中所述鹵素為F、Cl或Br。
- 一種藥物組合物,所述藥物組合物包含:(1)請求項1至8中任一項所述的化合物或者其藥物可接受的鹽或立體異構物;(2)任選的一種或多種其他活性成分;以及(3)藥物可接受的載體和/或賦形劑。
- 一種請求項1至8中任一項所述的化合物或者其藥物可接受的鹽或立體異構物或請求項9所述的藥物組合物在製備抗腫瘤藥物中的用途。
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