WO2022258007A1 - 含吡唑多环类衍生物的盐、晶型及其制备方法和应用 - Google Patents
含吡唑多环类衍生物的盐、晶型及其制备方法和应用 Download PDFInfo
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- WO2022258007A1 WO2022258007A1 PCT/CN2022/097828 CN2022097828W WO2022258007A1 WO 2022258007 A1 WO2022258007 A1 WO 2022258007A1 CN 2022097828 W CN2022097828 W CN 2022097828W WO 2022258007 A1 WO2022258007 A1 WO 2022258007A1
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- Prior art keywords
- acid
- crystal form
- diffraction peak
- alkyl
- cyano
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- 239000013078 crystal Chemical group 0.000 title claims abstract description 238
- 150000003839 salts Chemical group 0.000 title claims abstract description 126
- 238000002360 preparation method Methods 0.000 title claims abstract description 98
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims description 31
- 125000003367 polycyclic group Chemical group 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 287
- 239000002253 acid Substances 0.000 claims abstract description 114
- 229940079593 drug Drugs 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 102100040460 P2X purinoceptor 3 Human genes 0.000 claims abstract description 15
- 101710189970 P2X purinoceptor 3 Proteins 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 230000001272 neurogenic effect Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 174
- -1 amino, hydroxyl Chemical group 0.000 claims description 151
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 128
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 127
- 125000003545 alkoxy group Chemical group 0.000 claims description 112
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 85
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 82
- 125000003118 aryl group Chemical group 0.000 claims description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 76
- 150000002367 halogens Chemical group 0.000 claims description 76
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 125000000623 heterocyclic group Chemical group 0.000 claims description 70
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 229910052805 deuterium Inorganic materials 0.000 claims description 63
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 60
- 125000001072 heteroaryl group Chemical group 0.000 claims description 52
- 238000003756 stirring Methods 0.000 claims description 52
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 49
- 150000002431 hydrogen Chemical group 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 49
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
- 206010011224 Cough Diseases 0.000 claims description 45
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 41
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 38
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 37
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 34
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 34
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 29
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 28
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 27
- 238000010586 diagram Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 26
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 26
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 26
- 125000004104 aryloxy group Chemical group 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 24
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 23
- 125000001188 haloalkyl group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000004043 oxo group Chemical group O=* 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 22
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 22
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 21
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 21
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 19
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 17
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 17
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 15
- 208000013116 chronic cough Diseases 0.000 claims description 15
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 15
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 14
- 229910021529 ammonia Inorganic materials 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 12
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 12
- 239000001530 fumaric acid Substances 0.000 claims description 12
- 229940045996 isethionic acid Drugs 0.000 claims description 12
- 235000011090 malic acid Nutrition 0.000 claims description 12
- 235000006408 oxalic acid Nutrition 0.000 claims description 12
- 229940116315 oxalic acid Drugs 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 11
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 10
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 10
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 10
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 10
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 10
- 235000003704 aspartic acid Nutrition 0.000 claims description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 10
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 10
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 10
- QCXJEYYXVJIFCE-UHFFFAOYSA-N para-acetamidobenzoic acid Natural products CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 claims description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 10
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 10
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 9
- 208000002193 Pain Diseases 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 230000036407 pain Effects 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000001361 adipic acid Substances 0.000 claims description 7
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- 229960000250 adipic acid Drugs 0.000 claims description 7
- 238000005119 centrifugation Methods 0.000 claims description 7
- 229940116298 l- malic acid Drugs 0.000 claims description 7
- 239000011976 maleic acid Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 7
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
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- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 5
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- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 5
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 5
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 claims description 5
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- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
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- HHJIZLMOCIYWJF-HNNXBMFYSA-N methyl (3S)-3-[[2-[2,6-difluoro-4-(methylcarbamoyl)phenyl]-7-methylimidazo[1,2-a]pyridin-3-yl]methyl]piperidine-1-carboxylate Chemical compound CNC(=O)c1cc(F)c(-c2nc3cc(C)ccn3c2C[C@@H]2CCCN(C2)C(=O)OC)c(F)c1 HHJIZLMOCIYWJF-HNNXBMFYSA-N 0.000 description 1
- WUKSVVOCYHTIMV-UHFFFAOYSA-N methyl 3-amino-1h-pyrazole-5-carboxylate Chemical compound COC(=O)C=1C=C(N)NN=1 WUKSVVOCYHTIMV-UHFFFAOYSA-N 0.000 description 1
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- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention belongs to the field of biomedicine, and specifically relates to a salt, a crystal form, a preparation method and an application of a pyrazole-containing polycyclic derivative.
- P2X receptors or P2X purinoreceptors are a family of cation-permeable ATP ligand-gated ion channels that bind to extracellular ATP.
- P2X receptors have seven subunits and exist in the form of homotrimers or heterotrimers. They are mainly expressed in nerve terminals (pre-synaptic and post-synaptic) of the nervous system and regulate synaptic transmission.
- the P2X3 receptor is one of the members of the P2X family. It is a key sensory receptor for sensing upper airway stimuli and triggering cough reflexes. It is believed to play a key role in the sensitization of specific sensory nerves, participate in pain and cough, and In bone cancer pain perception, blocking P2X3 suppresses cough signaling.
- Cough is a defensive nerve reflex of the body, which is beneficial to clear respiratory secretions and harmful factors, but frequent and severe coughing will seriously affect the work, life and social activities of patients. Cough is divided into acute, subacute and chronic cough.
- Chronic cough (Chronic cough) refers to the cough duration > 8 weeks, with cough as the main or only symptom, and no obvious lesions in the lungs by chest imaging examination. Chronic cough has long been recognized as a consequence of various conditions such as asthma/eosinophilic bronchitis, rhinitis, and gastroesophageal acid reflux disease. However, recent evidence suggests that chronic cough is a clinical symptom of neuroticism with unique intrinsic pathophysiological features.
- Unexplained chronic cough or idiopathic cough which is mainly manifested by chronic irritating dry cough, is more sensitive to external stimuli, and cough hypersensitivity is common, and cough hypersensitivity is its physiological and pathological mechanism.
- Cough-related afferent abnormalities may be the cause of refractory or unexplained chronic cough.
- Chronic cough can cause complications in cardiovascular, digestive, nervous, urinary, musculoskeletal systems, such as urinary incontinence, syncope, insomnia, anxiety, etc.
- treatment should aim at reducing cough sensitivity.
- Current treatment options are limited, including pharmacological and non-pharmacological approaches.
- Clinical research results show that the neuromodulator drug gabapentin is effective in treatment, and other drugs such as amitriptyline, baclofen, carbamazepine, and pregabalin can also be used.
- Severe cough can be appropriately given antitussive treatment, and antitussive drugs are mainly divided into central antitussives and peripheral antitussives.
- Central antitussive drugs are divided into dependent antitussives (morphine alkaloids and their derivatives) and non-dependent antitussives (synthetic dextromethorphan and pentoxyverine), the former is addictive and narcotic Sex and other side effects, the latter clinical application is very extensive.
- Peripheral antitussives also known as peripheral antitussives, play an antitussive effect by inhibiting a certain link in the cough reflex arc, including local anesthetics (narcotine, benzonatate) and mucosal protective agents (benzonatate) properine and mogisteine).
- P2X3 receptor antagonists there is no approved small-molecule drug for P2X3 receptor antagonists on the market.
- the P2X3 receptor antagonist drugs currently in the clinical stage include Merck&Co's MK-7264, which is used to treat diseases such as chronic cough, pain and pulmonary fibrosis. It has low selectivity for P2X3/P2X2/3 and is safe. It has good sex but has side effects such as loss of taste.
- the current indication for chronic cough has entered clinical phase III research. Bellus Health's BLU5937 has high selectivity and no side effects such as taste in Phase I clinical trials.
- the object of the present invention is to provide an acid salt of a compound represented by general formula (I-a) or a stereoisomer thereof,
- R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, -(CH 2 ) n C(O )R a , 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 Alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 ring Alkyl, -(CH 2 ) n C(O)
- R is selected from hydrogen, deuterium , halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally deuterium, halogen
- R is selected from hydrogen , deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14 aryl and 5-14 membered heteroaryl, optionally replaced by deuterium, hal
- R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl or 5-14 membered heteroaryl; and
- x is an integer of 0 to 3, preferably 0, 1 or 2, more preferably 0 or 1;
- n is an integer of 0 to 3, preferably 0, 1 or 2, more preferably 0 or 1;
- the acid in the acid salt is an inorganic acid or an organic acid; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxy Benzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-Acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamate, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucosinolate
- said R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , -(CH 2 ) n C(O) Ra , 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1- 6 hydroxyalkyl, C 3-8 cycloalkyl, -(CH 2 )
- R a is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl , C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1 -3 alkoxy, C 1-3 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally deuterium, hal
- R is selected from hydrogen, halogen, amino, cyano, C 1-3 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1 -6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -(CH 2 ) n C(O)R a , 3 containing 1-3 atoms selected from nitrogen, oxygen or sulfur -8-membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur, the amino group, C 1-6 alkyl group, C 2- 6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, containing 1-3 3-8 membered heterocyclic group selected from nitrogen, oxygen or sulfur atom, C 6-10 aryl group
- R a is selected from hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 Alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl or a 4-6 membered heterocyclic group containing 1-2 selected from N or O, the amino C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl or 1 -2 4-6 membered heterocyclic groups selected from N or O, optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, C 1-3 alkyl, C 1-3 Deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C
- R is selected from the following groups :
- R is selected from hydrogen , deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, amino, cyano, fluorine, chlorine, bromine, methyl, isopropyl, trifluoromethyl, methoxy, cyclopropyl or morpholine base;
- R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Base, C 6-10 aryl or 5-1. membered heteroaryl, preferably hydrogen or cyano.
- the acid in the acid salt is selected from isethionic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalene disulfonic acid, methanesulfonic acid, hydrobromic acid, ethanesulfonic acid, phosphoric acid, Benzenesulfonic acid, oxalic acid, maleic acid, adipic acid, hydrochloric acid, citric acid, malonic acid, L-malic acid, pamoic acid, p-toluenesulfonic acid or fumaric acid; preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or ethanesulfonic acid.
- the acid salt of the compound is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, 1 is further preferred.
- the acid salt of the compound is a hydrate or anhydrous; when the acid salt is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.
- the acid salt of the compound, the acid salt is a crystalline form
- the crystal form is the compound 2-(2-(tert-butyl)-5-oxopyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl)-N Acid salt crystal form of -(5-fluoropyridin-2-yl)acetamide;
- compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e]pyrimidine is provided -4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide mesylate form A, ethanesulfonate form A, sulfate form A-B, hydrochloride Crystal forms A-B and hydrobromide salt forms A-C.
- the acid salt crystal form of the compound is mesylate salt crystal form A, and its X-ray powder diffraction pattern has a diffraction peak at 13.7 ⁇ 0.2°; or at 21.9 ⁇ 0.2° or have a diffraction peak at 20.4 ⁇ 0.2°; or have a diffraction peak at 15.4 ⁇ 0.2°; or have a diffraction peak at 19.6 ⁇ 0.2°; or have a diffraction peak at 16.4 ⁇ 0.2°; Or have a diffraction peak at 9.3 ⁇ 0.2°; or have a diffraction peak at 5.3 ⁇ 0.2°; or have a diffraction peak at 7.9 ⁇ 0.2°; or have a diffraction peak at 11.9 ⁇ 0.2°; preferably included in the above-mentioned diffraction peaks Any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them ;
- the X-ray powder diffraction pattern of mesylate salt crystal form A contains at least one or more diffraction peaks at 2 ⁇ of 13.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 21.9 ⁇ 0.2°, preferably two of them strips, more preferably comprising three strips; optionally, it may further comprise at least one of the One, preferably including 2, 3, 4 or 5 of them;
- the X-ray powder diffraction pattern of the mesylate salt crystal form A optionally further comprises a position at 2 ⁇ of 7.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 21.0 ⁇ 0.2°,
- One or more diffraction peaks in 23.3 ⁇ 0.2°, 24.1 ⁇ 0.2° preferably at least include any 2-3, or 4-5, or 6-7 of them; more preferably, include at least any 2 of them , 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the mesylate salt crystal form A includes 2 ⁇ at 5.3 ⁇ 0.2°, 7.9 ⁇ 0.2°, 9.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.7 ⁇ 0.2°, 13.9 ⁇ 0.2 °, 15.4 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.1 ⁇ 0.2
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3, 2-e]Pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide mesylate salt form A, using Cu-K ⁇ radiation, at 2 ⁇ angle and interplanar spacing
- the X-ray characteristic diffraction peaks represented by d values are shown in Table 1.
- the acid salt crystal form of the compound is ethanesulfonate crystal form A, and its X-ray powder diffraction pattern has a diffraction peak at 15.0 ⁇ 0.2°; or at 21.1 ⁇ Diffraction peak at 0.2°; or diffraction peak at 23.1 ⁇ 0.2°; or diffraction peak at 19.8 ⁇ 0.2°; or diffraction peak at 12.5 ⁇ 0.2°; or diffraction peak at 9.0 ⁇ 0.2° or have a diffraction peak at 12.3 ⁇ 0.2°; or have a diffraction peak at 24.6 ⁇ 0.2°; or have a diffraction peak at 10.3 ⁇ 0.2°; or have a diffraction peak at 6.1 ⁇ 0.2°; preferably include the above-mentioned diffraction peaks Any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them place;
- the X-ray powder diffraction pattern of ethanesulfonate crystal form A contains at least one or more diffraction peaks at 2 ⁇ of 15.0 ⁇ 0.2°, 21.1 ⁇ 0.2°, and 23.1 ⁇ 0.2°, preferably including Two, more preferably three;
- it may further include at least one of 2 ⁇ of 19.8 ⁇ 0.2°, 12.5 ⁇ 0.2°, 9.0 ⁇ 0.2°, 12.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, preferably including 2, 3, 4 or 5 of them;
- the X-ray powder diffraction pattern of ethanesulfonate salt crystal form A optionally further comprises a position at 2 ⁇ of 10.3 ⁇ 0.2°, 6.1 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.2 ⁇ 0.2°, 23.6 ⁇ 0.2° , 30.7 ⁇ 0.2°, 9.6 ⁇ 0.2°, one or more diffraction peaks; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, at least include any 2 place, 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of ethanesulfonic acid salt crystal form A contains 2 ⁇ at 15.0 ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.1 ⁇ 0.2°, 19.8 ⁇ 0.2°, 12.5 ⁇ 0.2°, 9.0 ⁇ One of 0.2°12.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 10.3 ⁇ 0.2°, 6.1 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.2 ⁇ 0.2°, 23.6 ⁇ 0.2°, 30.7 ⁇ 0.2°, 9.6 ⁇ 0.2° or multiple diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Form A of the ethanesulfonate salt of pyrimidin-4(5H)-N-(5-fluoropyridin-2-yl)acetamide, expressed in 2 ⁇ angles and interplanar spacing d values using Cu-K ⁇ radiation
- the X-ray characteristic diffraction peaks are shown in Table 2.
- the acid salt of the compound is sulfate crystal form A, and its X-ray powder diffraction pattern has a diffraction peak at 22.5 ⁇ 0.2°; or has a diffraction peak at 15.9 ⁇ 0.2° or have a diffraction peak at 22.3 ⁇ 0.2°; or have a diffraction peak at 16.8 ⁇ 0.2°; or have a diffraction peak at 22.9 ⁇ 0.2°; or have a diffraction peak at 32.1 ⁇ 0.2°; or have a diffraction peak at 14.0 ⁇ 0.2 or have a diffraction peak at 21.1 ⁇ 0.2°; or have a diffraction peak at 11.2 ⁇ 0.2°; or have a diffraction peak at 26.1 ⁇ 0.2°; preferably include any 2-5 of the above-mentioned diffraction peaks , or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them;
- the X-ray powder diffraction pattern of sulfate crystal form A contains at least one or more diffraction peaks located at 2 ⁇ of 22.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, and 22.3 ⁇ 0.2°, preferably two of them, More preferably, it contains three; optionally, it can further include at least one of 2 ⁇ of 16.8 ⁇ 0.2°, 22.9 ⁇ 0.2°, 32.1 ⁇ 0.2°, 14.0 ⁇ 0.2°, 21.1 ⁇ 0.2°, preferably two of them , 3, 4 or 5;
- the X-ray powder diffraction pattern of the sulfate salt crystal form A optionally further comprises 11.2 ⁇ 0.2°, 26.1 ⁇ 0.2°, 28.2 ⁇ 0.2°, 37.8 ⁇ 0.2°, 15.5 ⁇ 0.2°, One or more diffraction peaks in 26.5 ⁇ 0.2°, 36.4 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7 of them; more preferably, include at least any 2 of them , 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the sulfate salt crystal form A includes 2 ⁇ at 22.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, 22.3 ⁇ 0.2°, 16.8 ⁇ 0.2°, 22.9 ⁇ 0.2°, 32.1 ⁇ 0.2°, One or more of 14.0 ⁇ 0.2°, 21.1 ⁇ 0.2°, 11.2 ⁇ 0.2°, 26.1 ⁇ 0.2°, 28.2 ⁇ 0.2°, 37.8 ⁇ 0.2°, 15.5 ⁇ 0.2°, 26.5 ⁇ 0.2°, 36.4 ⁇ 0.2° Diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Form A of sulfate salt of pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide, X- The X-ray characteristic diffraction peaks are shown in Table 3.
- the acid salt of the compound is sulfate crystal form B, and its X-ray powder diffraction pattern has a diffraction peak at 15.3 ⁇ 0.2°; or has a diffraction peak at 21.5 ⁇ 0.2° or have a diffraction peak at 10.6 ⁇ 0.2°; or have a diffraction peak at 19.8 ⁇ 0.2°; or have a diffraction peak at 20.1 ⁇ 0.2°; or have a diffraction peak at 12.6 ⁇ 0.2°; or have a diffraction peak at 25.2 ⁇ 0.2 or have a diffraction peak at 9.2 ⁇ 0.2°; or have a diffraction peak at 9.9 ⁇ 0.2°; or have a diffraction peak at 23.4 ⁇ 0.2°; preferably include any 2-5 of the above-mentioned diffraction peaks , or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them;
- the X-ray powder diffraction pattern of sulfate crystal form B contains at least one or more diffraction peaks located at 2 ⁇ of 15.3 ⁇ 0.2°, 21.5 ⁇ 0.2°, and 10.6 ⁇ 0.2°, preferably two of them, More preferably, it contains three; optionally, it can further include at least one of 2 ⁇ of 19.8 ⁇ 0.2°, 20.1 ⁇ 0.2°, 12.6 ⁇ 0.2°, 25.2 ⁇ 0.2°, 9.2 ⁇ 0.2°, preferably two of them , 3, 4 or 5;
- the X-ray powder diffraction pattern of the sulfate crystal form B optionally further comprises One or more diffraction peaks in 0.2°, 16.3 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, at least include any 2, 3 place, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of sulfate salt crystal form B includes 15.3 ⁇ 0.2°, 21.5 ⁇ 0.2°, 10.6 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.1 ⁇ 0.2°, 12.6 ⁇ 0.2°, One or more of 25.2 ⁇ 0.2°, 9.2 ⁇ 0.2°, 9.9 ⁇ 0.2°, 23.4 ⁇ 0.2°, 6.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 23.9 ⁇ 0.2°, 33.8 ⁇ 0.2°, 16.3 ⁇ 0.2° Diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Form B of sulfate salt of pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide, X-
- Table 4 The X-ray characteristic diffraction peaks are shown in Table 4.
- the acid salt of the compound is hydrochloride crystal form A, and its X-ray powder diffraction pattern has a diffraction peak at 15.0 ⁇ 0.2°; or has a diffraction peak at 23.9 ⁇ 0.2° or have a diffraction peak at 9.7 ⁇ 0.2°; or have a diffraction peak at 5.3 ⁇ 0.2°; or have a diffraction peak at 24.8 ⁇ 0.2°; or have a diffraction peak at 29.5 ⁇ 0.2°; or have a diffraction peak at 7.5 ⁇ 0.2°
- the X-ray powder diffraction pattern of hydrochloride crystal form A contains at least one or more diffraction peaks located at 2 ⁇ of 15.0 ⁇ 0.2°, 23.9 ⁇ 0.2°, 9.7 ⁇ 0.2°, preferably two of them , more preferably include three; optionally, further may include at least one of 2 ⁇ of 5.3 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.5 ⁇ 0.2°, 7.5 ⁇ 0.2°, 21.8 ⁇ 0.2°, preferably including 2 strips, 3 strips, 4 strips or 5 strips;
- the X-ray powder diffraction pattern of the hydrochloride salt form A optionally further comprises One or more diffraction peaks in ⁇ 0.2°, 28.4 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7 of them; more preferably, at least include any 2, 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the hydrochloride salt crystal form A contains 2 ⁇ at 15.0 ⁇ 0.2°, 23.9 ⁇ 0.2°, 9.7 ⁇ 0.2°, 5.3 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.5 ⁇ 0.2° , 7.5 ⁇ 0.2°, 21.8 ⁇ 0.2°, 21.3 ⁇ 0.2°, 10.6 ⁇ 0.2°, 16.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 18.4 ⁇ 0.2°, 25.8 ⁇ 0.2°, 28.4 ⁇ 0.2° or Multiple diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide hydrochloride salt form A, using Cu-K ⁇ radiation, X in terms of 2 ⁇ angle and interplanar spacing d value - Ray characteristic diffraction peaks are shown in Table 5.
- the acid salt of the compound is hydrochloride crystal form B
- the X-ray powder diffraction pattern of hydrochloride crystal form B has a diffraction peak at 15.9 ⁇ 0.2°; or at 22.2° Diffraction peak at ⁇ 0.2°; or diffraction peak at 5.2 ⁇ 0.2°; or diffraction peak at 21.7 ⁇ 0.2°; or diffraction peak at 26.0 ⁇ 0.2°; or diffraction peak at 4.6 ⁇ 0.2° or have a diffraction peak at 28.4 ⁇ 0.2°; or have a diffraction peak at 9.2 ⁇ 0.2°; or have a diffraction peak at 17.3 ⁇ 0.2°; or have a diffraction peak at 15.2 ⁇ 0.2°; preferably include the above-mentioned diffraction Any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the peaks, more preferably including any 6, 7 or 8 places;
- the X-ray powder diffraction pattern of hydrochloride crystal form B contains at least one or more diffraction peaks located at 2 ⁇ of 15.9 ⁇ 0.2°, 22.2 ⁇ 0.2°, 5.2 ⁇ 0.2°, preferably two of them , more preferably include three; optionally, further may include at least one of 2 ⁇ at 21.7 ⁇ 0.2°, 26.0 ⁇ 0.2°, 4.6 ⁇ 0.2°, 28.4 ⁇ 0.2°, 9.2 ⁇ 0.2°, preferably including 2 strips, 3 strips, 4 strips or 5 strips;
- the X-ray powder diffraction pattern of the hydrochloride salt crystal form B optionally further comprises a position at 2 ⁇ of 17.3 ⁇ 0.2°, 15.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, 38.0 ⁇ 0.2°, 20.3 ⁇ 0.2° , 23.8 ⁇ 0.2°, 29.5 ⁇ 0.2°, one or more diffraction peaks; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, at least include any 2 place, 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the hydrochloride salt crystal form B includes 2 ⁇ at 15.9 ⁇ 0.2°, 22.2 ⁇ 0.2°, 5.2 ⁇ 0.2°, 21.7 ⁇ 0.2°, 26.0 ⁇ 0.2°, 4.6 ⁇ 0.2° , 28.4 ⁇ 0.2°, 9.2 ⁇ 0.2°, 17.3 ⁇ 0.2°, 15.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, 38.0 ⁇ 0.2°, 20.3 ⁇ 0.2°, 23.8 ⁇ 0.2°, 29.5 ⁇ 0.2°, or Multiple diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the acid salt crystal form of the compound is hydrobromide salt crystal form A, and its X-ray powder diffraction pattern has a diffraction peak at 5.3 ⁇ 0.2°; or at 22.7 ⁇ 0.2° or have a diffraction peak at 14.8 ⁇ 0.2°; or have a diffraction peak at 10.5 ⁇ 0.2°; or have a diffraction peak at 22.5 ⁇ 0.2°; or have a diffraction peak at 28.0 ⁇ 0.2°; Or have a diffraction peak at 30.0 ⁇ 0.2°; or have a diffraction peak at 23.4 ⁇ 0.2°; or have a diffraction peak at 23.3 ⁇ 0.2°; or have a diffraction peak at 26.5 ⁇ 0.2°; preferably include the above-mentioned diffraction peaks Any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them ;
- the X-ray powder diffraction pattern of hydrobromide crystal form A contains at least one or more diffraction peaks located at 2 ⁇ of 5.3 ⁇ 0.2°, 22.7 ⁇ 0.2°, and 14.8 ⁇ 0.2°, preferably two of them Strips, more preferably three strips;
- at least one of 2 ⁇ of 10.5 ⁇ 0.2°, 22.5 ⁇ 0.2°, 28.0 ⁇ 0.2°, 30.0 ⁇ 0.2°, 23.4 ⁇ 0.2° can be included, preferably included 2, 3, 4 or 5 strips;
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form A optionally further comprises a position at 2 ⁇ of 23.3 ⁇ 0.2°, 26.5 ⁇ 0.2°, 34.9 ⁇ 0.2°, 15.8 ⁇ 0.2°, 25.0 ⁇ 0.2°, One or more diffraction peaks in 31.9 ⁇ 0.2°, 37.0 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, include any 2, 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form A comprises 2 ⁇ at 5.3 ⁇ 0.2°, 22.7 ⁇ 0.2°, 14.8 ⁇ 0.2°, 10.5 ⁇ 0.2°, 22.5 ⁇ 0.2°, 28.0 ⁇ 0.2°, 30.0 ⁇ 0.2°, 23.4 ⁇ 0.2°, 23.3 ⁇ 0.2°, 26.5 ⁇ 0.2°, 34.9 ⁇ 0.2°, 15.8 ⁇ 0.2°, 25.0 ⁇ 0.2°, 31.9 ⁇ 0.2°, 37.0 ⁇ 0.2°
- One or more diffraction peaks preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form A using Cu-K ⁇ radiation, expressed in 2 ⁇ angle and interplanar spacing d value X-ray characteristic diffraction peaks are shown in Table 7.
- the acid salt of the compound is hydrobromide crystal form B, and its X-ray powder diffraction pattern has a diffraction peak at 23.4 ⁇ 0.2°; or has a diffraction peak at 15.9 ⁇ 0.2° Diffraction peak; or have a diffraction peak at 16.2 ⁇ 0.2°; or have a diffraction peak at 14.2 ⁇ 0.2°; or have a diffraction peak at 5.3 ⁇ 0.2°; or have a diffraction peak at 10.6 ⁇ 0.2°; or have a diffraction peak at 23.1
- the X-ray powder diffraction pattern of hydrobromide salt crystal form B includes at least one or more diffraction peaks at 2 ⁇ of 23.4 ⁇ 0.2°, 15.9 ⁇ 0.2°, and 16.2 ⁇ 0.2°, preferably including Two of them, more preferably including three;
- it can further include at least one of 2 ⁇ being 14.2 ⁇ 0.2°, 5.3 ⁇ 0.2°, 10.6 ⁇ 0.2°, 23.1 ⁇ 0.2°, 24.1 ⁇ 0.2°, preferably Contains 2, 3, 4 or 5 of these;
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form B optionally further comprises a position at 2 ⁇ of 14.8 ⁇ 0.2°, 9.5 ⁇ 0.2°, 16.9 ⁇ 0.2°, 13.9 ⁇ 0.2°, 29.5 ⁇ 0.2°, One or more diffraction peaks in 32.2 ⁇ 0.2°, 22.2 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, include any 2, 3 places, 4 places, 5 places, 6 places, 7 places;
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form B includes 2 ⁇ at 23.4 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 14.2 ⁇ 0.2°, 5.3 ⁇ 0.2°, 10.6 ⁇ 0.2 °, 23.1 ⁇ 0.2°, 24.1 ⁇ 0.2°, 14.8 ⁇ 0.2°, 9.5 ⁇ 0.2°, 16.9 ⁇ 0.2°, 13.9 ⁇ 0.2°, 29.5 ⁇ 0.2°, 32.2 ⁇ 0.2°, 22.2 ⁇ 0.2° or multiple diffraction peaks, preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form B using Cu-K ⁇ radiation, expressed in 2 ⁇ angle and interplanar spacing d value X-ray characteristic diffraction peaks are shown in Table 8.
- the acid salt of the compound is hydrobromide crystal form C, and its X-ray powder diffraction pattern has a diffraction peak at 5.2 ⁇ 0.2°; or has a diffraction peak at 15.7 ⁇ 0.2°; or Have a diffraction peak at 22.3 ⁇ 0.2°; or have a diffraction peak at 10.5 ⁇ 0.2°; or have a diffraction peak at 17.4 ⁇ 0.2°; or have a diffraction peak at 38.0 ⁇ 0.2°; or have a diffraction peak at 26.3 ⁇ 0.2°
- the X-ray powder diffraction pattern of hydrobromide crystal form C contains at least one or more diffraction peaks located at 2 ⁇ of 5.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, and 22.3 ⁇ 0.2°, preferably two of them Strips, more preferably three strips;
- at least one of 2 ⁇ of 10.5 ⁇ 0.2°, 17.4 ⁇ 0.2°, 38.0 ⁇ 0.2°, 26.3 ⁇ 0.2°, 28.0 ⁇ 0.2° can be included, preferably included 2, 3, 4 or 5 strips;
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form C comprises 5.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 22.3 ⁇ 0.2°, 10.5 ⁇ 0.2°, 17.4 ⁇ 0.2°, 38.0 ⁇ 0.2 °, 26.3 ⁇ 0.2°, 28.0 ⁇ 0.2°, one or more diffraction peaks, preferably, including optional 4, 5, 6 or 8 diffraction peaks;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridine[3,2-e] Pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form C, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle and interplanar spacing d value X-ray characteristic diffraction peaks are shown in Table 9.
- the relative peak intensity is the top ten diffraction peak positions and the 2 ⁇ error of the diffraction peak at the corresponding position in Figure 1 is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°.
- a in the X-ray powder diffraction pattern relative peak intensity is the top ten diffraction peak positions and
- the 2 ⁇ error of the diffraction peak corresponding to the position in Fig. 1 is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the relative peak intensity is the top ten diffraction peak positions and the corresponding positions in Figure 4
- the 2 ⁇ error of the peak is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the relative peak intensity is the position of the top ten diffraction peaks and the corresponding position of the diffraction peaks in Figure 12
- the 2 ⁇ error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl )-N-(5-fluoropyridin-2-yl)acetamide hydrochloride crystal form B X-ray powder diffraction pattern relative peak intensity for the top ten diffraction peak position and the corresponding position of the diffraction peak in Figure 15
- the 2 ⁇ error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl )-N-(5-fluoropyridin-2-yl) acetamide hydrobromide crystal form A X-ray powder diffraction pattern relative peak intensity for the top ten diffraction peak positions and corresponding position diffraction peaks in Figure 16
- the 2 ⁇ error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide crystal form B X-ray powder diffraction pattern relative peak intensity for the top ten diffraction peak positions and corresponding position diffraction peaks in Figure 18
- the 2 ⁇ error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°;
- the compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl In the X-ray powder diffraction pattern of the hydrobromide crystal form C of )-N-(5-fluoropyridin-2-yl)acetamide, the relative peak intensity is the top ten diffraction peak positions and the corresponding position diffraction peaks in Figure 21
- the 2 ⁇ error is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2°.
- the acid salt crystal form of the above compound is a hydrate or anhydrate, and when the acid salt crystal form is a hydrate, the number of water is 0.2-3, preferably 0.2, 0.5, 1 , 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3; further, the water in the hydrate is pipeline water or crystal water or a combination of both.
- the preparation method of the above-mentioned acid salt comprises the following steps:
- the solvent is an organic solvent, preferably methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, isopropyl acetate, tert-butanol, n-butanol, acetone, 2-butanone, dichloromethane, ethyl acetate or 1, At least one of 4-dioxane;
- Acid selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid , Acetohydroxamic Acid, Adipic Acid, Benzenesulfonic Acid, 4-Chlorobenzenesulfonic Acid, Benzoic Acid, 4-Acetamidobenzoic Acid, 4-Aminobenzoic Acid, Capric Acid, Caproic Acid, Caprylic Acid, Cinnamic Acid, Citric Acid , Cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric
- the preparation method of the acid salt of the above-mentioned compound and its crystal form comprises the following steps:
- the solvent is an organic solvent, preferably methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, isopropyl acetate, tert-butanol, n-butanol, acetone, 2-butanone, dichloromethane, ethyl acetate or 1, At least one of 4-dioxane;
- Acid selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid , Acetohydroxamic Acid, Adipic Acid, Benzenesulfonic Acid, 4-Chlorobenzenesulfonic Acid, Benzoic Acid, 4-Acetamidobenzoic Acid, 4-Aminobenzoic Acid, Capric Acid, Caproic Acid, Caprylic Acid, Cinnamic Acid, Citric Acid , Cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric
- the present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which contains a therapeutically effective amount of the acid salt of the above compound or its crystal form, and one or more pharmaceutically acceptable carriers and diluents or excipients.
- the present invention further relates to the use of any acid salt of the compound of general formula (I-a) or its crystal form or the pharmaceutical composition in the preparation of P2X3 inhibitor drugs.
- the pharmaceutically acceptable salts of the compounds of the present invention and their crystal forms or compositions are used in the preparation of drugs for the treatment of neurogenic diseases; preferably, the neurogenic diseases are selected from gynecological diseases, urinary tract A disease state, a respiratory disorder or a pain-related disease or condition, more preferably endometriosis, overactive bladder, pulmonary fibrosis or chronic cough.
- said pain-related disease or condition is selected from neuropathic pain or pain or discomfort associated with uterine fibroids.
- Another object of the present invention is to provide a method for preparing pyrazole-containing polycyclic derivatives
- general formula (I) is:
- R 1 , R 2 , and R 3 are independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy radical, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, heteroaryloxy or -(CH 2 ) n1 C(O) R a ;
- R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl radical, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, heteroaryloxy, or -( CH2 ) n1C (O) Ra ;
- R is selected from hydrogen or a protecting group
- the protecting group can be an amino protecting group, such as a common amino protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, p-toluenesulfonyl, trityl, methyl Acyl, trifluoroacetyl, etc.;
- the compound of the general formula (I) whose R is a protecting group it can be obtained by reacting the compound of the general formula (I) whose R is H with a corresponding protecting reagent, and the protecting group can be removed as required;
- R is selected from hydrogen, deuterium , halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, hetero Cycloalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl or heteroaryloxy;
- n1 0, 1, 2, 3 or 4;
- R 5 is not -C(CH 3 ) 3 or -COOCH 3 ;
- R 1 is -CF 3
- R 2 , R 3 , R 4 and R 6 are hydrogen at the same time
- R 5 is not -CH 2 CH 3 , H or Br
- R 4 is not -CN.
- the present invention provides a compound of general formula (I-1), general formula (I-1) is:
- the structure of the compound is selected from formula (I-1-1), formula (I-1-2) or formula (I-1-3):
- R is selected from hydrogen, deuterium, halogen, cyano, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 haloalkyl or C 1-8 haloalkoxy;
- cyano Preferably cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy;
- R is selected from hydrogen, deuterium , halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy or -C (O) R a ;
- R is selected from hydrogen, deuterium , halogen, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy;
- the present invention provides a kind of preparation method of the compound of general formula (I) or the compound of general formula (I '), comprising step (a):
- the reaction is optionally carried out in the presence of an acid, the acid is preferably hydrochloric acid, more preferably an organic solution of hydrochloric acid, the concentration of hydrochloric acid in the organic solution of hydrochloric acid can be 1 to 10M/L, preferably 3 to 6M /L, more preferably 4M/L, the molar ratio of the acid to the compound of general formula (II) is more than 1, preferably 1 to 5:1, more preferably 3:1;
- the reaction is optionally carried out in a solvent, the solvent is preferably an organic solvent, and the concentration of the compound of general formula (II) in the solvent is 0.05g/ml ⁇ 0.5g/ml;
- the organic solvent is preferably dioxane, tetrahydrofuran, toluene, methyl tetrahydrofuran, ethyl acetate, trimethylbenzene, ethylene glycol, methanol, ethanol, isopropanol or dimethyl ether, more preferably dioxane;
- the organic solvent can also preferably be N,N dimethylformamide, N,N dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, more preferably N,N dimethylformamide;
- the molar ratio of the compound of general formula (III) to the compound of general formula (II) may be 0.5-5.0:1, preferably 1-1.5:1, more preferably 1.2:1;
- the reaction temperature may be -20-200°C, preferably 50-150°C, more preferably 80-120°C, further preferably 105-110°C;
- the reaction time may be 1 to 48 hours, preferably 10 to 30 hours, more preferably 16 to 24 hours;
- the M 1 and M 2 are independently selected from H, Li, Na, K or Cs, M 1 is preferably H, and M 2 is preferably Na or K;
- R 1 , R 2 , R 3 , R 4 , and R 5 are as described for the compound of general formula (I) or (I-1).
- the present invention also provides a method for preparing a compound of general formula (VII), comprising step (b):
- the compound of general formula (I) reacts with the compound of general formula (VI) to obtain the compound of general formula (VII);
- the molar ratio of the compound of the general formula (VI) to the compound of the general formula (I) may be 0.8-3:1, preferably 0.9-1.2:1, more preferably 1:1;
- reaction is optionally carried out in the presence of a base
- reaction is optionally carried out in a solvent
- the base is preferably one or more of organic bases and inorganic bases; more preferably one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, DIPEA, DBU, DABCO , the molar ratio of the base to the compound of general formula (I) is more than 1, preferably 1 to 10:1, more preferably 2:1;
- the solvent is preferably an organic solvent, more preferably one or more of DMF, DMA, THF; further preferably one or more of DMF, DMA, the concentration of the compound of general formula (I) in the solvent 0.05g/ml ⁇ 0.5g/ml;
- the temperature of the reaction may be 0-50°C, preferably 20-25°C or 45°C;
- X is halogen; preferably fluorine, chlorine or bromine; more preferably chlorine or bromine;
- L 1 is selected from -(CH 2 ) n2 -, -(CH 2 ) n2 O-, -(CH 2 ) n2 S-, -(CH 2 ) n2 NR c -, -(CH 2 ) n2 C(O) NR c -or -(CH 2 ) n2 NR c C(O)-; preferably -CH 2 C(O)NH-;
- R b and R c are independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl radical, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl or heteroaryloxy;
- the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl , aryloxy, heteroaryl, heteroaryloxy, -(CH 2 ) n2 -(-(CH 2 ) n2 - can also be -(CH 2 ) n2 O-, -(CH 2 ) n2 S -, -(CH 2 ) n 2 NR c -, -(CH 2 ) n 2 C(O)NR c - or -(CH 2 ) n 2 NR c C(O)- the alkylene chain in), optionally Hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl,
- Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably and / or,
- the compound of general formula (VI) is preferably more preferably is further preferably
- R 1 , R 2 , R 3 , R 4 , and R 5 are as described in the compound of general formula (I) or (I-1);
- the preparation method of the compound of general formula (VII) further includes the step of preparing the compound of general formula (I).
- the present invention also provides a method for preparing a compound of general formula (I-3), comprising step (c-1):
- the compound of the general formula (I-2) is subjected to an amination reduction reaction under the condition of ammonia gas or an ammonia gas equivalent to obtain a compound of the general formula (I-3);
- the ammonia gas equivalent is an organic solution of ammonia or ammonia water;
- the organic solution of ammonia is preferably a methanol solution of ammonia, an ethanol solution of ammonia, an isopropanol solution of ammonia or a dioxane solution of ammonia;
- the compound of general formula (I-2) carries out amination reduction reaction under the condition of ammoniacal liquor and/or the organic solution of ammonia, obtains the compound of general formula (I-3); More preferably, general formula (I- 2) the compound is subjected to an amination reduction reaction under the conditions of ammonia water and/or methanol solution of ammonia to obtain a compound of general formula (I-3);
- the reaction temperature can be 0-50°C, preferably room temperature 25°C;
- the reaction time is 1 to 72 hours, preferably 48 to 60 hours;
- R a is selected from hydrogen, deuterium, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy or heteroaryloxy; the alkoxy, haloalkoxy, aryloxy, heteroaryl Oxygen, optionally replaced by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne
- R 1 , R 2 , R 3 , R 4 , and R 6 are as described for the compound of general formula (I) or (I-1).
- the present invention also provides a method for preparing a compound of general formula (I-4), comprising step (d-1):
- the dehydrating agent is preferably one or more of acetic anhydride, trifluoroacetic anhydride, P 2 O 5 , cyanuric chloride, phosphorus oxychloride, phosphorus trichloride, and concentrated sulfuric acid.
- the molar ratio of the compound of formula (I-3) is 1 or more, preferably 1-10:1, more preferably 2-2.5:1;
- the reaction is optionally carried out in the presence of pyridine, and the molar ratio of the pyridine to the compound of general formula (I-3) is 1 or more, preferably 1-10:1, more preferably 2.5-3:1; More preferably 3:1;
- the reaction is optionally carried out in a solvent;
- the solvent is preferably an organic solvent, more preferably one or more of DMF, DMA, THF; further preferably one or more of DMF, THF, so
- the compound concentration of general formula (I-3) in the solvent is 0.05g/ml ⁇ 0.5g/ml;
- the temperature of the reaction may be -20 to 80°C, preferably room temperature;
- the reaction time is 0.1 to 10 hours, preferably 0.5 to 4 hours, more preferably 1 to 2 hours;
- R 1 , R 2 , R 3 , R 4 , and R 6 are as defined in general formula (I) or (I -1) Compounds described.
- the present invention also relates to a preparation method of a compound of general formula (VII-4), characterized in that, the structure of the compound of general formula (VII-4) is:
- L 1 , x, R b , ring A, R 1 , R 2 , R 3 , and R 4 are as described for the compound of general formula (I) or (I-1) and the compound of general formula (VII);
- Described preparation method comprises the following steps:
- the present invention also provides a compound of the general formula (I), a compound of the general formula (II) and a compound of the general formula (III), the compound of the general formula (I), the compound of the general formula (II) and the compound of the general formula
- the compound of (III) is used as an intermediate for the preparation of P2X3 inhibitors, such as substances with P2X3 inhibitory activity disclosed in patent PCT/CN2020/134264, which is incorporated in this application in its entirety.
- the P2X3 inhibitor is preferably a P2X3 inhibitor containing a core structure of 4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine, more preferably a general formula (VII- 4) compound;
- L 1 , x, R b , ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , M 1 , M 2 are defined as compounds of general formula (I) or (I-1), The compound of general formula (I') and the compound of general formula (VII) are described.
- the present invention also relates to the preparation method of the compound of general formula (II') or the compound of general formula (V'), the method also includes step (e) and/or step (c); or optionally further includes step (g),
- the base is preferably LDA, butyllithium or hydroxide Sodium etc.;
- the solvent is preferably tetrahydrofuran, toluene, ethylene glycol dimethyl ether or dichloromethane;
- the molar ratio of the compound of formula (II-1) to the base is 1:1-10, preferably 1:1-5, more preferably 1:1-1.5;
- the solvent is preferably hydrazine hydrate, methanol, ethanol, isopropanol or tert-butanol;
- the molar ratio of the compound of formula (II-2) to hydrazine hydrate is 1:1-10, preferably 1:1-5, more preferably 1:1-1.5;
- the molar ratio of the compound of formula (V-1) to acetonitrile is 1:1-10, preferably 1:1-5, more preferably 1:1-1.5;
- R 1 , R 2 , R 3 , R 4 , and R 5 are as described for the compound of general formula (I) or (I-1).
- the preparation method of pyrazole-containing polycyclic derivatives of the present invention avoids the use of expensive raw materials such as pyrazolamide derivatives and noble metal catalysts, the reaction raw materials are cheap and easy to obtain, the cost is low, the reaction conditions are mild, and the yield is high. Mature, stable quality, suitable for industrial scale-up, more in line with the requirements of safety and environmental protection.
- alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group, most preferably an alkyl group of 1 to 3 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
- lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
- Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
- Deuterated alkyl refers to an alkyl group in which one or more hydrogens have been replaced by deuterium, wherein alkyl is as defined above.
- alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, and the like.
- alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
- Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
- Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- the membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiroheterocyclic groups or nitrogen-containing condensed heterocyclic groups.
- Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, Dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepine Cycloheptyl, pyranyl or tetrahydrothiopyranyl dioxide, etc., preferably oxetanyl, thietanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl , tetrahydrothio
- the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
- Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
- the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
- Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
- Aryloxy means -O-(aryl), wherein aryl is as defined above.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
- Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidyl, thiadiazole, pyridazinyl, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, furyl, thienyl, pyridazinyl, pyrazinyl or thiazoly
- Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- Heteroaryloxy means -O-(heteroaryl), wherein heteroaryl is as defined above.
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, alkoxy can is optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Thio group, carboxyl
- alkylthio refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkylthio include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy
- alkylthio can be is optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane
- Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above; eg trifluoromethyl.
- Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
- Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
- alkenyl refers to alkenyl, also known as alkenyl, wherein said alkenyl can be further substituted by other related groups, such as: hydrogen, deuterium, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkane radical, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, heterocyclyl, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
- Alkynyl refers to (CH ⁇ C-), wherein said alkynyl group can be further substituted by other related groups, such as: hydrogen, deuterium, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Heterocyclyl, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
- other related groups such as: hydrogen, deuterium, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy
- alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
- alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
- Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- Haldroxy means an -OH group.
- Halogen means fluorine, chlorine, bromine or iodine.
- Amino refers to -NH2 .
- Cyano refers to -CN.
- Niro refers to -NO2 .
- Carbonyl refers to -C(O)-.
- Carboxy refers to -C(O)OH.
- Alcohol solvents refer to alkane compounds containing hydroxyl groups in their molecules, such as methanol, ethanol, and isopropanol.
- THF tetrahydrofuran
- EtOAc means ethyl acetate
- MeOH means methanol
- DMF N,N-dimethylformamide
- TFA trifluoroacetic acid
- MeCN refers to acetonitrile
- DMA refers to N,N-dimethylacetamide.
- Et2O means diethyl ether.
- DCE 1,2 dichloroethane
- DIPEA N,N-diisopropylethylamine
- DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.
- DABCO refers to 1,4-diazabicyclo[2.2.2]octane.
- NBS N-bromosuccinimide
- NIS N-iodosuccinimide
- Cbz-Cl refers to benzyl chloroformate
- Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
- Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
- HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
- KHMDS refers to potassium hexamethyldisilazide
- LiHMDS refers to lithium bistrimethylsilylamide.
- MeLi means methyllithium
- n-BuLi refers to n-butyllithium
- NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
- X is selected from A, B, or C
- X is selected from A, B, and C
- X is A, B, or C
- X is A, B, and C
- many of the multiple, multiple, etc. refer to 2, 3, 4, 5, 6, 7, etc.
- the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
- Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
- Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
- “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
- X-ray powder diffraction pattern refers to the experimentally observed diffraction pattern or the parameters derived from it, and the X-ray powder diffraction pattern is characterized by peak position (abscissa) and peak intensity (ordinate).
- peak position abcissa
- peak intensity ordinate
- the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor.
- the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, those skilled in the art can understand that any crystal form having the same or similar characteristic peaks as the spectrum of the present invention falls within the scope of the present invention.
- Figure 1 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide methanesulfonate Form A.
- Figure 2 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of Form A of )-N-(5-fluoropyridin-2-yl)acetamide mesylate salt.
- Figure 3 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl TGA diagram of Form A of )-N-(5-fluoropyridin-2-yl)acetamide mesylate salt.
- Figure 4 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide ethanesulfonate Form A.
- Figure 5 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of Form A of )-N-(5-fluoropyridin-2-yl)acetamide ethanesulfonate salt.
- Figure 6 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl TGA diagram of Form A of )-N-(5-fluoropyridin-2-yl)acetamide ethanesulfonate salt.
- Figure 7 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide sulfate salt Form A.
- Figure 8 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide sulfate salt Form A.
- Figure 9 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide sulfate salt Form B.
- Figure 10 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide sulfate salt form B.
- Figure 11 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl TGA diagram of )-N-(5-fluoropyridin-2-yl)acetamide sulfate salt Form B.
- Figure 12 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrochloride Form A.
- Figure 13 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrochloride Form A.
- Figure 14 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl TGA diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrochloride Form A.
- Figure 15 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrochloride Form B.
- Figure 16 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form A.
- Figure 17 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of Form A of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt.
- Figure 18 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form B.
- Figure 19 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form B.
- Figure 20 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl TGA diagram of Form B of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt.
- Figure 21 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide hydrobromide salt form C.
- Figure 22 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD pattern of )-N-(5-fluoropyridin-2-yl)acetamide free base Form I.
- Figure 23 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide free base Form I.
- Figure 24 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl XRPD diagram of )-N-(5-fluoropyridin-2-yl)acetamide free base Form II.
- Figure 25 is 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl DSC diagram of )-N-(5-fluoropyridin-2-yl)acetamide free base Form II.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
- the determination of NMR is to use Bruker AVANCE-400 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is four Methylsilane (TMS).
- Agilent 1200 Infinity Series mass spectrometer was used for LC-MS determination.
- the determination of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 ⁇ 4.6mm chromatographic column).
- Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
- the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- HPLC detection method among the present invention is as follows:
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
- Example 1-2 To a solution of Example 1-2 (1.5 g, 6.19 mmol) in DMF (30 mL) was added potassium carbonate (4.28 g, 30.96 mmol) and Example 1-3 (4.33 g, 18.57 mmol) at room temperature. The mixture was heated to 80°C and the reaction was stirred for 2h. After cooling, water was added, the precipitate was filtered and washed with ethyl acetate, purified to obtain Example 1 (656 mg, yield: 27%).
- Example 2 (100mg, 0.24mmol), isopropenylboronic acid (41.2mg, 0.48mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex ( 19.2mg, 0.024mmol) and cesium carbonate (232.8mg, 0.72mmol) in dioxane (4mL) and water (1mL) were stirred at 100°C for 1 hour by microwave. The reaction solution was spin-dried and purified by preparative liquid phase to obtain Example 6 (54 mg, yield 60%).
- Step 1 Preparation of 5-oxo-4,5-dihydropyrazol[1,5-a]pyridin[3,2-e]pyrimidine-2-carboxylic acid methyl
- Example 8-1 refers to the synthetic method of Example 1-2, replace 3-(tert-butyl)-1H-pyrazole-5 with 5-amino-1H-pyrazole-3-carboxylic acid methyl ester -Amine, to obtain Example 8-1 (500 mg, 73%).
- Example 8-2 For the synthesis method of Example 8-2, refer to the synthesis method of Example 1, and use Example 8-1 as the raw material to obtain the title compound Example 8-2 (500 mg, 51%).
- the third step 4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-5-oxo-4,5-dihydropyrazol[1,5-a] Preparation of pyridin[3,2-e]pyrimidine-2-carboxylic acid
- Example 8-2 To a solution of Example 8-2 (490 mg, 1.24 mmol) in tetrahydrofuran (10 mL) was added a solution of LiOH (519 mg, 12.36 mmol) in water (2 mL) at room temperature. The mixture was stirred at room temperature for 3 h, then the pH was adjusted to about 3 with 1M HCl, and concentrated to dryness to obtain Example 8-3 (470 mg, 99%).
- Example 8-3 450 mg, 1.2 mmol
- Et3N 33 ⁇ L, 0.24 mmol
- BOP reagent 598 mg, 1.35 mmol
- Sodium azide 160 mg, 2.46 mmol
- tetrabutylammonium bromide 786 mg, 2.46 mmol
- the reaction was then diluted with 1,4-dioxane (12 mL), 2M aqueous H 2 SO 4 (4 mL) was added, and heated at 100° C. for 2 h.
- Example 8 (360 mg, 86%).
- Example 9 The synthesis method of Example 9, referring to the synthesis method of Example 6, replaced ethylene propylene boronic acid with cyclopropylboronic acid to obtain the title compound Example 9 (8mg, 51%).
- Example 10 For the synthesis method of Example 10, refer to the synthesis method of Example 1, and use 2-chloro-6-trifluoromethylnicotinic acid as a raw material to obtain the title compound Example 10 (25 mg, 46%).
- Example 11 The synthesis method of Example 11 was referred to the synthesis method of Example 2 to obtain the title compound Example 11 (18 mg, 30%).
- Step 1 Preparation of tert-butyl 5-amino-3-ethyl-1H-pyrazole-1-carboxylate
- the second step the preparation of tert-butyl 5-amino-3-ethyl-1H-pyrazole-1-carboxylate
- Example 12-1 (3.4g, 16.1mmol) was dissolved in anhydrous dichloromethane (60mL), triethylamine (5.4g, 53.1mmol) was added, and the now-prepared 2- Chloro-6-trifluoromethylnicotinic acid chloride (4.3g, 17.7mmol) in dichloromethane solution (50mL) was added and reacted at room temperature for 30 minutes.
- the reaction solution was washed with water (200mL*2) and saturated sodium chloride solution (200mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the third step the preparation of N-(3-ethyl-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide
- Example 12-2 Dissolve Example 12-2 (2.6g, 6.2mmol) in anhydrous dichloromethane (10mL), add dioxane hydrochloride solution (4M, 20mL), and react at room temperature for 4 hours. The reaction solution was directly spin-dried to obtain Example 12-3 (1.9 g), yield: 96.0%.
- Example 12-3 (1.9g, 6.0mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (2.5g, 18.0mmol) was added, and heated to 120°C for 2 hours. The reaction solution was cooled to room temperature and used directly in the next reaction.
- the fifth step 2-(2-ethyl-5-oxo-8-(trifluoromethyl)pyrazol[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl )-N-(5-fluoropyridin-2-yl)acetamide
- Example 12-4 In the N,N-dimethylformamide (20mL) reaction solution of Example 12-4 (1.0g, 3.5mmol), add potassium carbonate (1.5g, 10.6mmol) and 2-bromo-N-(5- Fluoropyridin-2-yl)acetamide (0.99g, 4.2mmol) was reacted at 40°C for 2 hours.
- the reaction solution was cooled to room temperature, poured into 300 mL of water, and extracted with ethyl acetate (200 mL*3).
- Example 12 The organic phases were combined, washed with water (200mL*2) and saturated sodium chloride solution (200mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate to obtain Example 12.
- Example 13 The synthesis method of Example 13 was referred to the synthesis method of Example 1 to obtain the title compound Example 13 (17 mg, 28%).
- Example 14 The synthesis method of Example 14 was referred to the synthesis method of Example 4 to obtain the title compound Example 31 (10 mg, 22%).
- Step 1 Preparation of tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate
- 3-Bromo-1H-pyrazol-5-amine (10.0 g, 61.7 mmol) was dissolved in anhydrous dichloromethane (100 mL), triethylamine (7.48 g, 74.1 mmol) and di-tert-butyl dicarbonate were added (16.0 g, 74.1 mmol), react at room temperature for 16 hours.
- the second step the preparation of tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate
- Example 15-1 (14.5 g, 55.3 mmol) was dissolved in anhydrous dichloromethane (200 mL), and triethylamine ( 18.5g, 183mmol), under the protection of nitrogen, add dropwise the dichloromethane solution (50mL) of the now prepared 2-chloro-6-trifluoromethyl nicotinic acid chloride (13.0g, 61.0mmol) at 0°C, and react at room temperature 30 minutes.
- the third step the preparation of N-(3-bromo-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide
- Example 15-3 (6.2 g, 16.8 mmol) was dissolved in N,N- Potassium carbonate (6.96 g, 50.4 mmol) was added to dimethylformamide (80 mL), and heated to 120° C. for 2 hours. The reaction solution was cooled to room temperature and used directly in the next reaction.
- the fifth step 2-(2-bromo-5-oxo-8-(trifluoromethyl)pyrazol[1,5-a]pyridin[3,2-e]pyrimidin-4(5H)-yl)- Preparation of N-(5-fluoropyridin-2-yl)acetamide
- Example 16 The synthesis method of Example 16 was referred to the synthesis method of Example 1 to obtain the title compound Example 16 (10 mg, 33%).
- the first step 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e]pyrimidine-4(5H)- base)-N-(5-fluoropyridin-2-yl)acetamide
- Example 15 (300mg, 0.619mmol) and Zn(CN) 2 (300mg, 2.56mmol), Pd 2 (dba) 3 (20mg, 0.022mmol), Pd(dppf)Cl 2 (30mg, 0.036mmol) were mixed at room temperature ) and Zn powder (10 mg, 0.154 mmol) were dissolved in DMA (10 mL), and nitrogen was blown inward for 2 minutes. Then microwave heating at 140°C for 8 hours. Cool to room temperature, and extract with ethyl acetate (50 mL), and wash the organic phase twice with saturated brine. The organic phase was dried ( Na2SO4 ) , concentrated under reduced pressure and sent to p-HPLC (FA) to give 100 mg (38% yield) of the title compound.
- the title compound can also be prepared by:
- the third step 2-cyano-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine preparation
- Example 18-1 (2.0 g, 90%).
- the second step the preparation of pyrazol[1,5-a]pyridin[3,2-e]pyrimidin-5(4H)-one
- Example 18-2 To a solution of Example 18-2 (1.5 g, 8.06 mmol) in DMF (30 mL) were added potassium carbonate (2.23 g, 16.11 mmol) and Example 1-3 (2.25 g, 9.67 mmol) at room temperature. The mixture was heated to 80°C and the reaction was stirred for 2h. After cooling, water was added, the precipitate was filtered and washed with ethyl acetate, purified to obtain Example 18 (2.1 g, yield: 78%).
- Example 19 Referring to the method of Example 1, the target compound (31 mg, 26 % yield).
- Step 1 Preparation of tert-butyl 5-amino-4-cyano-1H-pyrazole-1-carboxylate
- Example 20-1 Dissolve tert-butyl 5-amino-4-cyano-1H-pyrazole-1-carboxylate
- Example 20-1 (3.5 g, 16.8 mmol) in anhydrous dichloromethane (50 mL) and add triethylamine (5.35g, 7.37mmol), under the protection of nitrogen, add dropwise the dichloromethane solution (50mL) of the now prepared 2-chloro-6-trifluoromethyl nicotinic acid chloride (4.3g, 17.6mmol) at 0 °C, and add React at room temperature for 1 hour.
- the third step the preparation of 2-chloro-N-(4-cyano-1H-pyrazol-5-yl)-6-(trifluoromethyl)nicotinamide
- Step 4 Preparation of 5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyridin[3,2-e]pyrimidine-3-carbonitrile
- Example 20-4 (500mg, 1.79mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (371mg, 2.69mmol) and 2-bromo-N-(5-fluoropyridin-2-yl)acetamide were added (501mg, 2.15mmol), react at 40°C for 2 hours. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (50 mL*2).
- Example 22-1 100 mg, 0.22 mmol (the synthesis method of Example 21-1 refers to
- Example 8-2 To a solution of Example 8-2) in THF (2 mL) was added diisobutylaluminum hydride (1M in toluene, 0.66 mL, 0.66 mmol), and the mixture was stirred at room temperature overnight. Rochelle's salt solution (1.0M, 5ml) was added; ethyl acetate (5mL) was then added, the resulting suspension was stirred at room temperature until separation of the clear phases was achieved, the organic phase was separated and the aqueous phase was extracted with EtOAc (3 x 40ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified to obtain the title compound (32 mg, 34% yield).
- Test example 1 Determination of the influence of the compound of the present invention on the flow capacity of calcium ions in cells stably expressing 1321N1-hP2X3 receptors
- the purpose of the experiment to determine the inhibitory activity of the compound on the 1321N1-hP2X3 receptor.
- 384-well-cell plate (Corning; 3712); 384-well-compound plate (Corning; 3657);
- DMEM Gibco; 11965
- FBS Gibco; 10099-141
- Hygromycin B (Invitrogen, 10687010); Matrix (Thermo; 5416);
- DMSO (Sigma; D2650); HBSS (Invitrogen; 14025);
- ⁇ , ⁇ -meATP (Sigma; M6517); ATP hydrolytic enzyme (Sigma; A7646);
- Assay buffer 1*HBSS+20mM HEPES;
- Cell culture medium DMEM+10%FBS+75 ⁇ g/mL hygromycin B+300 ⁇ g/mL G418;
- Plating medium DMEM+10%DPBS
- Cell lines are cultured in cell culture medium at 37°C, 5% CO 2 to 70% to 90% confluence, discard the medium, take out the cells, add 2mL Versene, place in a 37°C incubator for 2-5min, add 10mL for plating Cells were collected in the culture medium, counted, and 50 ⁇ L (1 ⁇ 10 4 cells/well density) was added to each well and seeded into a 384-well test plate and incubated for 16-24 hours (at least overnight).
- On-machine detection Take 15 ⁇ L of 3X compound from each well and add it to the cell plate, add the sample to the FLIPR instrument, and detect the calcium signal. After 15 minutes, add 22.5 ⁇ L of the 3X agonist (EC 80 concentration) to each well to detect the calcium signal.
- Calcium signal values were read by FLIPR.
- the calculated output of each sampling time point in the experiment is the ratio of 340/510nm to 380/510nm wavelength signals.
- the maximum minus minimum calculation is derived from the ratio signal curve.
- IC50 values of compounds were calculated by fitting percent inhibition and ten-point concentration data to parametric nonlinear logic formulas using GraphPad prism.
- Test Example 2 Determination of the Effects of Compounds of the Present Invention on Calcium Ion Flow Capacity in Cells Stably Expressing 1321N1-hP2X2/3 Receptors
- the purpose of the experiment to determine the inhibitory activity of the compound on the 1321N1-hP2X2/3 receptor.
- 384-well-cell plate (Corning; 3712); 384-well-compound plate (Corning; 3657);
- DMEM Gibco; 11965
- FBS Gibco; 10099-141
- Hygromycin B (Invitrogen, 10687010); Matrix (Thermo; 5416);
- DMSO (Sigma; D2650); HBSS (Invitrogen; 14025);
- ⁇ , ⁇ -meATP (Sigma; M6517); ATP hydrolytic enzyme (Sigma; A7646);
- Assay buffer 1*HBSS+20mM HEPES;
- Cell culture medium DMEM+10%FBS+75 ⁇ g/mL hygromycin B+150 ⁇ g/mL G418;
- Plating medium DMEM+10%DPBS
- Cell lines are cultured in cell culture medium at 37°C, 5% CO 2 to 70% to 90% confluence, discard the medium, take out the cells, add 2mL Versene, place in a 37°C incubator for 2-5min, add 10mL for plating Cells were collected in the culture medium, counted, and 50 ⁇ L (1 ⁇ 10 4 cells/well density) was added to each well and seeded into a 384-well test plate and incubated for 16-24 hours (at least overnight).
- On-machine detection Take 15 ⁇ L of 3X compound from each well and add it to the cell plate, add the sample to the FLIPR instrument, and detect the calcium signal. After 15 minutes, add 22.5 ⁇ L of the 3X agonist (EC 80 concentration) to each well to detect the calcium signal.
- Calcium signal values were read by FLIPR.
- the calculated output of each sampling time point in the experiment is the ratio of 340/510nm to 380/510nm wavelength signals.
- the maximum minus minimum calculation is derived from the ratio signal curve.
- IC50 values of compounds were calculated by fitting percent inhibition and ten-point concentration data to parametric nonlinear logic formulas using GraphPad prism.
- Test example 3 Balb/C mouse pharmacokinetic determination
- Test drug the embodiment of the present invention, self-made.
- HEC hydroxyethyl cellulose
- CMC-Na viscosity: 800-1200Cps
- Tween80 10g
- liquid A is 0.1% formic acid aqueous solution
- liquid B is acetonitrile
- Test example 4 rat pharmacokinetic determination
- Test drug the embodiment of the present invention, self-made.
- HEC hydroxyethyl cellulose
- CMC-Na viscosity: 800-1200Cps
- Tween80 10g
- liquid A is 0.1% formic acid aqueous solution
- liquid B is acetonitrile
- the purpose of this experiment is to test the stability of the compounds of the examples in mice, rats, dogs and human liver microsomes.
- liver microsome working solution dilute with 100mM phosphate buffer to a final concentration of 0.625mg/mL.
- NADPH and UDPGA Weigh NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronic acid), add 100 mM phosphate buffer, and the final concentration is 20 mM.
- reaction termination solution cold acetonitrile containing 100ng/mL labetalol hydrochloride and 400ng/mL tolbutamide as internal standard.
- liver microsomes 0.5mg/mL compound 1 ⁇ M NADPH 2mM UDPGA 2mM Alamethicin 2.5 ⁇ g/mL
- Ion source electrospray ionization source (ESI); dry gas: N 2 , temperature 500°C;
- Electrospray voltage 5000V; detection method: positive ion detection;
- Experimental purpose The purpose of this experimental method is to detect the plasma protein binding of the compounds of the examples in plasma.
- the ion source is an electrospray ionization source (ESI); the drying gas (N 2 ) temperature is 500°C;
- the electrospray voltage is 5500V; the detection method is positive ion detection;
- the scanning method is selective reaction monitoring (MRM); the scanning time is 0.1s.
- Test example 7 CYP enzyme single-point inhibition test
- Solution preparation 2.5mM NADPH, weigh 4.165mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) and add 100mM phosphate buffer to 2mL. 0.25mg/mL microsomes, 50 ⁇ L 20mg/mL microsomes, add 4mL 100mM phosphate buffer, mix well.
- NADPH reduced nicotinamide adenine dinucleotide phosphate
- test compound reaction solution Weigh the test compound, dilute to 10 mM with DMSO, and then dilute to 100 ⁇ M with 100 mM phosphate buffer.
- CHO-hERG cells were cultured in a 175cm 2 culture flask. When the cell density grew to 60-80%, the culture medium was removed, washed once with 7mL PBS, and then digested by adding 3mL Detachin.
- the single-cell high-impedance sealing and whole-cell pattern formation processes are all automatically completed by the Qpatch instrument.
- the cell After obtaining the whole-cell recording pattern, the cell is clamped at -80 mV, before giving a 5-second +40 mV depolarization stimulus , give a pre-voltage of -50 mV for 50 milliseconds, then repolarize to -50 mV for 5 seconds, and then return to -80 mV. Apply this voltage stimulus every 15 seconds, record for 2 minutes, give extracellular fluid for recording for 5 minutes, and then start the administration process.
- the compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes. At least 3 cells are tested for each concentration. (n ⁇ 3).
- the highest test concentration is 40 ⁇ M, and there are 6 concentrations in total of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 ⁇ M respectively.
- the experimental reagents used were purchased from Sigma, with a purity of >98%
- Table 21 The results of inhibition of hERG current by the compounds of the examples at multiple concentrations hERG results
- Inhibition of cardiac hERG potassium channels by drugs is the main cause of long QT syndrome caused by drugs. It can be seen from the experimental results that the compound of the embodiment of the present invention has no obvious inhibitory effect on the heart hERG potassium ion channel, and can avoid the cardiotoxic side effects at high doses.
- mice BALB/c mice, 6-8 weeks old, ⁇ , purchased from Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.
- mice were randomly divided into groups according to the requirements according to body weight, and water and food were deprived 12-16 hours before administration.
- Drug administration and animal quinine drinking water test drug administration and fasting: on the day of the experiment, the animals were weighed, fasted, litter changed, and administered according to the experimental design.
- Rate of dysgeusia (Drinking water is quinine hydrochloric acid aqueous solution and given to the test drug group ⁇ pWW-drinking water is quinine hydrochloric acid aqueous solution and given solvent to the control group ⁇ pWW)/(Drinking water is ultrapure water and given solvent at the same time
- the control group ⁇ pWW-drinking water is quinine hydrochloric acid aqueous solution and the solvent control group ⁇ pWW) ⁇ 100%.
- Test example 10 drug effect study on guinea pig acute cough induced by citric acid
- the purpose of this experiment is to evaluate the efficacy of the compound in the acute cough model of guinea pigs induced by citric acid.
- Cough induction method put the guinea pig into the whole-body volume scanning box to adapt to it for 3-5 minutes, then perform 2 minutes of ATP atomization, with an interval of 3 minutes, and then give 5 minutes of citric acid atomization. From the start of citric acid nebulization, record the number of coughs and cough latency of animals within 10 minutes.
- test compound was administered to guinea pigs by single gavage 2 hours before citric acid nebulization, and placed in the breath plethysmography cavity of DSI Buxco whole body plethysmography detection system (WBP) at the scheduled time for citric acid nebulization to induce cough. From the start of citric acid nebulization, the WBP system recorded the total number of coughs (CCnt) and cough latency (CIP) of guinea pigs within 10 minutes.
- WBP whole body plethysmography detection system
- Mobile phase A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)
- Salt formation by dissolution or suspension reaction Weigh 10 mg of compound 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyridin[3,2-e ]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide, add solvent 200 ⁇ L ⁇ 400 ⁇ L, heat and stir at 40 ⁇ 50°C, add different acids respectively, stir overnight, drop to room temperature, filtered and dried to obtain the salt of the compound.
- liquid A is 0.1% formic acid aqueous solution
- liquid B is acetonitrile
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Abstract
Description
序号 | 2θ(±0.2°) |
1 | 5.328 |
2 | 7.917 |
3 | 9.277 |
4 | 11.865 |
5 | 13.674 |
6 | 13.852 |
7 | 15.444 |
8 | 16.353 |
9 | 17.584 |
10 | 18.763 |
11 | 19.553 |
12 | 20.422 |
13 | 20.967 |
14 | 21.921 |
15 | 23.346 |
16 | 24.093 |
17 | 24.819 |
18 | 25.503 |
成分 | 含量 |
肝微粒体 | 0.5mg/mL |
化合物 | 1μM |
NADPH | 2mM |
UDPGA | 2mM |
Alamethicin | 2.5μg/mL |
试剂名称 | 厂家 | 货号 |
羧甲基纤维素钠 | Sigma | C5678 |
吐温80 | Sigma | P4780 |
ATP | Sigma | A2383 |
柠檬酸 | Sigma | C2404 |
仪器名称 | 型号 |
分析天平 | METTLER TOLEDO XA105 |
纯水机 | Milli-Q Plus,Millipore |
高效液相色谱仪 | Agilent1260 |
泵 | Agilent G1311B |
进样器 | G1329B |
柱温箱 | G1316A |
检测器 | G1315D |
T(min) | A(%) | B(%) |
0.00 | 60 | 40 |
12.00 | 25 | 75 |
12.01 | 60 | 40 |
15.00 | 60 | 40 |
名称 | 型号 | 来源 |
分析天平 | XA105 | METTLER TOLEDO |
超声波清洗仪 | SK5200LHC | 上海科导超声仪器 |
移液枪 | Eppendorf(50mL,100μL) | Eppendorf |
仪器 | Thermo Ultimate 3000 |
稀释剂 | DMSO |
色谱柱 | Waters x-bridge(150*4.6mm,3.5um) |
流动相 | A:25mM Phosphate buffer(NH 4H 2PO 4,pH2.0),B:MeOH |
进样体积 | 5μL |
流速 | 1.0ml/min |
柱温箱稳定 | 35℃ |
运行时间 | 12min |
梯度洗脱时间(min) | B相(体积百分数) |
0 | 50 |
10 | 80 |
10.01 | 50 |
12 | 50 |
仪器 | Agilent 1200 |
稀释剂 | DMSO |
色谱柱 | ZIC-HILIC(150*4.6mm,5μm) |
流动相 | A:75mM醋酸铵溶液(pH4.80)、B:乙腈(A:B=30:70) |
进样体积 | 5μL |
流速 | 1.0ml/min |
ELSD温度 | 80℃ |
运行时间(min) | 10 |
仪器型号 | SMS Intrinsic |
实验温度 | 25℃ |
干燥时间 | 0%RH 120min |
平衡dm/dt | 0.02%/min(最小10min,最大180min) |
RH(%)测量步长 | 10% |
测量梯度 | 0-95-0% |
循环次数 | 2 |
Claims (20)
- 通式(I-a)所示化合物或其立体异构体的酸式盐,其中:R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、-(CH 2) nC(O)R a、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、-(CH 2) nC(O)R a、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地被氘、卤素、氨基、羟基、氰基、硝基、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代;R a选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基,所述的氨基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基,任选地被氘、卤素、氨基、硝基、羟基、氰基、羧基、氧代基、硫代基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地被氘、卤素、氨基、羟基、氰基、硝基、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟 烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代;R 3选自氢、氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-8环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基;且x为0~3的整数,优选0、1或2,更优选0或1;n为0~3的整数,优选0、1或2,更优选0或1;酸式盐中的酸为无机酸或有机酸;优选地,无机酸选自盐酸、硫酸、硝酸、氢溴酸、氢氟酸、氢碘酸或磷酸;有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、乙烷磺酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙烷磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸或L-苹果酸;优选盐酸、硫酸、磷酸、乙烷磺酸、苯磺酸、甲磺酸、富马酸、羟乙基磺酸、草酸或氢溴酸。
- 根据权利要求1或2所述的酸式盐,其特征在于,R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) nC(O)R a、3-8元杂环基、C 6-10芳基或5-10元杂芳基,所述的 氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) nC(O)R a、3-8元杂环基、C 6-10芳基和5-10元杂芳基,任选地被氘、卤素、氨基、羟基、氰基、硝基、氧代基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;R a选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基,所述的氨基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基,任选地被氘、卤素、氨基、硝基、羟基、氰基、羧基、氧代基、硫代基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;优选地,R 1选自氢、卤素、氨基、氰基、C 1-3烷基、C 2-6烯基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) nC(O)R a、含1-3个选自氮、氧或硫原子的3-8元杂环基、C 6-10芳基或含1-3个选自氮、氧或硫原子5-10元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、-(CH 2) nC(O)R a、C 3-8环烷基、含1-3个选自氮、氧或硫原子的3-8元杂环基、C 6-10芳基或含1-3个选自氮、氧或硫原子5-10元杂芳基,任选地被氘、卤素、氨基、羟基、氰基、硝基、氧代基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;R a选自氢、氘、卤素、氨基、氰基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 3-6环烷基或含1-2个选自N或O的4-6元杂环基,所述的氨基C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 3-6环烷基或含1-2个选自N或O的4-6元杂环基,任选地被氘、卤素、氨基、羟基、氰基、硝基、氧代基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;更优选地,R 1选自以下基团:R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基,优选氢、氨基、氰基、氟、氯、溴、甲基、异丙基、三氟甲基、甲氧基、环丙基或吗啉基;R 3选自氢、氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-1.元杂芳基,优选氢或氰基。
- 根据权利要求1-4任一项所述的酸式盐,其特征在于,酸式盐中酸的个数为0.2-3;优选0.2、0.5、1、1.5、2、2.5或3;更优选0.5、1、2或3,进一步优选1。
- 根据权利要求1-5任一项所述的酸式盐,其特征在于,酸式盐为水合物或无水物;当酸式盐为水合物时,水的个数为0.2-3;优选0.2、0.5、1、1.5、2、2.5或3;更优选0.5、1、2或3。
- 根据权利要求1-6任一项所述的酸式盐,其特征在于,所述酸式盐为晶型;优选地,晶型为化合物2-(2-(叔丁基)-5-氧吡唑并[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;2-(2-(叔丁基)-5-氧代-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;2-(2-乙基-5-氧代-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;2-(2-环丙基-5-氧代-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;2-(2,5-二甲基吡啶-4-基)-5-氧代-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;N-(5-氟吡啶-2-基)-2-(2-(1-甲基环丙基)-5-氧代-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)乙酰胺的酸式盐晶型;2-(2-溴-5-氧-8-(三氟甲基)吡唑[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;2-(2-氰基-5-氧代-8-(三氟甲基)吡唑并[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;N-(5-氟吡啶-2-基)-2-(5-氧代-8-(三氟甲基)吡唑并[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)乙酰胺的酸式盐晶型;2-(3-氰基-5-氧代-8-(三氟甲基)吡唑并[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型;更优选地,酸式盐晶型为羟乙基磺酸盐晶型、硫酸盐晶型、盐酸盐晶型、1,5-萘二磺酸盐晶型、甲磺酸盐晶型、乙烷磺酸盐晶型、氢溴酸盐晶型、磷酸盐晶型、苯磺酸盐晶型、草酸盐晶型、马来酸盐晶型、己二酸盐晶型、盐酸盐晶型、柠檬酸盐晶型、丙二酸盐晶型、L-苹果酸盐晶型、帕莫酸盐晶型、对甲苯磺酸盐晶型或富马酸盐晶型。
- 根据权利要求7所述的酸式盐晶型,其特征在于,2-(2-氰基-5-氧代-8-(三氟甲基)吡唑并[1,5-a]吡啶[3,2-e]嘧啶-4(5H)-基)-N-(5-氟吡啶-2-基)乙酰胺的酸式盐晶型为:甲磺酸盐晶型A,其X-射线粉末衍射图谱在13.7±0.2°处具有衍射峰;或者在21.9±0.2°处具有衍射峰;或者在20.4±0.2°处具有衍射峰;或者在15.4±0.2°处 具有衍射峰;或者在19.6±0.2°处具有衍射峰;或者在16.4±0.2°处具有衍射峰;或者在9.3±0.2°处具有衍射峰;或者在5.3±0.2°处具有衍射峰;或者在7.9±0.2°处具有衍射峰;或者在11.9±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,甲磺酸盐晶型A的X-射线粉末衍射图谱至少包含位于2θ为13.7±0.2°、16.4±0.2°、21.9±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为13.9±0.2°、20.4±0.2°、15.4±0.2°、5.3±0.2°、11.9±0.2°、9.3±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,甲磺酸盐晶型A的X-射线粉末衍射图谱任选还包含位于2θ为7.9±0.2°、19.6±0.2°、17.6±0.2°、18.8±0.2°、21.0±0.2°、23.3±0.2°、24.1±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,甲磺酸盐晶型A的X-射线粉末衍射图谱包含位于2θ为5.3±0.2°、7.9±0.2°、9.3±0.2°、11.9±0.2°、13.7±0.2°、13.9±0.2°、15.4±0.2°、16.4±0.2°、17.6±0.2°、18.8±0.2°、19.6±0.2°、20.4±0.2°、21.0±0.2°、21.9±0.2°、23.3±0.2°、24.1±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,甲磺酸盐晶型A的X-射线粉末衍射图谱如图1所示;或其DSC图谱基本如图2所示,或其TGA图谱基本如图3所示;或,为乙烷磺酸盐晶型A,其X-射线粉末衍射图谱在15.0±0.2°处具有衍射峰;或者在21.1±0.2°处具有衍射峰;或者在23.1±0.2°处具有衍射峰;或者在19.8±0.2°处具有衍射峰;或者在12.5±0.2°处具有衍射峰;或者在9.0±0.2°处具有衍射峰;或者在12.3±0.2°处具有衍射峰;或者在24.6±0.2°处具有衍射峰;或者在10.3±0.2°处具有衍射峰;或者在6.1±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,乙烷磺酸盐晶型A的X-射线粉末衍射图谱至少包含位于2θ为15.0±0.2°、21.1±0.2°、23.1±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为19.8±0.2°、12.5±0.2°、9.0±0.2°、12.3±0.2°、24.6±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,乙烷磺酸盐晶型A的X-射线粉末衍射图谱任选还包含位于2θ为10.3±0.2°、6.1±0.2°、16.1±0.2°、19.2±0.2°、23.6±0.2°、30.7±0.2°、9.6±0.2° 中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,乙烷磺酸盐晶型A的X-射线粉末衍射图谱包含位于2θ为15.0±0.2°、21.1±0.2°、23.1±0.2°、19.8±0.2°、12.5±0.2°、9.0±0.2°12.3±0.2°、24.6±0.2°、10.3±0.2°、6.1±0.2°、16.1±0.2°、19.2±0.2°、23.6±0.2°、30.7±0.2°、9.6±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,乙烷磺酸盐晶型A的X-射线粉末衍射图谱如图4所示;或其DSC图谱基本如图5所示,或其TGA图谱基本如图6所示;或,为硫酸盐晶型A,其X-射线粉末衍射图谱在22.5±0.2°处具有衍射峰;或者在15.9±0.2°处具有衍射峰;或者在22.3±0.2°处具有衍射峰;或者在16.8±0.2°处具有衍射峰;或者在22.9±0.2°处具有衍射峰;或者在32.1±0.2°处具有衍射峰;或者在14.0±0.2°处具有衍射峰;或者在21.1±0.2°处具有衍射峰;或者在11.2±0.2°处具有衍射峰;或者在26.1±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,硫酸盐晶型A的X-射线粉末衍射图谱至少包含位于2θ为22.5±0.2°、15.9±0.2°、22.3±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为16.8±0.2°、22.9±0.2°、32.1±0.2°、14.0±0.2°、21.1±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,硫酸盐晶型A的X-射线粉末衍射图谱任选还包含位于2θ为11.2±0.2°、26.1±0.2°、28.2±0.2°、37.8±0.2°、15.5±0.2°、26.5±0.2°、36.4±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,硫酸盐晶型A的X-射线粉末衍射图谱包含位于2θ为22.5±0.2°、15.9±0.2°、22.3±0.2°、16.8±0.2°、22.9±0.2°、32.1±0.2°、14.0±0.2°、21.1±0.2°、11.2±0.2°、26.1±0.2°、28.2±0.2°、37.8±0.2°、15.5±0.2°、26.5±0.2°、36.4±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,硫酸盐晶型A的X-射线粉末衍射图谱如图7所示;或其DSC图谱基本如图8所示;或,为硫酸盐晶型B,其X-射线粉末衍射图谱在15.3±0.2°处具有衍射峰;或者在21.5±0.2°处具有衍射峰;或者在10.6±0.2°处具有衍射峰;或者在19.8±0.2°处具有衍射峰;或者在20.1±0.2°处具有衍射峰;或者在12.6±0.2°处具有衍射峰;或者在25.2±0.2°处具有衍射峰;或者在9.2±0.2°处具有衍射峰;或者在9.9±0.2° 处具有衍射峰;或者在23.4±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,硫酸盐晶型B的X-射线粉末衍射图谱至少包含位于2θ为15.3±0.2°、21.5±0.2°、10.6±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为19.8±0.2°、20.1±0.2°、12.6±0.2°、25.2±0.2°、9.2±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,硫酸盐晶型B的X-射线粉末衍射图谱任选还包含位于2θ为9.9±0.2°、23.4±0.2°、6.3±0.2°、16.7±0.2°、23.9±0.2°、33.8±0.2°、16.3±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,硫酸盐晶型B的X-射线粉末衍射图谱包含位于2θ为15.3±0.2°、21.5±0.2°、10.6±0.2°、19.8±0.2°、20.1±0.2°、12.6±0.2°、25.2±0.2°、9.2±0.2°、9.9±0.2°、23.4±0.2°、6.3±0.2°、16.7±0.2°、23.9±0.2°、33.8±0.2°、16.3±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,硫酸盐晶型B的X-射线粉末衍射图谱如图9所示;或其DSC图谱基本如图10所示,或其TGA图谱基本如图11所示;或,为盐酸盐晶型A,其X-射线粉末衍射图谱在15.0±0.2°处具有衍射峰;或者在23.9±0.2°处具有衍射峰;或者在9.7±0.2°处具有衍射峰;或者在5.3±0.2°处具有衍射峰;或者在24.8±0.2°处具有衍射峰;或者在29.5±0.2°处具有衍射峰;或者在7.5±0.2°处具有衍射峰;或者在21.8±0.2°处具有衍射峰;或者在21.3±0.2°处具有衍射峰;或者在10.6±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,盐酸盐晶型A的X-射线粉末衍射图谱至少包含位于2θ为15.0±0.2°、23.9±0.2°、9.7±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为5.3±0.2°、24.8±0.2°、29.5±0.2°、7.5±0.2°、21.8±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,盐酸盐晶型A的X-射线粉末衍射图谱任选还包含位于2θ为21.3±0.2°、10.6±0.2°、16.9±0.2°、16.0±0.2°、18.4±0.2°、25.8±0.2°、28.4±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,盐酸盐晶型A的X-射线粉末衍射图谱包含位于2θ为15.0±0.2°、23.9±0.2°、9.7±0.2°、5.3±0.2°、24.8±0.2°、29.5±0.2°、7.5±0.2°、21.8±0.2°、 21.3±0.2°、10.6±0.2°、16.9±0.2°、16.0±0.2°、18.4±0.2°、25.8±0.2°、28.4±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,盐酸盐晶型A的X-射线粉末衍射图谱如图12所示;或其DSC图谱基本如图13所示,或其TGA图谱基本如图14所示;或,为盐酸盐晶型B,其X-射线粉末衍射图谱在15.9±0.2°处具有衍射峰;或者在22.2±0.2°处具有衍射峰;或者在5.2±0.2°处具有衍射峰;或者在21.7±0.2°处具有衍射峰;或者在26.0±0.2°处具有衍射峰;或者在4.6±0.2°处具有衍射峰;或者在28.4±0.2°处具有衍射峰;或者在9.2±0.2°处具有衍射峰;或者在17.3±0.2°处具有衍射峰;或者在15.2±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,盐酸盐晶型B的X-射线粉末衍射图谱至少包含位于2θ为15.9±0.2°、22.2±0.2°、5.2±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为21.7±0.2°、26.0±0.2°、4.6±0.2°、28.4±0.2°、9.2±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,盐酸盐晶型B的X-射线粉末衍射图谱任选还包含位于2θ为17.3±0.2°、15.2±0.2°、10.5±0.2°、38.0±0.2°、20.3±0.2°、23.8±0.2°、29.5±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,至少包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,盐酸盐晶型B的X-射线粉末衍射图谱包含位于2θ为15.9±0.2°、22.2±0.2°、5.2±0.2°、21.7±0.2°、26.0±0.2°、4.6±0.2°、28.4±0.2°、9.2±0.2°、17.3±0.2°、15.2±0.2°、10.5±0.2°、38.0±0.2°、20.3±0.2°、23.8±0.2°、29.5±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,盐酸盐晶型B的X-射线粉末衍射图谱如图15所示;或,为氢溴酸盐晶型A,其X-射线粉末衍射图谱在5.3±0.2°处具有衍射峰;或者在22.7±0.2°处具有衍射峰;或者在14.8±0.2°处具有衍射峰;或者在10.5±0.2°处具有衍射峰;或者在22.5±0.2°处具有衍射峰;或者在28.0±0.2°处具有衍射峰;或者在30.0±0.2°处具有衍射峰;或者在23.4±0.2°处具有衍射峰;或者在23.3±0.2°处具有衍射峰;或者在26.5±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,氢溴酸盐晶型A的X-射线粉末衍射图谱至少包含位于2θ为5.3±0.2°、22.7±0.2°、14.8±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三 条;任选的,进一步还可以包含位于2θ为10.5±0.2°、22.5±0.2°、28.0±0.2°、30.0±0.2°、23.4±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,氢溴酸盐晶型A的X-射线粉末衍射图谱任选还包含位于2θ为23.3±0.2°、26.5±0.2°、34.9±0.2°、15.8±0.2°、25.0±0.2°、31.9±0.2°、37.0±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,氢溴酸盐晶型A的X-射线粉末衍射图谱包含位于2θ为5.3±0.2°、22.7±0.2°、14.8±0.2°、10.5±0.2°、22.5±0.2°、28.0±0.2°、30.0±0.2°、23.4±0.2°、23.3±0.2°、26.5±0.2°、34.9±0.2°、15.8±0.2°、25.0±0.2°、31.9±0.2°、37.0±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,氢溴酸盐晶型A的X-射线粉末衍射图谱如图16所示;或其DSC图谱基本如图17所示;或,为氢溴酸盐晶型B,其X-射线粉末衍射图谱在23.4±0.2°处具有衍射峰;或者在15.9±0.2°处具有衍射峰;或者在16.2±0.2°处具有衍射峰;或者在14.2±0.2°处具有衍射峰;或者在5.3±0.2°处具有衍射峰;或者在10.6±0.2°处具有衍射峰;或者在23.1±0.2°处具有衍射峰;或者在24.1±0.2°处具有衍射峰;或者在14.8±0.2°处具有衍射峰;或者在9.5±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,氢溴酸盐晶型B的X-射线粉末衍射图谱至少包含位于2θ为23.4±0.2°、15.9±0.2°、16.2±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为14.2±0.2°、5.3±0.2°、10.6±0.2°、23.1±0.2°、24.1±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,氢溴酸盐晶型B的X-射线粉末衍射图谱任选还包含位于2θ为14.8±0.2°、9.5±0.2°、16.9±0.2°、13.9±0.2°、29.5±0.2°、32.2±0.2°、22.2±0.2°中的一处或多处衍射峰;优选至少包含其中任意2-3处,或者4-5处,或者6-7处;进一步优选,包含其中任意2处、3处、4处、5处、6处、7处;进一步优选地,氢溴酸盐晶型B的X-射线粉末衍射图谱包含位于2θ为23.4±0.2°、15.9±0.2°、16.2±0.2°、14.2±0.2°、5.3±0.2°、10.6±0.2°、23.1±0.2°、24.1±0.2°、14.8±0.2°、9.5±0.2°、16.9±0.2°、13.9±0.2°、29.5±0.2°、32.2±0.2°、22.2±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处、8处或10处有衍射峰;更进一步优选地,氢溴酸盐晶型B的X-射线粉末衍射图谱如图18所示;或 其DSC图谱基本如图19所示;或其TGA图谱基本如图20所示;或,为氢溴酸盐晶型C,其X-射线粉末衍射图谱在5.2±0.2°处具有衍射峰;或者在15.7±0.2°处具有衍射峰;或者在22.3±0.2°处具有衍射峰;或者在10.5±0.2°处具有衍射峰;或者在17.4±0.2°处具有衍射峰;或者在38.0±0.2°处具有衍射峰;或者在26.3±0.2°处具有衍射峰;或者在28.0±0.2°处具有衍射峰;优选包含上述衍射峰中的任意2-5处,或者3-5处,或者3-6处,或者3-8处,或者5-8处,或者6-8处,更优选包含其中任意6处、7处或8处;优选地,氢溴酸盐晶型C的X-射线粉末衍射图谱至少包含位于2θ为5.2±0.2°、15.7±0.2°、22.3±0.2°中的一处或多处衍射峰,优选包含其中两条,更优选包含三条;任选的,进一步还可以包含位于2θ为10.5±0.2°、17.4±0.2°、38.0±0.2°、26.3±0.2°、28.0±0.2°中的至少一条,优选包含其中2条、3条、4条或5条;更优选地,氢溴酸盐晶型C的X-射线粉末衍射图谱包含位于2θ为5.2±0.2°、15.7±0.2°、22.3±0.2°、10.5±0.2°、17.4±0.2°、38.0±0.2°、26.3±0.2°、28.0±0.2°中的一处或多处衍射峰,优选的,包含其中任选的4处、5处、6处或8处有衍射峰;进一步优选地,氢溴酸盐晶型C的X-射线粉末衍射图谱如图21所示。
- 根据权利要求8所述的酸式盐晶型,其特征在于,各晶型中X-射线粉末衍射图谱中相对峰强度为前十强的衍射峰位置与其对应的X-射线粉末衍射附图位置衍射峰的2θ误差为±0.2°~±0.5°,优选±0.2°~±0.3°,最优选±0.2°。
- 根据权利要求8或9所述的酸式盐晶型,其特征在于,酸式盐晶型为水合物或无水物。
- 制备权利要求1-7任一项所述的酸式盐或权利要求8-10任一项所述的酸式盐晶型的方法,包括如下步骤:1)称取适量的游离碱,加溶剂溶解;2)加入适量的酸,搅拌;3)快速离心或静置得到酸式盐;或者,包括如下步骤:1)称取适量的游离碱,加溶剂溶解;2)加入适量的酸,搅拌;3)离心干燥后,得到酸式盐晶型;溶剂为有机溶剂,优选甲醇、乙醇、四氢呋喃、2-甲基四氢呋喃、甲苯、乙 酸异丙酯、叔丁醇、正丁醇、丙酮、2-丁酮、二氯甲烷、乙酸乙酯或1,4-二氧六环中的至少一种;酸选自盐酸、硫酸、硝酸、氢溴酸、氢氟酸、氢碘酸、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、甲磺酸、乙烷磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸或L-苹果酸;优选盐酸、硫酸、磷酸、乙烷磺酸、苯磺酸、甲磺酸、富马酸、羟乙基磺酸、草酸或氢溴酸。
- 一种药物组合物,其含有治疗有效量的权利要求1-7任一项所述的酸式盐或权利要求8-10任一项所述的酸式盐晶型以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
- 根据权利要求1-7中任一项所述的酸式盐或权利要求8-10任一项所述的酸式盐晶型,或权利要求11所述的药物组合物在制备P2X3抑制剂药物中的应用。
- 根据权利要求1-7中任一项所述的酸式盐或权利要求8-10任一项所述的酸式盐晶型,或权利要求11所述的药物组合物在制备治疗神经源性疾病药物中的用途;优选地,所述神经源性疾病选自妇科疾病、泌尿道疾病状态、呼吸障碍疾病或疼痛相关疾病或病症;更优选地,所述神经源性疾病选自子宫内膜异位症、膀胱过度活动症、肺纤维化或慢性咳嗽;所述疼痛相关疾病或病症选自神经性疼痛或子宫肌瘤相关的疼痛或不适。
- 通式(I)的化合物或其药学上可接受的盐:其中:R 1、R 2、R 3分别独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基、杂芳基氧基或-(CH 2) n1C(O)R a;R 4、R 5分别独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基、杂芳基氧基或-(CH 2) n1C(O)R a;R 6选自氢或保护基;R a选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基或杂芳基氧基;所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基、杂芳基氧基、-(CH 2) n1-,任选地被氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧、杂芳基或杂芳基氧基中的一个或多个取代基所取代;n1为0、1、2、3或4;优选地,当R 1、R 2、R 3、R 4及R 6同时为氢时,R 5不为-C(CH 3) 3或-COOCH 3;当R 1为-CF 3,且R 2、R 3、R 4及R 6同时为氢时,R 5不为-CH 2CH 3、H或Br;当R 1为-CF 3,且R 2、R 3、R 5及R 6同时为氢时,R 4不为-CN;更优选地,所述化合物通式(I)的结构如通式(I-1)所示:进一步优选地,所述化合物的结构选自式(I-1-1)、式(I-1-2)或式(I-1-3):其中,R 1选自氢、氘、卤素、氰基、C 1-8烷基、C 1-8烷氧基、C 1-8卤代烷基或C 1-8卤代烷氧基,优选氰基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基或C 1-3卤代烷氧基,更优选甲基、乙基、三氟甲基、甲氧基或氰基;R 5选自氢、氘、卤素、氰基、C 1-8烷基、C 1-8烷氧基、C 1-8卤代烷基、C 1-8卤代烷氧基或-C(O)R a,优选氢、氘、卤素、氰基或-C(O)R a,更优选氢、氘、氟、氯、溴或-C(O)R a;R a选自氢、氘、卤素、氨基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基或C 1-3卤代烷氧基,优选氨基、甲氧基、乙氧基或异丙氧基。
- 一种通式(VII)的化合物的制备方法,其特征在于,包含步骤(b):通式(I)的化合物与通式(VI)的化合物反应得到通式(VII)的化合物;X为卤素;优选为氟、氯或溴;更优选为氯或溴;L 1选自-(CH 2) n2-、-(CH 2) n2O-、-(CH 2) n2S-、-(CH 2) n2NR c-、-(CH 2) n2C(O)NR c-或-(CH 2) n2NR cC(O)-;优选为-CH 2C(O)NH-;n2为0、1、2或3;x为0、1、2或3;R b、R c分别独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基或杂芳基氧基;所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧基、杂芳基、杂芳基氧基、-(CH 2) n2-,任选地被氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧、杂芳基或杂芳基氧基中的一个或多个取代基所取代;R b优选为卤素;R c优选为H;R 1、R 2、R 3、R 4、R 5、R 6的定义如权利要求15所述;任选地,所述通式(VII)的化合物的制备方法中还包括制备通式(I)的化合物的步骤,所述制备通式(I)的化合物的步骤包括权利要求16的制备方法。
- 一种通式(I-3)的化合物的制备方法,其特征在于,包括步骤(c-1):通式(I-2)的化合物在氨气或氨气等价物的条件下进行胺化还原反应,得到通式(I-3)的化合物;所述氨气等价物为氨的有机溶液或氨水;所述氨的有机溶液优选为氨的甲醇溶液、氨的乙醇溶液、氨的异丙醇溶液或氨的二氧六环溶液;R a选自氢、氘、卤素、羟基、烷氧基、卤代烷氧基、芳基氧基或杂芳基氧基;所述的烷氧基、卤代烷氧基、芳基氧基或杂芳基氧基,任选地被氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、杂环基烷基、环烷基、杂环基、芳基、芳基氧、杂芳基或杂芳基氧基中的一个或多个取代基所取代;R 1、R 2、R 3、R 4、R 6的定义如权利要求15所述。
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