CN116354937A - Pyridine (pyrimidine) amine derivative and application thereof - Google Patents
Pyridine (pyrimidine) amine derivative and application thereof Download PDFInfo
- Publication number
- CN116354937A CN116354937A CN202211671622.8A CN202211671622A CN116354937A CN 116354937 A CN116354937 A CN 116354937A CN 202211671622 A CN202211671622 A CN 202211671622A CN 116354937 A CN116354937 A CN 116354937A
- Authority
- CN
- China
- Prior art keywords
- amine
- isobutoxybenzyl
- fluorobenzyl
- formula
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Pyridine (pyrimidine) amine Chemical class 0.000 title claims description 102
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 239000003814 drug Substances 0.000 claims abstract description 17
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 14
- 208000028017 Psychotic disease Diseases 0.000 claims abstract description 7
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 5
- 206010012289 Dementia Diseases 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000003542 behavioural effect Effects 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 abstract description 68
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 abstract description 4
- 229960003634 pimozide Drugs 0.000 abstract description 4
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 3
- 206010000117 Abnormal behaviour Diseases 0.000 abstract description 2
- 206010048610 Cardiotoxicity Diseases 0.000 abstract description 2
- 231100000259 cardiotoxicity Toxicity 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000002360 preparation method Methods 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 27
- 239000002904 solvent Substances 0.000 description 25
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 22
- 239000012528 membrane Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
- 239000000164 antipsychotic agent Substances 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 229940005529 antipsychotics Drugs 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 210000002442 prefrontal cortex Anatomy 0.000 description 7
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000006399 behavior Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- JBVKKHDTYSDPHA-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine Chemical compound CC(C)COC1=CC=C(CN)C=C1 JBVKKHDTYSDPHA-UHFFFAOYSA-N 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 208000010877 cognitive disease Diseases 0.000 description 4
- 238000012875 competitive assay Methods 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 210000003722 extracellular fluid Anatomy 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- PTPTZLXZHPPVKG-UHFFFAOYSA-N 4-bromo-2-fluoropyridine Chemical compound FC1=CC(Br)=CC=N1 PTPTZLXZHPPVKG-UHFFFAOYSA-N 0.000 description 3
- DSUFRPVVBZLHPI-UHFFFAOYSA-N 4-fluoro-n-methoxy-n-methylbenzamide Chemical compound CON(C)C(=O)C1=CC=C(F)C=C1 DSUFRPVVBZLHPI-UHFFFAOYSA-N 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 102000015554 Dopamine receptor Human genes 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 239000003693 atypical antipsychotic agent Substances 0.000 description 3
- 229940127236 atypical antipsychotics Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NEGMMXJPQLJRPS-UHFFFAOYSA-N tert-butyl 3-(2-chloropyrimidin-4-yl)-2,5-dihydropyrrole-1-carboxylate Chemical compound ClC1=NC=CC(=N1)C=1CN(CC=1)C(=O)OC(C)(C)C NEGMMXJPQLJRPS-UHFFFAOYSA-N 0.000 description 3
- GZYDEJABHMSOIM-UHFFFAOYSA-N tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=NC(Cl)=N1 GZYDEJABHMSOIM-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- PNCQADGCPAWJJM-UHFFFAOYSA-N 5-fluoro-n-methoxy-n-methylpyridine-2-carboxamide Chemical group CON(C)C(=O)C1=CC=C(F)C=N1 PNCQADGCPAWJJM-UHFFFAOYSA-N 0.000 description 2
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 2
- 101710138091 5-hydroxytryptamine receptor 2A Proteins 0.000 description 2
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 2
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 239000007805 chemical reaction reactant Substances 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000001153 interneuron Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 210000001176 projection neuron Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229960001534 risperidone Drugs 0.000 description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 2
- 230000000698 schizophrenic effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YEBDZDMYLQHGGZ-UHFFFAOYSA-N tert-butyl 2,5-dihydropyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC1 YEBDZDMYLQHGGZ-UHFFFAOYSA-N 0.000 description 2
- RQJYHMVZCQQCSR-UHFFFAOYSA-N tert-butyl 3-(2-chloropyrimidin-4-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C1)C1=CC=NC(Cl)=N1 RQJYHMVZCQQCSR-UHFFFAOYSA-N 0.000 description 2
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 2
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 230000003936 working memory Effects 0.000 description 2
- 229960000607 ziprasidone Drugs 0.000 description 2
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- BQWITNWSJLFTCF-UHFFFAOYSA-N 1,2-dichloro-2h-pyrimidine Chemical group ClC1N=CC=CN1Cl BQWITNWSJLFTCF-UHFFFAOYSA-N 0.000 description 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- JWTZSVLLPKTZJP-UHFFFAOYSA-N 2-bromo-6-chloropyridine Chemical group ClC1=CC=CC(Br)=N1 JWTZSVLLPKTZJP-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical class ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- FPCCSQOGAWCVBH-PSQIVULCSA-N 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]-1,1,2,2-tetratritioethyl]-1h-quinazoline-2,4-dione Chemical compound O=C1NC2=CC=CC=C2C(=O)N1C([3H])([3H])C([3H])([3H])N(CC1)CCC1C(=O)C1=CC=C(F)C=C1 FPCCSQOGAWCVBH-PSQIVULCSA-N 0.000 description 1
- GTXVVUOOEODRKX-UHFFFAOYSA-N 4-pyrrolidin-3-ylpyrimidin-2-amine Chemical compound NC1=NC=CC(C2CNCC2)=N1 GTXVVUOOEODRKX-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- NCUJAQQGXPNDQN-UHFFFAOYSA-N FC1=CC(=CC=N1)[N+]#[C-] Chemical compound FC1=CC(=CC=N1)[N+]#[C-] NCUJAQQGXPNDQN-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101150013372 Htr2c gene Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000021824 exploration behavior Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000021061 grooming behavior Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229950008693 mesulergine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- IRQWCOFOSMREBQ-UHFFFAOYSA-N n,n-dimethylazetidin-3-amine Chemical compound CN(C)C1CNC1 IRQWCOFOSMREBQ-UHFFFAOYSA-N 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940081837 nuplazid Drugs 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 description 1
- 229960003300 pimavanserin Drugs 0.000 description 1
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of chemical medicine, and provides a compound shown in a formula I, which acts on 5-HT 2A 、5‑HT 2C Receptors for 5-HT 2A Is superior or similar to pimozide. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The compounds of the present application have antipsychotic activity comparable to pimecroline and less cardiotoxicity than pimecroline.
Description
Technical Field
The invention relates to the field of chemical medicines, in particular to pyridine (pyrimidine) amine derivatives and application thereof.
Background
The Schizophrenia (Schizophrenia) has hidden incidence, low cure rate and higher incidence rate in life. About 0.3-0.7% of the world population is currently affected by schizophrenia during its lifetime, with a global estimated over 2100 tens of thousands of schizophrenic patients in 2016; the existing anti-schizophrenia drugs mainly comprise typical anti-schizophrenia drugs and atypical anti-schizophrenia drugs, but the current anti-schizophrenia therapeutic drugs block dopamine receptors strongly, so that adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, increase of prolactin and the like are caused. In the medical field, although various types of active compounds acting on different targets are available for the treatment of Sleep disorders (Sleep disorders), adverse reactions such as addiction, drug resistance and sequelae remain unsolved.
Traditionally, it is customary to block dopamine D by 2 Antipsychotics whose receptors exert pharmacological effects are known as first-generation antipsychotics, i.e. "typical" antipsychotics (e.g. haloperidol), which are breakthrough in the treatment of positive symptoms of schizophrenia but fail to treat negative symptoms and cognitive disorders. Typical antipsychotics generally have severe EPS side effects and are ineffective in one third of schizophrenic patients.
After the 60 s of the 20 th century, a series of new generation antipsychotics including Ziprasidone (Ziprasidone), risperidone (Risperidone) and the like, which are called second generation antipsychotics, i.e., novel antipsychotics, which have common pharmacological characteristics, i.e., 5-hydroxytryptamine (5-HT) receptor (5-HT), although their respective pharmacological actions are not completely consistent 1A、2A、2C ) And Norepinephrine (NA) receptor (alpha) 1 、α 2 ) Far aligned with D 2 The receptor is high. Compared with the first-generation antipsychotics, the clinical effect of the traditional Chinese medicine composition has more advantages, is effective on positive symptoms and traditional antipsychotics, is effective on negative symptoms and cognition deficiency symptoms, has a wider action spectrum, and has adverse reactions such as QT interval prolongation, hyperprolactinemia, weight gain and the like. Thus, finding drugs that are effective against positive, negative symptoms and cognitive impairment of schizophrenia with small side effects is a hotspot of current research.
The 5-hydroxytryptamine system plays a role in the function of the regulated prefrontal cortex (PFC)Plays an important role, including emotion control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons comprise several 5-HT with a particularly high density of serotonin receptor subtypes 1A And 5-HT 2A . PFC and NMDA receptor channels have recently been demonstrated to be 5-HT 1A The targets of R, these two receptors regulate cortical excitatory neurons, affecting cognitive function. Indeed, various preclinical data indicate 5-HT 1A R may be a new target for the development of antipsychotic drugs. Atypical antipsychotics (such as olanzapine, aripiprazole, etc.) against 5-HT 1A The high affinity of R and its low EPS side effects both indicate that the 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons comprise several 5-HT with a particularly high density of 5-hydroxytryptamine receptor subtypes 1A And 5-HT 2A . Recent studies have shown 5-HT 1A Agonists are associated with atypical antipsychotic therapy and improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic drug clozapine, 5-HT has been found 2A Play an important role in this context, involving various aspects of perception, mood regulation and motor control. Blocking 5-HT 2A The receptor can normalize dopamine release and act as an antipsychotic. In addition, 5-HT 2C The receptors are closely related to weight gain.
Pimavanserin is a p-5-HT 2A Inverse agonists with high affinity, 5-HT 2C Antagonists, shown by in vitro experiments, against 5-HT 2A Affinity of receptor [ inhibition constant (Ki) of 0.4nm]Compared with 5-HT 2C High (ki=16 nm), for 5-HT 2B Receptors, dopamine receptors (including D 2 None of the receptors, adrenergic receptors, muscarinic receptors or calcium channel receptors have significant affinity (Ki)>300 nm). The medicine was approved by the U.S. food and drug administration for 4 months in 2016 to be marketed under the trade name Nuplazid TM The Chinese medicinal composition is mainly used for treating parkinsonism symptoms such as illusion and illusion.
Therefore, there is a need to find a composition that is effective against both positive and negative symptoms, improves cognitive impairment and prevents extrapyramidal side effects, including tardive dyskinesia, parkinson's disease; and can reduce weight gain.
The invention comprises the following steps:
the present invention aims to solve at least one of the technical problems existing in the prior art, and therefore, an object of the present invention is to provide pyridine (pyrimidine) amine derivatives and uses thereof, such as compounds represented by formula I or pharmaceutically acceptable salts thereof:
Z, Q are each independently selected from C, N and Z, Q are not simultaneously C;
R 13 is C 1 -C 5 Straight or branched alkyl of (a);
R 1 selected from the structures of H and formula II,
R 2 in the absence of the H or formula II structure,
a is C or N;
R 6 is H or halogen; r is R 7 Is H or OH;
R 5 selected from H,
R 4 Is H, halogen or a structure of formula III, or R 5 And R is R 4 Forming benzene ring;
wherein in formula III, n1 is an integer of 0 to 3, W 3 Is C or N;
R 8 is C 1 -C 3 Straight or branched alkyl of (a);
R 3 is H, of formula IV, V or VI:
wherein in the formula IV, n2 is an integer of 0-3, and n4 and n5 are respectively and independently selected from integers of 1-3; w (W) 1 、W 2 Each independently selected from one of C, N;
R 9 h, C of a shape of H, C 1 -C 3 Straight or branched alkyl, formaldehyde, acetaldehyde, dimethylamino;
in the formula VI, n3 is an integer of 0-1;
in the formula V, R 10 、R 11 Are respectively and independently selected from H, C 1 -C 3 Straight or branched alkyl of (a).
In one embodiment, the compounds of formula I shown above are preferably of formula I-1
Z is selected from C, N.
In one embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine in the compound shown in the formula I or pharmaceutically acceptable salt thereof; the C is 1 -C 5 The straight or branched alkyl of (a) is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl.
In a particular embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from any one of the compounds shown below:
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (piperazin-1-yl) pyrimidin-2-amine;
4- [2- [ (4-fluorobenzyl) (4-isobutoxybenzyl) amino ] pyrimidin-4-yl ] piperazine-1-carbaldehyde;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (piperidin-4-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine;
4- (azetidin-3-yl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine; 5-fluoro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine; 5-chloro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine; 4- [3- (dimethylamino) azetidin-1-yl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine;
N-benzyl-N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylazetidin-3-yl) pyrimidin-2-amine; n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) quinazolin-2-amine;
4- [3- (dimethylamino) cyclobutyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine; 4- [ (dimethylamino) methyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine; 4- (aminomethyl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyridin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -6- (pyrrolidin-3-yl) pyridin-2-amine; 3- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine;
(4-fluorophenyl) [2- [ (4-isobutoxybenzyl) amino ] -4- (1-methylpyrrolidin-3-yl) pyridin-3-yl ] methanol;
3- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine; 3- [ (5-fluoropyridin-2-yl) methyl ] -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine;
3- [ (5-fluoropyridin-2-yl) methyl ] -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In another aspect, the invention provides an application of the compound shown in the formula I or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing a medicament for treating mental diseases. The mental disease is schizophrenia. The mental diseases are Parkinson's disease, dementia related behavioral disorder and psychosis.
In one particular embodiment, in formula VI, when n3 is 0, the structure of formula I is a particular structure
Term interpretation:
the term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects. It should be understood that the term "comprising" may cover the closed meaning, i.e. "consisting of …".
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above or as specified in the examples, subclasses, and examples. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optionally substituted group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly stated otherwise, the description as used in this application is to be construed broadly as meaning that the terms "independently of each other" and "independently of each other" may refer to the fact that, in different groups, specific terms expressed between the same symbols do not affect each other, or may mean that, in the same groups, specific terms expressed between the same symbols do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each of the individual members of these group classes and ranges, independently, in subcombinations. For example, the term "C 1 -C 5 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) Etc.
Ranges recited herein (e.g., numerical ranges) can encompass each and every subrange within the range as well as each subrange formed by each value. Thus, for example, the expression "n 2 An "integer of 0 to 3" includes, for example, an integer of 0 to 2, an integer of 2 to 3, and the like, such as 1, 2, and 3.
The expression "one or more" may denote 1, 2, 3, 4, 5, 6 or more.
The term "hydrogen (H)" means a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "formaldehyde radical" is
"acetaldehyde radical" is>
The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound of the invention.
Compounds of formula I
The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof
Wherein Z, Q is independently selected from C, N and Z, Q is not both C; r is R 13 Is C 1 -C 5 Straight or branched alkyl of (a);
R 1 selected from the structures of H and formula II,
R 2 in the absence of the H or formula II structure,
a is C or N;
R 6 is H or halogen, R 7 Is H or OH;
R 5 is H or
R 4 Is H, halogen or a structure of formula III, or R 5 And R is R 4 A benzene ring is formed and is formed,
wherein in formula III, n1 is an integer of 0 to 3, W 3 Is C or N;
R 8 is C 1 -C 3 Straight or branched alkyl of (a);
R 3 is H, formula IV, V or VI,
wherein in the formula IV, n2 is an integer of 0-3, and n4 and n5 are respectively and independently selected from integers of 1-3;
W 1 、W 2 each independently selected from C, N;
R 9 selected from H, C 1 -C 3 Straight or branched alkyl, formaldehyde, acetaldehyde, dimethylamino;
in the formula VI, n3 is an integer of 0-1;
in the formula V, R 10 、R 11 Are respectively and independently selected from H, C 1 -C 3 Straight or branched alkyl of (a).
In one embodiment, the compound of formula I is of formula I-1:
wherein Z is C or N.
In one embodiment, R 1 Is H or of formula II, R 2 Is absent, H or of the structure of formula II:
In one embodiment, formula II is a structure
Wherein A is C or N; r is R 6 Is H or halogen, R 7 H or OH. In a preferred embodiment, the structure of formula II is +. >
Wherein A is C or N; r is R 6 Is H, fluorine, chlorine, bromine or iodine, R 7 H or OH. In a particularly preferred embodiment, the structure of formula II is
Wherein A is C or N; r is R 6 Is H or fluorine, R 7 H or OH. In a specific embodiment, the structure of formula II is +.>
In another specific embodiment, the structure of formula II is +.>
In a further particular embodiment, the structure of formula II is +.>
In another specific embodiment, the structure of formula II is +.>
In one embodiment, R 13 Is C 1 -C 5 Straight or branched alkyl of (a). In a preferred embodiment, R 13 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl. In a more preferred embodiment, R 13 Is isopropyl, butyl, isobutyl or pentyl. In a particularly preferred embodiment, R 13 Is isobutyl.
In one embodiment, R 5 Is H or
In a specific embodiment, R 5 H. In another specific embodiment, R 5 Is->
In one embodiment, R 4 Is H, halogen or a structure of formula III:
in the formula III, n1 is an integer of 0-3, W 3 Is C or N; r is R 8 Is C 1 -C 3 Straight or branched alkyl of (a). In a preferred embodiment, R 4 Selected from H, fluorine, chlorine, bromine, structure III- >
In formula III, n1 is an integer of 0, 1, 2, W 3 Is C or N; r is R 8 Methyl, ethyl, propyl or isopropyl. In a particularly preferred embodiment, R 4 Selected from H, fluorine, chlorine,
In formula III, n1 is 0, W 3 Is N; r is R 8 Is methyl.
In one embodiment, R 5 And R is R 4 Forming a benzene ring.
In one embodiment, R 3 Is H, formula IV, V or VI;
wherein in the formula IV, n2 is an integer of 0-3, and n4 and n5 are integers of 1-3;
W 1 、W 2 each independently selected from C, N;
R 9 selected from H, C 1 -C 3 Straight or branched alkyl, formaldehyde, acetaldehyde, dimethylamino;
in the formula VI, n3 is an integer of 0-1;
in the formula V, R 10 、R 11 Are respectively and independently selected from H, C 1 -C 3 Straight or branched alkyl of (a).
In a more preferred embodiment, R 3 Is H, formula IV, V or VI;
wherein in the formula IV, n2 is 0, and n4 and n5 are respectively and independently selected from 1 and 2;
W 1 、W 2 each independently selected from C, N;
R 9 is H, methyl, ethyl, propyl, isopropyl, formaldehyde or dimethylamino;
in the formula V, R 10 、R 11 Each independently selected from H, methyl;
in formula VI, n3 is 0 or 1.
In a particularly preferred embodiment, R 3 Is H, formula IV, V or VI;
wherein in the formula IV, n2 is 0, and n4 and n5 are respectively and independently selected from 1 and 2;
W 1 、W 2 Each independently selected from one of C, N;
R 9 selected from H, methyl, formaldehyde, dimethylamino;
in the formula V, R 10 、R 11 Each independently selected from H, methyl;
in formula VI, n3 is 0.
In one embodiment, C 1 -C 5 Straight-chain or branched alkyl and C 1 -C 3 The straight or branched alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl. In a more specific embodiment, C 1 -C 5 Straight-chain or branched alkyl and C 1 -C 3 The straight or branched alkyl groups are each independently selected from methyl, isobutyl.
In one embodiment, the propyl group includes, but is not limited to, n-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Or isopropyl (i-Pr, -CH (CH) 3 ) 2 ). The butyl includes, but is not limited to, n-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Or tert-butyl (t-Bu, -C (CH) 3 ) 3 ). The pentyl group includes, but is not limited to, n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) Or 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 )。
In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine, iodine. In a particular embodiment, the halogen is selected from fluorine, chlorine.
The beneficial technical effects of the invention are as follows:
the compounds provided herein act on 5-HT2A, 5-HT2C receptors with selectivity for 5-HT2A over or similar to pimecrin. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The compounds of the present application have antipsychotic activity comparable to pimecroline and less cardiotoxicity than pimecroline.
Detailed description of the preferred embodiments
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
TABLE 1 Structure of Compounds and names of Compounds
Detailed description of the preferred embodiments
The following examples are for illustrative purposes only and are not intended to be limiting of the invention. The general formula is synthesized:
the substituted 2-chloropyrimidine or pyridine derivative is condensed with substituted 4-alkoxyl benzylamine and then condensed with substituted benzyl bromide to obtain the structural formula of the compound.
The general synthetic methods are only used to briefly summarize the synthetic methods of some of the compounds of the present invention, and the specific synthetic routes and synthetic steps are subject to the examples.
The examples are for illustrative purposes and are not to be construed as limiting the invention.
Examples of synthetic aspects
Example 1.4- (5-benzyl-1- (4-isobutoxybenzyl) -1H-pyrazol-3-yl) -1-methylpiperidine (1) reaction scheme 1
1.1 Preparation of 3- (2-chloropyrimidin-4-yl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester
2, 4-dichloropyrimidine (1.00 g, 6.719 mmol), water (10 mL,111.017 mmol), tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (2.38 g,8.055 mmol), na 2 CO 3 (1.42 g, 13.426 mmol) and Pd (dppf) Cl 2 (0.25 g, 0.336 mmol) was added to 10mL dioxane, nitrogen blanketed, and the mixture was stirred at 80℃for 2 hours. After completion of the reaction, the solid was removed by filtration, 20mL of water was added to the reaction solution, extraction was performed with ethyl acetate (3×30 mL), the organic phase (1×30 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under pressure, and the column chromatography was performed to purify (PE: ea=2:1) to obtain 1.5g of tert-butyl 3- (2-chloropyrimidin-4-yl) -2, 5-dihydropyrrole-1-carboxylate, yield 79.31% as pale yellow solid.
1.2 Preparation of 3- (2-chloropyrimidin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (2-Chloropyrimidin-4-yl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (1.50 g,5.324 mmol), tetrahydrofuran (15.00 mL,185.145 mmol) and Pd/C (0.15 g,1.410 mmol) were charged into a 50mL round-bottomed flask, and the system was purged with hydrogen and reacted overnight at room temperature. After the completion of the reaction, the mixture was filtered to obtain a solution, and the solvent was distilled off under reduced pressure to obtain 1.2g of t-butyl 3- (2-chloropyrimidin-4-yl) pyrrolidine-1-carboxylate as a yellow oil in a yield of 79.43%.
1.3 preparation of tert-butyl 3- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] pyrrolidine-1-carboxylate
3- (2-Chloropyrimidin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g,3.524 mmol), dimethyl sulfoxide (10.00 mL), 1- [4- (2-methylpropyloxy) phenyl ] methanamine (0.63 g,3.524 mmol), DIEA (0.91 g,7.048 mmol) were added respectively to a 40mL round bottom flask and reacted at 150℃for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 40mL of ice water was added, the mixture was extracted with ethyl acetate (3X 30 mL), the organic phase (1X 30 mL) was washed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled under reduced pressure, and the compound tert-butyl 3- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] pyrrolidine-1-carboxylate was obtained by column chromatography separation and purification (PE: EA=1:1) in 0.9g, yield 59.87%, yellow.
1.4 Preparation of tert-butyl 3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyrimidin-4-yl) pyrrolidine-1-carboxylate
Tert-butyl 3- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] pyrrolidine-1-carboxylate (300.00 mg,0.703 mmol) and DMF (6.00 mL,77.531 mmol) were added to a 50mL round bottom flask, nitrogen was purged, cooled to 0 ℃, naH (33.76 mg,1.407 mmol) was added, reacted at 0℃for 0.5 hours, and 1- (bromomethyl) -4-fluorobenzene (265.89 mg,1.407 mmol) was added dropwise at 0℃for 2 hours. After the completion of the reaction, 30mL of ice water was added to quench the reaction, the organic phase (3X 30 mL) was washed with ethyl acetate, dried over saturated brine (1X 30 mL), and the solvent was removed under reduced pressure to give 320mg of tert-butyl 3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyrimidin-4-yl) carboxylate, the compound, in a yield of 85.10%, as a yellow oil.
1.5 preparation of N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (pyrrolidin-3-yl) pyrimidin-2-amine
3- (2- [ [ (4-fluorophenyl) methyl)]([ [4- (2-methylpropyloxy) phenyl ]]Methyl group]) Amino group]Pyrimidine-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (300.00 mg,0.561 mmol) was added to HCl 1, 4-dioxane (5.00 mL,137.134 mmol) and stirred at room temperature for 1 hour. After the reaction is finished, addThe reaction was quenched with 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (3×30 mL), dried over anhydrous sodium sulfate, the solvent evaporated under reduced pressure, and purified by column chromatography in portions (DCM: meoh=20:1) to give compound N- [ (4-fluorophenyl) methyl]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-4- (pyrrolidin-3-yl) pyrimidin-2-amine 76.3mg in 28.86% yield. 1 H NMR(400MHz,DMSO-d 6 ):δ9.36(s,1H),9.20(s,1H),8.35(d,J＝5.0Hz,1H),7.28(dd,J＝8.4,5.5Hz,2H),7.18(s,1H),7.19–7.08(m,3H),6.86(d,J＝8.4Hz,2H),6.70(d,J＝5.0Hz,1H),4.77(t,J＝4.3Hz,4H),3.71(d,J＝6.5Hz,2H),3.48(q,J＝7.1,6.5Hz,2H),3.31(s,2H),3.21(d,J＝11.6Hz,2H),2.27(q,J＝6.7Hz,1H),1.99(dp,J＝13.3,6.7Hz,2H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):435[M+H] + 。
EXAMPLE 2N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyrimidin-2-amine (2)
Reaction 2
The title compound N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (pyrrolidin-3-yl) pyrimidin-2-amine was prepared as in example 1.
N- [ (4-fluorophenyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]4- (pyrrolidin-3-yl) pyrimidin-2-amine (200.00 mg,0.460 mmol) was added to 5.00mL of methanol, followed by AcOH (55.28 mg,0.921 mmol) and HCHO (69.10 mg,2.301 mmol), reacted at room temperature for 0.5 hours, followed by STAB (292.63 mg,1.381 mmol) and reacted at room temperature for 1 hour. After the reaction, saturated NaHCO is used 3 The reaction solution was adjusted to PH 8, extracted with ethyl acetate (2×10 mL), washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified product (DCM: meoh=20:1) was isolated by column chromatography to give the compound N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyrimidin-2-amine 45.5g in 20.38% yield, 1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),10.48(s,1H),8.36(dd,J＝5.0,3.1Hz,1H),7.28(dt,J＝8.8,5.3Hz,2H),7.21–7.09(m,4H),6.91–6.83(m,2H),6.69(dd,J＝5.0,3.7Hz,1H),4.78(t,J＝5.3Hz,4H),3.54(d,J＝8.4Hz,1H),3.38(s,1H),3.01(s,1H),2.84(d,J＝5.0Hz,1H),2.72(d,J＝4.9Hz,2H),2.29(q,J＝8.1,6.6Hz,1H),1.99(hept,J＝6.7Hz,1H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):449[M+H] + 。
EXAMPLE 3N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (piperazin-1-yl) pyrimidin-2-amine (3)
Reaction 2
3.1 Preparation of tert-butyl 4- (2-chloropyrimidin-4-yl) piperazine-1-carboxylate
2, 4-dichloropyrimidine (3.00 g,20.138 mmol), DMSO (30.00 mL), tert-butyl piperazine-1-carboxylate (4125.94 mg,22.152 mmol) and DIEA (5205.47 mg,40.277 mmol) were added to a 100mL reaction flask, nitrogen blanketed, and stirred at 150℃for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×30 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by column chromatography (PE: ea=3:2) to give 5.4g of tert-butyl 4- (2-chloropyrimidin-4-yl) piperazine-1-carboxylate as a compound in a yield of 89.75% as a pale yellow oil.
3.2 Preparation of tert-butyl 4- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] piperazine-1-carboxylate
Tert-butyl 4- (2-chloropyrimidin-4-yl) piperazine-1-carboxylate (2.00 g,6.694 mmol), dimethyl sulfoxide (20.00 mL), 1- [4- (2-methylpropyloxy) phenyl ] methanamine (1.32 g, 7.284 mmol), DIEA (1.73 g, 13.3838 mmol) were added separately to a 50mL round bottom flask and reacted at 150℃for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 40mL of ice water was added, the mixture was extracted with ethyl acetate (3X 30 mL), the organic phase (1X 30 mL) was washed with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the compound 4- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester 1g was obtained by column chromatography separation and purification (PE: EA=1:1) in a yield of 33.83% as a yellow solid.
3.3 Preparation of tert-butyl 4- (2- [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyrimidin-4-yl) piperazine-1-carboxylate
4- [2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyrimidin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester (1.00 g,2.265 mmol) and DMF (10.00 mL) were added to a 25mL round bottom flask, nitrogen was purged, the temperature was lowered to 0 ℃, naH (0.11 g,4.529 mmol) was added, the reaction was carried out at 0℃for 0.5 hours, and 1- (bromomethyl) -4-fluorobenzene (265.89 mg,1.407 mmol) was added dropwise at 0℃for 2 hours. After completion of the reaction, the reaction was quenched with 30mL of ice water, extracted with ethyl acetate (3X 30 mL), the organic phase (1X 30 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 1g of tert-butyl 4- (2- [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyrimidin-4-yl) piperazine-1-carboxylate as a compound in a yield of 80.33% as a yellow solid.
3.4 preparation of N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (piperazin-1-yl) pyrimidin-2-amine
4- (2- [ (4-fluorophenyl) methyl)]([ [4- (2-methylpropyloxy) phenyl ]]Methyl group]) Amino group]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (230.00 mg,0.418 mmol) was added to HCl 1, 4-dioxane (2.00 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched by adding 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (3×30 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography in portions (DCM: meoh=20:1) to give compound N- [ (4-fluorophenyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-4- (pyrrolidin-3-yl) pyrimidin-2-amine 56.5mg in 27.25% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.90(d,J＝6.0Hz,1H),7.29–7.21(m,2H),7.18–7.06(m,4H),6.88–6.81(m,2H),6.10(d,J＝6.1Hz,1H),4.67(s,4H),3.70(d,J＝6.5Hz,2H),3.47(t,J＝5.0Hz,4H),2.73(t,J＝5.3Hz,4H),1.99(dp,J＝13.3,6.6Hz,1H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):450[M+H] + 。
Example 4.4- (2- ((4-fluorobenzyl) (4-isobutoxybenzyl) amino) pyrimidin-4-yl) piperazine-1-carbaldehyde
Substitution of piperazine-1-carboxylic acid tert-butyl ester as reaction materialThe title compound was prepared as described in example 3, which is 1-formaldehyde piperazine, and the structural formula is shown in table 1 under number (4). 1 H NMR(400MHz,DMSO-d 6 ):δ8.07(s,1H),7.95(d,J＝6.0Hz,1H),7.34–7.19(m,2H),7.19–7.04(m,4H),6.89–6.80(m,2H),6.17(d,J＝6.0Hz,1H),4.69(s,4H),3.70(d,J＝6.5Hz,2H),3.55(d,J＝20.3Hz,4H),3.37(d,J＝6.5Hz,4H),1.99(dt,J＝13.3,6.7Hz,1H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):418[M+H] + 。
EXAMPLE 5N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (piperidin-4-yl) pyrimidin-2-amine
The title compound was prepared by the method of example 1 by substituting tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) -2, 5-dihydropyrrole-1-carboxylate with 4- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate. 1 H NMR(400MHz,DMSO-d 6 )δ8.31(d,J＝5.0Hz,1H),7.28(dd,J＝8.4,5.6Hz,2H),7.21–7.08(m,4H),6.90–6.82(m,2H),6.59(d,J＝5.1Hz,1H),4.75(d,J＝4.4Hz,4H),3.71(d,J＝6.5Hz,2H),3.20(d,J＝12.3Hz,2H),2.88–2.66(m,3H),1.99(dp,J＝13.3,6.6Hz,1H),1.89(d,J＝13.2Hz,2H),1.76(q,J＝12.5Hz,2H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):449[M+H] + 。
EXAMPLE 6N- (4-Fluorobenzyl) -4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine
The piperazine-1-carboxylic acid tert-butyl ester serving as a reaction raw material is replaced by octahydropyrrole [1,2-a ] pyrazine]The target compound was prepared as in example 1, and the structural formula is shown in the number (6) in table 1. 1 H-NMR(400MHz,Methanol-d 4 )δ7.88(d,J＝6.2Hz,1H),7.27–7.17(m,2H),7.17–7.09(m,2H),7.06–6.96(m,2H),6.88–6.80(m,2H),6.14(d,J＝6.2Hz,1H),4.80–4.65(m,4H),4.47(d,J＝12.9Hz,1H),4.32(d,J＝13.1Hz,1H),3.72(d,J＝6.5Hz,2H),3.14–3.02(m,2H),2.99(ddd,J＝14.9,11.8,3.3Hz,1H),2.63(dd,J＝12.8,10.5Hz,1H),2.25–2.13(m,2H),2.10–1.94(m,1H),1.86(s,1H),1.84(dddd,J＝20.8,16.1,12.7,9.3Hz,2H),1.51–1.33(m,1H),1.35(s,1H),1.31(d,J＝3.6Hz,1H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):490[M+H] + 。
Example 7.4- (azetidin-3-yl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine
The title compound was prepared by the method of example 1 by substituting tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) -2, 5-dihydropyrrole-1-carboxylate with 3- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) azetidine-1-carboxylate. 1 H NMR(400MHz,Methanol-d 4 )δ8.36(d,J＝4.9Hz,1H),7.31–7.23(m,2H),7.21–7.14(m,2H),7.08–6.98(m,2H),6.89–6.82(m,2H),6.58(d,J＝4.9Hz,1H),4.90(s,4H),4.26(qd,J＝10.1,8.0Hz,4H),4.17–4.04(m,1H),3.73(d,J＝6.5Hz,2H),2.05(dp,J＝13.3,6.6Hz,1H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):421[M+H] + 。
Example 8.5-fluoro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine
The title compound was prepared as in example 1 by substituting 2, 4-dichloropyrimidine for 2, 4-dichloro-5-fluoropyrimidine, and the structural formula is shown in table 1 as number (8). 1 H NMR(400MHz,Methanol-d4)δ8.55(s,1H),8.28(d,J＝1.9Hz,1H),7.24(dd,J＝8.4,5.4Hz,2H),7.15(d,J＝8.3Hz,2H),7.02(t,J＝8.6Hz,2H),6.88–6.81(m,2H),4.81(d,J＝5.5Hz,4H),3.88(p,J＝7.5Hz,1H),3.72(d,J＝6.5Hz,2H),3.60–3.46(m,2H),3.33–3.24(m,2H),2.39(dq,J＝14.1,7.1Hz,1H),2.08(ddq,J＝33.2,13.3,7.0Hz,2H),1.03(d,J＝6.7Hz,6H).LCMS(ES,m/z):453[M+H] + 。
Example 9.5-chloro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine
The title compound was prepared by the method of example 1 by substituting 2, 4-dichloropyrimidine for 2, 4-dichloro-5-chloropyrimidine, and the structural formula is shown in Table 1 as number (9). 1 H NMR(400MHz,Methanol-d4)δ8.56(s,1H),8.36(s,1H),7.25(dd,J＝8.4,5.3Hz,2H),7.15(d,J＝8.2Hz,2H),7.08–6.98(m,2H),6.90–6.82(m,2H),4.83(d,J＝6.9Hz,4H),3.96(p,J＝7.2Hz,1H),3.73(d,J＝6.5Hz,2H),3.53–3.46(m,2H),3.25(dp,J＝11.7,4.3Hz,2H),2.39(dq,J＝14.5,7.4Hz,1H),2.06(ddq,J＝17.0,13.3,6.8Hz,2H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):469[M+H] + 。
EXAMPLE 10.4- (3- (dimethylamino) azetidin-1-yl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine
The title compound was prepared as in example 1 by substituting tert-butyl piperazine-1-carboxylate with N, N-dimethyl azetidin-3-amine, and the structural formula is shown in Table 1 under number (10). 1 H NMR(400MHz,Methanol-d 4 )δ8.28(d,J＝1.9Hz,1H),7.24(dd,J＝8.4,5.4Hz,2H),7.15(d,J＝8.3Hz,2H),7.02(t,J＝8.6Hz,2H),6.88–6.81(m,2H),4.81(d,J＝5.5Hz,4H),3.88(p,J＝7.5Hz,1H),3.72(d,J＝6.5Hz,2H),3.60–3.46(m,2H),3.33–3.24(m,2H),2.39(dq,J＝14.1,7.1Hz,1H),2.08(ddq,J＝33.2,13.3,7.0Hz,2H),1.03(d,J＝6.7Hz,6H).LCMS(ES,m/z):382[M+H] + 。
EXAMPLE 11N-benzyl-N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine
The title compound was prepared as in example 1 by substituting benzyl bromide for 1- (bromomethyl) -4-fluorobenzene, and the structural formula is shown in table 1 under number (11). 1 H NMR(400MHz,DMSO-d6):δ9.48(s,1H),9.28(s,1H),8.34(d,J＝5.0Hz,1H),7.36–7.28(m,2H),7.28–7.15(m,5H),6.90–6.80(m,2H),6.71(d,J＝5.0Hz,1H),4.87–4.69(m,4H),3.70(d,J＝6.5Hz,2H),3.51–3.44(m,2H),3.31(s,2H),3.24–3.15(m,2H),2.26(dd,J＝13.2,6.8Hz,1H),1.99(dt,J＝13.2,6.6Hz,1H),1.94(s,1H),0.96(d,J＝6.7Hz,6H).LCMS(ES,m/z):417[M+H] + 。
EXAMPLE 12N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylazetidin-3-yl) pyrimidin-2-amine
The title compound was prepared as in example 2 by substituting tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) -2, 5-dihydropyrrole-1-carboxylate with 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-diboranoxy-2-yl) azetidine. 1 H NMR(400MHz,DMSO-d 6 )δ8.23(s,1H),7.29(dd,J＝8.4,5.6Hz,2H),7.19(d,J＝8.2Hz,2H),7.16–7.07(m,2H),6.90–6.83(m,2H),6.62(d,J＝5.0Hz,1H),4.78(d,J＝4.0Hz,4H),3.70(d,J＝6.5Hz,2H),3.68–3.55(m,3H),3.31(d,J＝7.3Hz,2H),2.27(s,3H),1.99(dp,J＝13.3,6.6Hz,1H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):435[M+H] + 。
EXAMPLE 13N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) quinazolin-2-amine
The target compound was prepared as in example 1, with the replacement of the reaction starting material 2, 4-dichloropyrimidine with 2, 4-dichloropquinazoline, and the structural formula is shown in table 1 under number (13). 1 H NMR(400MHz,Methanol-d 4 )δ8.04(dd,J＝8.4,1.3Hz,1H),7.70(ddd,J＝8.3,6.7,1.4Hz,1H),7.62(dd,J＝8.5,1.2Hz,1H),7.29(td,J＝6.7,3.2Hz,3H),7.19(d,J＝8.1Hz,2H),7.07–6.95(m,2H),6.88–6.78(m,2H),4.94(t,J＝5.3Hz,4H),4.24(ddd,J＝10.9,8.0,5.4Hz,1H),3.71(d,J＝6.5Hz,2H),3.31–3.23(m,1H),2.99(t,J＝7.2Hz,2H),2.38–2.24(m,1H),2.06(ddp,J＝26.5,13.2,6.6,6.0Hz,2H),1.30(s,1H),1.02(d,J＝6.7Hz,6H).LCMS:(ES,m/z):485[M+H] + 。
EXAMPLE 14.4- (3- (dimethylamino) cyclobutyl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine
The title compound was prepared as in example 1, substituting 2, 3-dichloropyrimidine for the reaction starting material 2, 4-dichloropyrimidine, substituting N, N-dimethyl-3- (4, 5-tetramethyl-1, 3, 2-diboranyloxy-2-yl) -2, 5-dihydropyrrole-1-carboxylate for N, N-dimethyl-3- (4, 5-tetramethyl-1, 3, 2-diboranyloxy-2-yl) cyclobutan-1-amine, and having the structural formula shown in table 1 under number (14). 1 H NMR:(400MHz,Methanol-d 4 )δ8.28(d,J＝6.4Hz,1H),7.34(dd,J＝8.3,5.2Hz,2H),7.23(d,J＝8.3Hz,2H),7.19–7.06(m,3H),7.02–6.86(m,2H),4.95(s,4H),3.85(p,J＝8.3Hz,1H),3.75(d,J＝6.5Hz,2H),3.70–3.52(m,1H),2.95–2.65(m,10H),2.07(dh,J＝13.2,6.6Hz,1H),1.04(d,J＝6.7Hz,6H).
EXAMPLE 15.4- [ (dimethylamino) methyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine
Reaction 3
15.1 preparation of N- (4-isobutoxybenzyl) -4-isocyano-pyridin-2-amine
2-fluoro-4-isocyanopyridine (5.00 g,40.98 mmol), (4-isobutoxyphenyl) methanamine (8.07 g,45.08 mmol), DIEA (10.57 g,81.94 mmol) and 30mL DMSO were reacted with a 100mL round bottom flask, warmed to 150℃and reacted for 2 hours. After the completion of the reaction, the temperature was lowered to room temperature, 100mL of water was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (3X 50 mL), the organic phase (1X 50 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the purified by column chromatography (PE: EA=1:1) to give 4.6g of the compound N- (4-isobutoxybenzyl) -4-isocyano-pyridin-2-amine in 39.97% yield.
15.2 preparation of N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4-isocyanatopyridin-2-amine
N- (4-isobutoxybenzyl) -4-isocyanatopyridin-2-amine (2.00 g,7.12 mmol) was added to 10mL of DMF, cooled to 0deg.C, 60% sodium hydride (0.34 g,8.52 mmol) was slowly added thereto, stirred for 10 minutes after the addition was completed, 4-fluorobenzyl bromide (1.48 g,7.83 mmol) was added thereto, and the reaction was allowed to proceed to room temperature for 1 hour after the addition was completed. After the completion of the reaction, 40mL of water was slowly added to quench the reaction, the reaction mixture was extracted with ethyl acetate (3X 30 mL), the organic phase (1X 30 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified by column chromatography (PE: EA=5:1) to give 2.1g of the compound N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4-isocyanatopyridin-2-amine in a yield of 75.81%.
15.3 Preparation of 4- (aminomethyl) -N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4-isocyanatopyridin-2-amine (2.00 g,5.14 mmol), and Raney Ni (198.00 mg,2.31 mmol) were added to 50.00mL tetrahydrofuran, and the system was purged with hydrogen and reacted overnight at room temperature. After the completion of the reaction, the mixture was suction-filtered to obtain a solution, and the solvent was distilled off under reduced pressure to obtain 1.4g of the compound 4- (aminomethyl) -N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine in a yield of 69.31%.
15.4 Preparation of 4- [ (dimethylamino) methyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine
4- (aminomethyl) -N- [ (4-fluorophenyl) methyl]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Pyridin-2-amine (0.6 g,1.53 mmol), acOH (184.33 mg,3.06 mmol) and HCHO (229.73 mg,7.65 mmol) were added and reacted at room temperature for 0.5 hours, and STAB (972.61 mg,4.59 mmol) was added and reacted at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (2X 10 mL), the organic phase was washed with saturated brine, the solvent was distilled off under reduced pressure, and purified by column chromatography (DCM: meOH=30:1) to give compound 4- [ (dimethylamino) methyl group]-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine 0.2g in 31.25% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.66(s,1H),8.14(d,J＝6.1Hz,1H),7.56(s,1H),7.41–7.33(m,2H),7.28–7.21(m,2H),7.21–7.09(m,3H),6.93–6.85(m,2H),4.93(s,2H),4.88(s,2H),4.31(d,J＝4.6Hz,2H),3.71(d,J＝6.5Hz,2H),2.67(d,J＝3.8Hz,6H),1.99(dp,J＝13.3,6.7Hz,1H),0.96(d,J＝6.7Hz,6H).LCMS(ES,m/z):422[M+H] + 。
EXAMPLE 16.4- (aminomethyl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine
The title compound was prepared as in example 15 and has the structural formula shown in Table 1 under number (16). 1 HNMR(400MHz,DMSO-d 6 )δ8.64(s,3H),8.12(d,J＝5.8Hz,1H),7.35–7.28(m,2H),7.26(s,1H),7.23–7.11(m,4H),6.96–6.85(m,3H),4.82(d,J＝17.7Hz,4H),4.02(q,J＝5.8Hz,2H),3.72(d,J＝6.5Hz,2H),1.99(hept,J＝6.7Hz,1H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):394[M+H] + 。
EXAMPLE 17N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyridin-2-amine reaction formula 4
17.1 Preparation of 4-bromo-N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
4-bromo-2-fluoropyridine (1100.00 mg,6.250 mmol) and 1- [4- (2-methylpropyloxy) phenyl ] methanamine (1232.52 mg,6.875 mmol) were added to 11.00mL DMSO, warmed to 80℃and DIEA (2423.48 mg,18.751 mmol) added and reacted overnight. After completion of the reaction, the reaction was quenched with 5.00mL of water, extracted with ethyl acetate (3X 5 mL), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and purified by column chromatography (PE: etoac=5:1) to give 900mg of the compound 4-bromo-N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine in a yield of 42.95% as a colorless oil. 17.2 Preparation of 4-bromo-N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
4-bromo-N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine (900.00 mg,2.685 mmol) and NaH (96.64 mg,4.027 mmol) were added to 10.00mL of DMF, cooled to 0℃and reacted for 1 hour, and 1- (bromomethyl) -4-fluorobenzene (608.96 mg,3.222 mmol) was added and the reaction was completed and warmed to room temperature and reacted for 2 hours. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified product (DCM: meoh=9:1) was separated by column chromatography to give the compound 4-bromo-N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine 800mg, yield 67.21%, as a white solid.
Preparation of 3-tert-butyl-3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyridin-4-yl) -2, 5-dihydropyrrole-1-carboxylate
4-bromo-N- [ (4-fluorophenyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Pyridin-2-amine (800.00 mg,1.804 mmol) and sodium tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-dioxal-2-yl) -2, 5-dihydropyrrole-1-carboxylate (870.83 mg,2.165 mmol) were added to 8.00mL dioxane followed by Pd (dppf) Cl 2 (132.03mg，0.180mmol)，Na 2 CO 3 (382.49 mg, 3.319 mmol) and H 2 O (2.00 mL,0.111 mmol), nitrogen protection, and reaction at 80℃for 2 hours. After the completion of the reaction, the reaction was quenched with 5.00mL of water, extracted with ethyl acetate (3×5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the extract was purified by column chromatography (PE: etoac=5:1) Obtaining the compound tert-butyl-3- (2- [ [ (4-fluorophenyl) methyl)]([ [4- (2-methylpropyloxy) phenyl ]]Methyl group]) Amino group]Pyridin-4-yl) -2, 5-dihydropyrrole-1-carboxylate 900mg, yield 93.81%, white solid.
17.3 Preparation of tert-butyl 3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyridin-4-yl) pyrrolidine-1-carboxylate
Raney nickel (85.00 mg) was added to 10.00mL of tetrahydrofuran, and tert-butyl-3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyridin-4-yl) -2, 5-dihydropyrrole-1-carboxylate (850.00 mg) was added thereto, followed by hydrogen gas and reaction at room temperature overnight. After the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 800mg of tert-butyl 3- (2- [ [ (4-fluorophenyl) methyl ] ([ [4- (2-methylpropyloxy) phenyl ] methyl) amino ] pyridin-4-yl) carboxylate as a compound in 93.76% yield.
17.preparation of 4N- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (pyrrolidin-3-yl) pyridin-2-amine
3- (2- [ [ (4-fluorophenyl) methyl)]([ [4- (2-methylpropyloxy) phenyl ]]Methyl group]) Amino group]Pyridine-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (500.00 mg,0.937 mmol) was added to a solution of 5.00mL HCl in dioxane and reacted at room temperature for 0.5 h. After the reaction, the solvent was evaporated under reduced pressure, and purified by column chromatography (DCM: meoh=20:1) to give compound N- [ (4-fluorophenyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-4- (pyrrolidin-3-yl) pyridin-2-amine 300mg in 73.92% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.57(s,1H),8.08(d,J＝5.3Hz,1H),7.29–7.21(m,2H),7.18–7.10(m,2H),7.08–6.98(m,2H),6.90–6.81(m,2H),6.61(dd,J＝5.3,1.5Hz,1H),6.49(t,J＝0.9Hz,1H),4.79(s,2H),4.73(s,2H),3.72(d,J＝6.5Hz,2H),3.54(dd,J＝11.4,7.9Hz,1H),3.42–3.34(m,1H),3.33–3.18(m,1H),3.02(dd,J＝11.4,9.8Hz,1H),2.39–2.27(m,1H),2.06(dq,J＝13.3,6.6Hz,1H),2.02–1.87(m,1H),1.33(d,J＝17.7Hz,1H),1.03(d,J＝6.7Hz,6H).LCMS(ES,m/z):434[M+H] + 。
EXAMPLE 18N- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -6- (pyrrolidin-3-yl) pyridin-2-amine
The title compound was prepared as in example 17, substituting 2-bromo-6-chloropyridine for 4-bromo-2-fluoropyridine, and the structural formula is shown in table 1 under (18). 1 H NMR(400MHz,DMSO-d 6 ):δ7.35(t,J＝7.8Hz,1H),7.26(dd,J＝8.4,5.5Hz,2H),7.13(q,J＝8.1Hz,4H),6.86(d,J＝8.2Hz,2H),6.51(t,J＝7.3Hz,1H),6.38(d,J＝8.5Hz,1H),4.74(s,2H),4.69(s,2H),3.70(d,J＝6.5Hz,2H),3.23–3.14(m,4H),3.00–2.87(m,2H),1.99(tq,J＝13.2,7.1,6.6Hz,2H),1.92–1.79(m,1H),0.96(d,J＝6.7Hz,6H).LCMS(ES,m/z):434[M+H] + 。
EXAMPLE 19.3- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine
Reaction 5
19.1 Preparation of 4-bromo-2-fluoro-3- (4-fluorobenzoyl) pyridine
4-bromo-2-fluoropyridine (3.00 g,17.047 mmol) and LDA (2.01 g,18.763 mmol) were added to 30.00mL of THF, nitrogen-protected, cooled to-78℃and 4-fluoro-N-methoxy-N-methylbenzamide (3.12 g,17.047 mmol) was added thereto and reacted for 1 hour. After the reaction is finished, saturated NH is added 4 The reaction was quenched with Cl solution, extracted with ethyl acetate (3X 10 mL), the organic phase (1X 10 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified product (PE: etOAc=3:1) was isolated by column chromatography to give 3g of the compound in 59.04% yield as a pale yellow solid.
19.2 Preparation of 4-bromo-3- (4-fluorobenzoyl) -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
4-bromo-2-fluoro-3- (4-fluorobenzoyl) pyridine (3.60 g,12.077 mmol), 1- [4- (2-methylpropyloxy) phenyl ] methanamine (2.60 g,14.504 mmol) and DIEA (3.12 g,24.154 mmol) were added to 36.00mL of MSO, and the mixture was allowed to react at 80℃under nitrogen for 3 hours. After completion of the reaction, the temperature was lowered to room temperature, the reaction was quenched by addition of water, extracted with ethyl acetate (3×20 ml), the organic phase (2×10 ml) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified (PE: etoac=3:1) was separated by column chromatography to give 3.1g of the compound 4-bromo-3- (4-fluorobenzoyl) -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine in a yield of 56.13% as a yellow solid.
19.3 Preparation of 3- [3- (4-fluorobenzoyl) -2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyridin-4-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester
4-bromo-3- (4-fluorobenzoyl) -N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Pyridin-2-amine (4.40 g,9.621 mmol), tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (3.57 g,11.545 mmol), na 2 CO 3 (2.04 g,19.242 mmol) and Pd (dppf) Cl 2 CH 2 Cl 2 (0.39 g,0.481 mmol) was added to 40.00mL of 1, 4-dioxane and 10.00mL of water, nitrogen blanketed, and the temperature was raised to 80℃for 2 hours. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (3×30 mL), the organic phase (1×10 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified (PE: etoac=3:1) was separated by column chromatography to give the compound 3- [3- (4-fluorobenzoyl) -2- ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) pyridin-4-yl]3.5g of tert-butyl 2, 5-dihydropyrrole-1-carboxylate, yield 94.63% as yellow solid.
19.preparation of 4-tert-butyl-3- [3- [ (4-fluorophenyl) (hydroxy) methyl ] -2- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) pyridin-4-yl ] -2, 5-dihydropyrrole-1-carboxylate
3- [3- (4-fluorobenzoyl) -2- ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) pyridin-4-yl]Tert-butyl-2, 5-dihydropyrrole-1-carboxylate (2.00 g,3.665 mmol) was added to a mixture of 14.00mL THF and 7.00mL water under nitrogen, cooled to 0deg.C, and NaBH was added 4 (208.01 mg,5.498 mmol) for 2 hours. After the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (3X 10 mL), the organic phase (1X 10 mL) was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the purified product (PE: etOAc=3:1) was separated by column chromatography to give the compound tert-butyl-3- [3- [ (4-fluorophenyl) (hydroxy) methyl]-2- ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) pyridin-4-yl]-2, 5-dihydroPyrrole-1-carboxylate 1.9g, yield 94.65% as yellow solid.
19.5 Preparation of 3- [ chloro (4-fluorophenyl) methyl ] -4- (2, 5-dihydro-1H-pyrrol-3-yl) -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
Tert-butyl-3- [3- [ (4-fluorophenyl) (hydroxy) methyl)]-2- ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) pyridin-4-yl]-2, 5-Dihydropyrrole-1-carboxylate (500.00 mg, 0.89mmol) was added to DCM (5.00 mL), nitrogen blanket, cooled to 0deg.C, and SOCl was slowly added dropwise 2 (529.51 mg, 4.457 mmol). After the reaction is finished, the solvent is distilled off under reduced pressure to obtain the compound 3- [ chloro (4-fluorophenyl) methyl]-4- (2, 5-dihydro-1H-pyrrol-3-yl) -N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]1g of pyridin-2-amine.
19.6 Preparation of 3- [ (4-fluorophenyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -4- (pyrrolidin-3-yl) pyridin-2-amine
3- [ chloro (4-fluorophenyl) methyl group]-4- (2, 5-dihydro-1H-pyrrol-3-yl) -N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Pyridin-2-amine (1.00 g,2.146 mmol) and Pd/C (0.20 g,1.88 mmol) were added to CH 3 To COOH (10.00 mL) was added hydrogen gas, and the mixture was allowed to react overnight at room temperature. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure to obtain the compound 3- [ (4-fluorophenyl) methyl]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-4- (pyrrolidin-3-yl) pyridin-2-amine 500mg, yield 53.74% as pale yellow solid.
19.7 Preparation of 3- [ (4-fluorophenyl) methyl ] -5- (1-methylpiperidin-4-yl) -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] pyridin-2-amine
3- [ (4-fluorophenyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]4- (pyrrolidin-3-yl) pyridin-2-amine (500.00 mg,1.153 mmol), HCHO (86.57 mg,2.883 mmol) and AcOH (207.76 mg,3.460 mmol) were added to 5.00mL of methanol, nitrogen protected, reacted at room temperature for 30 minutes and STAB (293.30 mg, 1.284 mmol) was added. After the reaction, adding water to quench the reaction, using CH 2 Cl 2 (3X 5 mL) extraction, washing the organic phase (1X 5 mL) with saturated brine, drying over anhydrous sodium sulfate, and evaporating the solvent under reduced pressure, and column chromatography to isolate and purify (DCM: meOH=20:1) to give compound 3- [ (4-fluorophenyl) methyl ]5- (1-methylpiperidin-4-yl) the preparation ofN- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]37.3mg of pyridin-2-amine was obtained in 7.23% yield. 1 H NMR(400MHz,Methanol-d4)δ7.93(d,J＝6.6Hz,1H),7.18–7.03(m,7H),6.88–6.80(m,2H),4.61–4.56(m,2H),4.24(s,2H),3.88(s,2H),3.72(d,J＝6.5Hz,2H),3.42(s,1H),3.01(s,4H),2.34(s,1H),2.23(s,2H),2.05(dp,J＝13.3,6.7Hz,1H),1.03(d,J＝6.8Hz,6H).LCMS(ES,m/z):434[M+H] + 。
EXAMPLE 20 (4-fluorophenyl) (2- ((4-isobutoxybenzyl) amino) -4- (1-methylpyrrolidin-3-yl) pyridin-3-yl) methanol
The title compound was prepared as in example 19 and has the structural formula shown in Table 1 under number (20). 1 H NMR(400MHz,DMSO-d 6 )δ7.88(d,J＝5.4Hz,1H),7.22(td,J＝6.9,5.8,2.0Hz,2H),7.18–7.03(m,2H),6.94–6.84(m,2H),6.74(dd,J＝8.8,2.7Hz,2H),6.67(dd,J＝6.5,5.4Hz,1H),6.51–6.37(m,2H),6.23(d,J＝3.6Hz,1H),4.42(dd,J＝14.9,5.8Hz,1H),4.29(dt,J＝14.8,5.0Hz,1H),3.69(s,1H),3.67(s,2H),2.77–2.52(m,4H),2.28(d,J＝1.9Hz,3H),1.97(dh,J＝13.0,6.5Hz,2H),1.72(dq,J＝14.4,7.3Hz,1H),0.96(d,J＝6.6Hz,6H).LCMS(ES,m/z):464[M+H] + 。
EXAMPLE 21.3- (4-Fluorobenzyl) -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine
The title compound was prepared by the method of example 19 substituting tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate with N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester, the structural formula of which is shown in the number (21) in table 1. 1 H NMR(400MHz,Methanol-d 4 )δ7.78(d,J＝2.3Hz,1H),7.21–7.13(m,3H),7.07–6.97(m,4H),6.82–6.74(m,2H),4.46(s,2H),3.85(s,2H),3.71(d,J＝6.5Hz,2H),2.99(dt,J＝12.2,3.2Hz,2H),2.44(tt,J＝12.0,4.0Hz,1H),2.33(s,3H),2.17(td,J＝12.0,2.8Hz,2H),2.05(dq,J＝13.3,6.7Hz,1H),1.85–1.77(m,2H),1.77–1.63(m,2H),1.03(d,J＝6.7Hz,6H).LCMS(ES,m/z):462[M+H] + 。
EXAMPLE 22 (3- ((5-fluoropyridin-2-yl) methyl) -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine
The reaction is carried outThe title compound was prepared by the method of example 19 by substituting 5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide for 4-fluoro-N-methoxy-N-methylbenzamide and has the structural formula shown in table 1 under number (22). 1 H NMR(400MHz,Methanol-d4)δ8.24(d,J＝2.9Hz,1H),7.79(d,J＝2.3Hz,1H),7.53(td,J＝8.6,3.0Hz,1H),7.39–7.31(m,2H),7.17–7.09(m,2H),6.88–6.79(m,2H),4.46(s,2H),3.99(s,2H),3.74(d,J＝6.5Hz,2H),3.04–2.96(m,2H),2.45(ddt,J＝11.9,8.1,4.2Hz,1H),2.34(s,3H),2.17(td,J＝11.9,2.9Hz,2H),2.06(dp,J＝13.3,6.6Hz,1H),1.86–1.66(m,4H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):463[M+H] + 。
EXAMPLE 23.3- [ (5-Fluoropyridin-2-yl) methyl ] -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine
The title compound was prepared as in example 19, substituting 4-fluoro-N-methoxy-N-methylbenzamide for 5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide, tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-diboron-oxy-2-yl) -2, 5-dihydropyrrole-1-carboxylate for N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester, and having the structural formula shown in table 1 under number (23). 1 H NMR(400MHz,Methanol-d 4 )δ8.26(d,J＝2.9Hz,1H),7.91(d,J＝5.5Hz,1H),7.50(td,J＝8.6,3.0Hz,1H),7.22(dd,J＝8.7,4.4Hz,1H),7.17–7.09(m,2H),6.87–6.78(m,2H),6.74(d,J＝5.6Hz,1H),4.47(s,2H),4.14(s,2H),3.89–3.76(m,1H),3.72(d,J＝6.5Hz,2H),2.96(dd,J＝9.8,8.1Hz,1H),2.92–2.81(m,1H),2.76(td,J＝8.9,5.9Hz,1H),2.56(dd,J＝9.8,8.0Hz,1H),2.44(s,3H),2.27(dddd,J＝17.2,15.0,10.5,6.7Hz,1H),2.05(hept,J＝6.6Hz,1H),1.88(dtd,J＝13.5,8.1,6.3Hz,1H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):449[M+H] + 。
Pharmacological examples:
in vitro receptor binding assay
1. Experimental method
1.1 Preparation of solutions required for experiments
A: (for the preparation of 5-HT 2C Receptor membrane): 50mM Tris-HCl buffer: 96.8g Tris was dissolved in double distilled water to a total volume of 4000ml, pH adjusted to 7.5 with HCl, diluted to 16000mL, pH＝7.4
B: (for the preparation of 5-HT 2A Receptor membrane): weighing 11.7mg EDTA,380.84mg MgCl 2 The total volume of 50mM Tris-HCl buffer was 400mL and pH=7.4 was adjusted. So that the final concentration is EDTA0.1mM and MgCl respectively 2 10mM。
C: (for preparing a Dopamine receptor film): weighing 2.978gHEPES,1.17g NaCl,0.119g MgCl 2 36.5mg EDTA was added to a total volume of 250ml of purified water to adjust pH=7.4. To final concentrations of 50mM HEPES,50mM NaCl,5mM MgCl respectively 2 ,0.5mM EDTA,pH 7.4。
1.2 preparation of receptor membranes
1)CHO-5-HT 2A Preparation of acceptor membranes
CHO-5-HT 2A The cells were removed from the freezer at-80℃and naturally thawed and centrifuged at 2000g for 15 minutes at 4 ℃. Taking the precipitate, and discarding the supernatant. Adding solution B into the sediment. The cells were mixed for 20-30 seconds and then centrifuged at 50000g for 25min at 4 ℃. Carefully discarding the supernatant, adding the solution B again, mixing well, centrifuging at 4 ℃ for 25min and 50000 g. The precipitate was stored at-80 ℃.
2)5-HT 2C Preparation of the film
Taking out rat cortex at-80deg.C, naturally thawing, adding solution A, homogenizing for 4 times at 4 th gear for 3-4s, centrifuging at-80deg.C for 25min, discarding supernatant, adding solution A, mixing with vortex mixer, centrifuging at-80deg.C for 25min, repeating the centrifugation twice, discarding supernatant, and storing at-80deg.C.
3)CHO-D 2 Preparation of acceptor membranes
Cell CHO-D 2 Naturally thawing after taking out by a refrigerator at-80 ℃, centrifuging 2000g for 15min, adding the precipitate into homogenate C, uniformly mixing by a vortex mixer, centrifuging at 50000g and 4 ℃ for 25min, discarding the supernatant, taking the precipitate, adding the buffer solution C again for washing, resuspending and centrifuging, discarding the supernatant after centrifuging, and storing the precipitate at-80 ℃ for later use.
1.3 receptor competitive binding assay
1)5-HT 2A Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 10mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, non-specific binding tube (NB) was filled with methyl 100. Mu.L (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Ketanserin 10. Mu.L, final concentration 2.98nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/C plate under reduced pressure to soak the combined ligand with 0.5% PEI for more than 1h, drying the filter membrane at 60 ℃ after filtering, adding 40 mu L of scintillation liquid after attaching a bottom membrane, sealing the upper membrane, and standing.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
2)5-HT 2C Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 210mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, nonspecific binding tube (NB) was filled with Ketansert (final concentration 1.0X10) -5 M) 100. Mu.L of each test compound tube (CB) was charged with 100. Mu.L of test compound.
Fourth step: the radioligand is added into each reaction tube 3 H-Mesulergine 10. Mu.L, final concentration 3nM.
Fifth step: after the reaction tube was incubated at 37℃for 25min, the bound ligands were rapidly filtered under reduced pressure, whatman paper GF/C was saturated with 0.5% PEI solution 1h ahead, washed well with ice-cold Tris buffer, the filter was removed and placed in a 4mL scintillation cup, 1mL toluene scintillation solution was added and mixed well.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
3)CHO-D 2 Receptor competitive binding assay
The first step: the prepared membrane is prepared into 8mg/mL membrane suspension by homogenate C for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L C solution and non-specific binding tube (NB) was filled with 100. Mu.L Haloposteridol (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound-binding tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Spiponone 10. Mu.L, final concentration 1.176nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/B plate by decompression, soaking the combined ligand in 0.5% PEI for more than 1h, filtering, drying the filter membrane at 60 ℃, attaching a bottom membrane, adding 40 mu L of scintillation liquid, sealing the upper membrane, and standing.
Sixth step: and (5) putting the filter plate into a liquid flash counter for counting.
2 experimental results
Pimozide 5-HT 2A 、5-HT 2C The receptor Ki values were 0.036, 2.94nM, compound 1 and 5-HT, respectively 2A 、5-HT 2C Receptor Ki values of 0.005 and 8.19nM, respectively, are superior to pimozide; compound 7 and 5-HT 2A 、5-HT 2C Receptor Ki values of 0.0064 and 162.1nM, respectively, are superior to pimozide. The details are given in the following table.
Table 2 in vitro receptor binding Activity (Ki value, nM) of the compounds
In vitro hERG assay
Cells were seeded onto slides with cell densities below 50% and cultured overnight. The experimental cells were transferred to a bath of about 1ml embedded in an inverted microscope platform, and the extracellular fluid was perfused at a perfusion rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment was started. Membrane current was recorded using a HEKAEPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKAInstruments inc. D-67466lambrecht, pfalz, germany). All experiments were performed at room temperature (22-24 ℃).
A P-97 microelectrode drawing instrument (Sutter Instrument Company, one Digital Drive, novat, calif. 94949) was used in the experiment to straighten the electrode (BF 150-110-10). The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after being filled with the internal liquid is 2-4MΩ.
The electrophysiological stimulation scheme of hERG potassium channel is that first, the membrane voltage is clamped at-80 mV, the cell is stimulated for 2s, +20mV voltage, the hERG potassium channel is activated, and then repolarized to-50 mV for 5s, so as to generate outward tail current, and the stimulation frequency is once every 15 s. The current value is the peak value of the tail current.
The channel current was recorded using a whole cell recording mode in the experiment. Extracellular fluid (approximately 2 ml per minute) was first perfused and recorded continuously, and current stabilization was awaited (current decay (Run-Down) less than 5% in 5 minutes), at which point the tail current peak was the control current value. And then, the extracellular fluid containing the drug to be detected is perfused and continuously recorded until the inhibition effect of the drug on hERG current reaches a stable state, and at the moment, the tail current peak value is the current value after drug addition. The steady state criteria is determined by whether the nearest 3 consecutive current traces overlap. After reaching the steady state, if hERG current reverts to or approaches the magnitude prior to drug administration after rinsing with extracellular fluid perfusion, then perfusion testing may continue for other concentrations or drugs.
Experimental results:
pimecrin hERG assay IC50 is 208nM, compound 6, compound 10, compound 11, compound 15, compound 23 are less cardiotoxic than pimecrin. The results are shown in the following table.
Table 3 in vitro hERG test results of compounds
| Numbering of compounds | hERG(nM) |
| 6 | 564 |
| 10 | 319 |
| 11 | 355 |
| 15 | 643 |
| 23 | 356 |
| Pimozhen lin | 208 |
Animal experiment
Mouse head-shaking test
1 test method
Mice were randomly divided into model control groups, blank control groups, and each dosing group after weight stratification. 1h after the animal is subjected to gastric lavage administration of the solvent or the drug, the animal is placed in a beaker (with the diameter of 13cm and the height of 19 cm) paved with fresh padding, the molding drug DOI ((+ -.) -1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride, (+ -.) -2, 5-dimethoxy-4-iodoamphetamine hydrochloride) is injected intraperitoneally according to the dosage of 1mg/kg, and the number of times of head throwing of the mice within 0-20 minutes after the intraperitoneal injection of the DOI is recorded. The head-flick behavior is defined as rapid rotational twitching or wet dog-like shaking of the mouse head, which is distinguished from normal grooming or exploratory behavior.
2 test results
The test result shows that the ED50 of the pimecrin for inhibiting DOI from inducing the head throwing behavior of the mice is 0.39mg/kg, the ED50 of the compound 7 for inhibiting DOI from inducing the head throwing behavior of the mice is 0.83mg/kg, and the compound has better effect of resisting the mental diseases, and the animal model result is equivalent to that of the pimecrin. The detailed results are shown in the following table.
Table 4 ED50 of pimecrin and like compounds for inhibiting DOI-induced mice head-flick behavior
| Numbering of compounds | ED50(mg/kg) |
| Pimozhen lin | 0.39 |
| 7 | 0.83 |
Note that: ED50, the half of the effective amount.
Claims (9)
1. A compound of formula 1 or a pharmaceutically acceptable salt thereof:
z, Q are each independently selected from C, N and Z, Q are not simultaneously C; r is R 13 Is C 1 -C 5 Straight or branched alkyl of (a);
R 1 selected from the structures of H and formula II,
R 2 in the absence of the H or formula II structure,
a is C or N;
R 6 is H or halogen; r is R 7 Is H or OH;
R 5 is H or
R 4 Is H, halogen or a structure of formula III, or R 5 And R is R 4 Forming benzene ring;
in the formula III, n1 is an integer of 0-3, W 3 Is C or N;
R 8 is C 1 -C 3 Straight or branched alkyl of (a);
R 3 is H, of formula IV, V or VI:
wherein in the formula IV, n2 is an integer of 0-3, and n4 and n5 are respectively and independently selected from integers of 1-3;
W 1 、W 2 each independently selected from C, N;
R 9 selected from H, C 1 -C 3 Straight or branched alkyl, formaldehyde, acetaldehyde, dimethylamino;
in the formula VI, n3 is an integer of 0-1;
in the formula V, R 10 、R 11 Are respectively and independently selected from H, C 1 -C 3 Straight or branched alkyl of (a).
2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 is a compound of formula I-1
Z is C, N.
3. A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the halogen is selected from fluorine, chlorine, bromine and iodine.
4. A compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein C 1 -C 5 The straight or branched alkyl of (a) is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl.
5. A compound of formula I as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following:
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (piperazin-1-yl) pyrimidin-2-amine;
4- [2- [ (4-fluorobenzyl) (4-isobutoxybenzyl) amino ] pyrimidin-4-yl ] piperazine-1-carbaldehyde;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (piperidin-4-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine;
4- (azetidin-3-yl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine;
5-fluoro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
5-chloro-N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
4- [3- (dimethylamino) azetidin-1-yl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine;
N-benzyl-N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylazetidin-3-yl) pyrimidin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) quinazolin-2-amine;
4- [3- (dimethylamino) cyclobutyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyrimidin-2-amine; 4- [ (dimethylamino) methyl ] -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine;
4- (aminomethyl) -N- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) pyridin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (pyrrolidin-3-yl) pyridin-2-amine;
n- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -6- (pyrrolidin-3-yl) pyridin-2-amine;
3- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine;
(4-fluorophenyl) [2- [ (4-isobutoxybenzyl) amino ] -4- (1-methylpyrrolidin-3-yl) pyridin-3-yl ] methanol;
3- (4-fluorobenzyl) -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine;
3- [ (5-fluoropyridin-2-yl) methyl ] -N- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) pyridin-2-amine;
3- [ (5-fluoropyridin-2-yl) methyl ] -N- (4-isobutoxybenzyl) -4- (1-methylpyrrolidin-3-yl) pyridin-2-amine.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of psychotic disorders.
8. The use according to claim 7, wherein the psychotic disorder is schizophrenia.
9. The use according to claim 8, wherein the psychotic disorder is parkinson's disease, dementia-related behavioral disorders and psychoses.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111618063X | 2021-12-27 | ||
| CN202111618063 | 2021-12-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116354937A true CN116354937A (en) | 2023-06-30 |
Family
ID=86938482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211671622.8A Pending CN116354937A (en) | 2021-12-27 | 2022-12-23 | Pyridine (pyrimidine) amine derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116354937A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020013460A1 (en) * | 1997-10-02 | 2002-01-31 | Eisai Co., Ltd | Condensed pyridine compound |
| US20030203922A1 (en) * | 2001-01-12 | 2003-10-30 | Amgen Inc. | Substituted amine derivatives and methods of use |
| US20030225106A1 (en) * | 2001-01-12 | 2003-12-04 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
| CN1551866A (en) * | 2001-08-09 | 2004-12-01 | СҰҩƷ��ҵ��ʽ���� | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
| US20060040966A1 (en) * | 2004-07-22 | 2006-02-23 | Yuan Chester C | Substituted aryl-amine derivatives and methods of use |
| CN101223146A (en) * | 2005-05-24 | 2008-07-16 | 沃泰克斯药物股份有限公司 | Modulators of ATP-binding cassette transporters |
| CN102118969A (en) * | 2008-06-12 | 2011-07-06 | 詹森药业有限公司 | Histamine H4Diaminopyridine, diaminopyrimidine, and diaminopyridazine modulators of receptors |
| CN102725291A (en) * | 2009-10-29 | 2012-10-10 | 西特里斯药业公司 | Bicyclic pyridines and analogs as sirtuin modulators |
| US20160024060A1 (en) * | 2013-03-15 | 2016-01-28 | Daiichi Sankyo Company, Limited | Benzothiophene derivative |
| JP2016056143A (en) * | 2014-09-11 | 2016-04-21 | 第一三共株式会社 | Improving drug for behavioral symptoms and mental symptoms of dementia |
-
2022
- 2022-12-23 CN CN202211671622.8A patent/CN116354937A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020013460A1 (en) * | 1997-10-02 | 2002-01-31 | Eisai Co., Ltd | Condensed pyridine compound |
| US20030203922A1 (en) * | 2001-01-12 | 2003-10-30 | Amgen Inc. | Substituted amine derivatives and methods of use |
| US20030225106A1 (en) * | 2001-01-12 | 2003-12-04 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
| CN1551866A (en) * | 2001-08-09 | 2004-12-01 | СҰҩƷ��ҵ��ʽ���� | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
| US20060040966A1 (en) * | 2004-07-22 | 2006-02-23 | Yuan Chester C | Substituted aryl-amine derivatives and methods of use |
| CN101223146A (en) * | 2005-05-24 | 2008-07-16 | 沃泰克斯药物股份有限公司 | Modulators of ATP-binding cassette transporters |
| CN102118969A (en) * | 2008-06-12 | 2011-07-06 | 詹森药业有限公司 | Histamine H4Diaminopyridine, diaminopyrimidine, and diaminopyridazine modulators of receptors |
| CN102725291A (en) * | 2009-10-29 | 2012-10-10 | 西特里斯药业公司 | Bicyclic pyridines and analogs as sirtuin modulators |
| US20160024060A1 (en) * | 2013-03-15 | 2016-01-28 | Daiichi Sankyo Company, Limited | Benzothiophene derivative |
| JP2016056143A (en) * | 2014-09-11 | 2016-04-21 | 第一三共株式会社 | Improving drug for behavioral symptoms and mental symptoms of dementia |
Non-Patent Citations (1)
| Title |
|---|
| ACS: ""STN检索记录"", STN, 24 July 2020 (2020-07-24) * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3033335B1 (en) | Pyridinones | |
| CN103889987B (en) | Imidazopyrazine as the selection of BTK inhibitor | |
| JP7311583B2 (en) | Difluoromethyl-phenyltriazoles as GABA receptor modulators | |
| AU2002220195B2 (en) | Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto | |
| DK2805940T3 (en) | PYRAZINE CARBOXAMIDE COMPOUND | |
| ES2656198T3 (en) | Octahydro-cyclobuta [1,2-c; 3,4-c '] dipyrrole derivatives as autotaxin inhibitors | |
| KR20130028732A (en) | 4-aminopyrimidine derivatives and their as as adenosine a2a receptor antagonists | |
| CA2771775A1 (en) | Compounds and compositions as protein kinase inhibitors | |
| AU2006213634A1 (en) | Substituted bis aryl and heteroaryl compounds as selective 5HT2A antagonists | |
| KR20140040774A (en) | Imidazopyridine compound | |
| CA2644672A1 (en) | Quinazoline derivatives as phosphodiesterase 10 inhibitors | |
| EA014918B1 (en) | Substituted bicyclic pyrimidone derivatives | |
| EP1740578A1 (en) | 4- 2- (cycloalkylamino) pyrimidin-4-yl ] - (phenyl) - imidazolin-2- one derivatives as p38 map- kinase inhibitors for the treatment of inflammatory diseases | |
| WO2014042263A1 (en) | Novel renin inhibitor | |
| JP2017100950A (en) | Oxo heterocyclic derivative | |
| CN111032630B (en) | Compound, pharmaceutical composition, application and application thereof | |
| JP5290293B2 (en) | Substituted piperazinyl pyrazines and pyridines as 5-HT7 receptor antagonists | |
| AU2021440841A1 (en) | Alkynylphenylbenzamide compound and use thereof | |
| CN104447765A (en) | Tricyclic compound and pharmaceutical compositions thereof and application thereof | |
| AU2017327304B9 (en) | Use of morphinan derivative for therapeutic treatment of opioid δ receptor agonist-related disease | |
| CN111936144A (en) | JAK inhibitors | |
| WO2024099168A1 (en) | 2,4,5-trisubstituted pyrimidine compound, preparation method therefor, and use thereof | |
| WO2004087679A1 (en) | 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases | |
| CN116354937A (en) | Pyridine (pyrimidine) amine derivative and application thereof | |
| EP3700890A1 (en) | New alcoxyamino derivatives for treating pain and pain related conditions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |