CN112341477B - Imidazo pyrimidine compound containing fused ring group, preparation method and application thereof - Google Patents
Imidazo pyrimidine compound containing fused ring group, preparation method and application thereof Download PDFInfo
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- CN112341477B CN112341477B CN201910733001.XA CN201910733001A CN112341477B CN 112341477 B CN112341477 B CN 112341477B CN 201910733001 A CN201910733001 A CN 201910733001A CN 112341477 B CN112341477 B CN 112341477B
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- Prior art keywords
- compound
- alkyl
- hydrogen
- pharmaceutically acceptable
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- -1 Imidazo pyrimidine compound Chemical class 0.000 title abstract description 76
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- 238000000034 method Methods 0.000 claims abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 201000007270 liver cancer Diseases 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 76
- 238000006243 chemical reaction Methods 0.000 claims description 45
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 24
- 229910052805 deuterium Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 18
- 125000002757 morpholinyl group Chemical group 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 201000011176 T-cell adult acute lymphocytic leukemia Diseases 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 abstract description 21
- 229940002612 prodrug Drugs 0.000 abstract description 21
- 239000002207 metabolite Substances 0.000 abstract description 19
- 150000002148 esters Chemical class 0.000 abstract description 16
- 239000012453 solvate Substances 0.000 abstract description 16
- 150000004677 hydrates Chemical class 0.000 abstract description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 56
- 150000002431 hydrogen Chemical class 0.000 description 47
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 230000005764 inhibitory process Effects 0.000 description 32
- 239000012071 phase Substances 0.000 description 32
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 26
- 238000012360 testing method Methods 0.000 description 26
- 125000001424 substituent group Chemical group 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 150000002367 halogens Chemical class 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 23
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 20
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 14
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000004193 piperazinyl group Chemical group 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 238000002875 fluorescence polarization Methods 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
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- 229910052717 sulfur Inorganic materials 0.000 description 5
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- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 4
- XRZKBPWNHCCBRK-UHFFFAOYSA-N CC1=NC(=CC=C1)C2=NC3=C(C(=N2)Cl)N=CN3CC4=CC=C(C=C4)OC Chemical compound CC1=NC(=CC=C1)C2=NC3=C(C(=N2)Cl)N=CN3CC4=CC=C(C=C4)OC XRZKBPWNHCCBRK-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
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- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
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- 150000007530 organic bases Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000700 radioactive tracer Substances 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
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- 239000012312 sodium hydride Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
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- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
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Classifications
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- 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
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
Technical Field
The invention relates to an imidazo pyrimidine compound containing a fused ring group, a pharmaceutical composition and a kit containing the same, a preparation method of the imidazo pyrimidine compound and application of the imidazo pyrimidine compound in preparation of medicines for treating diseases mediated by TGF beta R1 (especially cancers such as liver cancer).
Background
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates a variety of cellular responses, such as cell proliferation, differentiation, migration, and apoptosis. TGF-beta superfamily includes TGF-beta 1, TGF-beta 2, TGF-beta 3, activin, inhibin, bone morphogenic proteins, and the like. TGF- β transduces signals through two highly conserved single transmembrane serine/threonine kinases, tgfβr1 and tgfβr2 (ACS Med Chem lett.2018,9,1117).
Smads are important TGF- β signaling and regulatory molecules in cells that can transduce TGF- β signaling directly from the cell membrane into the nucleus, TGF- β/Smads signaling pathways play an important role in tumor development and progression. In TGF-beta/Smads signaling, activated TGF-beta first binds to TGF-beta R2 at the surface of the cell membrane to form a heterodimeric complex, and TGF-beta R1 recognizes and binds to the binary complex. Activated tgfβr1 further phosphorylates Smad2/Smad3 proteins which in turn bind further to Smad4 into heterotrimeric complexes which enter the nucleus and act synergistically with co-activators/inhibitors to regulate transcription of target genes (nature. 2003,425, 577). Any link change in the TGF-beta/Smads signaling pathway results in abnormalities in the signaling pathway (PNAS.2019, 116, 9166).
TGF- β signaling pathways are deregulated in many diseases including cancer, and tgfβr1 protein levels are significantly elevated in gastric, colorectal, prostate, ovarian, pancreatic, liver, lung, cervical and head and neck cancer cell lines and tumor tissues. Activation of TGF- β signaling pathways causes significant pathological effects in tumor stroma, including immunosuppression, angiogenesis, and connective tissue hyperplasia. Furthermore, TGF- β signaling pathway can enhance the invasiveness of tumor cells, promote epithelial transformation into mesenchymal stem cells, and enhance tolerance to tumor epithelial cell therapy (Nat neurosci.2014,17,943).
Currently, the development of tgfβr1 inhibitors against key targets of TGF- β signaling pathways has been gaining attention in the pharmaceutical industry, and published patent applications include WO2002094833A1, WO2009150547A1, WO2017035118A1, WO2018019106A1, and the like. There remains a need in the art for novel tgfβr1 inhibitors, particularly tgfβr1 inhibitors having high activity and selectivity.
Disclosure of Invention
Through a great deal of research, the invention surprisingly discovers an imidazo pyrimidine compound containing a fused ring group, which can remarkably inhibit the activity of TGF beta R1, has good selectivity between TGF beta R1 and TGF beta R2 and good pharmacokinetic property, and can be used as a TGF beta R1 inhibitor for treating proliferative diseases and apoptosis dysregulation diseases caused by TGF-beta signaling channels, especially TGF beta R1 mediated diseases such as cancers, for example, liver cancers.
The first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof,
wherein,,
a is selected from 3-8 membered heterocycloalkyl and a single bond;
y, Z are each independently selected from carbon atoms and nitrogen atoms;
R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 6 Substitution;
R 6 each at each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
when the A ring is 3-8 membered heterocycloalkyl, R 2 Each at each occurrence is independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a 、-S(O) q NR b R c 、-O-(C 2-6 alkylene-O) t -R a and-O-C 2-6 alkylene-NR b R c The C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 7 Substitution;
when A is a single bond, the group A is a single bond,is->R 2 Z and the carbon atom adjacent to Z together form a group optionally substituted with one or more R 10 Substituted 5-to 10-membered heteroaryl or C 6-10 An aryl group;
R 10 each at each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a and-C (O) NR b R c The C is 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 7 Substitution;
R 7 each at each occurrence is independently selected from deuterium, halogen, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a and-S (O) q NR b R c ;
R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
R 5 selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl;
R a each occurrence of which is independently selected from hydrogen, deuterium, -C (O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more groups selected from: deuterium, C 1-6 Alkyl, halogen, hydroxy, -NR d R e 、-C(O) w R 9 and-S (O) w R 9 ;
R b 、R c Each occurrence of which is independently selected from hydrogen, deuterium, -C (O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups selected from: deuterium, C 1-6 Alkyl, halogen, hydroxy, -NR d R e 、-C(O) w R 9 and-S (O) w R 9 The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively
R b 、R c And together with the atoms to which they are attached form a 3-7 membered ring;
R 8 and R is 9 At each occurrenceEach independently selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;
R d 、R e each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl; or alternatively
R d 、R e And together with the atoms to which they are attached form a 3-7 membered ring;
q, w are each independently at each occurrence selected from 1 and 2;
t is independently at each occurrence selected from 1, 2, 3 and 4; and is also provided with
m, n are each independently selected from 0, 1, 2 and 3.
In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
In another aspect, the invention provides a kit comprising:
a) A compound of the invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention as a first pharmaceutical composition;
And b) optionally packaging and/or instructions.
In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a kit of parts of the invention, for use in the treatment of a disease or disorder mediated by tgfβr1 (particularly cancer, e.g., liver cancer).
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, solvate (e.g. hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, or a kit of parts of the invention, for the manufacture of a medicament for the treatment of a disease or condition mediated by tgfβr1 (in particular cancer, e.g. liver cancer).
In another aspect, the invention provides a method of preventing or treating a disease or disorder mediated by tgfβr1 (particularly cancer, e.g., liver cancer), comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a kit of the invention.
In another aspect, the invention provides a process for preparing a compound of the invention comprising the steps shown in scheme 1 below:
scheme 1
Wherein,,
R 1 、R 2 、R 3 、R 4 a, Y, Z, m, n are as defined above;
R 5 is hydrogen;
PG is a protecting group of amino; and is also provided with
LG is a leaving group.
The compound of formula e can be prepared by the method of scheme 2, scheme 3 or patent WO 2017035118:
scheme 2
Or alternatively
Scheme 3
Wherein,,
R 1 、R 4 LG, PG are as defined above, X is halogen; and is also provided with
M is selected from-SnBu 3 、-SnMe 3 、-B(OH) 2 And
definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 8, for example 1 to 4 carbon atoms. For example, as used herein, the term "C 1-6 Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.
As used herein, the term "alkylene" refers to a straight or branched divalent alkyl radical.
As used hereinThe term "cycloalkyl" as used herein refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems, such as bicyclo [1.1.1 ]]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15, for example 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. For example, as used herein, the term "C 3-8 Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 8 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), optionally substituted with one or more (such as 1 to 3) suitable substituents, e.g., methyl substituted cyclopropyl.
As used herein, the term "alkoxy" refers to an "alkyl" as defined above, e.g., C, attached to the parent molecular moiety through an oxygen atom 1-6 Alkoxy, C 1-3 Alkoxy or C 3-8 A cycloalkoxy group. C (C) 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.
As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine or iodine.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms. For example, the term "C 1-6 Haloalkyl "means haloalkyl having 1 to 6 carbon atoms, for example-CF 3 、-C 2 F 5 、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 Cl or-CH 2 CH 2 CF 3 Etc.
As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "C 1-6 Haloalkoxy "refers to haloalkoxy groups having 1 to 6 carbon atoms, e.g. -OCF 3 、-OC 2 F 5 、-OCHF 2 、-OCH 2 F、-OCH 2 CF 3 、-OCH 2 Cl or-OCH 2 CH 2 CF 3 Etc.
As used herein, the term "heterocycloalkyl" refers to a saturated mono-or bicyclic group having, for example, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4) selected from O, S, N, S (=o), S (=o) in the ring 2 A heteroatom-containing group of (2). The heterocycloalkyl group may be attached to the remainder of the molecule through any carbon or heteroatom (if valence permits) in the ring. Representative examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl (oxytanyl), tetrahydrofuranyl, dioxolyl (dioxanyl), pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, the term "C 6-10 Aryl "refers to an aromatic group containing 6 to 10 carbon atoms such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO) 2 、C 1-6 Alkyl, etc.) substitution.
As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly having 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in addition, may be benzofused in each caseA kind of electronic device. For example, as used herein, the term "5-10 membered heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring system having 5-10 ring atoms, and which contains at least one heteroatom (which may be the same or different) (e.g., N, O or S). Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives. Heteroaryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, C 1-6 Alkyl, etc.) substitution.
As used herein, the term "alkenyl" refers to a hydrocarbon group containing at least one c=c double bond. Alkenyl groups may be straight or branched and contain 2 to 15 carbon atoms. For example, "C" herein 2-6 Alkenyl "is alkenyl having 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. Alkenyl groups may be unsubstituted or substituted with one or more substituents which may be the same or different.
As used herein, the term "alkynyl" refers to a hydrocarbon group having at least one c≡c triple bond. Alkynyl groups may be straight or branched chain and contain 2 to 15 carbon atoms. For example, "C" herein 2-6 Alkynyl "is alkynyl containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups may be unsubstituted or substituted with one or more substituents which may be the same or different.
The term "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted with …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced or unsubstituted individually and/or together with an independently selected substituent. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with a independently selected substituent or not.
If substituents are described as "independently selected from" a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g 2 H、 3 H. Deuterium D, tritium T); isotopes of carbon (e.g 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 37 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S)。
The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs thereof, which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and/or toxicologically compatible with the other components of the formulation and/or the mammal being treated therewith.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, and which, when administered into or onto the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T. Higuchi and V. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "room temperature" as used herein refers to 20 ℃ + -5 ℃.
The term "about" as used herein when used in reference to a value or range of values is intended to encompass the value or range of values as well as ranges of errors that are acceptable to those skilled in the art of values, such as, for example, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.
The term "pharmaceutical composition" as used herein includes products comprising a therapeutically effective amount of a compound of the invention, as well as any product that results, directly or indirectly, from the combination of compounds of the invention.
Compounds of formula (I)
It is an object of the present invention to provide a compound of formula I or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof,
wherein,,
a is selected from 3-8 membered heterocycloalkyl and a single bond;
y, Z are each independently selected from carbon atoms and nitrogen atoms;
R 1 selected from C 6-10 Aryl and 5-10 membered heteroaryl, said C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 6 Substitution;
R 6 each at each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
when the A ring is 3-8 membered heterocycloalkyl, R 2 Each at each occurrence is independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a 、-S(O) q NR b R c 、-O-(C 2-6 alkylene-O) t -R a and-O-C 2-6 alkylene-NR b R c The C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 7 Substitution;
when A is a single bond, the group A is a single bond,is->R 2 Z and the carbon atom adjacent to Z together form a group optionally substituted with one or more R 10 Substituted 5-to 10-membered heteroaryl or C 6-10 An aryl group;
R 10 each at each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a and-C (O) NR b R c The C is 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 7 Substitution;
R 7 each at each occurrence is independently selected from deuterium, halogen, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a and-S (O) q NR b R c ;
R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;
R 5 selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl;
R a each occurrence of which is independently selected from hydrogen, deuterium, -C (O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more groups selected from: deuterium, C 1-6 Alkyl, halogen, hydroxy, -NR d R e 、-C(O) w R 9 and-S (O) w R 9 ;
R b 、R c Each occurrence of which is independently selected from hydrogen, deuterium, -C (O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups selected from: deuterium, C 1-6 Alkyl, halogen, hydroxy, -NR d R e 、-C(O) w R 9 and-S (O) w R 9 The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively
R b 、R c And together with the atoms to which they are attached form a 3-7 membered ring;
R 8 and R is 9 Each at each occurrence is independently selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;
R d 、R e each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl; or alternatively
R d 、R e And together with the atoms to which they are attached form a 3-7 membered ring;
q, w are each independently at each occurrence selected from 1 and 2;
t is independently at each occurrence selected from 1, 2, 3 and 4; and is also provided with
m, n are each independently selected from 0, 1, 2 and 3.
According to some embodiments of the invention, a is a 5-6 membered heterocycloalkyl.
In some embodiments of the invention, a is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
According to some embodiments of the invention, when A is a 3-8 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),
R 2 At each time go outEach of which is independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OR a 、-NR b R c 、-COOR a and-C (O) NR b R c The C is 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl optionally substituted with one or more halo;
R a each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 A haloalkyl group;
R b 、R c each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl groups.
In some embodiments of the invention, when A is a 3-8 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 8 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups. In some embodiments of the invention, when A is a 3-8 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c At each occurrence of eachIndependently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 8 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups.
In some embodiments of the invention, when A is a 3-8 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),
R 2 each occurrence is independently selected from the group consisting of hydrogen, cyano, amino, methyl, ethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, difluoromethoxy, -NHCH 3 、-N(CH 3 ) 2 Morpholinyl, pyrrolidinyl, -NHC (O) CH 3 And
in some embodiments of the invention, when A is a 3-8 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),
R 2 each occurrence is independently selected from hydrogen, cyano, amino, methyl, trifluoromethyl, cyclopentyl, methoxy, difluoromethoxy, -NHCH 3 、-N(CH 3 ) 2 Morpholinyl, pyrrolidinyl, -NHC (O) CH 3 And
according to some embodiments of the invention, a is a single bond.
According to some embodiments of the invention, when a is a single bond,
is- >Wherein B is optionally substituted with one or more R 10 Substituted 5-6 membered heteroaryl or C 6-10 Aryl groups.
In some embodiments of the invention, when A is a single bond, B is unsubstituted 5-6 membered heteroaryl or C 6-10 Aryl groups.
In some embodiments of the invention, when a is a single bond, B is a furan ring or a benzene ring.
According to some embodiments of the invention, Y is a nitrogen atom.
According to some embodiments of the invention, Z is a carbon atom.
According to some embodiments of the invention, R 1 To optionally be covered by one or more R 6 Substituted 5-10 membered heteroaryl.
In some embodiments of the invention, R 1 To optionally be covered by one or more R 6 Substituted 5-6 membered heteroaryl.
In some embodiments of the invention, R 1 To optionally be covered by one or more R 6 Substituted 6 membered heteroaryl.
In some embodiments of the invention, R 1 To optionally be covered by one or more R 6 Substituted pyridyl.
In some embodiments of the invention, R 1 To optionally be C 1-6 Alkyl or C 1-6 Haloalkyl substituted 6 membered heteroaryl.
In some embodiments of the invention, R 1 To optionally be C 1-6 Alkyl or C 1-6 Haloalkyl-substituted pyridinyl.
In some embodiments of the invention, R 1 Is quilt C 1-6 Alkyl or C 1-6 Haloalkyl-substituted pyridinyl.
In some embodiments of the invention, R 1 Is a pyridyl group substituted with methyl, difluoromethyl or trifluoromethyl.
In some embodiments of the invention, R 1 Selected from the group consisting ofWherein the wavy line->Representing the point of attachment of the group to the remainder of the molecule.
In some embodiments of the invention, R 1 To optionally be C 1-6 Alkyl substituted pyridinyl.
In some embodiments of the invention, R 1 Is quilt C 1-6 Alkyl substituted pyridinyl.
In some embodiments of the invention, R 1 Is a pyridyl group substituted with a methyl group.
In some embodiments of the invention, R 1 Is thatWherein the wavy line->Representing the point of attachment of the group to the remainder of the molecule.
According to some embodiments of the invention, R 3 Each at each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C (O) R a 、-COOR a and-C (O) NR b R c ,R a 、R b And R is c Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl.
In some embodiments of the invention, R 3 Each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group.
In some embodiments of the invention, R 3 Each independently at each occurrence selected from hydrogen and methyl.
According to some embodiments of the invention, R 4 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl groups.
In some embodiments of the invention, R 4 Is hydrogen.
According to some embodiments of the invention, R 5 Selected from hydrogenAnd C 1-6 An alkyl group.
In some embodiments of the invention, R 5 Is hydrogen.
According to some embodiments of the invention, m, n are each independently selected from 0, 1 and 2.
In some embodiments of the invention, m is selected from 0 and 1.
In some embodiments of the invention, n is 0.
In some embodiments of the invention, m is selected from 0 and 1; and n is 0.
According to some embodiments of the invention, in the compounds of formula I,
a is 5-6 membered heterocycloalkyl;
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
y is a nitrogen atom;
z is a carbon atom;
R 1 to optionally be C 1-6 Alkyl or C 1-6 Haloalkyl substituted 6 membered heteroaryl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 4 is hydrogen;
R 5 Is hydrogen; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, in the compounds of formula I,
a is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl;
R 2 at each occurrence ofIndependently selected from hydrogen, cyano, C 1 -6 alkyl, C 3 -6 cycloalkyl, morpholinyl, pyrrolidinyl, C 1 -6 alkoxy, C 1 -6 haloalkyl, C 1 -6 haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1 -6 alkyl and-C (O) R 8 ;
R 8 Selected from C 1 -6 alkyl and C 3 -8 cycloalkyl;
y is a nitrogen atom;
z is a carbon atom;
R 1 is quilt C 1-6 Alkyl-substituted pyridinyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 4 is hydrogen;
R 5 is hydrogen; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, in the compounds of formula I,
a is a single bond;
is->
B is unsubstituted 5-6 membered heteroaryl or C 6-10 An aryl group;
y is a nitrogen atom;
z is a carbon atom;
R 1 to optionally be C 1-6 Alkyl or C 1-6 Haloalkyl substituted 6 membered heteroaryl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 4 is hydrogen;
R 5 is hydrogen;and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, in the compounds of formula I,
A is a single bond;
is->
B is furan ring or benzene ring;
y is a nitrogen atom;
z is a carbon atom;
R 1 is quilt C 1-6 Alkyl-substituted pyridinyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 4 is hydrogen;
R 5 is hydrogen; and is also provided with
m, n are each independently selected from 0, 1 and 2.
The present invention encompasses compounds of formula I resulting from any combination of the above preferred groups.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-1:
wherein,,
a is 3-8 membered heterocycloalkyl;
R 2 each at each occurrence is independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OR a 、-NR b R c 、-COOR a and-C (O) NR b R c The C is 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl optionally taken by one or more halogenSubstitution;
R a each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 A haloalkyl group;
R b 、R c each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl; and is also provided with
R 3 、R 6 M and n are as defined above.
According to some embodiments of the invention, in the compounds of formula I-1,
a is 5-6 membered heterocycloalkyl;
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 selected from C 1-6 Alkyl and C 1-6 A haloalkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, in the compounds of formula I-1,
a is 5-6 membered heterocycloalkyl;
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 is C 1-6 An alkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-1-1:
wherein R is 2 、R 3 、R 6 M and n are as defined above.
According to some embodiments of the invention, in the compounds of formula I-1-1,
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 is C 1-6 An alkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-1-2:
wherein R is 2 、R 3 、R 6 M and n are as defined above.
According to some embodiments of the invention, among the compounds of formula I-1-2,
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 is C 1-6 An alkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-1-3:
wherein R is 2 、R 3 、R 6 M and n are as defined above.
According to some embodiments of the invention, among the compounds of formula I-1-3,
R 2 Each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 is C 1-6 An alkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-1-4:
wherein R is 2 、R 3 、R 6 M and n are as defined above.
According to some embodiments of the invention, among the compounds of formula I-1-4,
R 2 each at each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and-NR b R c ;
R b 、R c Each at each occurrence is independently selected from hydrogen, C 1-6 Alkyl and-C (O) R 8 ;
R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;
R 3 each at each occurrence is independently selected from hydrogen and C 1-6 An alkyl group;
R 6 is C 1-6 An alkyl group; and is also provided with
m, n are each independently selected from 0, 1 and 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula I-2:
wherein,,
B is unsubstituted 5-6 membered heteroaryl or C 6-10 An aryl group; and is also provided with
R 6 Selected from C 1-6 Alkyl and C 1-6 A haloalkyl group.
According to some embodiments of the invention, in the compounds of formula I-2,
b is furan ring or benzene ring; and is also provided with
R 6 Is C 1-6 An alkyl group.
According to some embodiments of the invention, the compound of the invention is selected from:
preparation method
It is another object of the present invention to provide a process for preparing the compounds of the present invention, comprising the steps shown in scheme 1 below:
scheme 1
Wherein,,
R 1 、R 2 、R 3 、R 4 a, Y, Z, m, n are as defined above;
R 5 is hydrogen;
PG is a protecting group of amino; preferably, PG is selected from methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Cbz), benzyl, p-methoxybenzyl; more preferably, PG is p-methoxybenzyl; and is also provided with
LG is a leaving group; preferably, LG is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyl and phenoxy; more preferably, LG is selected from halogen, phenoxy; particularly preferably, LG is chloro or phenoxy.
Step 1: the compound e is subjected to substitution reaction with the compound f to obtain a compound g.
When LG is a group of chlorine, the group,
the reaction is preferably carried out in a suitable organic solvent which may be selected from DMF, DMA, DMSO, N-methylpyrrolidone, ethers (e.g. ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (e.g. toluene, xylene, etc.), and any combination thereof, preferably DMSO;
The reaction is preferably carried out in the presence of a suitable base, including organic or inorganic bases, which may be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate, preferably triethylamine; the inorganic base may be selected from potassium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate;
the reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 50 to 150 ℃.
When the LG is a phenoxy group, the amino acid is substituted,
the reaction is preferably carried out in a suitable organic solvent which may be selected from the group consisting of halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1, 2-dichloroethane, etc.), nitriles (e.g. acetonitrile, etc.), N-methylpyrrolidone, DMF, DMA, tetrahydrofuran, dioxane, DMSO, and any combination thereof, preferably DMSO or DMF;
the reaction is preferably carried out in the presence of a suitable base, including an organic base which may be selected from DIPEA, triethylamine, potassium tert-butoxide and pyridine, or an inorganic base which may be selected from potassium phosphate, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate and sodium hydroxide, preferably potassium carbonate or sodium hydride;
the reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 25 to 70 ℃.
Step 2: removing the amino protecting group from compound g to obtain the compound of formula I.
The reaction is preferably carried out in the presence of a suitable acid which may be selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 20 to 80 ℃.
The compounds of formula e above may be prepared by the following methods in scheme 2, scheme 3 or patent WO 2017035118:
scheme 2
Wherein,,
R 1 、R 4 LG, PG are as defined hereinabove.
Step one: compound a reacts with compound b to form compound c.
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from DMF, DMA, N-methylpyrrolidone, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g., toluene, xylene), water, and any combination thereof, preferably DMA.
The reaction is carried out in the presence of a suitable reducing agent. The reducing agent may be selected from anhydrous sodium sulfite, sodium bisulfite, and sodium metabisulfite; preferably, the reducing agent is sodium bisulfite or sodium metabisulfite.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 90 to 160 ℃.
Step two: and carrying out substitution reaction on the compound c and a substitution reagent to obtain a compound d.
When LG is halogen, the substitution reagent is a halogenated reagent. When LG is chlorine, the halogenating agent is phosphorus oxychloride, thionyl chloride, oxalyl chloride, preferably phosphorus oxychloride.
The reaction is preferably carried out in a suitable organic solvent. When LG is halogen (particularly chlorine), the organic solvent may be selected from phosphorus oxychloride, thionyl chloride, oxalyl chloride, DMF, acetonitrile, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), methylene chloride, aromatic hydrocarbons (e.g., toluene, xylene), and any combination thereof, with phosphorus oxychloride being preferred.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, preferably from 90 to 150 ℃.
Step three: protecting the amino group of compound d to give compound e.
The amino protecting agent used in the reaction is p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, preferably p-methoxybenzyl chloride.
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from DMF, DMA, N-methylpyrrolidone, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g., toluene, xylene), and any combination thereof, preferably DMF.
The reaction is preferably carried out in the presence of a suitable base. The base includes an organic base selected from triethylamine, DIPEA, pyridine, NMM, sodium t-butoxide, potassium acetate and sodium acetate, or an inorganic base selected from potassium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 20 to 50 ℃.
Scheme 3
Wherein,,
R 1 、R 4 LG, PG are as defined above, X is halogen; and is also provided with
M is-SnBu 3 、-SnMe 3 、-B(OH) 2 And
step one': protecting the amino group of compound i to give compound j.
The amino protecting agent used in the reaction is p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, preferably p-methoxybenzyl chloride.
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from DMF, DMA, N-methylpyrrolidone, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g., toluene, xylene), and any combination thereof, preferably DMF.
The reaction is preferably carried out in the presence of a suitable base. The base includes an organic base which may be selected from triethylamine, DIPEA, pyridine, NMM, sodium t-butoxide, potassium acetate and sodium acetate, or an inorganic base which may be selected from potassium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 20 to 90 ℃.
Step two': diazotizing and halogenating the compound j to obtain a compound k;
the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from ethers (e.g., ethylene glycol dimethyl ether, THF, dioxane, and any combination thereof), preferably THF.
The diazotisation reagent used in the reaction may be selected from sodium nitrite and isoamyl nitrite, preferably isoamyl nitrite.
The halogenating reagent used in the reaction may be selected from diiodomethane, copper iodide, elemental iodine and hydroiodic acid, with diiodomethane being preferred.
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 20 to 90 ℃.
Step three': coupling reaction is carried out on the compound k to obtain a compound e;
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), methanol, ethanol, DMF, acetonitrile, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g., toluene, xylene), water, and any combination thereof, preferably 1, 2-dichloroethane.
The reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst, e.g. tetrakis (triphenylphosphine) palladium, palladium acetate, pd 2 (dba) 3 、Pd(PPh 3 ) 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 Dichloromethane complex or Pd (dppf) Cl 2 Preferably Pd 2 (dba) 3 。
The reaction is carried out at a suitable temperature, preferably from 0 to 200 ℃, more preferably from 50 to 150 ℃.
Pharmaceutical composition and kit
It is another object of the present invention to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
It is another object of the present invention to provide a kit comprising:
a) A compound of the invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention;
And b) optionally packaging and/or instructions.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions or pharmaceutical formulations of the present invention include, but are not limited to: a) Diluents such as water, hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, docosahexaenoic acid or esters thereof, triglycerides, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, glucose, glycine, or mixtures thereof; b) Lubricants, for example, silica, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, polyethylene glycol, or mixtures thereof; c) Binders, for example magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or β -lactose), corn sweeteners, natural and synthetic gums (such as acacia, sodium alginate), waxes, polyvinylpyrrolidone, or mixtures thereof; d) Disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or sodium salts thereof, effervescent agents, or mixtures thereof; e) Absorbents, colorants, flavors and/or sweeteners; f) Emulsifying or dispersing agents, such as caprylic/capric polyethylene glycol glycerides, polyethylene glycol glycerides oleate, glycerol oleate, diethylene glycol monoethyl ester, or other acceptable emulsifying agents: and/or g) substances that enhance absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, polyethylene glycol 200, polyethylene glycol 400, and the like.
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as an inhalant.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
When administered orally, the pharmaceutical compositions of the present invention may be formulated into any orally acceptable formulation, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like. The carrier used in the tablets generally comprises lactose and corn starch, and optionally lubricants such as magnesium stearate. Diluents used in capsules generally include lactose and dried corn starch. Aqueous suspensions are typically prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetening agent, flavoring agent, coloring agent, etc. can be added into the above oral preparation.
When administered topically, the pharmaceutical compositions of the present invention may be formulated as appropriate ointments, lotions or creams, where the active ingredient is suspended or dissolved in one or more carriers. Carriers used in ointments include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water. Carriers used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate (such as tween 60), 2-octyldodecanol, benzyl alcohol and water.
The pharmaceutical compositions of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable aqueous or oleaginous solutions. Among the carriers and solvents that can be used include, but are not limited to: water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oils may also be used as solvents or suspending media, such as mono-or diglycerides.
The pharmaceutical composition of the present invention may comprise 0.01mg to 1000mg of the compound of the present invention.
In some embodiments, the invention provides methods of preparing a pharmaceutical composition of the invention, comprising combining a compound of the invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, with one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions of the present invention may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases. In some embodiments, the invention provides a combination formulation of a compound of the invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
Therapeutic methods and uses
It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, or a kit of parts of the present invention, for use in the prevention or treatment of a disease or disorder mediated by tgfβr1.
It is another object of the present invention to provide the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, or a kit of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or disorder mediated by tgfβr1.
It is another object of the present invention to provide a method for preventing or treating a disease or condition mediated by tgfβr1, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a kit of the invention.
According to some embodiments of the invention, the disease or disorder mediated by tgfβr1 is cancer, such as lung cancer, colorectal cancer, multiple myeloma, acute myelogenous leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors, or other hematological cancers.
The term "effective amount" as used herein refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, e.g., an amount that achieves alleviation of one or more symptoms associated with a disease to be treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is from about 0.001 mg/kg body weight/day to about 10000 mg/kg body weight/day. In suitable cases, the effective dose is from about 0.01 mg/kg body weight/day to about 1000mg/kg body weight/day. About 0.01 to 1000mg/kg of subject body weight, typically 0.1 to 500mg/kg of subject body weight, may be administered daily, every two days, or every three days. An exemplary treatment regimen is one or more daily or one or more weekly or one or more monthly dosing. The formulation is typically administered multiple times, and the interval between individual doses may be daily, weekly, monthly or yearly. Alternatively, the formulation may be administered in the form of a slow release formulation, in which case a lower frequency of administration is required. Dosages and frequencies will vary depending on the half-life of the formulation in the subject. And may also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered at relatively low frequency intervals over a long period of time. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a patient prophylactic regimen may be administered.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
The term "treatment" as used herein is intended to reduce or eliminate the disease state or condition for which it is intended. A subject is successfully "treated" if the subject has received a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as per the methods described herein, and the subject exhibits an observable and/or detectable decrease or improvement in one or more indications and symptoms. It is also to be understood that the treatment of the disease state or condition described includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result.
"treatment" means any administration of a compound of the invention, including:
(1) Preventing disease in an animal that may be predisposed to the disease but has not undergone or displayed disease pathology or symptomology;
(2) Inhibiting the disease (i.e., preventing further development of pathology and/or symptomology) in an animal experiencing or exhibiting disease pathology or symptomology; or alternatively
(3) Disease improvement (i.e., reversal of pathology and/or symptomology) occurs in animals that are experiencing or exhibiting pathology or symptomology of the disease.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Detailed Description
In order to make the objects and technical solutions of the present invention more apparent, embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific conditions not specified in the examples were either conventional or manufacturer-recommended. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In the conventional synthesis methods and examples of intermediate synthesis, the meanings of the abbreviations are shown in the following table.
The structures of the compounds described in the examples below were prepared by nuclear magnetic resonance 1 H-NMR) or Mass Spectrometry (MS).
Nuclear magnetic resonance 1 H-NMR) using Bruker 400MHz NMR, the solvent was deuterated methanol (CD) 3 OD), deuterated chloroform (CDCl) 3 ) Hexadeuterated dimethyl sulfoxide (DMSO-d 6 ) The method comprises the steps of carrying out a first treatment on the surface of the The internal standard substance is Tetramethylsilane (TMS).
Abbreviations in Nuclear Magnetic Resonance (NMR) spectra in the following examples represent the following meanings:
s: single peak (single), d: dual peak (doubelet), t: triplet (triplet), q: quartet (quaternion), dd: double doublet (double), qd: four doublets (quatet doubelet), ddd: double doublet (double double doublet), ddt: double triplet (double double triplet), dddd: double peak (double double double doublet), m: multiple peaks (multiplet), br: broad peak (broad), J: coupling constant, hz: hertz, DMSO-d 6 : deuterated dimethyl sulfoxide.
All chemical shift (delta) values are given in parts per million (ppm).
The Mass Spectrum (MS) measuring instrument used was an Agilent (ESI) mass spectrometer model Agilent 6120B.
The examples of the present invention were purified by preparative high performance liquid chromatography using the methods shown below.
Method A:
chromatographic column: geLai Prep C18 ODS 10 μm 150X 450mm
Mobile phase a: acetonitrile; mobile phase B: water (containing 0.05% trifluoroacetic acid)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 10.0 | 90.0 | 200 |
7.00 | 10.0 | 90.0 | 200 |
40.00 | 40.0 | 60.0 | 200 |
Method B:
chromatographic column: geLai Prep C18 ODS 8 μm 45X 450mm
Mobile phase a: acetonitrile; mobile phase B: water (containing 0.05% trifluoroacetic acid)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 15.0 | 85.0 | 60 |
7.00 | 15.0 | 85.0 | 60 |
50.00 | 60.0 | 40.0 | 60 |
Method C:
chromatographic column: sunFire Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (0.05% formic acid)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 10.0 | 90.0 | 26 |
16.00 | 90.0 | 10.0 | 26 |
Method D:
chromatographic column: XBIridge Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (containing 0.05% ammonium bicarbonate)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 10.0 | 90.0 | 26 |
2.00 | 10.0 | 90.0 | 26 |
18.00 | 90 | 10 | 26 |
Method E:
chromatographic column: sunFire Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (0.05% formic acid)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 30.0 | 70.0 | 28 |
16.00 | 70.0 | 30.0 | 28 |
Method F:
chromatographic column: waters XBridge Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (0.05% formic acid)
Time [ min] | Mobile phase A [% ] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 5.0 | 95.0 | 28 |
4.00 | 5.0 | 95.0 | 28 |
20.00 | 85.0 | 15.0 | 28 |
Method G:
chromatographic column: waters XBridge Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (with 0.05% TFA)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 10.0 | 90.0 | 28 |
16.00 | 90.0 | 10.0 | 28 |
Method H:
chromatographic column: waters XBridge Prep C18 OBD 5 μm 19X 150mm
Mobile phase a: acetonitrile; mobile phase B: water (with 0.05% TFA)
Time [ min] | Mobile phase A [%] | Mobile phase B [%] | Flow Rate [ mL/min] |
0.00 | 10.0 | 90.0 | 28 |
4.00 | 10.0 | 90.0 | 28 |
Examples
Example 1: synthesis of 1- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -1,2,3, 4-tetrahydro-1, 6-naphthyridine (Compound 1)
Step one: synthesis of 1- (9- (4-methoxybenzyl) -2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -1,2,3, 4-tetrahydro-1, 6-naphthyridine (Compound 1-2)
Compound 1-1 (100 mg,0.24mmol, methods of synthesis are described in WO 2017035118), 1,2,3, 4-tetrahydro-1, 6-naphthyridine (47.53 mg,0.35 mmol) is dissolved in DMF (2 mL) and sodium hydride (47.23 mg,1.18mmol,60% dispersed in mineral oil) is added in one portion and reacted for 16h at 25 ℃. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by preparative HPLC (method C), and the preparation was freeze-dried to give the title compound (10 mg).
ESI-MS(m/z):464.2[M+H] + 。
Step two: synthesis of 1- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -1,2,3, 4-tetrahydro-1, 6-naphthyridine (Compound 1)
Compound 1-2 (20 mg,0.043 mmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 80℃for 16h. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography (method D) and lyophilized to give the title compound (1.74 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ13.55(s,1H),8.45(s,1H),8.34(s,1H),8.21(d,J=5.9Hz,1H),8.09(d,J=7.8Hz,1H),7.81(t,J=7.7Hz,1H),7.75(d,J=5.9Hz,1H),7.33(d,J=7.6Hz,1H),4.50(t,J=5.8Hz,2H),2.88(t,J=6.4Hz,2H),2.57(s,3H),2.12-1.98(m,2H)。
ESI-MS(m/z):344.2[M+H] + 。
example 2: synthesis of 1- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -2, 3-dihydro-1H-pyrido [3,4-b ] [1,4] oxazine (Compound 2)
Step one: synthesis of 1- (9- (4-methoxybenzyl) -2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -2, 3-dihydro-1H-pyrido [3,4-b ] [1,4] oxazine (Compound 2-1)
Compound 1-1 (50 mg,0.12 mmol), 2, 3-dihydro-1H-pyrido [3,4-b ] [1,4] oxazine (24.11 mg,0.18 mmol) was dissolved in DMF (2 mL), sodium hydride (23.61 mg,0.59mmol,60% dispersed in mineral oil) was added in one portion, and the mixture was stirred at 25℃for 3H. To the reaction mixture was added water (0.5 mL) to quench the reaction, and the crude product was purified by preparative HPLC (method E) and lyophilized to give the title compound (30 mg).
ESI-MS(m/z):466.2[M+H] + 。
Step two: synthesis of 1- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -2, 3-dihydro-1H-pyrido [3,4-b ] [1,4] oxazine (Compound 2)
Compound 2-1 (30 mg,0.064 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 80℃and reacted for 16h, the reaction solution was slowly added to methyl tert-butyl ether (40 mL), stirred for 0.5h, the solid was precipitated, filtered, the solid was dissolved with water and lyophilized to give the trifluoroacetate salt of the title compound (4 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ13.85(s,1H),8.64(s,1H),8.56(s,2H),8.28(d,J=6.6Hz,1H),8.20(d,J=7.8Hz,1H),7.90(t,J=7.7Hz,1H),7.42(d,J=7.6Hz,1H),4.73(t,J=4.4Hz,2H),4.59(t,J=4.4Hz,2H),2.62(s,3H)。
ESI-MS(m/z):346.1[M+H] + 。
example 3: synthesis of 6- (2, 3-dihydro-1H-pyrrolo [3,2-c ] pyridin-1-yl) -2- (6-methylpyridin-2-yl) -9H-purine (Compound 3)
Step one: synthesis of 2- (6-methylpyridin-2-yl) -9H-purin-6-ol (Compound 3-3)
Compound 3-1 (8.64 g,71.36 mmol), 5-amino-1H-imidazole-4-carboxamide (compound 3-2,9g,71.36 mmol) was dissolved in DMA (150 mL) and NaHSO was added 3 (5.57 g,53.52 mmol), warmed to 150℃and reacted for 24h. The reaction solution was cooled to room temperature, water (1.5L) was then added thereto, and after stirring for 0.5h, the filtrate was filtered and purified by preparative high performance liquid chromatography (method A) and lyophilized to give the title compound (3.1 g).
ESI-MS(m/z):228.2[M+H] + 。
Step two: synthesis of 6-chloro-2- (6-methylpyridin-2-yl) -9H-purine (Compound 3-4)
Compound 3-3 (1.3 g,5.72 mmol) was dissolved in phosphorus oxychloride (7 mL), warmed to 117℃and reacted for 12h. Phosphorus oxychloride was removed by concentration, ice water (100 mL) was added to the concentrate, the pH was adjusted to 8 with solid sodium bicarbonate under stirring, the solid precipitated, filtered, and the filter cake was washed with water (30 ml×3) and dried to give the title compound (0.8 g).
ESI-MS(m/z):246.7[M+H] + 。
Step three: synthesis of 6-chloro-9- (4-methoxybenzyl) -2- (6-methylpyridin-2-yl) -9H-purine (Compound 3-5)
Compound 3-4 (0.8 g,3.26 mmol), 4-benzyloxy chlorobenzyl (509.99 mg,3.26 mmol), K 2 CO 3 (900.11 mg,6.51 mmol) was dissolved in DMF (15 mL) and reacted at 25℃for 12h. The reaction solution was poured into water, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (method B) and lyophilized to give the title compound (527 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ8.83(s,1H),8.26(d,J=7.8Hz,1H),7.90(t,J=7.8Hz,1H),7.42(dd,J=8.4,3.0Hz,3H),6.96–6.87(m,2H),5.52(s,2H),3.71(s,3H),2.61(s,3H)。
ESI-MS(m/z):366.8[M+H] + 。
step four: preparation of 6- (2, 3-dihydro-1H-pyrrolo [3,2-c ] pyridin-1-yl) -9- (4-methoxybenzyl) -2- (6-methylpyridin-2-yl) -9H-purine (Compound 3-6)
Compound 3-5 (100 mg,0.27 mmol), 2, 3-dihydro-1H-pyrrolo [3,2-c ] pyridine hydrochloride (46.51 mg,0.30 mmol), potassium carbonate (75.56 mg,0.55 mmol) were dissolved in DMSO (5 mL), heated to 80℃and reacted for 12H. The reaction solution was cooled to room temperature, poured into water (20 mL), and the solid was precipitated, suction-filtered and the cake was dried to give the title compound (100 mg).
ESI-MS(m/z):450.2[M+H] + 。
Step five: preparation of 6- (2, 3-dihydro-1H-pyrrolo [3,2-c ] pyridin-1-yl) -2- (6-methylpyridin-2-yl) -9H-purine (Compound 3)
Compound 3-6 (50 mg,0.11 mmol) was dissolved in trifluoroacetic acid (5 mL), heated to 80℃and reacted for 4h. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography (method F) and lyophilized to give the trifluoroacetate salt of the title compound (8 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ:13.71(s,1H),9.39(d,J=8.0Hz,1H),8.63(d,J=8.0Hz,1H),8.53(s,2H),8.23(d,J=8.0Hz,1H),7.89(t,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),4.99(t,J=8.0Hz,2H),3.45(t,J=8.0Hz,2H),2.66(s,3H)。
ESI-MS(m/z):330.1[M+H] + 。
example 4: synthesis of N- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -quinolin-4-amine (Compound 18)
Step one: preparation of N- (9- (4-methoxybenzyl) -2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -quinolin-4-amine (Compound 18-1)
Compound 1-1 (20 mg,0.05 mmol) and 4-aminoquinoline (14 mg,0.09 mmol) were dissolved in DMF (2 mL), naH (9.45 mg,0.24 mmol) was added, stirred at 25℃for 3h, the reaction was quenched by the addition of water (60 mL), the solid precipitated, filtered and the filter cake dried to give the title compound (20 mg) which was used directly in the next reaction without further purification.
ESI-MS(m/z):474.2[M+H] + 。
Step two: preparation of N- (2- (6-methylpyridin-2-yl) -9H-purin-6-yl) -quinolin-4-amine (Compound 18)
Compound 18-1 (30 mg,0.063 mmol) was dissolved in trifluoroacetic acid (3 mL), warmed to 80℃and reacted for 16h, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography (method D) and lyophilized to give the title compound (5.0 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ8.83(d,J=5.1Hz,1H),8.51(d,J=5.1Hz,1H),8.38(d,J=9.8Hz,2H),8.09(d,J=7.8Hz,1H),8.02(d,J=8.2Hz,1H),7.82-7.72(m,2H),7.65-7.58(m,1H),7.31(d,J=7.6Hz,1H),2.59(s,3H)。
ESI-MS(m/z):354.2[M+H] + 。
example 5: synthesis of N- [2- (6-methylpyridin-2-yl) -9H-purin-6-yl ] -furo [3,2-b ] pyridin-7-amine (Compound 19)
Step one: preparation of N- [9- (4-methoxyphenyl) -2- (6-methylpyridin-2-yl) -9H-purin-6-yl ] -furo [3,2-b ] pyridin-7-amine (Compound 19-1)
Compound 3-5 (50 mg,0.14 mmol), furo [3,2-b ] pyridin-7-amine (20.17 mg,0.15 mmol), potassium carbonate (37.8 mg,0.27 mmol) were dissolved in DMSO (1 mL), heated to 80℃and reacted for 12h. The reaction solution was cooled to room temperature, purified by preparative high performance liquid chromatography (method G), and lyophilized to give the title compound (29 mg).
ESI-MS(m/z):464.2[M+H] + 。
Step two: preparation of N- [2- (6-methylpyridin-2-yl) -9H-purin-6-yl ] -furo [3,2-b ] pyridin-7-amine (Compound 19)
Compound 19-1 (29 mg,0.11 mmol) was dissolved in trifluoroacetic acid (1 mL), heated to 80℃and reacted for 6h. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography (method H) and lyophilized to give the trifluoroacetate salt of the title compound (3.67 mg).
The structural characterization is as follows:
1 H-NMR(400MHz,DMSO-d 6 )δ8.50(d,J=5.7Hz,3H),8.31(d,J=2.2Hz,1H),8.09(d,J=7.8Hz,1H),7.84(t,J=7.7Hz,1H),7.37(d,J=7.6Hz,1H),7.17(d,J=2.3Hz,1H),2.61(s,3H)。
ESI-MS(m/z):343.9[M+H] + 。
pharmacological Activity test
Test example 1: in vitro enzymatic Activity inhibition assay (TGF beta R1)
The experimental method comprises the following steps: according to ADP-Glo TM Description of kinase assay kit (Promega, cat V9102) the inhibition of tgfβr1 enzymatic activity by the compounds of the invention was determined as follows:
after preincubation of TGF-beta R1 enzyme with test compounds (1000 nM, 100nM, 10 nM) at 30℃for 30min, TGF-beta R1 peptide and triphosphate were addedAdenosine monophosphate (ATP) initiates the reaction. After incubation at 30℃for 3h ADP-Glo was added TM The reagent is incubated for 90min at room temperature, then kinase detection reagent is added, and after incubation for 30min at room temperature, the chemiluminescent signal value is detected.
Solvent (DMSO) was used as a negative control and buffer (without tgfβr1enzyme) was used as a blank.
The percent inhibition of compounds at different concentrations was calculated according to the following formula:
percentage inhibition = (1- (chemiluminescent signal value of test compound-chemiluminescent signal value of control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of control)) = (100%.
When the percent inhibition was between 30-80%, the half Inhibition Concentration (IC) of the compound on tgfβr1 was calculated according to the following formula 50 ):
IC 50 =x× (1-percent inhibition)/percent inhibition,
wherein X is the test concentration of the compound.
The experimental results are shown in table 1 below:
TABLE 1 inhibition of TGF beta R1 enzyme by the compounds of the invention
Examples numbering | IC 50 (nM) |
1 | 2.47±0.16 |
2 | 2.92±0.21 |
3 | 3.47±0.07 |
As can be seen from Table 1, the compounds of the present invention have a remarkable inhibitory effect on TGF-beta R1 enzyme.
Test example 2: in vitro enzymatic Activity inhibition assay (TGF beta R2)
The experimental method comprises the following steps: according to ADP-Glo TM Description of kinase assay kit (Promega, cat#v9102) the inhibition of tgfβr2 enzymatic activity by the compounds of the invention was determined as follows:
after preincubation of tgfβr2 enzyme with test compounds (1000 nM, 100nM, 10 nM) at different concentrations for 30min at 30 ℃, myelin Basic Protein (MBP) and Adenosine Triphosphate (ATP) were added to initiate the reaction. After incubation at 30℃for 3h ADP-Glo was added TM The reagent is incubated for 90min at room temperature, and then kinase detection reagent is added. After incubation for 30min at room temperature, the chemiluminescent signal value was measured.
Solvent (DMSO) was used as a negative control and buffer (without tgfβr2enzyme) was used as a blank.
The percent inhibition of compounds at different concentrations was calculated according to the following formula:
percentage inhibition = (1- (chemiluminescent signal value of test compound-chemiluminescent signal value of control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of control)) = (100%.
When the percent inhibition was between 30-80%, the half Inhibition Concentration (IC) of tgfβr2 by the compound was calculated according to the following formula 50 ) Or range of:
IC 50 =x× (1-percent inhibition)/percent inhibition,
wherein X is the test concentration of the compound.
The experimental results are shown in table 2 below:
TABLE 2 inhibition of TGF-beta R2 enzyme by the compounds of the invention
Examples numbering | IC 50 (nM) |
1 | 1248.18±77.14 |
3 | 665.55±174.86 |
As can be seen from Table 2, the compounds of the present invention have a weak inhibitory activity against TGF-beta R2.
As can be seen from tables 1 and 2, the compounds of the present invention have highly selective inhibition of TGF-beta R1.
Test example 3: in vitro cell Activity inhibition assay
The experimental method comprises the following steps: the inhibition of HEK293-SBE cells by the compounds of the invention was determined according to the instructions of the Bright-Glo luciferase assay kit (Promega, cat#E2620) as follows:
HEK293-SBE cells (Bpsbioscience, cat # 60653) were plated in 96-well plates (10% FBS medium), 3 ten thousand per well, 37℃at 5% CO 2 Culturing overnight. The medium was changed to 0.5% fbs medium and 0.5% fbs medium diluted test compound was added at a final concentration of up to 10 μm, 4-fold dilution, and a total of 8 concentration gradients. After 4-5 hours of incubation, 10. Mu.l TGF-beta was added. The final concentration of TGF-beta was 0.5ng/ml. Mu.l of medium was added instead of TGF beta as negative control. No test compound was added to the blank and tgfβ was added. Bright Glo reagent was added to each well and chemiluminescent signal values were read on a microplate reader.
The percent inhibition of compounds at different concentrations was calculated according to the following formula:
percentage inhibition = (1- (test compound chemiluminescent signal value-blank chemiluminescent signal value)/(negative control chemiluminescent signal value-blank chemiluminescent signal value)) = (100%.
The percent inhibition of compounds at different concentrations was plotted against compound concentration, and IC was calculated by fitting a curve according to a four parameter model, by the following formula 50 Value:
y=Min+(Max-Min)/(1+(x/IC 50 )^(-Hillslope))
wherein y is the percent inhibition; max and Min are the maximum value and the minimum value of the fitting curve respectively; x is the test concentration of the compound; hillslope is the slope of the curve.
The experimental results are shown in table 3 below:
TABLE 3 inhibition of HEK293-SBE cell luciferase reporter by the compounds of the invention
Examples numbering | IC 50 (nM) |
1 | 10.79±3.78 |
2 | 5.08±2.78 |
3 | 2.67±0.73 |
As can be seen from Table 3, the compounds of the present invention have significant inhibitory effects on TGF-beta induced HEK293-SBE cell luciferase reporter genes.
Test example 4 Biochemical hERG inhibition assay
Test system:
the kit comprises: preconductor TM hERG Fluorescence Polarization Assay,(ThermoFisher Catalog:PV5365),
The kit comprises:
positive control compound: hERG potassium channel blocker E-4031;
hERG cell membrane;
affinity Tracer tracker
hERG buffer.
Test parameters:
hERG concentration: 1X
Tracer concentration: 1nM
Incubation time: 2h
BMG PHERAstar FS FP
The test method comprises the following steps:
the test was performed according to the kit instructions, the steps were as follows:
test group: 10. Mu.M and 1. Mu.M of the test compound were added to each well of a microplate containing hERG cell membrane, and a Tracer tracker having high hERG affinity was added thereto, and after incubating the microplate at room temperature for 2 hours, the change in fluorescence polarization (Excitation: 540nm; emission:590 nm) was detected using a multifunctional microplate reader.
Positive control group: the test compound was replaced with 30. Mu.M positive control compound E4031, and the experimental procedure was the same as that of the test group.
Blank control group: the test compounds were replaced with hERG buffer and hERG cell membranes were not added, and the experimental procedure was the same as for the test group.
And (3) data processing:
the percent inhibition of hERG by the compounds of the invention at various concentrations was calculated according to the following formula, and the half inhibition concentration (IC 50 ) Is not limited in terms of the range of (a).
Percentage inhibition = (1- (fluorescence polarization value of test compound-fluorescence polarization value of positive control group)/(fluorescence polarization value of blank control group-fluorescence polarization value of positive control group)) = (100%)
Experimental results:
inhibition of hERG by compounds was determined using the methods described above and the results are shown in table 4 below.
TABLE 4 hERG inhibition assay results
Examples numbering | IC 50 (μM) |
2 | >10 |
The test results show that the compounds of the invention have low affinity for hERG and compete with the affinity Tracer for IC 50 All > 10. Mu.M. The compounds of the invention demonstrate lower risk of cardiac toxicity associated with hERG ion channels.
Claims (11)
1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof,
wherein,,
a is selected from pyrrolidinyl, piperidinyl and morpholinyl;
R 6 selected from deuterium and C 1-6 An alkyl group;
R 2 selected from hydrogen;
R 3 selected from hydrogen;
m, n are each independently selected from 0, 1, 2 and 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
R 6 is methyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I-1-1, I-1-2, or I-1-3:
4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
5. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
6. A kit comprising:
a) A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 5;
And b) optionally packaging and/or instructions.
7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, or a kit according to claim 6, in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by tgfβr1.
8. The use of claim 7, wherein the disease or condition mediated by tgfβr1 is selected from cancer.
9. The use of claim 8, wherein the cancer is selected from lung cancer, colorectal cancer, multiple myeloma, acute myelogenous leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors, or other hematological cancers.
10. A process for preparing a compound of any one of claims 1-4, comprising the steps shown in scheme 1:
scheme 1
Wherein,,
R 1 is that
R 4 Is hydrogen;
R 5 is hydrogen;
y is N; z is CH;
R 2 、R 3 、R 6 a, m, n are as defined in any one of claims 1 to 4;
PG is a protecting group of amino; and is also provided with
LG is a leaving group.
11. The method of claim 10, wherein the compound of formula e is prepared by reaction scheme 2 or scheme 3:
Scheme 2
Wherein,,
R 1 、R 4 LG, PG are as defined in claim 10, X is halogen; and is also provided with
M is selected from-SnBu 3 、-SnMe 3 、-B(OH) 2 And
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