CN110770214B - 杂环p2x7拮抗剂 - Google Patents
杂环p2x7拮抗剂 Download PDFInfo
- Publication number
- CN110770214B CN110770214B CN201880027662.4A CN201880027662A CN110770214B CN 110770214 B CN110770214 B CN 110770214B CN 201880027662 A CN201880027662 A CN 201880027662A CN 110770214 B CN110770214 B CN 110770214B
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- CN
- China
- Prior art keywords
- diazole
- ones
- dihydro
- methyl
- fluorophenyl
- 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.)
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- 101710189965 P2X purinoceptor 7 Proteins 0.000 title claims abstract description 55
- 102100037602 P2X purinoceptor 7 Human genes 0.000 title claims abstract description 53
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 16
- 239000005557 antagonist Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 238000011282 treatment Methods 0.000 claims abstract description 33
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- -1 C 1 -C 4 Alkoxy Chemical group 0.000 claims description 447
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 140
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 208000002193 Pain Diseases 0.000 claims description 20
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 14
- ZRHUHDUEXWHZMA-UHFFFAOYSA-N 1,4-dihydropyrazol-5-one Chemical class O=C1CC=NN1 ZRHUHDUEXWHZMA-UHFFFAOYSA-N 0.000 claims description 13
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002723 alicyclic group Chemical group 0.000 claims description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 208000028017 Psychotic disease Diseases 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 9
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 8
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000000094 Chronic Pain Diseases 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 2
- 208000023783 Genitourinary tract disease Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 2
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 claims description 2
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- JLXZMLLNPNOODV-UHFFFAOYSA-N imidazol-4-one Chemical class O=C1C=NC=N1 JLXZMLLNPNOODV-UHFFFAOYSA-N 0.000 claims 150
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims 46
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 35
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- AVJOUSHOVKNORK-UHFFFAOYSA-N 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclohexylmethyl)-1,2,4-thiadiazol-5-one Chemical compound ClC1=C(C(=CC=C1)F)CC1=NSC(N1CC1CCCCC1)=O AVJOUSHOVKNORK-UHFFFAOYSA-N 0.000 claims 1
- DEIJAHIKUBFYAG-UHFFFAOYSA-N 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-1,2,4-thiadiazol-5-one Chemical compound ClC1=C(C(=CC=C1)F)CC1=NSC(N1CC1CCC(CC1)(F)F)=O DEIJAHIKUBFYAG-UHFFFAOYSA-N 0.000 claims 1
- JTYNHLKXAXSNGZ-UHFFFAOYSA-N 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-1,2,4-thiadiazol-5-one Chemical compound ClC1=C(C(=CC=C1)F)CC1=NSC(N1CC1=CC=C(C=C1)F)=O JTYNHLKXAXSNGZ-UHFFFAOYSA-N 0.000 claims 1
- WEVIBJAPRUVZLE-UHFFFAOYSA-N 3-[(4,4-difluorocyclohexyl)methyl]-4-[(4-fluorophenyl)methyl]-1,2,4-thiadiazol-5-one Chemical compound FC1(CCC(CC1)CC1=NSC(N1CC1=CC=C(C=C1)F)=O)F WEVIBJAPRUVZLE-UHFFFAOYSA-N 0.000 claims 1
- AHMVEMHRDZOBQY-UHFFFAOYSA-N 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4,4-difluorocyclohexyl)methyl]-1,2,4-thiadiazol-5-one Chemical compound ClC1=C(C(=CC=C1)F)CN1C(=NSC1=O)CC1CCC(CC1)(F)F AHMVEMHRDZOBQY-UHFFFAOYSA-N 0.000 claims 1
- 208000018522 Gastrointestinal disease Diseases 0.000 claims 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 claims 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 51
- 208000035475 disorder Diseases 0.000 abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 8
- 239000001257 hydrogen Substances 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 125000000304 alkynyl group Chemical group 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 233
- 238000006243 chemical reaction Methods 0.000 description 186
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 62
- VVBAHFKQTKRMAS-UHFFFAOYSA-N 4-(bromomethyl)-1,1-difluorocyclohexane Chemical compound FC1(F)CCC(CBr)CC1 VVBAHFKQTKRMAS-UHFFFAOYSA-N 0.000 description 52
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 48
- MJGOLNNLNQQIHR-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(Cl)=C1CCl MJGOLNNLNQQIHR-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 27
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- 239000000243 solution Substances 0.000 description 19
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- PHGMUOJCQCLPBD-UHFFFAOYSA-N 1-(1-bromoethyl)-4-fluorobenzene Chemical compound CC(Br)C1=CC=C(F)C=C1 PHGMUOJCQCLPBD-UHFFFAOYSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 4
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及下式(I)的化合物或其可药用盐、包含它们的药物组合物以及制备所述化合物的方法,其中,在式(I)中:R1独立地选自氢原子、胺基团、单环或双环脂环族、芳香族、杂环族或杂芳族环,其任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1‑C4烷基、卤素、C1‑C4烷氧基或任选地被C1‑C4烷基取代的苯基;R2独立地选自单环或双环脂环族、杂环族、芳香族或杂芳族环、C1‑C6烷基、链烯基或炔基链,其任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1‑C4烷基、卤素、C1‑C4烷氧基、氰基、C1‑C4烷硫基、SO‑C1‑C4烷基、SO2‑C1‑C4烷基、N(C1‑C4烷基)2;n是1或2;优选n是1;m是0、1或2;优选m是0;R3和R4可以独立地是‑H、‑F、C1‑C4烷基、‑OH、‑OC1‑C4烷基;优选它们均是–H;X是O或S;R5是‑H或任选地被一个或多个氟原子取代的–CH3;优选R5是氢。本发明的化合物可用于治疗P2X7受体介导的病症或疾病。
Description
本发明涉及具有P2X7受体(P2X7)拮抗特性的新型式(I)杂环化合物、包含这些化合物的药物组合物、制备这些化合物的化学方法及其在治疗或预防动物、特别是人类的与P2X7受体活性有关的疾病中的用途。
P2X7属于P2X离子通道型受体家族。P2X7被细胞外核苷酸,特别是三磷酸腺苷(ATP)激活。P2X7与其他P2X家族成员的不同之处在于其特定的定位(特别是CNS和免疫活性细胞)、激活它所需的高浓度ATP(在mM范围内)以及其在受到长时间或重复刺激时形成大孔的能力。P2X7是一个配体门控离子通道,存在于多种细胞类型、主要是那些已知与炎症和/或免疫过程有关的细胞类型中,特别是巨噬细胞、肥大细胞和淋巴细胞(T和B)。细胞外核苷酸(例如ATP)激活P2X7受体会导致白介素-1β(1L-1β)释放和巨细胞(巨噬细胞/小胶质细胞)形成、脱粒(肥大细胞)和L-选择素脱落(淋巴细胞)。P2X7受体也位于抗原呈递细胞(APC)、角质形成细胞、唾液腺泡细胞(腮腺细胞)、肝细胞、红细胞、红白血病细胞、单核细胞、成纤维细胞、骨髓细胞、神经元和肾小球膜细胞上。还已知P2X7受体是神经系统中的疼痛传感器。使用P2X7缺陷型小鼠的实验证明了P2X7在疼痛发生中的作用,因为这些小鼠未出现佐剂诱导的炎性疼痛和部分神经结扎引起的神经性疼痛。还有越来越多的证据表明,P2X7或其下游效应子(例如IL-1β)参与多种神经系统障碍、例如阿尔茨海默氏病的病理生理学(J.I.Diaz-Hernandez等,Neurobiol.Aging 2012,1816-1828:In vivo P2X7inhibition reduces Aβ plaques in AD through GSK3β)。P2X7被认为通过其在突触后和/或突触前神经元和神经胶质上的激活而在CNS内的神经传递中具有重要作用。使用原位杂交的数据已经显示P2X7受体mRNA在整个大鼠脑中广泛分布。具体而言,在前嗅核、大脑皮质、梨状皮质(Pir)、外侧隔核(LS)、海马CA1、CA3、CA4锥体细胞层、桥脑核、楔外核和前庭内侧核发现了高P2X7 mRNA表达的区域。在三叉神经运动核、面神经核、舌下核和脊髓前角的运动神经元中也观察到了P2X7杂交信号。
因此,存在使用P2X7拮抗剂治疗多种疾病状态的治疗原理。这些状态包括但不限于与中枢神经系统相关的疾病,例如阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性侧索硬化、脊髓损伤、脑缺血、头部创伤、脑膜炎、睡眠障碍、情绪和焦虑障碍、HIV引起的神经炎症以及慢性神经性和炎性疼痛。此外,外周炎性障碍和自身免疫性疾病,包括但不限于类风湿性关节炎、骨关节炎、银屑病、过敏性皮炎、哮喘、慢性阻塞性肺疾病、气道高反应性、脓毒性休克、支气管炎、肾小球肾炎、肠易激综合征、脂肪肝、肝纤维化、皮肤损伤、肺气肿、肌营养不良、纤维化、动脉粥样硬化、烧伤、克罗恩病、溃疡性结肠炎、年龄相关性黄斑变性、恶性细胞的生长和转移、干燥综合征、成肌细胞白血病(myoblastic leukaemia)、糖尿病、骨质疏松症、缺血性心脏病都是其中涉及P2X7受体的疾病的例子。考虑到P2X7的临床重要性,鉴定可调节P2X7受体功能的化合物代表了开发新治疗剂的诱人途径。
P2X7抑制剂在许多专利申请中都有描述:
WO2004099146公开了P2X7受体的苯甲酰胺类抑制剂及其在治疗炎性疾病中的用途。
WO2009108551公开了杂芳基酰胺类似物及其在P2X7受体介导的病症中的用途。
WO2009132000公开了喹啉和异喹啉取代的P2X7受体拮抗剂及其在P2X7受体介导的病症中的用途。
WO2015119018公开了作为P2X7受体拮抗剂的噻唑和唑衍生物及其在P2X7受体介导的病症中的用途。
WO2015/099107A1公开了嘧啶酮取代的P2X7受体拮抗剂及其在P2X7受体介导的病症中的用途。
然而,仍然需要能够有效拮抗P2X7并且可以在不同靶器官(这些靶器官是P2X7介导的病理学的部位,包括大脑)中递送的化合物。本文提供了此类化合物。
以下给出本发明的各种实施方案。
本发明涉及下式(I)的二唑酮化合物或其可药用盐:
包括其任何立体化学异构形式,其中:
R1独立地选自氢、胺、单环或双环脂环族、芳香族、杂环族或杂芳族环,其任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1-C4烷基、卤素、C1-C4烷氧基或任选地被C1-C4烷基取代的苯基;
R2独立地选自单环或双环脂环族、杂环族、芳香族或杂芳族环、C1-C6烷基、链烯基或炔基链,其任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1-C4烷基、卤素、C1-C4烷氧基、氰基、C1-C4烷硫基、SO-C1-C4烷基、SO2-C1-C4烷基、N(C1-C4烷基)2;
n是1或2;优选n是1;
m是0、1或2;优选m是0;
R3和R4可以独立地是-H、-F、C1-C4烷基、-OH、-OC1-C4烷基;优选它们均是-H;
X是O或S;
R5是-H或任选地被一个或多个氟原子取代的-CH3;优选R5是氢。作为在上述定义中使用的:
术语“卤代”、“卤素”和“卤化物”可以互换使用,其是指取代基氟、氯、溴或碘。
上文所用的术语“立体化学异构形式”定义了式(I)化合物可能具有的所有可能的异构形式。除非另有说明或指示,否则化合物的化学命名表示所有可能的立体化学异构形式的混合物,所述混合物包含基础分子结构的所有非对映异构体和对映异构体。更具体地,立体中心可以具有R-或S-构型;二价环状(部分)饱和基团上的取代基可以具有顺式或反式构型。
式(I)化合物的立体化学异构形式显然旨在包含在本发明的范围内。
本领域技术人员可以使用众所周知的方法,例如X射线衍射,轻松确定式(I)化合物及其制备中所用的中间体的绝对立体化学构型。
此外,某些式(I)化合物及其制备中使用的某些中间体可能表现出多晶型。应当理解,本发明包括具有可用于治疗上述病症的性质的任何多晶型物。
上文提及的可药用盐包括式(I)化合物能够形成的具有治疗活性的无毒酸加成盐形式。这些可药用酸加成盐可以方便地通过用所述适当的酸处理碱形式而获得。适当的酸包括,例如,无机酸如氢卤酸,例如盐酸或氢溴酸、硫酸、硝酸、磷酸等酸;或有机酸如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环拉酸、水杨酸、对氨基水杨酸、帕莫酸等。
相反,可以通过用适当的碱处理将所述盐形式转化为游离碱形式。
式(I)化合物可以以非溶剂化物和溶剂化物的形式存在。术语“溶剂化物”在本文中用于描述分子缔合物,其包含本发明的化合物和一个或多个药学上可接受的溶剂分子,例如水或乙醇。当所述溶剂是水时,使用术语“水合物”。
优选地,R1独立地选自氢原子、单或取代的氨合物,或选自环戊基、环己基、哌啶、吗啉、吡咯烷、哌嗪、苯基、吡啶、唑、吡唑或噻唑的脂环族、芳香族、杂环族或杂芳族环,其中所述各个部分均可任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1-C4烷基、卤素、C1-C4烷氧基或任选地被C1-C4烷基取代的苯基,或者上述脂环族、芳香族、杂环族或杂芳族环可与另外的芳香族、杂芳族或杂环族环稠合。
优选地,R2独立地选自苯基、吡啶、嘧啶、吡唑、咪唑、萘、喹啉、噻唑、呋喃、唑、二唑、C3-C7环烷基、吡喃、四氢吡喃、二氧杂环己烷、C1-C4烷氧基、脂环族、芳香族或杂芳族二环、C1-C4烷基链或C3-C5炔基链,其中所述各个部分均可任选地被一个或多个任选地被一个或多个卤原子取代的C1-C4烷基、卤素或C1-C4烷氧基取代。
优选地,R3和R4独立地是H、F、-CH3、-OH、-OCH2CH3,更优选它们均是H。
X优选是O。
本发明的一个优选实施方案涉及如上定义的式(I)化合物,其中:
R1独立地选自氢原子或选自环戊基、环己基、哌啶、吗啉、吡咯烷、哌嗪、氨合物、苯基、吡啶、唑、吡唑或噻唑,其中所述各基团均任选地被甲基、甲氧基、卤素、三氟甲基或任选地被甲基取代的苯基取代;并且上述各脂环族、芳香族或杂环族或杂芳族环可与另外的芳香族或杂芳族环稠合;
R2独立地选自苯基、吡啶、嘧啶、吡唑、咪唑、萘、喹啉、噻唑、呋喃、唑、/>二唑、C3-C7环烷基、吡喃、四氢吡喃、二氧杂环己烷、脂环族二环、C1-C3烷氧基、C1-C4烷基链或C3-C5炔基链;其中上述脂环族、芳香族和杂环族环均任选地被甲基、甲氧基、卤素和/或三氟甲基取代)。
n是1或2;优选n是1;
m是0、1或2;优选m是0;
R3和R4独立地是-H、F、CH3、-OH或-OCH2CH3;优选它们均是氢;
X是O或S;优选O;
R5是H或-CH3;优选R5是H;
本发明的另一个优选实施方案涉及如上定义的式(I)化合物,其中:
R1独立地选自氢原子、3,3-二氟环戊基、环己基、4,4-二氟环己基、哌啶基、3,3-二氟哌啶基、4,4-二氟哌啶基、4,4-二氟-2-甲基哌啶基、3-(4-甲基苯基)哌啶基、4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基、1,2,3,4-四氢异喹啉-2-基、3,4-二氢-2H-1,4-苯并嗪-4-基、吡咯烷基、4-苯基哌嗪基、苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、2-三氟甲基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二氯苯基、2,4-二氯苯基、2-氯-3-三氟甲基苯基、2,4-二氟苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-、3-或4-吡啶、2-甲基吡啶-3-基、二甲基-1,2-/>唑-4-基、三甲基-1H-吡唑-4-基和4-甲基-1,3-噻唑-5-基;
R2独立地选自2-苯基甲基、1-苯基乙基、2-苯基乙基、苯基、2-、3-、4-氟苯基、2-、4-氯苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-、4-三氟甲基苯基、2-、4-甲基苯基、2,3-二氯苯基、2,4-二氯苯基、2,4-二氟苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-氯-3-三氟甲基苯基、2,4-二甲氧基苯基、3,5-二甲氧基苯基、2-溴-5-氟苯基、4-氟-2-甲基苯基、2-吡啶基、3-吡啶基、4-吡啶、2-甲基吡啶-3-基、6-三氟甲基吡啶-3-基、2-甲基-6-(三氟甲基)吡啶-3-基、萘-1-基、喹啉-5-基、1,3-噻唑-2-基、1,3-噻唑-5-基、4-甲基-1,3-噻唑-5-基、5-甲基-1,2-唑-3-基、1,2-/>唑-3-基、1,2-/>唑-5-基、1,3-/>唑-2-基、1,3-/>唑-5-基、二甲基-1,2-/>唑-4-基、3-(三氟甲基)-1H-吡唑-1-基、1,3-二甲基-1H-吡唑-5-基、1-甲基-1H-咪唑-2-基、呋喃-3-基、5-(三氟甲基)呋喃-2-基、5-甲基-1,3,4-/>二唑-2-基、5-甲基-1,2,4-/>二唑-3-基、3-甲基-1,2,4-/>二唑-5-基、嘧啶-2-基、嘧啶-5-基、5-氟嘧啶-2-基、环丙基、环丁基、环戊基、环戊-3-烯-1-基、环己基、1-氟环己基、2-甲基环己基、2,2-二甲基环己基、4,4-二甲基环己基、2,2-二氟环己基、4,4-二氟环己基、4-(三氟甲基)环己基、4-氟环己基、3,3-二氟环戊基、6,6-二氟二环[3.1.0]己-3-基、二环[2.2.1]庚-1-基、二环[2.2.1]庚-2-基、1,4-二氧杂螺[4.5]癸-8-基、氧杂环己烷-2-基、氧杂环己烷-3-基、氧杂环己烷-4-基、1,4-二氧杂环己烷-2-基、甲氧基、乙氧基、丙氧基、氢、甲基、乙基、丙基、2-甲基丙基、丁-1-炔基、丙-1-炔基、哌啶-1-基、4,4-二氟哌啶-1-基;
n是1或2;优选n是1;
m是0、1或2;优选m是0;
R3和R4独立地是-H、-CH3、-OH和-OCH2CH3;优选R3和R4均是氢;
X是O或S;优选X是O;
R5是-H或-CH3;优选R5是-H;
最优选地,本发明的式(I)化合物选自:
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式(I)化合物通常可以通过将式(II)化合物:
其中n、X和R1、R3和R4的含义如上所定义,
与式(III)化合物反应来制备:
其中R2、R5和m的含义如上所定义;W是适宜的离去基团;然后任选地将得到的式(I)化合物转化成其加成盐,和/或制备其立体化学异构形式。
式(II)化合物与式(III)化合物的反应可以在至少一种反应惰性溶剂中并且任选在至少一种合适的偶联剂和/或合适的碱的存在下进行。
式(III)化合物中的W是合适的离去基团,例如卤素,例如氯、溴,或在某些情况下,W也可以是醇等反应性离去基团。式(II)化合物与式(III)化合物的反应可以在反应惰性溶剂例如乙腈、二甲基乙酰胺、THF或DMF中进行,并且任选地在合适的碱例如碳酸钠、碳酸钾或甲醇钠的存在下进行。搅拌可以提高反应速度。反应可以方便地在室温至反应混合物的回流温度之间的温度下进行。
式(III)化合物是本领域已知的。
式(II)化合物可以按照如下流程制备:
其中n、R1、R3和R4如式(I)中所定义的式(II)化合物可以通过将相应的N’-羟基乙脒衍生物(IV)环化制得。
反应在适宜的溶剂例如1,4-二氧杂环己烷中、在作为环化剂的CDI和作为碱的DBU的存在下、优选在105℃的温度下进行。
其中n、R1、R3和R4如式(I)中所定义的式(IV)化合物可以从适当的腈衍生物(V)通过与盐酸羟胺在作为碱的K2CO3的存在下,使用EtOH作为溶剂,优选在室温至回流的温度下反应来制备。
腈衍生物(V)、起始原料和一些中间体是已知化合物,可商购或者可以根据本领域公知的常规反应程序制备。
式(IIa)化合物还可以按照如下流程制备:
其中n、R1、R3和R4如式(I)中所定义的式(IIa)化合物可以通过相应的N′-羟基乙脒(IV)的环化制备。
反应在合适的溶剂例如THF中,使用1,1′-硫代羰基二咪唑,在作为路易斯酸的三氟化硼二乙醚化物的存在下,优选在室温下进行。
其中n、R1、R3和R4如式(I)中所定义的式(IV)化合物可以从适当的腈衍生物(V)通过与盐酸羟胺在作为碱的K2CO3的存在下,使用EtOH作为溶剂,优选在室温至回流的温度下反应来制备。
腈衍生物(V)、起始原料和一些中间体是已知化合物,可商购获得或者可以根据本领域公知的常规反应方法制备。
所述方法还任选地包括使用基于手性助剂的合成(使用碳水化合物、手性胺或环酮亚胺)和/或催化不对称Strecker合成(使用胍、手性席夫碱或BINOL基催化剂)的不对称反应。
在上述方法中制备的式(I)化合物可以以对映异构体的外消旋混合物的形式合成,其可以按照本领域已知的拆分方法彼此分离。通过与合适的手性酸反应,可以将以外消旋形式获得的那些式(I)化合物转化为相应的非对映体盐形式。所述非对映体盐形式随后例如通过选择性或分步结晶分离,并通过碱从其中释放对映异构体。分离式(1)化合物的对映异构体形式的另一种方法涉及使用手性固定相的液相色谱法。所述纯立体化学异构形式也可以衍生自适当起始原料的相应纯立体化学异构形式,条件是反应立体定向地发生。如果需要特定的立体异构体,则优选通过立体有择的制备方法合成所述化合物。这些方法将有利地采用对映体纯的起始原料。
如药理学实施例中所证明的,式(I)化合物、其可药用盐和立体异构形式具有P2X7受体拮抗特性。将式(I)化合物转化为其它式(I)化合物的本领域已知的基团转化反应的其它实例是羧酸酯水解成相应的羧酸或醇;酰胺水解成相应的羧酸或胺;醇可以转化为酯和醚;伯胺可以转化为仲胺或叔胺;双键可以氢化成相应的单键。起始原料和一些中间体是已知化合物并且可商购获得,或者可以根据本领域公知的常规反应方法制备。在上述方法中制备的式(I)化合物可以以对映异构体的外消旋混合物的形式合成,其可以按照本领域已知的拆分方法彼此分离。通过与合适的手性酸反应,可以将以外消旋形式获得的那些式(I)化合物转化为相应的非对映体盐形式。所述非对映体盐形式随后例如通过选择性或分步结晶分离,并通过碱从其中释放对映异构体。分离式(I)化合物的对映异构体形式的另一种方法涉及使用手性固定相的液相色谱法。所述纯立体化学异构形式也可以衍生自适当起始原料的相应纯立体化学异构形式,条件是反应立体定向地发生。如果需要特定的立体异构体,则优选通过立体有择的制备方法合成所述化合物。这些方法将有利地采用对映体纯的起始原料。在制备式I化合物和本文所述的起始原料和/或中间体时,保护对反应条件敏感的某些基团可能是有用的。根据制备本发明化合物时所进行的反应以及所要保护的官能团来评价任选保护的有用性以及选择适合的保护试剂在技术人员的常识范围之内。根据常规技术除去任选的保护基团。有关在有机化学中使用保护基团的一般参考文献,请参阅TheodoraW.Greene和Peter G.M.Wuts“Protective groups in organic synthesis”,John Wiley&Sons,Inc.,II Ed.,1991。
式I化合物的盐的制备根据已知方法进行。因此,本发明的式(I)化合物可用作药物,特别是用于治疗由P2X7受体、特别是P2X7受体拮抗活性介导的病症或疾病。因此,本发明的化合物可用于制备治疗由P2X7受体活性、特别是P2X7受体拮抗活性介导的病症或疾病的药物。
本发明还提供式(I)化合物或其可药用盐在制备用于治疗选自P2X7受体介导的病症或疾病的药物中的用途。在一个实施方案中,本发明提供用作药物或用于治疗选自P2X7受体介导的病症或疾病式(I)化合物。此外,本发明还提供了治疗哺乳动物个体中由P2X7受体活性介导的病症的方法,该方法包括给需要这种治疗的哺乳动物施用治疗有效量的式(I)化合物或其可药用盐。鉴于上述作用机制,本发明化合物可用于治疗各种起源的神经变性疾病,例如阿尔茨海默氏病和其他痴呆症,如路易氏病、额颞痴呆和tau蛋白病;肌萎缩性侧索硬化、多发性硬化症、帕金森病和其他帕金森综合征;HIV诱导的神经炎症;特发性震颤;其他脊柱小脑退化和Charcot-Marie-Toot神经病变。本发明的化合物还可用于治疗神经病症,例如癫痫,包括单纯部分性发作、复杂部分性发作、继发性全身性发作,还包括失神发作、肌阵挛性发作、阵挛发作、强直性发作、强直性阵挛性发作和失张力发作。
本发明化合物还可用于治疗认知障碍和精神障碍。精神障碍包括并且不限于重度抑郁症、心境恶劣、躁狂症、双相情感障碍(例如I型双相情感障碍、II型双相情感障碍)、循环型情感障碍、快速循环型情感障碍、超日节律循环型情感障碍(ultradian cycling)、躁狂症、轻度躁狂症、精神分裂症、精神分裂症样障碍、分裂情感障碍、人格障碍、有或没有多动行为的注意力障碍、妄想障碍、短暂的精神障碍、共有型精神障碍、由一般医学状况引起的精神障碍、物质引起的精神障碍或其它未注明的精神障碍、焦虑症例如广泛性焦虑症、惊恐障碍、创伤后应激障碍、冲动控制障碍、恐怖症、分裂状态以及吸烟、药物成瘾和酒精中毒。特别是双相情感障碍、精神病、焦虑和成瘾。
本发明化合物可用于预防或治疗神经性疼痛。神经性疼痛综合征包括并且不限于:糖尿病性神经病;坐骨神经痛;非特异性下腰痛;多发性硬化疼痛;纤维肌痛;HIV相关神经病;神经痛,如疱疹后神经痛和三叉神经痛、莫顿神经痛、灼痛;以及由于身体创伤、截肢、幻肢、癌症、毒素或慢性炎症引起的疼痛;中枢性疼痛,例如在丘脑综合征中观察到的疼痛、混合的中枢和外周形式的疼痛,如复杂性局部疼痛综合征(CRPS),也被称为反射性交感神经营养不良。
本发明化合物也可用于治疗慢性疼痛。慢性疼痛包括但不限于由炎症或炎症相关病症、骨关节炎、类风湿性关节炎、急性损伤或创伤引起的慢性疼痛、上背部疼痛或下腰痛(由全身、区域性或原发性脊柱疾病引起,例如神经根病)、骨痛(由于骨关节炎、骨质疏松症、骨转移或未知原因导致)、骨盆疼痛、脊髓损伤相关疼痛、心脏性胸痛、非心脏性胸痛、中枢性中风后疼痛、肌筋膜疼痛、镰状细胞病疼痛、癌症疼痛、法布里病、艾滋病疼痛、老年疼痛或由头痛、颞下颌关节综合征、痛风、纤维化或胸廓出口综合征,特别是类风湿性关节炎和骨关节炎引起的疼痛。
本发明化合物还可用于治疗由急性损伤、疾病、运动-医学损伤、腕管综合症、烧伤、肌肉骨骼扭伤和拉伤、肌肉腱鞘炎、颈臂疼痛综合征、消化不良、胃溃疡、十二指肠溃疡、痛经、子宫内膜异位症或手术(如开胸或旁路手术)引起的急性痛、术后疼痛、肾结石疼痛、胆囊疼痛、胆结石疼痛、产科疼痛或牙痛。
本发明化合物还可用于治疗头痛,例如偏头痛、紧张型头痛、转换型偏头痛或进展型头痛、丛集性头痛以及继发性头痛症,例如源自感染、代谢障碍或其它系统性疾病的头痛症,以及由上述原发性和继发性头痛的恶化引起和其他急性头痛、阵发性偏头痛等。
本发明化合物还可用于治疗诸如眩晕、耳鸣、肌肉痉挛等疾病以及其他障碍,包括并且不限于心血管疾病(例如心律失常、心肌梗塞或心绞痛、高血压、心肌缺血、脑缺血)、其中病症的病理生理学涉及内源性物质(例如儿茶酚胺、激素或生长因子)过量或过度分泌或其他不适当的细胞分泌的内分泌紊乱(例如肢端肥大症或尿崩症)疾病。
本发明化合物还可用于选择性治疗肝脏疾病,例如炎性肝病,例如慢性病毒性乙型肝炎、慢性病毒性丙型肝炎、酒精性肝损伤、原发性胆汁性肝硬化、自身免疫性肝炎、肝纤维化、非酒精性脂肪性肝炎和肝移植排斥反应。
本发明化合物抑制影响所有身体系统的炎症过程。因此,它可用于治疗肌肉-骨骼系统的炎症过程,以下是所述炎症过程的示例列表,但并不全面涵盖所有目标疾病:关节炎病症,如强直性脊柱炎、颈椎关节炎、纤维肌痛、痛风、幼年型类风湿关节炎、腰骶关节炎、骨关节炎、骨质疏松症、银屑病关节炎、风湿性疾病;影响皮肤和相关组织的障碍:湿疹、银屑病、皮炎和炎性状况,如晒伤;呼吸系统障碍:哮喘、过敏性鼻炎和呼吸窘迫综合征、涉及炎症的肺疾病,如哮喘和支气管炎;慢性阻塞性肺病;免疫和内分泌系统疾病:结节性关节周围炎、甲状腺炎、再生障碍性贫血、硬皮病、重症肌无力、多发性硬化和其他脱髓鞘障碍、脑脊髓炎、结节病、肾病综合症、Bechet综合症、多肌炎、牙龈炎。
本发明化合物还可用于治疗胃肠(GI)道疾病,例如炎性肠病,包括但不限于溃疡性结肠炎、克罗恩病、回肠炎、直肠炎、乳糜泻、肠病、显微镜下结肠炎或胶原性结肠炎、嗜酸性胃肠炎或在直肠结肠切除术后和回肠吻合术后产生的隐窝炎、以及肠易激综合症,包括任何伴有腹痛和/或腹部不适的病症,如幽门痉挛、神经性消化不良、痉挛性结肠、痉挛性结肠炎、痉挛性肠、肠神经官能症、功能性结肠炎、粘液性结肠炎、轻泻性结肠炎和功能性消化不良;还可用于治疗萎缩性胃炎、变异型胃炎(gastritis varialoforme)、溃疡性结肠炎、消化性溃疡、胃灼热和例如由幽门螺杆菌、胃食管反流病、胃轻瘫如糖尿病胃轻瘫等引起的其他胃肠道损伤;和其他功能性肠病如非溃疡性消化不良(NUD);呕吐、腹泻和内脏炎症。
本发明化合物还可用于治疗生殖泌尿道疾病,例如膀胱过度活动症、前列腺炎(慢性细菌性和慢性非细菌性前列腺炎)、前列腺痛、间质性膀胱炎、尿失禁和良性前列腺增生、附件炎(annexities)、骨盆炎、前庭大腺炎和阴道炎。特别是膀胱过度活动症和尿失禁。
本发明化合物还可用于治疗眼科疾病,例如视网膜炎、视网膜病、葡萄膜炎和眼组织的急性损伤、年龄相关性黄斑变性或青光眼、结膜炎。
本发明化合物还可用于治疗进食障碍,例如神经性厌食症,包括限制型和暴食/导泻型亚型;神经性贪食症,包括导泻型和非导泻型亚型;肥胖症;强迫性进食障碍;暴饮症;以及其他未注明的进食障碍。
本发明化合物还可用于治疗过敏性皮炎、气道高反应性、慢性阻塞性肺病(COPD)、支气管炎、脓毒性休克、干燥综合征、肾小球肾炎、动脉粥样硬化、恶性细胞的生长和转移、成肌细胞白血病、糖尿病、脑膜炎、骨质疏松症、烧伤、缺血性心脏病、中风、外周血管疾病、静脉曲张、青光眼。
如本文所用,术语“治疗”是指治愈性、缓和性和预防性治疗,包括逆转、缓解、抑制或预防该术语所适用的疾病、障碍或病症或这类疾病、障碍或病症的一种或多种症状的进展。
另外,本发明还提供了药物组合物,其包含至少一种可药用的载体和治疗有效量的式(I)化合物。
为了制备本发明的药物组合物,将有效量的作为活性成分的碱或酸加成盐形式的特定化合物与至少一种可药用载体紧密混合,该载体可以采取多种形式,这取决于施用所期望的制剂形式。这些药物组合物理想地是适合的单位剂型,优选用于口服施用、直肠施用、经皮施用或肠胃外注射。
例如,在制备口服剂型的组合物时,可以使用任何常用的液体药物载体,例如在口服液体制剂如混悬液、糖浆、酏剂和溶液的情况下,使用水、乙二醇、油、醇等;或在粉末、丸剂、胶囊和片剂的情况下,使用固体药物载体如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等。由于它们易于施用,所以片剂和胶囊代表最有利的口服剂量单位形式,在这种情况下显然使用固体药物载体。对于肠胃外注射组合物,药物载体将主要包含无菌水,但也可包括其他成分以改善活性成分的溶解度。
可以例如通过使用包含盐溶液、葡萄糖溶液或两者的混合物的药物载体来制备可注射溶液。还可以通过使用适当的液体载体、助悬剂等制备可注射的混悬液。在适于经皮施用的组合物中,药物载体可任选地包含渗透增强剂和/或适合的润湿剂,任选地与少量比例的不会对皮肤产生显著有害作用的适合添加剂组合。可以选择所述添加剂以便于将活性成分施用于皮肤和/或有助于制备所需的组合物。这些局部用组合物可以以各种方式施用,例如透皮贴剂、点滴剂或软膏剂。式(1)化合物的加成盐由于其相对于相应碱形式的水溶性增加,显然更适合于制备含水组合物。
特别有利的是以剂量单位形式配制本发明的药物组合物,以便于施用和剂量的均匀性。
如本文所用的“剂量单位形式”是指适合作为单位剂量的物理上离散的单位,每个单位含有经计算可产生所需治疗效果的预定量的活性成分和所需的药物载体。这种剂量单位形式的实例是片剂(包括刻痕或包衣片剂)、胶囊、丸剂、粉末包、糯米纸囊剂、可注射溶液或混悬液、一茶匙量、一汤匙量等,以及它们的分离倍数。
对于口服施用,本发明的药物组合物可以采取固体剂型的形式,例如片剂(可吞咽和可咀嚼形式)、胶囊或软胶囊,其通过常规方法用可药用赋形剂和载体如粘合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素等)、填充剂(例如乳糖、微晶纤维素、磷酸钙等)、润滑剂(例如硬脂酸镁、滑石粉、二氧化硅等)、崩解剂(例如马铃薯淀粉、羟基乙酸淀粉钠等)、润湿剂(例如十二烷基硫酸钠)等制备。此类片剂也可以通过本领域熟知的方法包衣。
用于口服施用的液体制剂可以采取例如溶液、糖浆或混悬液的形式,或者它们可以配制成干燥产品,用于在使用前与水和/或另一种适合的液体载体混合。这些液体制剂可以通过常规方法制备,任选地使用其它可药用添加剂如助悬剂(例如山梨糖醇糖浆、甲基纤维素、羟丙基甲基纤维素或氢化食用脂肪)、乳化剂(例如卵磷脂或阿拉伯胶)、非水载体(例如杏仁油、油性酯或乙醇)、甜味剂、矫味剂、掩蔽剂和防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)。
可用于本发明药物组合物的可药用甜味剂优选包含至少一种强力甜味剂,例如阿斯巴甜、乙酰磺胺酸钾、环己基氨基磺酸钠、alitarne、二氢查耳酮甜味剂、莫内林、甜菊糖三氯蔗糖(4,1’,6’-三氯-4,1’,6’-三脱氧半乳蔗糖)或优选地,糖精、糖精钠或糖精钙,和任选的至少一种增量甜味剂,如山梨醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽酮糖醇、葡萄糖、氢化葡萄糖浆、木糖醇、焦糖或蜂蜜。强力甜味剂通常以低浓度使用。例如,在糖精钠的情况下,所述浓度可以为最终制剂的约0.04%至0.1%(重量/体积)。增量甜味剂可有效地以约10%至约35%,优选约10%至15%(重量/体积)的较大浓度使用。可以掩盖低剂量制剂中的苦味成分的可药用矫味剂优选包括水果矫味剂,例如樱桃、覆盆子、黑加仑或草莓矫味剂。两种矫味剂的组合可以得到非常好的结果。在高剂量制剂中,可能需要更强的可药用矫味剂,例如焦糖巧克力、薄荷清凉(Mint Cool)、梦幻(Fantasy)等。
每种矫味剂可以以约0.05%至1%(重量/体积)的浓度存在于最终组合物中。有利地使用所述强矫味剂的组合。优选使用在制剂环境下不发生味道和/或颜色的任何变化或损失的矫味剂。
式(I)化合物可以配制用于通过注射,通常为静脉内、肌内或皮下注射,例如通过推注或连续静脉内输注进行肠胃外施用。用于注射的制剂可以以单位剂量形式存在于例如安瓿或多剂量容器中,其中包含添加的防腐剂。它们可以采取诸如油性或水性载体中的混悬液、溶液或乳液的形式,并且可以含有配制剂,例如等渗剂、助悬剂、稳定剂和/或分散剂。或者,活性成分可以以粉末形式存在,用于在使用前与适合的媒介物,例如,无菌无热原的水混合。
式(I)化合物也可以配制成直肠组合物,例如含有常规栓剂基质如可可脂和/或其他甘油酯的栓剂或保留灌肠剂。
治疗与配体门控离子通道的介导相关的疾病的技术人员将容易地从下文给出的测试结果确定式(I)化合物的治疗有效量。通常,预期治疗有效剂量约为0.001mg/kg至约50mg/kg体重,更优选约0.01mg/kg至约10mg/kg待治疗患者体重。在一天中以适当的间隔以两个或更多个亚剂量的形式施用治疗有效剂量可能是适合的。可以将所述亚剂量配制成单位剂型,例如每个单位剂型含有约0.1mg至约1000mg,更特别是约1至约500mg活性成分。
如本文所用,化合物的“治疗有效量”是当施用于个体或动物时,导致个体或动物中足够高水平的该化合物以引起可辨别的P2X7受体拮抗响应的化合物的量。
施用的确切剂量和频率取决于所用的式(I)的具体化合物、所治疗的具体病症、所治疗病症的严重程度、特定患者的年龄、体重和一般身体状况以及患者可能服用的其他药物,这是本领域技术人员所熟知的。此外,取决于所治疗患者的反应和/或取决于开具本发明化合物处方的医生的评估,所述“治疗有效量”可以降低或增加。因此,上文提到的每日有效量的范围仅仅是指导原则。
命名和结构
通常,本申请中使用的命名法基于ChemSketchTM(ACDLabs)并根据IUPAC系统命名法生成。使用2.2版制备本文所示的化学结构。除非另有说明,否则本文结构中出现在碳、氧、硫或氮原子上的任何开放化合价都表明存在氢原子。当含氮杂芳基环在氮原子上显示开放化合价并且在杂芳基环上显示变量如R1、R2、R3等时,这些变量可以与开放化合价的氮结合或连接。当结构中存在手性中心但没有显示手性中心的具体立体化学时,与手性中心相关的两种对映体都包括在该结构中。当本文所示的结构可以以多种互变异构形式存在时,所有这些互变异构体都包含在该结构中。本文结构中表示的原子旨在包括这些原子的所有天然存在的同位素。因此,例如,本文表示的氢原子意在包括氘和氚,并且碳原子意在包括13C和14C同位素。
缩写
在描述流程和下文的实施例中可能用到的缩写是:
CC:柱色谱;DCM:二氯甲烷;DEAD:偶氮二甲酸二乙酯;DMF:二甲基甲酰胺;EP:石油醚;EtOAc:乙酸乙酯;EtOH:乙醇;hrs:小时;MeCN:乙腈;min:分钟;N:当量;NMR:核磁共振;PPh3:三苯基膦;PPh3O:三苯基膦氧化物;r.t.:室温;THF:四氢呋喃;LC-MS:液相色谱-质谱法;K2CO3:碳酸钾;Na2SO4:硫酸钠;HPLC:高效液相色谱法;o.n.:过夜;CH3ONa:甲醇钠;NaCl:氯化钠;CDI:1,1′-羰基二咪唑;DBU:1,5-二氮杂双环(5.4.0)十一碳-5-烯;HCI:盐酸;Y:收率
实验部分
下列实施例说明了本发明。除非另有明确说明,否则所有具体值(尤其是百分比和数量)均是指重量。
中间体的合成
用作原料的大部分取代的腈衍生物是从化学供应商处购买的:
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一些用作起始原料的腈衍生物根据该一般方法合成:
将K2COs(1.5当量)添加至适当的胺(1.0当量)和溴乙腈(1.1当量)的ACN(10mL)溶液中,并将混合物在室温下搅拌。然后,滤出沉淀的盐并在减压下蒸发滤液。残余物通过快速色谱法(DCM/AcOEt 1∶1v/v)纯化,得到纯的腈衍生物(y=61-97%)。
利用该方法,从相应的可购买到的起始原料制备中间体0a(y=64%)、0b(y=70%)。
N’-羟基乙脒衍生物(IV)的制备(典型方法)
将盐酸羟胺(2.5当量)和K2CO3(2.5当量)溶于EtOH(20-40mL)并将混合物在室温下搅拌30分钟;然后加入合适的腈衍生物(1.0当量)(V)并将反应混合物加热回流12小时。滤出沉淀的固体并在减压下浓缩滤液。残余物通过CC(DCM/EtOAc 1∶1v/v)纯化,得到纯净的N’-羟基乙脒。(y=35-97%)。
利用该方法,从相应的可购买到的腈衍生物制备中间体1a(y=64%)、1b(y=70%)、1c(y=72%)、1d(y=80%)、1e(y=55%)、1f(y=82%)、1g(y=79%)、1h(y=72%)、1i(y=46%)、1j(y=68%)、1k(y=69%)、1l(y=82%)、1m(y=96%)、1n(y=71%)、1o(y=79%)、1p(y=94%)、1q(y=95%)、1r(y=72%)、1s(y=97%)、1u(y=71%)、1v(y=47%)、1w(y=76%)、1x(y=92%)、1y(y=56%)、1z(y=91%)、1aa(y=76%)、1bb(y=90%)、Icc(y=79%)、1dd(y=72%)、1ee(y=87%)、1ff(y=85%)、1gg(y=61%)、1hh(y=69%)、1ii(y=66%)、1jj(y=88%)、1kk(y=95%)、1ll(y=90%)、1mm(y=84%)。
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1,2,4-二唑-5(4H)-酮(II)的制备(典型方法)
在室温下,向合适的中间体IV(1.0当量)在1,4-二氧杂环己烷(10-30mL)中的溶液中添加CDI(1.5当量)和DBU(1.1当量),然后将混合物在105℃下搅拌3小时。冷却后,将混合物用水稀释,用EtOAc洗涤,用3N HCl调节至pH 2并用EtOAc萃取。将EtOAc萃取液用盐水洗涤,经Na2SO4干燥并真空浓缩。通过CC(己烷/EtOAc 1∶1v/V)纯化粗残余物,得到纯的1,2,4-二唑-5(4H)-酮。(y=20-98%)
利用该方法:
从1a开始制备中间体2a(y=87%);
从1b开始制备中间体2b(y=86%);
从1c开始制备中间体2c(y=85%);
从1d开始制备中间体2d(y=61%);
从1e开始制备中间体2e(y=88%);
从1f开始制备中间体2f(y=59%)从开始制备1f;
从1g开始制备中间体2g(y=85%)从开始制备1g;
从1h开始制备中间体2h(y=61%)从开始制备1h;
从1i开始制备中间体2i(y=41%);
从1j开始制备中间体2j(y=90%);
从1k开始制备中间体2k(y=76%);
从1l开始制备中间体2l(y=77%);
从1m开始制备中间体2m(y=76%);
从1n开始制备中间体2n(y=76%);
从1o开始制备中间体2o(y=61%);
从1p开始制备中间体2p(y=48%);
从1q开始制备中间体2q(y=20%);
从1r开始制备中间体2r(y=46%);
从1s开始制备中间体2s(y=98%);
从1u开始制备中间体2u(y=72%);
从1v开始制备中间体2v(y=72%);
从1w开始制备中间体2w(y=75%);
从1x开始制备中间体2x(y=60%);
从1y开始制备中间体2y(y=40%);
从1z开始制备中间体2z(y=82%);
从1aa开始制备中间体2aa(y=86%);
从1bb开始制备中间体2bb(y=89%);
从1cc开始制备中间体2cc(y=67%);
从1dd开始制备中间体2dd(y=44%);
从1ee开始制备中间体2ee(y=52%);
从1ff开始制备中间体2ff(y=84%);
从1gg开始制备中间体2gg(y=61%);
从1hh开始制备中间体2hh(y=56%);
从1ii开始制备中间体2ii(y=83%);
从1jj开始制备中间体2jj(y=40%);
从1kk开始制备中间体2kk(y=57%);
从1ll开始制备中间体2ll(y=57%);
从1mm开始制备中间体2mm(y=50%);
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1,2,4-噻二唑-5(4H)-酮(IIa)的制备(典型方法)
将适当的中间体VI(1.0当量)和TCDI(1.5当量)在THF(20mL)中的混合物在室温下搅拌30分钟。将混合物用水稀释并用EtOAc萃取;萃取液用水洗涤并经Na2SO4干燥,过滤并真空蒸发溶剂。将获得的残余物溶解在THF(20mL)中并向溶液中加入三氟化硼二乙醚(3.0当量),将得到的混合物在室温下再搅拌1小时。混合物用水稀释并用EtOAc萃取;萃取液用水洗涤并用Na2SO4干燥,过滤并真空蒸发溶剂。产物无需纯化即可用于下一步。以这种方式获得了纯的1,2,4-噻二唑-5(4H)-酮。(y=66-82%)
利用该方法:
从中间体1g开始制备中间体3a(y=66%);
从中间体1v开始制备中间体3b(y=82%);
合成最终化合物的一般方法
方法A
实施例1-7的制备
在0℃下,向中间体2(1.0当量)、合适的可购买到的醇(1.0当量)和PPh3(4.0当量)在THF(5-10mL)中的溶液中滴加40wt%的DEAD甲苯溶液(4.0当量);将反应混合物在惰性气氛下室温搅拌24小时。减压浓缩溶剂;将残余物溶于少量二乙醚中并在-20℃冷却,形成白色沉淀物(PPh3O和还原的DEAD),将其滤出。减压浓缩滤液。粗产物通过HPLC纯化,得到纯净的所需化合物。(y=9%-66%)
按照该方法,用合适的中间体和醇制备如下化合物:
实施例 | 收率 | 中间体 | 醇 |
实施例1 | 60% | 中间体2a | 2-氯-6-氟苄基醇(CAS:56456-50-9). |
实施例2 | 34% | 中间体2a | 2,4-二甲氧基苄基醇(CAS:7314-44-5). |
实施例3 | 9% | 中间体2a | 4-甲氧基苄基醇(CAS:105-13-5). |
实施例4 | 66% | 中间体2a | 3,5-二甲氧基苄基醇(CAS:705-76-0). |
实施例5 | 39% | 中间体2a | 2-溴-5-氟苄基醇(CAS:202865-66-5). |
实施例6 | 26% | 中间体2o | 2-氯-6-氟苄基醇(CAS:56456-50-9). |
实施例7 | 16% | 中间体2d | 2-氯-6-氟苄基醇(CAS:56456-50-9). |
方法B
实施例8-49的制备
向冷却的(0℃)中间体2(1.0当量)的MeCN/DMF(5∶1v/v 5-10mL/1-3mL)溶液中加入K2CO3(2.5当量),然后加入合适的可购买到的卤化物(1.2当量)。使反应物升温至室温并在相同温度下搅拌过夜。加入水淬灭反应,并用EtOAc萃取。合并有机层,用盐水洗涤,经Na2SO4干燥并在减压下浓缩。粗产物通过HPLC纯化,得到纯净的所需化合物。(y=14%-83%)按照该方法,用合适的中间体和反应物制备如下化合物:
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方法C
实施例50-80的制备
向冷却的(0℃)中间体2(1.0当量)的MeCN/DMF(5∶1v/v 5-10mL/1-3mL)溶液中加入K2CO3(1.1当量),然后加入可购买到的卤化物(0.8当量)。使反应物升温至室温并在相同温度下搅拌3小时。加入水淬灭反应并用EtOAc萃取。合并有机层,用盐水洗涤,经Na2SO4干燥并在减压下浓缩。粗产物通过HPLC纯化,得到纯净的所需化合物。(y=12%-97%)按照该方法,用合适的中间体和反应物制备如下化合物:
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方法D
实施例81-134、实施例139-147和实施例150-251的制备
向冷却的(0℃)中间体2或3(1.0当量)的DMF(5-12mL)溶液中加入CH3ONa(1.5或3.0当量)并将混合物在相同温度下搅拌10分钟。然后,加入合适的可购买到的卤化物(2.5或5.0当量)并将反应混合物温热至室温,在合适的温度下搅拌适当的时间(参见具体实施例)。通过加入水淬灭反应并用EtOAc萃取。合并有机层,用饱和NaCl水溶液洗涤,经Na2SO4干燥并在减压下浓缩。通过HPLC纯化粗产物,得到纯的所需化合物。(y=3%-96%)
使用该方法:
从中间体2b和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例81(收率89%);反应条件:室温下过夜。
从中间体2g和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例82(收率64%);反应条件:70℃下过夜。
从中间体2g和(溴甲基)环丙烷(CAS:7051-34-5)开始制备实施例83(收率74%);反应条件:室温下过夜。
从中间体2g和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例84(收率67%);反应条件:70℃下过夜。
从中间体2g和(溴甲基)-环戊烷(CAS:3814-30-0)开始制备实施例85(收率58%);反应条件:80℃下过夜。
从中间体2g和4-(溴甲基)-1,1-二甲基环己烷(CAS:1432681-20-3)开始制备实施例86(收率50%);反应条件:60℃下24小时。
从中间体2g和1-(溴甲基)-1-甲基环己烷(CAS:408307-48-2)开始制备实施例87(收率28%);反应条件:60℃下2周。
从中间体2g和2-(溴甲基)-二环[2.2.1]庚烷(CAS:55932-58-6)开始制备实施例88(收率18%);反应条件:室温下2周,然后60℃下7天。
从中间体2g和3-(溴甲基)四氢-2H-吡喃(CAS:116131-44-3)开始制备实施例89(收率36%);反应条件:室温下5天。
从中间体2g和1-溴-2-戊炔(CAS:16400-32-1)开始制备实施例90(收率68%);反应条件:室温下2小时。
从中间体2g和1-(溴甲基)-二环[2.2.1]庚烷(CAS:61192-17-4)开始制备实施例91(收率34%);反应条件:70℃下5天。
从中间体2g和(溴甲基)-环庚烷(CAS:3814-32-2)开始制备实施例92(收率23%);反应条件:室温下9天。
从中间体2g和4-(溴甲基)四氢-2H-吡喃(CAS:125552-89-8)开始制备实施例93(收率35%);反应条件:室温下5天。
从中间体2g和2-(溴甲基)四氢-2H-吡喃(CAS:34723-82-5)开始制备实施例94(收率24%);反应条件:室温下5天。
从中间体2g和1-溴-2-丁炔(CAS:3355-28-0)开始制备实施例95(收率84%);反应条件:室温下3小时。
从中间体2g和1-(溴甲基)-1-氟-环己烷(CAS:17171-00-5)开始制备实施例96(收率3%);反应条件:70℃下7天。
从中间体2g和2-(溴甲基)-1,1-二氟-环己烷(CAS:1817326-97-4)开始制备实施例97(收率19%);反应条件:70℃下5天。
从中间体2g和2-(氯甲基)-1,4-二氧杂环己烷(CAS:21048-16-8)开始制备实施例98(收率14%);反应条件:60℃下1个月。
从中间体2g和2-(溴甲基)-1,1-二甲基-环己烷(CAS:1501249-61-1)开始制备实施例99(收率25%);反应条件:60℃下7天。
从中间体2g和溴甲氧基甲烷(CAS:13057-17-5)开始制备实施例100(收率37%);反应条件:室温下5天。
从中间体2g和溴甲氧基乙烷(CAS:53588-92-4)开始制备实施例101(收率70%);反应条件:室温下过夜。
从中间体2g和1-(溴甲氧基)-丙烷(CAS:59375-50-7)开始制备实施例102(收率37%);反应条件:室温下4天。
从中间体2p和4-氟苄基溴(CAS:459-46-1)开始制备实施例104(收率65%);反应条件:室温下2小时。
从中间体2s和4-氟苄基溴(CAS:459-46-1)开始制备实施例105(收率90%);反应条件:室温下2小时。
从中间体2b和4-氟苄基溴(CAS:459-46-1)开始制备实施例107(收率77%);反应条件:室温下3小时。
从中间体2o和4-氟苄基溴(CAS:459-46-1)开始制备实施例108(收率79%);反应条件:室温下2小时。
从中间体2d和4-氟苄基溴(CAS:459-46-1)开始制备实施例109(收率93%);反应条件:室温下2小时。
从中间体2p和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例110(收率28%);反应条件:室温下24小时,然后60℃下24小时。
从中间体2r和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例111(收率29%);反应条件:室温下过夜,然后80℃下3小时。
从中间体2e和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例112(收率88%);反应条件:60℃下过夜。
从中间体2l和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例113(收率59%);反应条件:70℃下过夜。
从中间体2n和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例114(收率84%);反应条件:70℃下过夜。
从中间体2j和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例115(收率31%);反应条件:60℃下48小时。
从中间体2s和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例116(收率50%);反应条件:60℃下过夜。
从中间体2f和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例117(收率61%);反应条件:60℃下过夜。
从中间体2m和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例118(收率29%);反应条件:60℃下过夜。
从中间体2k和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例119(收率80%);反应条件:70℃下过夜。
从中间体2c和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例120(收率89%);反应条件:70℃下过夜。
从中间体2h和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例121(收率53%);反应条件:70℃下过夜。
从中间体2i和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例122(收率50%);反应条件:70℃下过夜。
从中间体2q和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例123(收率21%);反应条件:60℃下过夜。
从中间体2b和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例125(收率78%);反应条件:70℃下过夜。
从中间体2o和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例126(收率75%);反应条件:60℃下过夜。
从中间体2d和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例127(收率90%);反应条件:60℃下过夜。
从中间体2g和3-(溴甲基)-1,1-二氟环戊烷(CAS:1695914-13-6)开始制备实施例128(收率70%);反应条件:60℃下24小时。
从中间体2u和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例129(收率96%);反应条件:70℃下过夜。
从中间体2u和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例130(收率93%);反应条件:室温下过夜。
从中间体2u和4-氟苄基溴(CAS:459-46-1)开始制备实施例131(收率85%);反应条件:室温下3小时。
从中间体2v和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例132(收率91%);反应条件:室温下过夜。
从中间体2v和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例133(收率64%);反应条件:70℃下过夜。
从中间体2v和4-氟苄基溴(CAS:459-46-1)开始制备实施例134(收率50%);反应条件:室温下3小时。
从中间体3a和4-氟苄基溴(CAS:459-46-1)开始制备实施例139(收率48%);反应条件:室温下过夜。
从中间体3a和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例140(收率24%);反应条件:60℃下过夜。
从中间体3a和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例141(收率44%);反应条件:60℃下过夜。
从中间体2g和1-溴-2-环己基乙烷(CAS:1647-26-3)开始制备实施例142(收率59%);反应条件:60℃下过夜。
从中间体2g和1-(2-溴乙基)哌啶(CAS:56477-57-7)开始制备实施例143(收率45%);反应条件:60℃下过夜。
从中间体2w和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例144(收率76%);反应条件:60℃下2小时。
从中间体2w和4-氟苄基溴(CAS:459-46-1)开始制备实施例145(收率60%);反应条件:室温下2小时。
从中间体2w和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例146(收率69%);反应条件:50℃下48小时。
从中间体2w和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例147(收率19%);反应条件:50℃下48小时。
从中间体2c和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例150(收率69%);反应条件:50℃下48小时。
从中间体2b和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例151(收率47%);反应条件:50℃下48小时。
从中间体2a和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例152(收率44%);反应条件:50℃下48小时。
从中间体2k和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例153(收率56%);反应条件:50℃下48小时。
从中间体2e和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例154(收率33%);反应条件:50℃下48小时。
从中间体2l和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例155(收率39%);反应条件:50℃下48小时。
从中间体2j和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例156(收率57%);反应条件:50℃下48小时。
从中间体2s和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例157(收率48%);反应条件:50℃下48小时。
从中间体2f和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例158(收率40%);反应条件:50℃下48小时。
从中间体2m和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例159(收率42%);反应条件:50℃下48小时。
从中间体2d和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例160(收率62%);反应条件:50℃下48小时。
从中间体2o和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例161(收率63%);反应条件:50℃下48小时。
从中间体2n和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例162(收率48%);反应条件:50℃下48小时。
从中间体2u和1-(1-溴乙基)-4-氟苯(CAS:65130-46-3)开始制备实施例163(收率47%);反应条件:室温下24小时。
从中间体2v和1-(1-溴乙基)-4-氟苯(CAS:65130-46-3)开始制备实施例164(收率48%);反应条件:室温下24小时。
从中间体2v和2-氟苄基溴(CAS:446-48-0)开始制备实施例165(收率72%);反应条件:60℃下过夜。
从中间体2v和4-(三氟甲基)苄基溴(CAS:402-49-3)开始制备实施例166(收率84%);反应条件:60℃下过夜。
从中间体2v和2-氯-3-(三氟甲基)苄基溴(CAS:261763-22-8)开始制备实施例167(收率71%);反应条件:60℃下过夜。
从中间体2v和2-(溴甲基)-5-(三氟甲基)呋喃(CAS:17515-77-4)开始制备实施例168(收率75%);反应条件:室温下2小时。
从中间体2v和3-溴甲基-5-甲基-异唑(CAS:130628-75-0)开始制备实施例169(收率74%);反应条件:室温下2小时。
从中间体2v和2-氯苄基氯(CAS:611-19-8)开始制备实施例170(收率86%);反应条件:60℃下过夜。
从中间体2v和(1-氯甲基)-4-氟-2-甲基苯(CAS:80141-92-0)开始制备实施例171(收率65%);反应条件:60℃下过夜。
从中间体2v和(2-溴乙基)苯(CAS:103-63-9)开始制备实施例172(收率53%);反应条件:60℃下过夜。
从中间体2g和3-(溴甲基)-6,6-二氟二环[3.1.0]己烷(CAS:1393569-74-8)开始制备实施例173(收率55%);反应条件:60℃下过夜。
从中间体2g和碘甲烷(CAS:74-88-4)开始制备实施例174(收率95%);反应条件:室温下2小时。
从中间体2g和溴乙烷(CAS:74-96-4)开始制备实施例175(收率58%);反应条件:室温下2小时。
从中间体2g和1-溴丙烷(CAS:106-94-5)开始制备实施例176(收率71%);反应条件:60℃下过夜。
从中间体2g和1-溴丁烷(CAS:109-65-9)开始制备实施例177(收率86%);反应条件:60℃下过夜。
从中间体2g和1-溴-2-甲基丙烷(CAS:78-77-3)开始制备实施例178(收率38%);反应条件:60℃下3天。
从中间体2g和3-环己基丙基溴(CAS:34094-21-8)开始制备实施例179(收率84%);反应条件:60℃下过夜。
从中间体2g和1-(3-溴丙基)哌啶氢溴酸盐(CAS:58689-34-2)开始制备实施例180(收率75%);反应条件:60℃下2天。
从中间体2g和1-(2-溴乙基)-4,4-二氟哌啶氢溴酸盐(CAS:1996969-81-3)开始制备实施例181(收率18%);反应条件:60℃下2天。
从中间体2g和1-(3-溴丙基)-4,4-二氟哌啶氢溴酸盐(CAS:1782084-16-5)开始制备实施例182(收率26%);反应条件:60℃下2天。
从中间体2g和4-(溴甲基)-1-环戊烯(CAS:80864-33-1)开始制备实施例183(收率57%);反应条件:室温下2小时,然后60℃下过夜。
从中间体2g和1-(溴甲基)-4-(三氟甲基)环己烷(CAS:858121-96-7)开始制备实施例184(收率47%);反应条件:60℃下过夜。
从中间体2g和1-(溴甲基)-4-氟环己烷(CAS:1784609-74-0)开始制备实施例185(收率56%);反应条件:60℃下过夜。
从中间体2kk和4-氟苄基溴(CAS:459-46-1)开始制备实施例186(收率23%);反应条件:室温下3小时。
从中间体2kk和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例187(收率23%);反应条件:室温下3小时。
从中间体2v和1-氯乙基苯(CAS:672-65-1)开始制备实施例188(收率18%);反应条件:60℃下1周。
从中间体2v和5-氯甲基-2-(三氟甲基)吡啶(CAS:386715-33-9)开始制备实施例189(收率76%);反应条件:60℃下3天。
从中间体2v和2-(氯甲基)-5-氟嘧啶(CAS:1196151-61-7)开始制备实施例190(收率83%);反应条件:60℃下3天。
从中间体2v和2-(氯甲基)噻唑(CAS:3364-78-1)开始制备实施例191(收率47%);反应条件:60℃下3天。
从中间体2v和3-溴甲基-2-甲基-6-三氟甲基-吡啶(CAS:917396-30-6)开始制备实施例192(收率84%);反应条件:室温下4小时。
从中间体2v和5-(氯甲基)噻唑盐酸盐(CAS:131052-44-3)开始制备实施例193(收率41%);反应条件:60℃下过夜。
从中间体2v和2-氯甲基-唑(CAS:185246-17-7)开始制备实施例194(收率46%);反应条件:60℃下过夜。
从中间体2v和5-(氯甲基)-1,3-二甲基-1H-吡唑(CAS:852227-86-2)开始制备实施例195(收率39%);反应条件:60℃下过夜。
从中间体2v和3-(氯甲基)-5-甲基-1,2,4-二唑(CAS:1192-80-9)开始制备实施例196(收率45%);反应条件:60℃下过夜。
从中间体2v和5-(氯甲基)-3-甲基-1,2,4-二唑(CAS:1192-81-0)开始制备实施例197(收率29%);反应条件:60℃下过夜。/>
从中间体2v和1-(氯甲基)-3-(三氟甲基)-1H-吡唑(CAS:860807-20-1)开始制备实施例198(收率37%);反应条件:60℃下过夜。
从中间体2v和5-(氯甲基)唑(CAS:172649-57-9)开始制备实施例199(收率35%);反应条件:60℃下过夜。
从中间体2v和5-(氯甲基)-4-甲基-噻唑盐酸盐(CAS 1301739-54-7)开始制备实施例200(收率54%);反应条件:60℃下过夜。
从中间体2v和2-(氯甲基)-1-甲基-1H-咪唑盐酸盐(CAS 19225-92-4)开始制备实施例201(收率35%);反应条件:室温下过夜。
从中间体3b和4-氟苄基溴(CAS 459-46-1)开始制备实施例202(收率39%);反应条件:室温下3小时。
从中间体3b和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例203(收率21%);反应条件:室温下过夜。
从中间体2gg和4-氟苄基溴(CAS:459-46-1)开始制备实施例204(收率70%);反应条件:室温下2小时。
从中间体2gg和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例205(收率67%);反应条件:60℃下过夜。
从中间体2gg和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例206(收率62%);反应条件:60℃下24小时。
从中间体2gg和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例207(收率70%);反应条件:60℃下24小时。
从中间体2ll和4-氟苄基溴(CAS:459-46-1)开始制备实施例208(收率72%);反应条件:室温下2小时。
从中间体2ll和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例209(收率86%);反应条件:60℃下过夜。
从中间体2ll和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例210(收率28%);反应条件:室温下2小时。
从中间体2ll和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例211(收率31%);反应条件:室温下2小时。
从中间体2mm和4-氟苄基溴(CAS:459-46-1)开始制备实施例212(收率41%);反应条件:室温下24小时。
从中间体2mm和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例213(收率32%);反应条件:60℃下过夜。
从中间体2mm和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例214(收率39%);反应条件:60℃下过夜。
从中间体2mm和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例215(收率46%);反应条件:60℃下过夜。
从中间体2x和4-氟苄基溴(CAS:459-46-1)开始制备实施例216(收率29%);反应条件:室温下2小时。
从中间体2x和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例217(收率49%);反应条件:60℃下过夜。
从中间体2x和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例218(收率37%);反应条件:60℃下24小时。
从中间体2x和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例219(收率36%);反应条件:60℃下34小时。
从中间体2y和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例220(收率20%);反应条件:室温下过夜。
从中间体2y和4-氟苄基溴(CAS:459-46-1)开始制备实施例221(收率22%);反应条件:室温下2小时。
从中间体2y和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例222(收率26%);反应条件:60℃下24小时。
从中间体2y和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例223(收率20%);反应条件:60℃下34小时。
从中间体2z和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例224(收率58%);反应条件:室温下3小时。
从中间体2z和4-氟苄基溴(CAS:459-46-1)开始制备实施例225(收率83%);反应条件:室温下3小时。
从中间体2cc和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例226(收率53%);反应条件:室温下3小时。
从中间体2cc和4-氟苄基溴(CAS:459-46-1)开始制备实施例227(收率68%);反应条件:室温下3小时。
从中间体2hh和4-氟苄基溴(CAS:459-46-1)开始制备实施例228(收率37%);反应条件:室温下3小时。
从中间体2hh和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例229(收率48%);反应条件:室温下过夜。
从中间体2hh和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例230(收率30%);反应条件:70℃下过夜。
从中间体2hh和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例231(收率36%);反应条件:70℃下过夜。
从中间体2dd和4-氟苄基溴(CAS:459-46-1)开始制备实施例232(收率34%);反应条件:室温下3小时。
从中间体2dd和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例233(收率28%);反应条件:室温下3小时。
从中间体2dd和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例234(收率23%);反应条件:70℃下过夜。
从中间体2dd和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例235(收率23%);反应条件:70℃下过夜。
从中间体2ii和4-氟苄基溴(CAS:459-46-1)开始制备实施例236(收率54%);反应条件:室温下3小时。
从中间体2ii和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例237(收率55%);反应条件:室温下3小时。
从中间体2ii和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例238(收率41%);反应条件:70℃下过夜。
从中间体2ii和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例239(收率44%);反应条件:70℃下过夜。
从中间体2aa和4-氟苄基溴(CAS:459-46-1)开始制备实施例240(收率19%);反应条件:室温下3小时。
从中间体2aa和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例241(收率66%);反应条件:室温下3小时。
从中间体2ee和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例242(收率65%);反应条件:室温下3小时。
从中间体2ee和4-氟苄基溴(CAS:459-46-1)开始制备实施例243(收率36%);反应条件:室温下3小时。
从中间体2bb和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例244(收率32%);反应条件:室温下3小时。
从中间体2bb和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例245(收率19%);反应条件:50℃下2天。
从中间体2ff和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例246(收率11%);反应条件:室温下3小时。
从中间体2jj和4-氟苄基溴(CAS:459-46-1)开始制备实施例247(收率20%);反应条件:室温下过夜。
从中间体2jj和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例248(收率20%);反应条件:室温下过夜。
从中间体2jj和(溴甲基)环己烷(CAS:2550-36-9)开始制备实施例249(收率25%);反应条件:70℃下过夜。
从中间体2jj和4-(溴甲基)-1,1-二氟环己烷(CAS:858121-94-5)开始制备实施例250(收率30%);反应条件:70℃下过夜。
从中间体2jj和3-(溴甲基)-1,1-二氟环戊烷(CAS:1695914-13-6)开始制备实施例251(收率35%);反应条件:70℃下过夜。
方法E
实施例135-138的制备
向中间体2(1.0当量)、Cs2CO3(1.0当量)和NaI(0.05当量)在DMSO(5-12mL)中的混合物中滴加合适的可购买到的卤化物(0.75或1.0当量),然后将反应混合物在室温下搅拌3小时。通过加入NH4Cl淬灭反应混合物并用EtOAc萃取。合并有机层并减压浓缩。粗产物通过HPLC纯化,得到纯净的所需化合物。(y=19%-39%)
利用该方法:
从中间体2l和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例135(收率33%)。
从中间体2l和苄基氯(CAS:100-44-7)开始制备实施例136(收率27%)。
从中间体2k和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例137(收率39%)。
从中间体2j和2-氯-6-氟苄基氯(CAS:55117-15-2)开始制备实施例138(收率19%)。
实施例148-149的制备
实施例148和实施例149的化合物通过对映体分离实施例128的外消旋体获得;分离方法参见分析方法部分。
表1列出了按照实施例1所述的实验方法制备的最终化合物。
表1
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纯化系统
HPLC制备型
HPLC系统:配备有设置为双波长UV检测的WATERS UV/可见光检测器2489的WATERSQuaternary Gradient Mobile 2535。使用两种流动相,流动相A:水(MilliQ)0.05%TFA;流动相B:乙腈(Chromasolv Sigma-Aldrich)0.05%TFA,并针对每种化合物专门设置了运行梯度条件。纯化是通过LUNA C18 Phenomenex色谱柱5μm 19x 150进行的。进样体积为100至500μl,流速为15ml/min。
外消旋体分离
通过使用配备有设置为220和260nm下的双波长UV检测的WATERS UV/可见光检测器2489的WATERS Quaternary Gradient Mobile 2535拆分外消旋混合物128获得两种对映体148和149。使用正己烷(Chromasolv Sigma-Aldrich)-乙醇(Chromasolv Sigma-Aldrich)90-10(v/v)作为等度流动相在Kromasil 5-Amycoat色谱柱(250mm×4.6mm,粒径5μm)上实现手性拆分;样品在室温(压力:≈600psi)下以1.0ml/min的流速从色谱柱上洗脱。将混合物以1%(w/v)的浓度溶于乙醇中,进样量为15μL。
LCMS
LCMS一般方法
使用Dionex 3000模块进行HPLC测量,所述模块包括带有脱气器的四元泵、自动进样器、柱温箱(设置为29℃)、二极管阵列检测器DAD和以下各方法中具体指定的色谱柱。将来自柱的流分流至MS光谱仪。MS检测器(LCQFleet Thermo Scientific)配置有电喷雾电离源。通过在0.48秒内从50扫描到800获得质谱。在正电离和负电离模式下,毛细管针电压为5kV,并且离子源温度保持在275℃。用氮气作为雾化器气体,流量为8l/min。数据采集通过Thermo Xcalibur Qual Browser进行。
LCMS-方法
除一般方法外,反相HPLC在Kinetex XB-C18色谱柱Phenomenex(1.7μm,50x2.1mm)上进行,流速为0.300ml/min。使用两种流动相,流动相A:pH 3.5的甲酸铵缓冲溶液;流动相B:乙腈(Chromasolv Sigma-Aldrich),并将其用于在梯度条件下运行:4.5分钟内从15%B到98%,保持该条件1.35分钟,然后在0.1分钟内回到15%B,保持该条件3分钟,以重新平衡色谱柱。进样量为1μl。
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NMR表征
1H NMR光谱在Varian Mercury NMR 400MHz光谱仪上记录,使用CDCl3、DMSO-d6或CD3OD作为溶剂。以相对于所选择的未完全氘代溶剂的残留信号的百万分之一(ppm)报道化学位移(δ),对于1H NMR,所选择的信号被制指定为:CHCl3 7.26ppm,CHD2OD 3.31ppm,DMSO-d5 2.50ppm。
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药理学实施例
使用QuestTM Fluo-8 No Wash钙含量测定试剂盒,发现本发明的实施例化合物为P2X7抑制剂。
Bz-ATP与P2X7受体的细胞外结合打开了通道并允许Ca2+流入细胞。使用ScreenQuestTM Fluo-8 No Wash钙含量测定试剂盒(AAt目录号36316)在稳定转染了P2X7受体的HEK-293细胞中测量Ca2+的进入。一旦进入细胞内部,Fluo-8的亲脂性封闭基团就会被非特异性细胞酯酶裂解,从而产生带负电荷的荧光染料并留在细胞内部。与钙结合后其荧光增强。当用Bz-ATP刺激HEK-293/P2X7细胞时,Ca2+进入细胞,Fluo-8 NW的荧光增加。该染料的吸收光谱可用氩激光源在488nm激发,并且其发射波长在515-575nm范围内。
将稳定转染了P2X7受体的HEK-293细胞以10,000至20,000个细胞/孔的密度接种在384孔板中的生长培养基中过夜。24小时后,除去培养基,并在室温下用20μL/孔的Fluo-8NW将细胞预加载1小时。然后,用FLIPRTETRA注入10μL/孔3倍浓度的测试化合物和参考拮抗剂A438079并监测动力学响应五分钟。用FLIPRTETRA进行第二次15μL/孔3倍浓度的参考激活剂(EC80浓度的Bz-ATP)注射,并另外记录发射的荧光信号三分钟。所有实验均在低二价阳离子检测缓冲液(0.3mM Ca2+和0mM Mg2+)中进行。以相对于参考拮抗剂的抑制百分数来测量测试化合物的效果,并相应地计算IC50值。此处报道的效价范围为A、B、C和D,其中A为<200nM;B为200nM-1μM,C为1-10μM,D为>10μM。
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使用摄取测定法发现本发明的实施例化合物是P2X7抑制剂。
是一种荧光DNA结合染料,分子量为374Da(Molecular/>目录号Y3603)。该方法基于推定的/>能够通过P2X7受体的扩张或“大孔形式”进入并与细胞内DNA结合从而使其荧光强度增加许多倍的能力。染料的吸收光谱可用氩激光源在488nm激发,并且其发射波长在515-575nm范围内。该测定法的目的是使用对Ca2+敏感的荧光染料的替代读数来验证拮抗剂与P2X7受体的相互作用。
将稳定转染了P2X7受体的HEK-293细胞以20,000个细胞/孔的密度接种在384孔板中的生长培养基中过夜。24小时后,除去培养基,用低二价阳离子检测缓冲液(0.3mM Ca2+和0mM Mg2+)洗涤细胞,然后用20μL/孔的5μM染料预加载。
立即开始FLIPRTETRA荧光测量。然后,用FLIPRTETRA注入10μL/孔3倍浓度的测试化合物和参考拮抗剂A438079并监测动力学响应五分钟。用FLIPRTETRA进行第二次10μL/孔3倍浓度的Bz-ATP EC80(30μM)注射,并另外记录发射的荧光信号60分钟。所有实验均在低二价阳离子检测缓冲液(0.3mM Ca2+和0mM Mg2+)中进行。
以相对于参考拮抗剂的抑制百分数来测量测试化合物的效果,并相应地计算IC50值。
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通过自动膜片钳技术发现本发明的实施例化合物对人P2X7通道测定有效。
为了直接监测P2X7通道的阻滞,开发并在QPatch16X自动电生理仪上实施电生理测定。
在改良的EMEM中培养表达P2X7通道的HEK-293细胞。
实验前72小时,将500万个细胞接种到T225烧瓶中。在临实验前洗涤细胞两次,将细胞用胰蛋白酶-EDTA从烧瓶中取出,重悬于悬浮液中并置于QPatch 16x上。
实验当天制备在-20℃下储存的化合物(20mM在100%DMSO中的溶液)(先在100%DMSO中以1∶20的比例稀释以制备1mM的储备溶液,然后制备在外部溶液中的1μM溶液+系列稀释液1∶10)。
标准全细胞电压钳实验在室温下进行。这些实验使用多孔技术,并以2KHz采样数据。
细胞内溶液含有(mM)135CsF,10NaCl,1EGTA,10HEPES,(用CsOH调至pH 7.2),细胞外溶液含有(mM)145NaCl,4KCl,0.5MgCl2,1CaCl2,10HEPES,10Glc(用NaOH调至pH 7.4)。
以全细胞模式建立封接和通道后,将细胞保持在-80mV。通过单独施加100μMBzATP(4次)和随后在浓度递增的被研究化合物(1、10、100和1000nM)的存在下诱发P2XR7电流。
如附图所示(应用方案),预孵育期5至8包含浓度递增的被研究化合物(1、10、100和1000nM)。
附图:应用方案。
在不存在或存在浓度递增的被研究化合物的情况下,测量BzATP引起的最大内向电流并将其标准化。测定潜在的激动剂作用,以对照组的百分数以及通过以下方程式拟合剂量反应曲线数据确定的IC50表示:
Y=100/(1+10^((LogIC50-X)*HillSlope))
其中:
X=log浓度
Y=标准化的响应值,100%下降至0%,随X的增加而降低。
LogIC50:与X相同的log单位
HillSlope:斜率因子或HS,无单位。
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Claims (13)
1.下式(I)的化合物或其可药用盐:
包括其任何立体化学异构形式,其中:
R1独立地是选自环戊基、环己基、哌啶、吗啉、吡咯烷、哌嗪、苯基、吡啶、唑、吡唑或噻唑的脂环族、芳香族、杂环族或杂芳族环,其中所述各个部分均可任选地被一个或多个选自下列的取代基取代:任选地被一个或多个卤原子取代的C1-C4烷基、卤素、C1-C4烷氧基或任选地被C1-C4烷基取代的苯基,或者上述脂环族、芳香族、杂环族或杂芳族环可与另外的芳香族、杂芳族或杂环族环稠合;
R2独立地选自苯基、吡啶、嘧啶、吡唑、咪唑、萘、喹啉、噻唑、呋喃、唑、/>二唑、C3-C7环烷基、吡喃、四氢吡喃、二氧杂环己烷、C1-C4烷氧基、脂环族、芳香族或杂芳族二环、C3-C5炔基链,其中所述各个部分均可任选地被一个或多个任选地被一个或多个卤原子取代的C1-C4烷基、或C1-C4烷氧基取代;
n是1或2;
m是0、1或2;
R3和R4独立地是-H、-F、C1-C4烷基、-OH、-OC1-C4烷基;
X是O或S;
R5是-H或任选地被一个或多个氟原子取代的-CH3。
2.根据权利要求1的式(I)化合物或其可药用盐,其中:
R1独立地是选自环戊基、环己基、哌啶、吗啉、吡咯烷、哌嗪、苯基、吡啶、唑、吡唑或噻唑,其中所述各基团均任选地被甲基、甲氧基、卤素、三氟甲基或任选地被甲基取代的苯基取代;并且上述各脂环族、芳香族或杂环族或杂芳族环可与另外的芳香族或杂芳族环稠合;
R2独立地选自苯基、吡啶、嘧啶、吡唑、咪唑、萘、喹啉、噻唑、呋喃、唑、/>二唑、C3-C7环烷基、吡喃、四氢吡喃、二氧杂环己烷、脂环族二环、C1-C3烷氧基或C3-C5炔基链;其中上述脂环族、芳香族和杂环族环均任选地被甲基、甲氧基、卤素和/或三氟甲基取代;
n是1或2;
m是0、1或2;
R3和R4独立地是-H、F、CH3、-OH或-OCH2CH3;
X是O或S;
R5是H或-CH3。
3.根据权利要求1的式(I)化合物或其可药用盐,其中:
R1独立地选自3,3-二氟环戊基、环己基、4,4-二氟环己基、哌啶基、3,3-二氟哌啶基、4,4-二氟哌啶基、4,4-二氟-2-甲基哌啶基、3-(4-甲基苯基)哌啶基、4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基、1,2,3,4-四氢异喹啉-2-基、3,4-二氢-2H-1,4-苯并嗪-4-基、吡咯烷基、4-苯基哌嗪基、苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、2-三氟甲基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二氯苯基、2,4-二氯苯基、2-氯-3-三氟甲基苯基、2,4-二氟苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-、3-或4-吡啶、2-甲基吡啶-3-基、二甲基-1,2-/>唑-4-基、三甲基-1H-吡唑-4-基和4-甲基-1,3-噻唑-5-基;
R2独立地选自2-苯基甲基、1-苯基乙基、2-苯基乙基、苯基、2-、3-、4-氟苯基、2-、4-氯苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-、4-三氟甲基苯基、2-、4-甲基苯基、2,3-二氯苯基、2,4-二氯苯基、2,4-二氟苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-氯-3-三氟甲基苯基、2,4-二甲氧基苯基、3,5-二甲氧基苯基、2-溴-5-氟苯基、4-氟-2-甲基苯基、2-吡啶基、3-吡啶基、4-吡啶、2-甲基吡啶-3-基、6-三氟甲基吡啶-3-基、2-甲基-6-(三氟甲基)吡啶-3-基、萘-1-基、喹啉-5-基、1,3-噻唑-2-基、1,3-噻唑-5-基、4-甲基-1,3-噻唑-5-基、5-甲基-1,2-唑-3-基、1,2-/>唑-3-基、1,2-/>唑-5-基、1,3-/>唑-2-基、1,3-/>唑-5-基、二甲基-1,2-/>唑-4-基、3-(三氟甲基)-1H-吡唑-1-基、1,3-二甲基-1H-吡唑-5-基、1-甲基-1H-咪唑-2-基、呋喃-3-基、5-(三氟甲基)呋喃-2-基、5-甲基-1,3,4-/>二唑-2-基、5-甲基-1,2,4-/>二唑-3-基、3-甲基-1,2,4-/>二唑-5-基、嘧啶-2-基、嘧啶-5-基、5-氟嘧啶-2-基、环丙基、环丁基、环戊基、环戊-3-烯-1-基、环己基、1-氟环己基、2-甲基环己基、2,2-二甲基环己基、4,4-二甲基环己基、2,2-二氟环己基、4,4-二氟环己基、4-(三氟甲基)环己基、4-氟环己基、3,3-二氟环戊基、6,6-二氟二环[3.1.0]己-3-基、二环[2.2.1]庚-1-基、二环[2.2.1]庚-2-基、1,4-二氧杂螺[4.5]癸-8-基、氧杂环己烷-2-基、氧杂环己烷-3-基、氧杂环己烷-4-基、1,4-二氧杂环己烷-2-基、甲氧基、乙氧基、丙氧基、丁-1-炔基、丙-1-炔基、哌啶-1-基、4,4-二氟哌啶-1-基;
n是1或2;
m是0、1或2;
R3和R4独立地是-H、-CH3、-OH和-OCH2CH3;
X是O或S;
R5是-H或-CH3。
4.根据前述权利要求任意一项的式(I)化合物,其中R3和R4均是H。
5.根据权利要求1的式(I)化合物,其中X是O。
6.根据权利要求1的式(I)化合物,其中n是1。
7.根据权利要求1的式(I)化合物,其中m是0。
8.根据权利要求1的式(I)化合物,其中R5是H或-CH3。
9.根据权利要求1的式(I)化合物,所述化合物是:
·4-[(2-氯-6-氟苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2,4-二甲氧基苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4-氟苯基)甲基]-4-[(4-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(3,5-二甲氧基苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-溴-5-氟苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-苄基-4-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(3-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4-氟苯基)甲基]-4-[(4-甲基-1,3-噻唑-5-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2,4-二氯苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4-氟苯基)甲基]-4-(1-苯基乙基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[1-(4-氟苯基)乙基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2,3-二氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-4-氟苯基)甲基]-4-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2,4-二氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-{[2-氯-3-(三氟甲基)苯基]甲基}-4-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2,4-二氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·二[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2-氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-苄基-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[2-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-甲基吡啶-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-氟-2-甲基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(3-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-甲基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(萘-1-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(喹啉-5-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-甲基-1,3-噻唑-5-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1,3-唑-2-基甲基)-4,5-二氢-1,2,4-/>二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1,3-噻唑-5-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1,3-噻唑-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[3-(三氟甲基)-1H-吡唑-1-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(二甲基-1,2-唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[6-(三氟甲基)吡啶-3-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(嘧啶-5-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(嘧啶-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1,3-唑-5-基甲基)-4,5-二氢-1,2,4-/>二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(5-甲基-1,3,4-二唑-2-基)甲基]-4,5-二氢-1,2,4-/>二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(吡啶-3-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(吡啶-4-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(呋喃-3-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(5-氟嘧啶-2-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(1-甲基-1H-咪唑-2-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[1-(4-氟苯基)乙基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1-苯基乙基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2,3-二氯苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-4-氟苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-{[2-氯-3-(三氟甲基)苯基]甲基}-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2,4-二氟苯基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·二[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(3-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-{[2-氯-3-(三氟甲基)苯基]甲基}-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2,3-二氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-4-氟苯基)甲基]-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2,4-二氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(吡啶-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[4-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[2-甲基-6-(三氟甲基)吡啶-3-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[5-(三氟甲基)呋喃-2-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-甲基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环丁基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{1,4-二氧杂螺[4.5]癸-8-基甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2,3-二氯苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-{[2-氯-3-(三氟甲基)苯基]甲基}-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-4-氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2,4-二氯苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[2-(2-氯-6-氟苯基)丙烷-2-基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[1-(2-氯-6-氟苯基)乙基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-(吡啶-4-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2,4-二氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(3-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环丙基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环戊基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4,4-二甲基环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2-甲基环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-{二环[2.2.1]庚-2-基甲基}-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(氧杂环己烷-3-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(戊-2-炔-1-基)-4,5-二氢-1,2,4-二唑-5-酮
·4-{二环[2.2.1]庚-1-基甲基}-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环庚基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(氧杂环己烷-4-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(氧杂环己烷-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(丁-2-炔-1-基)-3-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(1-氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2,2-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(1,4-di氧杂环己烷-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(2,2-二甲基环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(甲氧基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(乙氧基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(丙氧基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-(吡啶-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-{[2-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(3-氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-苄基-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-[(3-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-(吡啶-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-(吡啶-4-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(4-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-{[2-氯-3-(三氟甲基)苯基]甲基}-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-4-氟苯基)甲基]-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(2,3-二氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-{[2-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯苯基)甲基]-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(2,4-二氯苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮7
·4-(环己基甲基)-3-[(2,4-二氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(2-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[2-(2-氯-6-氟苯基)丙烷-2-基]-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[1-(2-氯-6-氟苯基)乙基]-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-(吡啶-3-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(3-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-苄基-4-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(3-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(3,3-二氟环戊基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·二(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-(环己基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-(环己基甲基)-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-{[2-氯-3-(三氟甲基)苯基](羟基)甲基}-4-[(2-氯-6-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-苄基-3-{[2-氯-3-(三氟甲基)苯基](羟基)甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2,4-二氟苯基)(羟基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2,3-二氯苯基)(羟基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-噻二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环己基甲基)-4,5-二氢-1,2,4-噻二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-噻二唑-5-酮
·3-(2-氯-6-氟苄基)-4-(2-环己基乙基)-1,2,4-二唑-5(4H)-酮
·3-(2-氯-6-氟苄基)-4-[2-(哌啶-1-基)乙基]-1,2,4-二唑-5(4H)-酮
·4-(2-氯-6-氟苄基)-3-[2-(2-氯-6-氟苯基)乙基]-1,2,4-二唑-5(4H)-酮
·3-[2-(2-氯-6-氟苯基)乙基]-4-(4-氟苄基)-1,2,4-二唑-5(4H)-酮
·3-[2-(2-氯-6-氟苯基)乙基]-4-(环己基甲基)-1,2,4-二唑-5(4H)-酮
·3-[2-(2-氯-6-氟苯基)乙基]-4-[(4,4-二氟环己基)甲基]-1,2,4-二唑-5(4H)-酮
·3-(2-氯-6-氟苄基)-4-[(3,3-二氟环戊基)甲基]-1,2,4-二唑-5(4H)-酮
·3-(2-氯-6-氟苄基)-4-[(3,3-二氟环戊基)甲基]-1,2,4-二唑-5(4H)-酮
·4-[(4,4-二氟环己基)甲基]-3-[(2-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(3-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(2,4-二氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(4-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-{[2-氯-3-(三氟甲基)苯基]甲基}-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2,3-二氯苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-{[2-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2,4-二氯苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(3-甲氧基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-苄基-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-4-氟苯基)甲基]-4-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-(环己基甲基)-4-[1-(4-氟苯基)乙基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[1-(4-氟苯基)乙基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(2-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-{[4-(三氟甲基)苯基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-{[2-氯-3-(三氟甲基)苯基]甲基}-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-{[5-(三氟甲基)呋喃-2-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(5-甲基-1,2-唑-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯苯基)甲基]-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(4-氟-2-甲基苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-(2-苯基乙基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-({6,6-二氟二环[3.1.0]己-3-基}甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(3-环己基丙基)-4,5-二氢-1,2,4-二唑-5-酮·3-[(2-氯-6-氟苯基)甲基]-4-[3-(哌啶-1-基)丙基]-4,5-二氢-1,2,4-/>二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[2-(4,4-二氟哌啶-1-基)乙基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[3-(4,4-二氟哌啶-1-基)丙基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-(环戊-3-烯-1-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(2-氯-6-氟苯基)甲基]-4-{[4-(三氟甲基)环己基]甲基}-1,2,4-二唑-5(4H)-酮
·3-[(2-氯-6-氟苯基)甲基]-4-[(4-氟环己基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-(1-苯基乙基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-{[6-(三氟甲基)吡啶-3-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(5-氟嘧啶-2-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-(1,3-噻唑-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-{[2-甲基-6-(三氟甲基)吡啶-3-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(1,3-唑-2-基)甲基]-1,2,4-/>二唑-5(4H)-酮·3-[(4,4-二氟环己基)甲基]-4-[(1,3-二甲基-1H-吡唑-5-基)甲基]-1,2,4-/>二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(5-甲基-1,2,4-二唑-3-基)甲基]-1,2,4-/>二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(3-甲基-1,2,4-二唑-5-基)甲基]-1,2,4-/>二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-{[3-(三氟甲基)-1H-吡唑-1-基]甲基}-1,2,4-二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(1,2-唑-5-基)甲基]-1,2,4-/>二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·3-[(4,4-二氟环己基)甲基]-4-[(1-甲基-1H-咪唑-2-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟环己基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-噻二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(4,4-二氟环己基)甲基]-4,5-二氢-1,2,4-噻二唑-5-酮
·3-[(3,3-二氟环戊基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(3,3-二氟环戊基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(3,3-二氟环戊基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(3,3-二氟环戊基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(二甲基-1,2-唑-4-基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(二甲基-1,2-唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(二甲基-1,2-唑-4-基)甲基]-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(二甲基-1,2-唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-[(三甲基-1H-吡唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(三甲基-1H-吡唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(三甲基-1H-吡唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(三甲基-1H-吡唑-4-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-[(2-甲基吡啶-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(2-甲基吡啶-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(2-甲基吡啶-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(2-甲基吡啶-3-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(4,4-二氟哌啶-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟哌啶-1-基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮/>
·4-(环己基甲基)-3-[(4,4-二氟哌啶-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-[(4,4-二氟哌啶-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(3,3-二氟哌啶-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(3,3-二氟哌啶-1-基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(4,4-二氟-2-甲基哌啶-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-[(4,4-二氟-2-甲基哌啶-1-基)甲基]-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·3-(3,4-二氢-2H-1,4-苯并嗪-4-基甲基)-4-[(4-氟苯基)甲基]-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-(3,4-二氢-2H-1,4-苯并嗪-4-基甲基)-4,5-二氢-1,2,4-/>二唑-5-酮
·4-(环己基甲基)-3-(3,4-二氢-2H-1,4-苯并嗪-4-基甲基)-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-(3,4-二氢-2H-1,4-苯并嗪-4-基甲基)-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(4-氟苯基)甲基]-3-{4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-{4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-{4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-{4H,5H,6H,7H-噻吩并[3,2-c]吡啶-5-基甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-[(4-苯基哌嗪-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(4-苯基哌嗪-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮
·4-(环己基甲基)-3-[(4-苯基哌嗪-1-基)甲基]-4,5-二氢-1,2,4-二唑-5-酮·4-[(4,4-二氟环己基)甲基]-3-[(4-苯基哌嗪-1-基)甲基]-4,5-二氢-1,2,4-/>二唑-5-酮
·4-[(4-氟苯基)甲基]-3-(哌啶-1-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-[(哌啶-1-基)甲基]-1,2,4-二唑-5(4H)-酮
·4-[(2-氯-6-氟苯基)甲基]-3-{[3-(4-甲基苯基)哌啶-1-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4-氟苯基)甲基]-3-{[3-(4-甲基苯基)哌啶-1-基]甲基}-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-(1,2,3,4-四氢异喹啉-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(4,4-二氟环己基)甲基]-3-(1,2,3,4-四氢异喹啉-2-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-[(2-氯-6-氟苯基)甲基]-3-(吡咯烷-1-基甲基)-4,5-二氢-1,2,4-二唑-5-酮
·4-(4-氟苄基)-3-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·4-(2-氯-6-氟苄基)-3-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·4-(环己基甲基)-3-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·4-[(4,4-二氟环己基)甲基]-3-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮
·4-[(3,3-二氟环戊基)甲基]-3-[(4-甲基-1,3-噻唑-5-基)甲基]-1,2,4-二唑-5(4H)-酮。
10.制备权利要求1所定义的式(I)化合物的方法,包括将式(II)的化合物:
其中n、X和R1、R3和R4的含义如权利要求1所定义,
与式(III)的化合物反应:
其中R2、R5和m的含义如权利要求1所定义并且W是离去基团;并且任选地将得到的式(I)化合物转化成其加成盐,和/或制备其立体化学异构形式。
11.包含根据权利要求1-9任意一项的式(I)化合物和可药用稀释剂和/或载体的药物组合物。
12.根据权利要求1-9任意一项的式(I)化合物在制备用于治疗选自P2X7受体介导的病症或疾病的病症或疾病的药物中的用途。
13.根据权利要求1-9任意一项的式(I)化合物在制备用于预防和/或治疗神经变性疾病、认知障碍、精神障碍、神经性疼痛、慢性疼痛、肌肉-骨骼系统的炎症过程、肝纤维化、胃肠道疾病、生殖泌尿道疾病、眼科疾病、慢性阻塞性肺病(COPD)、癌症和增殖性疾病的药物中的用途。
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PCT/EP2018/061180 WO2018202694A1 (en) | 2017-05-03 | 2018-05-02 | Heterocyclic p2x7 antagonists |
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DK3619200T3 (da) | 2022-04-04 |
IL270275B2 (en) | 2023-07-01 |
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