CN118161500A - 作为δ-5脱饱和酶抑制剂的杂环化合物以及使用方法 - Google Patents
作为δ-5脱饱和酶抑制剂的杂环化合物以及使用方法 Download PDFInfo
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- CN118161500A CN118161500A CN202410291075.3A CN202410291075A CN118161500A CN 118161500 A CN118161500 A CN 118161500A CN 202410291075 A CN202410291075 A CN 202410291075A CN 118161500 A CN118161500 A CN 118161500A
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- China
- Prior art keywords
- trifluoromethyl
- methyl
- pyrimidin
- pyrazol
- imidazo
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- 238000000034 method Methods 0.000 title claims abstract description 230
- 102100034542 Acyl-CoA (8-3)-desaturase Human genes 0.000 title abstract description 33
- 108010073542 Delta-5 Fatty Acid Desaturase Proteins 0.000 title abstract description 9
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 404
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 16
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 16
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 12
- 230000037396 body weight Effects 0.000 claims abstract description 11
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
- 208000008589 Obesity Diseases 0.000 claims abstract description 9
- 235000020824 obesity Nutrition 0.000 claims abstract description 9
- 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 8
- 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- -1 C 1-4 deuteroalkoxy Chemical group 0.000 claims description 133
- 150000003839 salts Chemical class 0.000 claims description 132
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 104
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 92
- 125000003545 alkoxy group Chemical group 0.000 claims description 78
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
- 125000003282 alkyl amino group Chemical group 0.000 claims description 75
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 61
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 17
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 14
- 125000006712 (C1-C4) deuteroalkyl group Chemical group 0.000 claims description 13
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 13
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 11
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 10
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- OLXICANIIDSKHB-VIFPVBQESA-N N=1C(=C(C(=O)N2C=1NC(C)=C2)C=1C=NN(C=1)C[C@@H]1CC1(F)F)C(F)(F)F Chemical compound N=1C(=C(C(=O)N2C=1NC(C)=C2)C=1C=NN(C=1)C[C@@H]1CC1(F)F)C(F)(F)F OLXICANIIDSKHB-VIFPVBQESA-N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- OLXICANIIDSKHB-SECBINFHSA-N N=1C(=C(C(=O)N2C=1NC(C)=C2)C=1C=NN(C=1)C[C@H]1CC1(F)F)C(F)(F)F Chemical compound N=1C(=C(C(=O)N2C=1NC(C)=C2)C=1C=NN(C=1)C[C@H]1CC1(F)F)C(F)(F)F OLXICANIIDSKHB-SECBINFHSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 3
- UXQAOSXEQWPTML-UHFFFAOYSA-N 2-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound FC(F)(F)C1=CN2C(=NC=CC2=O)S1 UXQAOSXEQWPTML-UHFFFAOYSA-N 0.000 claims description 2
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 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
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- SYAZNROLFDFSBS-UHFFFAOYSA-N C1(CC1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F Chemical compound C1(CC1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F SYAZNROLFDFSBS-UHFFFAOYSA-N 0.000 claims description 2
- WQCMEOJNDIZJKE-UHFFFAOYSA-N CC1=NN2C(=NC(=C(C2=O)C=2C=NN(C=2)CC2COC2)C(F)(F)F)S1 Chemical compound CC1=NN2C(=NC(=C(C2=O)C=2C=NN(C=2)CC2COC2)C(F)(F)F)S1 WQCMEOJNDIZJKE-UHFFFAOYSA-N 0.000 claims description 2
- JSTIPCLULBIZIU-UHFFFAOYSA-N CN1C(=CN2C1=NC(=C(C2=O)C=1C=NN(C=1)CC1COC1)C(F)(F)F)C Chemical compound CN1C(=CN2C1=NC(=C(C2=O)C=1C=NN(C=1)CC1COC1)C(F)(F)F)C JSTIPCLULBIZIU-UHFFFAOYSA-N 0.000 claims description 2
- JGMZRMSBXUFSAT-UHFFFAOYSA-N FC1(C(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F Chemical compound FC1(C(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F JGMZRMSBXUFSAT-UHFFFAOYSA-N 0.000 claims description 2
- PRXCFIVRDUSMSK-UHFFFAOYSA-N FC1(C(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F Chemical compound FC1(C(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F PRXCFIVRDUSMSK-UHFFFAOYSA-N 0.000 claims description 2
- FCYMVZCAKMHPPY-UHFFFAOYSA-N FC1(CC(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F Chemical compound FC1(CC(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F FCYMVZCAKMHPPY-UHFFFAOYSA-N 0.000 claims description 2
- AOJYQSOKJUIEEO-UHFFFAOYSA-N FC1(CC(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F Chemical compound FC1(CC(C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F AOJYQSOKJUIEEO-UHFFFAOYSA-N 0.000 claims description 2
- JGMZRMSBXUFSAT-JTQLQIEISA-N FC1([C@@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F Chemical compound FC1([C@@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F JGMZRMSBXUFSAT-JTQLQIEISA-N 0.000 claims description 2
- PRXCFIVRDUSMSK-QMMMGPOBSA-N FC1([C@@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F Chemical compound FC1([C@@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F PRXCFIVRDUSMSK-QMMMGPOBSA-N 0.000 claims description 2
- JGMZRMSBXUFSAT-SNVBAGLBSA-N FC1([C@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F Chemical compound FC1([C@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)C=C(N2C)C)C(F)(F)F)F JGMZRMSBXUFSAT-SNVBAGLBSA-N 0.000 claims description 2
- PRXCFIVRDUSMSK-MRVPVSSYSA-N FC1([C@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F Chemical compound FC1([C@H](C1)CN1N=CC(=C1)C1=C(N=C2N(C1=O)N=C(S2)C)C(F)(F)F)F PRXCFIVRDUSMSK-MRVPVSSYSA-N 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 145
- 239000000203 mixture Substances 0.000 abstract description 135
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 45
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 112
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 106
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 96
- 238000003818 flash chromatography Methods 0.000 description 81
- 230000002829 reductive effect Effects 0.000 description 81
- 229910004298 SiO 2 Inorganic materials 0.000 description 74
- 239000000243 solution Substances 0.000 description 71
- 239000011734 sodium Substances 0.000 description 70
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 67
- 235000019439 ethyl acetate Nutrition 0.000 description 64
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 63
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
- 239000012074 organic phase Substances 0.000 description 48
- 239000007787 solid Substances 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 42
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 42
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 40
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 239000013058 crude material Substances 0.000 description 37
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 36
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 29
- 235000019253 formic acid Nutrition 0.000 description 29
- 239000013543 active substance Substances 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
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- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 22
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- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 11
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
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- 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
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- A—HUMAN NECESSITIES
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Landscapes
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