CN107235960A - Amide derivatives, its preparation method and its in purposes pharmaceutically - Google Patents
Amide derivatives, its preparation method and its in purposes pharmaceutically Download PDFInfo
- Publication number
- CN107235960A CN107235960A CN201610187531.5A CN201610187531A CN107235960A CN 107235960 A CN107235960 A CN 107235960A CN 201610187531 A CN201610187531 A CN 201610187531A CN 107235960 A CN107235960 A CN 107235960A
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- Prior art keywords
- compound
- alkyl
- formula
- stereoisomer
- optionally further
- 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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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001408 amides Chemical class 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 67
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 132
- 125000000217 alkyl group Chemical group 0.000 claims description 91
- 229910052736 halogen Inorganic materials 0.000 claims description 64
- 150000002367 halogens Chemical class 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- -1 heterocyclic radical Chemical class 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000004429 atom Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 229940122904 Glucagon receptor antagonist Drugs 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 229940125425 inverse agonist Drugs 0.000 claims description 3
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- 206010022489 Insulin Resistance Diseases 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
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- 102000027430 HGF receptors Human genes 0.000 abstract 1
- 108091008603 HGF receptors Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 41
- 239000002585 base Substances 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 30
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 20
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 15
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- YXTROGRGRSPWKL-UHFFFAOYSA-N 1-benzoylpiperidine Chemical compound C=1C=CC=CC=1C(=O)N1CCCCC1 YXTROGRGRSPWKL-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 235000010233 benzoic acid Nutrition 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- 229940095102 methyl benzoate Drugs 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 102100040890 Glucagon receptor Human genes 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 229910052757 nitrogen Chemical group 0.000 description 9
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 208000015924 Lithiasis Diseases 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 239000000864 hyperglycemic agent Substances 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 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 6
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- DQZWTJKAULHSBX-UHFFFAOYSA-N piperazine;pyridine-3-carboxylic acid Chemical class C1CNCCN1.OC(=O)C1=CC=CN=C1 DQZWTJKAULHSBX-UHFFFAOYSA-N 0.000 description 6
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 6
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- GOUHYARYYWKXHS-UHFFFAOYSA-N para-formylbenzoic acid Natural products OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
Classifications
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a kind of amide derivatives, its preparation method and its in application pharmaceutically.Specifically, the present invention relates to the amide derivatives shown in a kind of logical formula (I), its preparation method and its pharmaceutically useful salt, and they are used as therapeutic agent, especially as the purposes of pancreas HGF receptor antagonist, each substituent in its formula of (I) it is defined as the description.
Description
Invention field
The present invention relates to a kind of new amide derivatives, its preparation method and contain the pharmaceutical composition of the derivative and its work
For purposes of the therapeutic agent especially as GCGR antagonists.
Background of invention
Hyperglycemic factor (Glucagon) is the straight-chain polypeptide being made up of 29 amino acid of alpha Cell of islet secretion, and molecular weight is
3485；Concentration in serum is 50-100ng/L, and the half-life period in blood plasma is 5~10 minutes.Hyperglycemic factor by with
The Type B g protein coupled receptor (glucagon receptor, GCGR) of the target cells such as liver kidney is specifically bound, activation
Downstream signal transduction path, plays physiological effect.Its effect with insulin on the contrary, be a kind of hormone for promoting catabolism,
With very strong promotion decomposition of glycogen and gluconeogenesis, make blood glucose significantly raised.1mol/L hormone can make 3 × 106Mol/L's
Glucose comes out (Johnson etc., J.Biol.Chem.1972,247,3229-3235) rapidly from decomposition of glycogen.
Glucagon receptor is located at cell surface, and the G- G-protein linked receptors with 7 cross-film sequences are distributed mainly on liver,
It is also distributed in addition in kidney, heart, muscle etc..
The first target organs of hyperglycemic factor effect are livers.After being combined with acceptor, with guanylic acid combination regulatory protein
Gs interacts, and Gs A subunits is discharged activated adenyl cyclase, catalysis ATP is converted into cAMP and plays its biology
Learn effect.The hyperglycemic factor of pharmacological dose can make cAMP contents increase in cardiac muscle cell, myocardial contraction enhancing.Pancreas hyperglycaemia
Hormone receptor antagonists can compete this receptor with hyperglycemic factor, so as to block it to act on.
Diabetes are a kind of disease characterized by the high level of plasma glucose.Uncontrolled hyperglycemia and capilary and big blood
The increase of pipe disease risks is relevant, and described disease includes nephrosis, PVR, hypertension, apoplexy and heart disease.Glucose
The control of dynamic equilibrium is the main method for the treatment of diabetes.In healthy animal and the animal model of I types and type ii diabetes
Middle research shows：Removing the hyperglycemic factor in circulation with selectivity and specific antibody causes blood sugar level to reduce.Therefore glycosuria
A kind of potential treatment method of sick and other diseases for being related to pathoglycemia is that glucagon receptor antagonist blocks hyperglycemic factor
Acceptor is to improve insulin replies, to reduce gluconeogenesis speed and/or to be reduced by reducing in patient hepatic glucose output speed
Plasma glucose levels.
Have been disclosed for the document of a series of GCGR antagonists at present, including WO2008042223,
WO2010098994A1, WO2015066252, WO2012009226A1, WO2012009226A1 etc., it is not all
All there is the characteristic as useful medicine as the compound of GCGR antagonists.Some in these characteristics are included to pancreas
The high-affinity of glucagon receptor, the duration of receptor activation effect, oral administration biaavailability and stability (for example preparation or
Ability, the shelf-life of crystallization).This class feature can cause security, tolerance, validity, therapeutic index, patient's compliance,
Cost effective, preparation easiness etc. are improved.Surprisingly find the specific spatial chemistry and function of the compounds of this invention
Group shows one or more in these required characteristics, including significantly improved receptor binding matter, oral administration biaavailability and/
Or it is other enhancing its be used for therapeutical uses well-formedness favorable characteristics.Include at present in the GCGR antagonist pharmaceuticals ground：It is in
The PF-06291874 (Pfizer) and LGD-6972 (Ligand) of clinical II phases, while Merck ＆ Co., Inc. once researches and develops MK-3577.The present invention
A kind of new GCGR receptor antagonists are provided, design is with the compound shown in logical formula (I), and the compounds of this invention is compared with technology
In specifically disclosed compound phase ratio, with larger architectural difference, and show excellent anti-diabetic effect and effect.
The content of the invention
In order to overcome the deficiencies in the prior art part, it is an object of the invention to provide a kind of new acid amides of the class shown in logical formula (I)
Analog derivative, and their stereoisomer, dynamic isomer, enantiomer, diastereomer or its pharmaceutically useful salt, and
Metabolite and metabolic precursor thereof or prodrug：
Wherein：
A1、A2、A3And A4It is each independently selected from CR5Or N, condition is A1、A2、A3And A4In no more than two be N；Wherein,
A1、A2、A3And A4Each independent is preferably CR5；
B1、B2、B3And B4It is each independently selected from CR6Or N, condition is B1、B2、B3And B4In no more than two be N；Its
In, B1、B2、B3And B4Each independent is preferably CR6；
L1Selected from CH2, O or NH, preferably O；
R1And R2Form 4~8 circle heterocycles bases together with N the or C atoms being connected, preferably 5~7 yuan, wherein described heterocyclic radical
It is interior to contain one or more N, O, S (O)mAtom, and described heterocyclic radical optionally further by it is one or more selected from alkyl,
Halogen, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,=O ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R3Selected from alkyl, cycloalkyl or heterocyclic radical, wherein described alkyl, cycloalkyl or heterocyclic radical optionally further by one or
It is multiple to be selected from alkyl, halogen, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,=O ,-NR7R8、
-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R4Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen by one or more
Element, hydroxyl, cyano group, nitro, alkoxy ,-NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8
Substituent replaced, wherein described alkyl or alkoxy are optionally further replaced by one or more halogens；
R5It is each independently selected from hydrogen atom, alkyl, alkoxy, halogen, hydroxyl, cyano group, nitro ,-NR7R8、-C(O)NR7R8、
-C(O)R9、-C(O)OR9Or-NR7C(O)R8, wherein described alkyl or alkoxy are optionally further selected from halogen by one or more
Element, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R6It is each independently selected from hydrogen atom, alkyl, alkoxy, halogen, hydroxyl, cyano group, nitro ,-NR7R8、-C(O)NR7R8、
-C(O)R9、-C(O)OR9Or-NR7C(O)R8, wherein described alkyl or alkoxy are optionally further selected from halogen by one or more
Element, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R7And R8Be each independently selected from hydrogen atom or alkyl, wherein the alkyl optionally further by it is one or more selected from hydroxyl,
Halogen, nitro, cyano group, alkoxy ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12Or-NR10C(O)R11
Substituent replaced；
Or, R7And R84~8 circle heterocycles bases are formed together with the N atoms being connected, wherein containing one in described heterocyclic radical
Individual or multiple N, O, S (O)mAtom, and described heterocyclic radical is optionally further selected from alkyl, halogen, hydroxyl by one or more
Base, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、
-C(O)OR12Or-NR10C(O)R11Substituent replaced；
R9Selected from hydrogen atom or alkyl, wherein the alkyl optionally further by it is one or more selected from hydroxyl, halogen, nitro,
Cyano group, alkoxy ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12Or-NR10C(O)R11Take
Replaced for base；
R10、R11And R12Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein institute
State alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl and be optionally further selected from hydroxyl, halogen, alkyl halide by one or more
Base, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, the substituent of carboxylic acid or carboxylate
Replaced；
M is selected from 0,1 or 2；And n is selected from 0,1 or 2.
The preferred scheme of the present invention, compound or its stereoisomer, dynamic isomer described in a kind of logical formula (I) or its is pharmaceutically acceptable
Salt, it is the compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in logical formula (II),
Wherein：A1~A4、B1~B4、L1、R1~R4Definition with n is as described in logical formula (I).
The preferred scheme of the present invention, compound or its stereoisomer, dynamic isomer described in a kind of logical formula (I) or its is pharmaceutically acceptable
Salt, it is the compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in logical formula (III),
Wherein：A1~A4、B1~B4、L1、R3And R4Definition with n is as described in logical formula (I).
The preferred scheme of the present invention, compound or its stereoisomer, dynamic isomer described in a kind of logical formula (I) or its is pharmaceutically acceptable
Salt, it is the compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in logical formula (IV),
Wherein：A1~A4、B1~B4、L1、R3And R4Definition with n is as described in logical formula (I).
The preferred scheme of the present invention, compound or its stereoisomer, tautomerism described in a kind of logical formula (I)~any one of (IV)
Body or its pharmaceutically useful salt, wherein R3Selected from C3-6Alkyl, preferably n-propyl.
The preferred scheme of the present invention, compound or its stereoisomer, tautomerism described in a kind of logical formula (I)~any one of (IV)
Body or its pharmaceutically useful salt, wherein R4Selected from 5~6 unit's heteroaryls, wherein described heteroaryl is optionally further by one or many
The substituent of individual halogen, alkyl or alkoxy is replaced, wherein described alkyl or alkoxy are optionally further one or more
Halogen is replaced；It is used as further preferred scheme, wherein R4Selected from pyrazolyl, wherein described pyrazolyl is optionally further by three
Methyl fluoride or trifluoromethoxy are replaced.
The preferred scheme of the present invention, compound or its stereoisomer, tautomerism described in a kind of logical formula (I)~any one of (IV)
Body or its pharmaceutically useful salt, wherein R5Be each independently selected from hydrogen atom, alkyl or halogen, wherein described halogen be preferably F,
Cl or Br.
The preferred scheme of the present invention, compound or its stereoisomer, tautomerism described in a kind of logical formula (I)~any one of (IV)
Body or its pharmaceutically useful salt, wherein R6Be each independently selected from hydrogen atom, alkyl or halogen, wherein described halogen be preferably F,
Cl or Br.
The preferred scheme of the present invention, compound or its stereoisomer, tautomerism described in a kind of logical formula (I)~any one of (IV)
Body or its pharmaceutically useful salt, wherein：
A1、A2、A3And A4It is each independently selected from CR5；
B1、B2、B3And B4It is each independently selected from CR6；
L1Selected from O；
R1And R24~8 circle heterocycles bases, preferably 5~7 yuan are formed together with N the or C atoms being connected；Wherein described heterocyclic radical
It is interior to contain one or more N, O, S (O)mAtom, and described heterocyclic radical optionally further replaces by one or more halogens；
Preferably F, Cl or Br, more preferably F；
R3Selected from alkyl, wherein described alkyl optionally further by it is one or more selected from halogen, hydroxyl, cyano group, nitro,
Cycloalkyl, heterocyclic radical or-NR7R8Substituent replaced；
R4Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen by one or more
Element, hydroxyl, cyano group, nitro, alkoxy ,-NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8
Substituent replaced, wherein described alkyl or alkoxy are optionally further replaced by one or more halogens；
R5Hydrogen atom, alkyl or halogen are each independently selected from, wherein described alkyl is optionally further by one or more halogens
Replaced；
R6Hydrogen atom, alkyl or halogen are each independently selected from, wherein described alkyl is optionally further by one or more halogens
Replaced；And
R7~R9Definition with n is as described in logical formula (I).
Preferred compounds of the invention includes but is not limited to：
Or its stereoisomer, dynamic isomer or its pharmaceutically useful salt.
Further, the present invention provides a kind of preparation method of the compound or its salt described in logical formula (I), comprises the following steps：
Formula (Ia) compound is hydrolyzed in the basic conditions, obtains formula (Ib) compound；Formula (Ib) compound or its salt and formula (Ic)
Compound or its salt is preferably double (2- oxo -3- oxazoles alkyl) secondary phosphoryl chloride phosphorus oxychloride and N, N- diisopropyl second in the presence of condensation reagent
Condensation reaction is carried out under the conditions of amine, formula (Id) compound is obtained；Formula (Id) compound and formula (Ie) compound in dehydrated reagent and
Mistunobu reactions are carried out in the presence of Phosphine ligands, reacts, obtains preferably in the presence of diisopropyl azodiformate and triphenylphosphine
To formula (IA) compound；Formula (IA) compound is hydrolyzed in the basic conditions, obtains logical formula (I) compound.
Wherein：
RaAnd RbAlkyl each is stood alone as, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in logical formula (I).
The present invention provides a kind of preparation method of the compound or its salt described in logical formula (II), comprises the following steps：
Formula (IIa) compound is hydrolyzed in the basic conditions, obtains formula (IIb) compound；Formula (IIb) compound or its salt and formula
(Ic) compound or its salt is preferably double (2- oxo -3- oxazoles alkyl) secondary phosphoryl chloride phosphorus oxychloride and N, N- diisopropyls in the presence of condensation reagent
Condensation reaction is carried out under the conditions of ethamine, formula (IIc) compound is obtained；Formula (IIc) compound is tried with formula (Ie) compound in dehydration
Mistunobu reactions are carried out in the presence of agent and Phosphine ligands, are reacted preferably in the presence of diisopropyl azodiformate and triphenylphosphine,
Obtain formula (IIA) compound；Formula (IIA) compound is hydrolyzed in the basic conditions, obtains logical formula (II) compound.
Wherein：
RaAnd RbAlkyl each is stood alone as, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in logical formula (I).
The present invention provides a kind of preparation method of the compound or its salt described in logical formula (III), comprises the following steps：
Formula (Ib) compound or its salt is preferably double (2- oxos -3- in the presence of condensation reagent with formula (IIIa) compound or its salt
Oxazole alkyl) condensation reaction is carried out under the conditions of secondary phosphoryl chloride phosphorus oxychloride and DIPEA, obtain formula (IIIb) compound；Formula
(IIIb) compound carries out Mistunobu reactions, preferably azo two with formula (Ie) compound in the presence of dehydrated reagent and Phosphine ligands
Reacted in the presence of formic acid diisopropyl ester and triphenylphosphine, obtain formula (IIIA) compound；Formula (IIIA) compound is in alkalescence condition
Lower hydrolysis, obtains logical formula (III) compound.
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in logical formula (I).
The present invention provides a kind of preparation method of the compound or its salt described in logical formula (IV), comprises the following steps：
Formula (IIb) compound or its salt is preferably double (2- oxos -3- in the presence of condensation reagent with formula (IIIa) compound or its salt
Oxazole alkyl) condensation reaction is carried out under the conditions of secondary phosphoryl chloride phosphorus oxychloride and DIPEA, obtain formula (IVa) compound；Formula
(IVa) compound carries out Mistunobu reactions, preferably azo two with formula (Ie) compound in the presence of dehydrated reagent and Phosphine ligands
Mistunobu reactions are carried out in the presence of formic acid diisopropyl ester and triphenylphosphine, formula (IVA) compound is obtained；Formula (IVA) chemical combination
Thing is hydrolyzed in the basic conditions, obtains logical formula (IV) compound.
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in logical formula (I).
In above-mentioned preparation method, alkalescence condition is provided by organic base or inorganic base, and organic base preferably is selected from diisopropylethylamine, two different
Propylamine, pyridine, triethylamine, piperidines, N methyl piperazine, more preferably 4- dimethylamino pyridines, diisopropylamine and triethylamine；Nothing
Machine alkali preferably is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, more preferably lithium hydroxide.
Further, the present invention provide compound or its stereoisomer shown in a kind of formula (IA)~(IVA), dynamic isomer or
Its pharmaceutically useful salt：
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
A1~A4、B1~B4、L1、R1~R4Definition with n is as described in logical formula (I).
Formula (IA)~(IA) preferred compound includes, but are not limited to：
Or its stereoisomer, dynamic isomer or its pharmaceutically useful salt.
Further, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains logical formula (I)~(IV) of effective dose
Described compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, and pharmaceutically useful carrier, excipient or it
Combination.
The present invention provides a kind of method of external glucagon suppression acceptor, and this method is included described glucagon receptor
With described in logical formula (I)~any one of (IV) or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, or its drug regimen
Thing is in contact.
The present invention provide compound or its stereoisomer described in a kind of logical formula (I)~any one of (IV), dynamic isomer or its can
Medicinal salt, or its pharmaceutical composition are supported preparing type i diabetes, type ii diabetes, hyperglycemia, obesity or insulin
Purposes in the medicine of anti-disease.
The present invention provide compound or its stereoisomer described in a kind of logical formula (I)~any one of (IV), dynamic isomer or its can
Medicinal salt, or purposes of its pharmaceutical composition in glucagon receptor antagonist or inverse agonist is prepared.
The present invention provide compound or its stereoisomer described in a kind of logical formula (I)~any one of (IV), dynamic isomer or its can
Medicinal salt, or its pharmaceutical composition are preparing treatment hyperlipidemia, dyslipidemia, hypercholesterolemia, Atherosclerosis
Purposes in change, the medicine of metablic syndrome.
The compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt of the invention led to described in formula (I)~any one of (IV),
Or its pharmaceutical composition can glucagon suppression acceptor in vitro, therefore can be used for preparing glucagon receptor antagonist or
Inverse agonist, at the same invention further provides can be used for treatment type i diabetes, type ii diabetes, hyperglycemia,
Obesity, insulin resistance, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis or Metabolic syndrome
The method of card, methods described includes applying animal the compound described in logical formula (I)~any one of (IV) of the present invention of therapeutically effective amount
Or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, or the step of its pharmaceutical composition.
Detailed description of the invention
Unless stated to the contrary, otherwise present invention part term used in the specification and in the claims is defined as follows：
" alkyl " as a group or a group a part when refer to include C1-C20Straight chain or the aliphatic group with side chain
Group.Preferably C1-C10Alkyl, more preferably C1-C6Alkyl.The embodiment of alkyl group include but is not limited to methyl, ethyl,
N-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl
Propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group,
1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2-
Ethyl-butyl, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be optionally substituted
Or it is unsubstituted.
" alkynyl " as a group or a group a part when refer to the aliphatic hydrocarbon group containing a triple carbon-carbon bonds, can be straight
Chain can also carry side chain.Prioritizing selection is C2-C10Alkynyl, more preferably C2-C6Alkynyl, most preferably C2-C4Alkynyl.Alkynes
The embodiment of base group includes, but are not limited to acetenyl, 1- propinyls, 2-propynyl, 1-, 2- or 3- butynyl etc..Alkynyl can
To be optionally substituted or unsubstituted.
" cycloalkyl " refers to the carbocyclic ring of saturation or the monocyclic of fractional saturation, condensed ring, bridged ring and loop coil, i.e., comprising monocyclic cycloalkyl,
Cycloalkyl, bridge ring alkyl and spiro cycloalkyl group.Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, be most preferably
C3-C6Cycloalkyl.The embodiment of monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, hexamethylene
Base, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.
" spiro cycloalkyl group " refers to 5 to 18 yuan, two or more cyclic structures, and it is monocyclic between each other share a carbon atom
Contain one or more double bonds in the polycyclic moiety of (title spiro-atom), ring, but neither one ring has the pi-electron of total conjugated
Aroma system.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to sharing the number of spiro-atom between ring and ring by spiral shell
Cycloalkyl is divided into single spiral shell, double spiral shells or many spiro cycloalkyl groups, is preferably single spiral shell and double spiro cycloalkyl groups, preferably 4 yuan/5 yuan, 4 yuan/6
Member, 5 yuan/5 yuan or 5 yuan/6 yuan.The non-limiting example of " spiro cycloalkyl group " includes but is not limited to：Spiral shell [4.5] decyl, spiral shell [4.4]
Nonyl, spiral shell [3.5] nonyl, spiral shell [2.4] heptyl.
" cycloalkyl " refers to 5 to 18 yuan, and the full carbon containing two or more cyclic structures public a pair of carbon atoms each other is more
Cyclic group, one or more rings can contain one or more double bonds, but neither one ring has the virtue of the pi-electron of total conjugated
Fragrant system, more preferably preferably 6 to 12 yuan, 7 to 10 yuan.According to composition ring number can be divided into bicyclic, three rings,
Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl." condensed ring alkane
The non-limiting example of base " includes but is not limited to：Two rings [3.1.0] hexyl, two rings [3.2.0] hept- 1- alkenyls, two rings [3.2.0] heptan
Base, decahydronaphthalene naphthyl or ten tetrahydrochysene phenanthryl.
" bridge ring alkyl " refers to 5 to 18 yuan, containing two or more cyclic structures, two are shared each other is not joined directly together and connect
The full carbon polycyclic moiety of carbon atom, one or more rings can contain one or more double bonds, but neither one ring is with completely common
The aroma system of the pi-electron of yoke, more preferably preferably 6 to 12 yuan, 7 to 10 yuan.Preferably 6 to 14 yuan, more preferably
For 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to the number of composition ring, preferably bicyclic,
Three rings or Fourth Ring, more elect bicyclic or three rings as.The non-limiting example of " bridge ring alkyl " includes but is not limited to：(1s,4s)-
Two rings [2.2.1] heptyl, two rings [3.2.1] octyl group, (1s, 5s)-two ring [3.3.1] nonyl, two rings [2.2.2] octyl group, (1r, 5r)-two ring [3.3.2]
Decyl.
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein the ring linked together with precursor structure
For cycloalkyl, non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can optionally be taken
It is generation or unsubstituted.
" heterocyclic radical ", " heterocycle " or " heterocycle " is used interchangeably in this application, all referring to non-aromatic heterocyclyl groups, its
In one or more cyclic atoms be hetero atom, such as oxygen, nitrogen, sulphur atom, including monocyclic, condensed ring, bridged ring and loop coil,
Include monocyclic heterocycles base, condensed hetero ring base, bridge heterocyclic radical and spiro heterocyclic radical.It is preferred that double with 5 to 7 unit monocycles or 7 to 10 yuan
- or three rings, it can be comprising 1,2 or 3 the atom in nitrogen, oxygen and/or sulphur.The example of " heterocyclic radical " includes but not limited
In morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, 1,1- dioxo-thiomorpholinyl, piperidyl, 2- oxo-pipehdinyls,
Pyrrolidinyl, 2- oxo-pyrrolidines, piperazine -2- ketone, 8- oxa- -3- aza-bicyclos [3.2.1] octyl groups and piperazinyl.Heterocyclic radical can
To be optionally substituted or unsubstituted.
" spiro heterocyclic radical " refers to 5 to 18 yuan, two or more cyclic structures, and it is monocyclic between each other share an atom
Polycyclic moiety, one or more double bonds are contained in ring, but neither one ring has the aroma system of the pi-electron of total conjugated,
Wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m be selected from 0,1 or 2), remaining annular atom is
Carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to sharing the number of spiro-atom between ring and ring by spiro heterocyclic radical
It is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals, is preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4
Member/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting reality of " spiro heterocyclic radical "
Example is applied to include but is not limited to：1,7- dioxo spiros [4.5] decyl, 2- oxa- -7- azaspiros [4.4] nonyl, 7- oxaspiros [3.5] nonyl
With 5- oxaspiros [2.4] heptyl.
" condensed hetero ring base " refers to the full carbon polycyclic moiety containing two or more cyclic structures public a pair of atoms each other, one
Or multiple rings can contain one or more double bonds, but neither one ring has the aroma system of the pi-electron of total conjugated, wherein
One or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.It is excellent
Elect 6 to 14 yuan, more preferably 7 to 10 yuan as.Bicyclic, three rings, Fourth Ring or polycyclic can be divided into according to the number of composition ring
Condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases." condensed hetero ring base "
Non-limiting example includes but is not limited to：Octahydro pyrrolo- [3,4-c] pyrrole radicals, octahydro -1H- isoindolyls, 3- azabicyclics
[3.1.0] hexyl, octahydro benzo [b] [Isosorbide-5-Nitrae] bioxin (dioxine).
" bridge heterocyclic radical " refers to 5 to 14 yuan, and 5 to 18 yuan, containing two or more cyclic structures, two are shared each other
The polycyclic moiety of the atom connect is not joined directly together, one or more rings can contain one or more double bonds, but neither one ring has
There is the aroma system of the pi-electron of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)m(wherein m is integer
0 to 2) hetero atom, remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to composition ring
Number can be divided into bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical, preferably bicyclic, three rings or Fourth Ring, more elect as bicyclic
Or three rings.The non-limiting example of " condensed hetero ring base " includes but is not limited to：2- azabicyclics [2.2.1] heptyl, 2- azabicyclics
[2.2.2] octyl group and 2- azabicyclics [3.3.2] decyl.
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring linked together with precursor structure
For heterocyclic radical.Heterocyclic radical can be optionally substituted or unsubstituted.
" aryl " refers to the carbocyclic aromatic system containing one or two rings, wherein the ring can be connected in the way of fusion
Together.Term " aryl " includes the aromatic group of such as phenyl, naphthyl, tetralyl.Preferred aryl groups are C6-C10Aryl,
More preferably aryl is phenyl and naphthyl, most preferably phenyl.Aryl can be optionally substituted or unsubstituted." aryl " can
With heteroaryl, heterocyclic radical or Cycloalkylfused, wherein with precursor structure link together for aryl rings, non-limiting example
Including but not limited to：
" heteroaryl " refers to the unit monocycle of aromatic series 5 to 6 or 9 to 10 membered bicyclics, and it can be selected from nitrogen, oxygen comprising 1 to 4
And/or the atom in sulphur.The embodiment of " heteroaryl " includes but is not limited to furyl, pyridine radicals, 2- oxo -1,2- dihydropyridines
Base, pyridazinyl, pyrimidine radicals, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyls, imidazole radicals, pyrrole radicals,
Pyrazolyl, triazolyl, tetrazole radical, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl groups, benzodioxole group,
Benzimidazolyl, indyl, isoindolyl, 1,3- dioxos-isoindolyl, quinolyl, indazolyl, benzisothia oxazolyl,
Benzoxazolyl and benzoisoxazole base.Heteroaryl can be optionally substituted or unsubstituted.The heteroaryl ring can condense in
On aryl, heterocyclic radical or cycloalkyl ring, wherein being heteroaryl ring, non-limiting example with the ring that precursor structure links together
Including but not limited to：
" alkoxy " refers to the group of (alkyl-O-).Wherein, alkyl is shown in relevant definition herein.C1-C6Alkoxy be preferential
Selection.The example includes, but are not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl oxygen
Base, tert-butoxy etc..
" hydroxyl " refers to-OH groups.
" halogen " refers to fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
" amino " refers to-NH2。
" cyano group " refers to-CN.
" nitro " refers to-NO2。
" benzyl " refers to-CH2- phenyl.
" carboxyl " refers to-C (O) OH.
" carboxylic acid ester groups " refers to-C (O) O (alkyl) or (cycloalkyl), and wherein alkyl, cycloalkyl is as defined above.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom that
This is independently replaced by the substituent of respective number.Self-evident, substituent is only in their possible chemical position, ability
Field technique personnel can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.Example
Such as, it is probably unstable when the amino or hydroxyl with free hydrogen are combined with the carbon atom with unsaturated (such as olefinic) key.
" substitution " or " substituted " described in this specification, as without particularly pointing out, each mean group can by it is one or more be selected from
Under substituent group：Alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, dredge base, hydroxyl, nitro,
Cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group,
Amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups=O ,-NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9
Or-NR7C(O)R8Wherein, R7、R8And R9Definition as described in logical formula (I).
" pharmaceutically useful salt " refers to that above-claimed cpd can keep original bioactivity and be suitable for some salts of medical usage.
The amine salt that the pharmaceutically useful salt of compound represented by formula (I) can be formed for metal salt, with suitable acid.The preferred alkali of metal salt
Metal, alkali salt；Suitable acid includes inorganic acid and organic acid, for example acetic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid,
Citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, horse
Come sour, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, butanedioic acid, sulfuric acid, tartaric acid, p-methyl benzenesulfonic acid etc., it is particularly preferred
It is hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, most preferably hydrochloride.
" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically pharmaceutically useful salt or precursor medicine
Thing and the mixture of other chemical constituents, and the pharmaceutically useful carrier of other components such as physiology and excipient.Pharmaceutical composition
Purpose be to promote administration to organism, the absorption beneficial to active component and then play bioactivity.
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the scope of the present invention.
Embodiment
Embodiment gives preparation and the dependency structure appraising datum of the representative compound represented by formula (I).Mandatory declaration, under
It is to be used to illustrate rather than limitation of the present invention to state embodiment.
1H NMR spectras are to be determined and obtained with Bruker instruments (400MHz), and chemical shift is represented with ppm.Use tetramethyl
Base silane internal standard (0.00ppm).1H NMR method for expressing：S=is unimodal, d=doublets, t=triplets, m=multiplets,
What br=broadened, the doublet of dd=doublets, the doublet of dt=triplets.If provide coupling constant, its unit is Hz.
Mass spectrum is to be determined to obtain with LC/MS instrument, and Ionization mode can be ESI or APCI.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC)
The specification that the silica gel plate that uses is used is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~
0.5mm。
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.In following Examples, unless otherwise specified,
All temperature are Celsius temperature, unless otherwise specified, and various initiation materials and reagent are from commercially available or according to known method
Synthesis, marketable material and reagent are directly used without further purification, and unless otherwise specified, commercially available producer includes but is not limited to
Aldrich Chemical Company, ABCR GmbH＆Co.KG, Acros Organics, Guang Zan Chemical Industry Science Co., Ltd
With Jing Yan Chemical Industry Science Co., Ltd etc. purchase.
CD3OD：Deuterated methanol.
CDCl3：Deuterochloroform.
DMSO-d6：Deuterated dimethyl sulfoxide.
Without specified otherwise in embodiment, reaction is carried out under an argon.
Without specified otherwise in embodiment, the solution in reaction refers to the aqueous solution.
Embodiment 1
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) piperidines -3-
Carboxylic acid
The first step
4- (1- hydroxybutyls) methyl benzoate
P formylbenzoic acid methyl esters 1a (10.0g, 60.92mmol) is dissolved in 100mL tetrahydrofurans, at -78 DEG C,
Propyl group magnesium bromide (33.5mL, 67.0mmol) is added, is reacted at room temperature 3 hours.300mL ethyl acetate is added, saturation chlorine is used
Change ammonium salt solution (200mL) and saturated nacl aqueous solution (200mL) washing, organic phase anhydrous sodium sulfate drying is concentrated under reduced pressure, obtained
The residue arrived silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying, obtain 4- (1- hydroxybutyls) benzene first
Sour methyl esters 1b (8.66g, colourless liquid), yield：68.0%
MS m/z(ESI)：209.0[M+1]
Second step
4- bytyry methyl benzoates
4- (1- hydroxybutyls) methyl benzoate 1b (6.58g, 31.6mmol) are dissolved in 100mL dichloromethane, at 0 DEG C,
Pyridine chlorochromate (8.17g, 37.9mmol) is added, is reacted at room temperature 18 hours.200mL dchloromethanes are added, are added
Anhydrous magnesium sulfate is stirred 10 minutes, filtering, is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：
Ethyl acetate system) purifying, obtain 4- bytyry methyl benzoates 1c (6.20g, white solid), yield：95.2%
MS m/z(ESI)：207.0[M+1]
3rd step
(R) -4- (1- hydroxybutyls) methyl benzoate
Borine borine-N, N- diethylaniline (5.53mL, 30.0mmol) is dissolved in 100mL tetrahydrofurans, (S) -2- is added
Methyl-CBS- oxazaborolidines (1.5mL, 1.50mmol), are then added dropwise 4- bytyry methyl benzoate 1c (6.20g, 30.0 dropwise
Mmol tetrahydrofuran (50mL) solution), is reacted at room temperature 0.5 hour.10mL methanol is added dropwise into reaction solution to be quenched
Reaction, then adds 1M hydrochloric acid (130mL) and petroleum ether (300mL), organic phase with 1M hydrochloric acid (120mL) and
Saturated nacl aqueous solution (100mL) is washed, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, is obtained (R) -4- (1- hydroxyl fourths
Base) methyl benzoate 1d (6.07g, colourless liquid), yield：97.0%
MS m/z(ESI)：209.0[M+1]
4th step
(R) -4- (1- hydroxybutyls) benzoic acid
(R) -4- (1- hydroxybutyls) methyl benzoate 1d (600mg, 2.88mmol) is dissolved in 10mL tetrahydrofurans and methanol
In the mixed solvent (V/V=1/1), adds the hydronium(ion) lithias (104mg, 14.4mmol) of 1mL mono-, reacts at room temperature 18 hours.
With 1M hydrochloric acid regulation pH=5 after reaction solution concentration, extracted with ethyl acetate (50mL), organic phase is molten with saturated sodium-chloride
Liquid (50mL) is washed, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, is obtained (R) -4- (1- hydroxybutyls) benzoic acid 1e (560
Mg, white solid), yield：100%.
MS m/z(ESI)：194.9[M+1]
5th step
(R) -1- (4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates
By (R) -4- (1- hydroxybutyls) benzoic acid 1e (194mg, 1.00mmol), (R)-piperidines -3- Ethyl formates 1f (157mg,
1.00mmol) it is dissolved in double (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (254mg, 1.00mmol) in 10mL dichloromethane,
DIPEA (0.89mL, 5.00mmol) is added, reaction solution reacts 2 hours at room temperature.Reaction solution is depressurized
Concentration, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying, obtain (R) -1- (4- (R) -1-
Hydroxyl butyl) benzoyl piperidine base) -3- Ethyl formates 1g (250mg, colorless oil), yield：75.0%.
MS m/z(ESI)：334.0[M+1]
6th step
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) piperidines -3- carboxylic acids
Ethyl ester
By (R) -1- (4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates 1g (200mg, 0.60mmol) is dissolved in 10mL
In tetrahydrofuran, diisopropyl azodiformate (243mg, 1.20mmol) and triphenylphosphine (315mg, 1.20mmol) are added,
Then add 3,5- dimethyl-4- (4-(trifluoromethyl)-1H- pyrazol-1-yls) phenol 1h (154mg, 0.60mmol) and be dissolved in tetrahydrochysene furan
The solution muttered, reaction solution reacts 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue silica gel thin-layer chromatography
Method (washing and dehydrating integrated machine：Petroleum ether：Ethyl acetate system) purifying, obtain (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H-
Pyrazol-1-yl) phenoxy group) butyl) benzoyl) piperidines -3- carboxylic acid, ethyl esters 1i (320mg, colourless liquid), yield：93.3%.
MS m/z(ESI)：571.9[M+1]
7th step
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) piperidines -3-
Carboxylic acid
By (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) piperidines
- 3- carboxylic acid, ethyl esters 1i (320mg, 0.56mmol) is dissolved in the in the mixed solvent (V/V=1/1) of 10mL tetrahydrofurans and methanol,
The aqueous solution of the hydronium(ion) lithias (235mg, 5.60mmol) of 1mL mono- is added, is reacted at room temperature 18 hours.After reaction solution concentration
PH=5 is adjusted with 0.5M hydrochloric acid, is extracted with ethyl acetate (100mL), organic phase is with saturated nacl aqueous solution (100mL)
Washing, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H-
Pyrazol-1-yl) phenoxy group) butyl) benzoyl) piperidines -3- carboxylic acids 1 (100mg, white solid), yield：32.9%
MS m/z(ESI)：543.9[M+1]
1H NMR(400MHz,CHLOROFORM-d)):δ8.03(s,1H),7.91(br.s.,1H),7.69(s,1H),7.42-
7.28(m,4H),6.58(s,1H),5.17(br.s.,1H),4.57(br.s.,1H),2.97(s,3H),2.89(s,3H),2.76-
2.61(m,1H),2.16-2.02(m,2H),1.86(br.s.,6H),1.56(br.s.,2H),1.47-1.38(m,1H),1.05-
0.90(m,3H)
Embodiment 2
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids
The first step
The fluoro- 4- of 2- (1- hydroxyls butyl) methyl benzoate
The fluoro- 4- acyl radical methyl benzoates 2a (3.0g, 16.5mmol) of 2- are dissolved in 60mL tetrahydrofurans, nitrogen protection exists
Under -78 DEG C of stirrings, propyl group magnesium bromide (8.6mL, 17.3mmol) is slowly added to, is reacted at room temperature 2 hours.Reaction solution is cooled to 0 DEG C,
Saturated ammonium chloride solution (30mL) is slowly added to, is extracted with ethyl acetate (20mL x3), organic phase anhydrous sodium sulfate drying,
It is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying, obtain the fluoro- 4- (1- of 2-
Hydroxyl butyl) methyl benzoate 2b (850mg, colourless liquid), yield：23.0%
1H NMR(400MHz,CDCl3):δ 7.86 (dd, J=6.9,2.1Hz, 1H), 7.53-7.44 (m, 1H), 7.09 (dd, J=
10.3,8.7Hz, 1H), 4.74-4.63 (m, 1H), 3.91 (s, 3H), 2.18 (s, 1H), 1.81-1.69 (m, 1H), 1.64 (ddd, J=
15.4,12.5,5.8Hz, 1H), 1.47-1.34 (m, 1H), 1.33-1.22 (m, 1H), 0.91 (t, J=7.4Hz, 3H)
Second step
The fluoro- 4- bytyries methyl benzoates of 2-
The fluoro- 4- of 2- (1- hydroxyls butyl) methyl benzoate 2b (850mg, 3.76mmol) is dissolved in 20mL dichloromethane, argon gas
Protection adds pyridine chlorochromate (970mg, 4.51mmol) at 0 DEG C, reacts at room temperature 18 hours.Add 200mL dichloros
Methane dilutes, and adds anhydrous sodium sulfate and stirs 10 minutes, and filtering is concentrated under reduced pressure, obtained residue silica gel column chromatography (is washed
De- agent：Petroleum ether：Ethyl acetate system) purifying, the fluoro- 4- bytyries methyl benzoate 2c of 2- (670mg, white solid) are obtained,
Yield：80.0%
MS m/z(ESI)：224.9[M+1]
3rd step
(R) the fluoro- 4- of -2- (1- hydroxybutyls) methyl benzoate
Borine borine-N, N- diethylaniline (0.88mL, 4.95mmol) is dissolved in 100mL tetrahydrofurans, (S) -2- is added
Methyl-CBS- oxazaborolidines (0.25mL, 0.25mmol), argon gas protection is stirred 3 minutes at 0 DEG C, and the fluoro- 4- of 2- are then added dropwise
The solution of bytyry methyl benzoate 2c (1.11g, 4.95mmol) tetrahydrofuran (8mL), 10 minutes completion of dropping, after
Continuous reaction 20 minutes.Reaction solution is cooled to after 0 DEG C, is slowly added to have obvious gas during reaction, dropwise addition is quenched in 0.6mL methanol
Bubble is produced, and adds 1M hydrochloric acid (6mL), is extracted with petroleum ether (10mL x4), merges organic phase 1M hydrochloric acid (10
ML) wash, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains (R) -2- fluoro- 4- (1- hydroxybutyls) benzoic acid first 2d (1.12
G, colourless liquid), yield：100%
1H NMR(400MHz,CDCl3):δ 7.86 (dd, J=6.9,2.1Hz, 1H), 7.53-7.44 (m, 1H), 7.09 (dd, J=
10.3,8.7Hz, 1H), 4.74-4.63 (m, 1H), 3.91 (s, 3H), 2.18 (s, 1H), 1.81-1.69 (m, 1H), 1.64 (ddd, J=
15.4,12.5,5.8Hz, 1H), 1.47-1.34 (m, 1H), 1.33-1.22 (m, 1H), 0.91 (t, J=7.4Hz, 3H)
4th step
(R) the fluoro- 4- of -2- (1- hydroxybutyls) benzoic acid
(R) -2- fluoro- 4- (1- hydroxybutyls) benzoic acid first 2d (600mg, 2.65mmol) are dissolved in 10mL tetrahydrofurans and methanol
In the mixed solvent (V/V=1/4), add the hydronium(ion) lithias (557mg, 13.25mmol) of 2.7mL mono-, room temperature reaction 2
Hour.With 1M hydrochloric acid regulation pH=2-3 after reaction solution concentration, extracted with ethyl acetate (10mL x3), merge organic phase,
With anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtain (R) -2- fluoro- 4- (1- hydroxybutyls) benzoic acid 2e (560mg, it is colourless
Liquid), yield：99%
MS m/z(ESI)：212.9[M+1]
5th step
(R) -1- (2- fluoro- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates
By (R) -2- fluoro- 4- (1- hydroxybutyls) benzoic acid 2e (150mg, 0.71mmol), (R)-piperidines -3- Ethyl formates 1f (142
UL, 0.92mmol), double (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (270mg, 1.06mmol) and DIPEA
(0.50mL, 2.82mmol) is dissolved in 5mL tetrahydrofurans, and reaction solution reacts 2 hours at room temperature.Reaction solution is depressurized dense
Contracting, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying, obtain (R) -1- (2- fluorine
- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates 2g (240mg, colourless liquid), yield：96.0%.
MS m/z(ESI)：352.0[M+1]
6th step
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperidines
- 3- carboxylic acid, ethyl esters
By (R) -1- (2- fluoro- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates 2g (151mg, 0.43mmol), 3,5-
Dimethyl-4- (4-(trifluoromethyl)-1H- pyrazol-1-yls) phenol 1h (100mg, 0.39mmol) and triphenylphosphine (204mg, 0.78
Mmol) it is dissolved in 6mL tetrahydrofurans, stirs 3 minutes, adds diisopropyl azodiformate (154uL, 0.78mmol),
Reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：
Petroleum ether：Ethyl acetate system) purifying, obtain (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls)
Phenoxy group) butyl) -2- fluoro benzoyls) piperidines -3- carboxylic acid, ethyl esters 2h (150mg, yellow liquid), yield：65.0%.
MS m/z(ESI)：589.9[M+1]
7th step
(R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids
By (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls)
Piperidines -3- carboxylic acid, ethyl esters 2h (150mg, 0.26mmol) and the hydronium(ion) lithias (55mg, 1.30mmol) of 0.26mL mono- water
Solution is dissolved in the in the mixed solvent (V/V=2/5) of 7mL tetrahydrofurans and methanol, reacts at room temperature 18 hours.After reaction solution concentration
PH=2-3 is adjusted with 1M hydrochloric acid, is extracted with ethyl acetate (8mL x4), merging organic phase, anhydrous sodium sulfate drying,
Filtering, is concentrated under reduced pressure, obtained residue silicon thin-layer chromatography (solvent：Petroleum ether：Ethyl acetate=1:2.5) purify,
Obtain (R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids 2 (8mg, yellow solid), yield：6.0%
MS m/z(ESI)：561.9[M+1]
1H NMR(400MHz,DMSO):δ 12.41 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.47 (d, J=31.3Hz, 2H),
7.28 (t, J=8.7Hz, 1H), 6.78 (s, 2H), 5.44 (d, J=5.3Hz, 1H), 3.26-3.09 (m, 2H), 3.10-2.85 (m,
2H), 1.96 (ddd, J=23.9,15.8,7.1Hz, 3H), 1.83 (s, 6H), 1.65 (ddd, J=30.8,15.4,6.5Hz, 3H),
1.50-1.32 (m, 3H), 0.91 (dd, J=12.4,6.9Hz, 3H)
Embodiment 3
(S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids
The first step
(S) -1- (2- fluoro- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates
By (R) -2- fluoro- 4- (1- hydroxybutyls) benzoic acid 2e (150mg, 0.71mmol), (S)-piperidines -3- Ethyl formates 3a (142
UL, 0.92mmol), double (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (270mg, 1.06mmol) and DIPEA
(0.50mL, 2.82mmol) is dissolved in 5mL tetrahydrofurans, and reaction solution reacts 2 hours at room temperature.Reaction solution is depressurized dense
Contracting, obtained residue silica gel column chromatography (solvent：Petroleum ether：Ethyl acetate system) purifying, obtain (S) -1- (2- fluorine
- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates 3b (250mg, colourless liquid), yield：99.0%.
MS m/z(ESI)：352.0[M+1]
Second step
(S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperidines -3-
Ethyl formate
By (S) -1- (2- fluoro- 4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates 3b (83mg, 0.24mmol), 3,5-
Dimethyl-4- (4-(trifluoromethyl)-1H- pyrazol-1-yls) phenol 1h (55mg, 0.21mmol) and triphenylphosphine (110mg, 0.42
Mmol) it is dissolved in 5mL tetrahydrofurans, the lower stirring of argon gas protection 3 minutes adds diisopropyl azodiformate (83uL, 0.42
Mmol), reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, the silica gel column chromatography (exhibition of obtained residue
Open agent：Petroleum ether：Ethyl acetate system) purifying, obtain (S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazoles
- 1- bases) phenoxy group) butyl) -2- fluoro benzoyls) piperidines -3- carboxylic acid, ethyl esters 3c (100mg, yellow liquid), yield：81.0%.
MS m/z(ESI)：589.9[M+1]
3rd step
(S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids
By (S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls)
Piperidines -3- carboxylic acid, ethyl esters 3c (100mg, 0.17mmol) and the hydronium(ion) lithias (37mg, 0.87mmol) of 0.17mL mono- water
Solution is dissolved in the in the mixed solvent (V/V=3/8) of 5.5mL tetrahydrofurans and methanol, reacts at room temperature 18 hours.Reaction solution is concentrated
Afterwards with 1M hydrochloric acid regulation pH=2-3, extracted with ethyl acetate (8mL x4), merging organic phase, anhydrous sodium sulfate drying,
Filtering, is concentrated under reduced pressure, obtained residue silicon thin-layer chromatography (solvent：Petroleum ether：Ethyl acetate=1:2.5) purify,
Obtain (S) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) -2- fluoro benzoyls) piperazine
Pyridine -3- carboxylic acids 3 (8mg, yellow solid), yield：10.0%
MS m/z(ESI)：561.9[M+1]
1H NMR(400MHz,DMSO):δ 12.41 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.51 (s, 2H), 7.28 (t, J=
8.7Hz, 1H), 6.78 (s, 2H), 5.44 (dd, J=11.6,6.3Hz, 1H), 3.28-3.16 (m, 2H), 3.15-2.92 (m, 2H),
1.96 (ddd, J=23.1,14.6,6.1Hz, 3H), 1.83 (s, 6H), 1.69 (ddd, J=43.4,23.9,10.5Hz, 3H), 1.51
-1.34(m,3H),0.95-0.87(m,3H).
Embodiment 4
2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -3- piperazines
Piperidinyl) acetic acid
The first step
(R) -1- (4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- Ethyl formates
By (R) -4- (1- hydroxybutyls) benzoic acid 1e (250mg, 1.29mmol), (R)-piperidines -3- ethyl acetate hydrochlorides 4a
(267mg, 1.29mmol) and double (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (392mg, 1.54mmol) are dissolved in 15mL dichloros
In methane, DIPEA (1.12mL, 6.44mmol) is added, reaction solution reacts 3 hours at room temperature.Will be anti-
Liquid is answered to be concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying, obtain
(R) -1- (4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- ethyl acetate 4b (300mg, colorless oil), yield：67.1%.
MS m/z(ESI)：348.0[M+1]
Second step
2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -3- piperidyls)
Ethyl acetate
By (R) -1- (4- (R) -1- hydroxyls butyl) benzoyl piperidine base) -3- ethyl acetate 4b (300mg, 0.86mmol), 3,5- diformazans
Base-4- (4-(trifluoromethyl)-1H- pyrazol-1-yls) phenol 1h (221mg, 0.86mmol) and triphenylphosphine (451mg, 1.72mmol)
It is dissolved in 30mL tetrahydrofurans, adds diisopropyl azodiformate (0.34mL, 1.72mmol), reaction solution is at room temperature
Reaction 4 hours.Reaction solution is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate
System) purifying, obtain 2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzene
Formoxyl) -3- piperidyls) ethyl acetate 4c (276mg, white solid), yield：54.6%.
MS m/z(ESI)：586.0[M+1]
3rd step
2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -3- piperazines
Piperidinyl) acetic acid
By 2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -3-
Piperidyl) ethyl acetate 4c (276mg, 0.47mmol) is dissolved in the in the mixed solvent of 20mL tetrahydrofurans and methanol
(V/V=1/1) aqueous solution of the hydronium(ion) lithias (196mg, 4.70mmol) of 1mL mono-, is added, is reacted at room temperature 6 hours.
Add with ethyl acetate (120mL) extraction, organic phase saturated ammonium chloride solution (100mL x2) and saturated nacl aqueous solution
(100mL) is washed, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, is obtained 2- ((R) -1- (4- ((S) -1- (3,5- dimethyl -4- (4- (three
Methyl fluoride) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -3- piperidyls) acetic acid 4 (220mg, white solid), yield：
84.0%
MS m/z(ESI)：558.0[M+1]
1H NMR(400MHz,CHLOROFORM-d):δ7.85(s,1H),7.70(br.s.,1H),7.32(br.s.,4H),6.75-
6.41(m,2H),5.33-5.16(m,1H),4.71-4.52(m,1H),3.82-3.70(m,1H),2.75-2.40(m,1H),
2.33-2.28(m,1H),2.01-1.70(m,11H),1.56-1.38(m,4H),1.31-1.18(m,2H),0.97-0.82
(m,3H).
Embodiment 5
1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoropiperdins -3-
Carboxylic acid
The first step
(R)-fluoro- 1- of ethyl -5,5- two (4- ((R) -1- hydroxyethyls) benzoyl) piperidines -3- carboxylate methyl esters
By (R) -4- (1- hydroxybutyls) benzoic acid 1e (306mg, 1.57mmol), (R)-ethyl -5,5- difluoropiperdin -3- carboxylate methyl esters
5a (282mg, 1.57mmol) and double (2- oxo -3- oxazoles alkyl) secondary phosphoryl chloride phosphorus oxychlorides (798mg, 3.14mmol) are dissolved in 20mL
In dichloromethane, DIPEA (2.73mL, 15.7mmol) is added, reaction solution reacts 3 hours at room temperature.
Reaction solution is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent：Petroleum ether：Ethyl acetate system) purifying,
Obtain the fluoro- 1- of (R)-ethyl -5,5- bis- (4- ((R) -1- hydroxyethyls) benzoyl) piperidines -3- carboxylate methyl esters 5b (500mg, colorless oil
Thing), yield：89.2%.
MS m/z(ESI)：356.0[M+1]
Second step
1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoropiperdins -3-
Carboxylate methyl ester
By the fluoro- 1- of (R)-ethyl -5,5- bis- (4- ((R) -1- hydroxyethyls) benzoyl) piperidines -3- carboxylate methyl esters 5b (250mg, 0.70
Mmol), 3,5- dimethyl-4- (4-(trifluoromethyl)-1H- pyrazol-1-yls) phenol 1h (180mg, 0.70mmol) is dissolved in 15mL
In tetrahydrofuran, argon gas protection is lower to add tri-n-butyl phosphine (0.26mL, 1.05mmol), is then slowly added into azoformic acid two
Isopropyl ester (265mg, 1.05mmol) is dissolved in the solution of 10mL tetrahydrofurans, and reaction solution reacts 12 hours at room temperature.Will
Reaction solution is concentrated under reduced pressure, obtained residue silicon thin-layer chromatography (washing and dehydrating integrated machine：Petroleum ether：Ethyl acetate system) purifying,
Obtain 1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoro piperazines
Pyridine -3- carboxylate methyl esters 5c (300mg, white solid), yield：71.8%.
MS m/z(ESI)：593.9[M+1]
3rd step
1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoropiperdins -3-
Carboxylic acid
By 1- (4- ((S) -1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoros
Piperidines -3- carboxylate methyl esters 5c (418mg, 0.70mmol) is dissolved in the in the mixed solvent of 20mL tetrahydrofurans and methanol
(V/V=1/1) aqueous solution of the hydronium(ion) lithias (295mg, 7.00mmol) of 2mL mono-, is added, is reacted at room temperature 3 hours.
Reaction solution adds 120mL ethyl acetate, successively with saturated ammonium chloride solution (100mL x2) and saturated nacl aqueous solution (100
ML) wash, organic phase anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains 1- (4- ((S) -1- (3,5- dimethyl -4- (4- (three
Methyl fluoride) -1H- pyrazol-1-yls) phenoxy group) butyl) benzoyl) -5,5- difluoropiperdin -3- carboxylic acids 5 (260mg, white solid), production
Rate：63.7%
MS m/z(ESI)：579.9[M+1]
1H NMR(400MHz,DMSO-d6):δ 12.84 (s, 1H), 8.57 (s, 1H), 8.12 (s, 1H), 7.52 (d, J=7.78Hz,
2H), 7.41 (d, J=7.03Hz, 2H), 6.79 (s, 2H), 5.47 (t, J=6.02Hz, 1H), 4.48 (br.s., 1H), 3.33 (m, 2H),
2.77(br.s.,1H),2.89(s,1H),2.40(br.s.,1H),2.12-2.34(m,1H),1.88-2.02(m,1H),1.70-1.88
(m,7H),1.28-1.54(m,2H),0.87-1.00(m,3H)
Biological assessment
The pharmacokinetics test of test case 1, preferred compound of the present invention
1st, experiment purpose
Using SD rats as animal subject, rat oral gavage is determined using LC/MS/MS methods and given after the compound of embodiment 1, it is determined
Drug concentration in the same time in blood plasma, does not study Pharmacokinetic Characteristics of the compounds of this invention in rat body.
2nd, experimental program
2.1 experimental drugs and animal
The compound of embodiment 1；
Healthy adult SD male rat 3, purchased from the magnificent experimental animal Technology Co., Ltd. of dimension tonneau, production licence number：
11400700109943。
2.2 medicine ordinances and administration
Appropriate experimental drug is weighed, 1mL ethanol is added, ultrasound to solution adds 1.5mL PEG400 and 2.5mL water,
Vortex mixed, is configured to 0.6mg/mL simultaneously；
Healthy adult SD male rat 3, distinguishes gastric infusion, dosage is 3mg/kg after overnight fasting.
2.3 sample collection
In before administration and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 after administration
Hour throat venous blood collection 0.15mL, is placed in heparinised tubes, 5500 revs/min, centrifuges 10 minutes, is preserved in -30 DEG C,
Administration is fed after 4 hours.
2.4 sample treatment
Plasma sample handles (For plasma samples):
20 μ L samples are taken, IS is added and (contains Verapamil 5ngmL-1With glibenclamide 50ngmL-1) 100 μ L acetonitriles
Solution in, vortex mixed 0.2 minute, 13000 revs/min centrifuge 8 minutes, then take 70 μ L of supernatant liquid add 70 μ L water in,
Vortex mixed 10 minutes, takes the supernatant of 10 μ L mixed liquors to be analyzed into LC-MS/MS systems.
Sample treatment (For dose sample) is administered:
Sample first alcohol and water (1 will be administered:1, v/v) mixed solvent is diluted to concentration for 100ngmL-1, take after 100 μ L dilutions
Sample and 100 μ L inner mark solutions (100ngmL-1) add to 500 μ L IS solution and 600 μ L water, then vortex mixed,
The supernatant of 10 μ L mixed liquors is taken to be analyzed into LC-MS/MS systems.
3rd, pharmacokinetic parameter result
The pharmacokinetic parameter of preferred compounds of the invention is as shown in table 1.
The pharmacokinetic data table of the compound of 1. embodiment of table 1
Conclusion：The compound of the embodiment of the present invention 1 has preferable medicine for power advantage.
The influence to db/db mouse random blood sugars is administered in test case 2, the compounds of this invention single oral
1st, experiment purpose
Influence after observation preferred compound single oral administration of the present invention to type ii diabetes model db/db mouse random blood sugars,
Using afterbody blood taking method, blood glucose numerical value is measured by portable glucose meter, and then the internal hypoglycemic of test-compound is made
With being evaluated.
2nd, experimental program
2.1 animal subject
Male db/db mouse 100,9-10 weeks, are provided, credit number by model animal research institute of Nanjing University：
SCXK (Soviet Union) 2010-0001, and positive controls and solvent control group are set.
2.2 tested material
Embodiment 1, uses ethanol：PEG400：Water=20：30：50 prepare required concentration.
2.3 administering mode
Oral administration gavage is administered, and blank control group fills the ethanol for giving same volume：PEG400：Water=20：30：50, administered volume
For 10ml/kg, dosage is 30mg/kg.
2.4 test method
Male db/db mouse, be grouped, every group 6 by non-fasting blood glucose and body weight, respectively solvent control and different compounds
Administration group.Single oral gives test medicine and solvent to each group animal respectively, respectively at administration before and administration after 1h, 2h, 4h,
6h, 8h, 12h and 24h carry out afterbody blood glucose value detection, observe tested material hypoglycemic effect and hold time, and draw 24 hours
Blood glucose curve.It is true compared with the blood glucose that compound passes through the db/db mouse with being given only Vehicle controls to the adjustment effect of blood glucose
It is fixed.
3rd, experimental result
The blood glucose rate of descent of preferred compound of the present invention is as shown in table 2.
The blood glucose rate of descent table of the embodiment 1 of table 2
Conclusion：The compound of the embodiment of the present invention 1 showed preferable blood sugar reducing function at 2 hours, 4 hours and 6 hours.
All documents referred in the present invention are all incorporated as reference in this application, and work is individually recited just as each document
For with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can be to this
Invention makes various changes or modifications, and these equivalent form of values equally fall within the application appended claims limited range.
Claims (21)
1. compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt shown in a kind of logical formula (I)：
Wherein：
A1、A2、A3And A4It is each independently selected from CR5Or N, condition is A1、A2、A3And A4In no more than two be N, its
In, A1、A2、A3And A4Each independent is preferably CR5；
B1、B2、B3And B4It is each independently selected from CR6Or N, condition is B1、B2、B3And B4In no more than two be N；Its
In, B1、B2、B3And B4Each independent is preferably CR6；
L1Selected from CH2, O or NH, preferably O；
R1And R2Form 4~8 circle heterocycles bases together with N the or C atoms being connected, preferably 5~7 yuan, wherein described heterocyclic radical
It is interior to contain one or more N, O, S (O)mAtom, and described heterocyclic radical optionally further by it is one or more selected from alkyl,
Halogen, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,=O ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R3Selected from alkyl, cycloalkyl or heterocyclic radical, wherein described alkyl, cycloalkyl or heterocyclic radical optionally further by one or
It is multiple to be selected from alkyl, halogen, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,=O ,-NR7R8、
-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R4Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen by one or more
Element, hydroxyl, cyano group, nitro, alkoxy ,-NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8
Substituent replaced, wherein described alkyl or alkoxy are optionally further replaced by one or more halogens；
R5It is each independently selected from hydrogen atom, alkyl, alkoxy, halogen, hydroxyl, cyano group, nitro ,-NR7R8、-C(O)NR7R8、
-C(O)R9、-C(O)OR9Or-NR7C(O)R8, wherein described alkyl or alkoxy are optionally further selected from halogen by one or more
Element, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R6It is each independently selected from hydrogen atom, alkyl, alkoxy, halogen, hydroxyl, cyano group, nitro ,-NR7R8、-C(O)NR7R8、
-C(O)R9、-C(O)OR9Or-NR7C(O)R8, wherein described alkyl or alkoxy are optionally further selected from halogen by one or more
Element, hydroxyl, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-C(O)NR7R8、-C(O)R9、
-C(O)OR9Or-NR7C(O)R8Substituent replaced；
R7And R8Be each independently selected from hydrogen atom or alkyl, wherein the alkyl optionally further by it is one or more selected from hydroxyl,
Halogen, nitro, cyano group, alkoxy ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12Or-NR10C(O)R11
Substituent replaced；
Or, R7And R84~8 circle heterocycles bases are formed together with the N atoms being connected, wherein containing one in described heterocyclic radical
Individual or multiple N, O, S (O)mAtom, and described heterocyclic radical is optionally selected from alkyl, halogen, hydroxyl, cyanogen by one or more
Base, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12
Or-NR10C(O)R11Substituent replaced；
R9Selected from hydrogen atom or alkyl, wherein the alkyl optionally further by it is one or more selected from hydroxyl, halogen, nitro,
Cyano group, alkoxy ,-NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12Or-NR10C(O)R11Take
Replaced for base；
R10、R11And R12Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein institute
State alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl and be optionally further selected from hydroxyl, halogen, alkyl halide by one or more
Base, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, the substituent of carboxylic acid or carboxylate
Replaced；
M is selected from 0,1 or 2；And
N is selected from 0,1 or 2.
2. compound according to claim 1 or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, it is logical
Compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in formula (II),
Wherein：A1~A4、B1~B4、L1、R1~R4Definition with n is as claimed in claim 1.
3. compound according to claim 1 or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, it is logical
Compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in formula (III),
Wherein：A1~A4、B1~B4、L1、R3And R4Definition with n is as claimed in claim 1.
4. compound according to claim 1 or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, it is logical
Compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt described in formula (IV),
Wherein：A1~A4、B1~B4、L1、R3And R4Definition with n is as claimed in claim 1.
5. compound or its stereoisomer, dynamic isomer according to any one of Claims 1 to 4 or its is pharmaceutically useful
Salt, wherein R3Selected from C3-6Alkyl, preferably n-propyl.
6. compound or its stereoisomer, dynamic isomer according to any one of Claims 1 to 4 or its is pharmaceutically useful
Salt, wherein R4Selected from 5~6 unit's heteroaryls, wherein described heteroaryl optionally further by one or more halogens, alkyl or
The substituent of alkoxy is replaced, wherein described alkyl or alkoxy are optionally further replaced by one or more halogens.
7. compound according to claim 6 or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, wherein
R4Selected from pyrazolyl, wherein described pyrazolyl optionally further replacing by trifluoromethyl or trifluoromethoxy.
8. compound or its stereoisomer, dynamic isomer according to any one of Claims 1 to 4 or its is pharmaceutically useful
Salt, wherein R5Hydrogen atom, alkyl or halogen are each independently selected from, wherein described halogen is preferably F, Cl or Br.
9. compound or its stereoisomer, dynamic isomer according to any one of Claims 1 to 4 or its is pharmaceutically useful
Salt, wherein R6Hydrogen atom, alkyl or halogen are each independently selected from, wherein described halogen is preferably F, Cl or Br.
10. compound or its stereoisomer, dynamic isomer according to any one of Claims 1 to 4 or its is pharmaceutically useful
Salt, wherein：
A1、A2、A3And A4It is each independently selected from CR5；
B1、B2、B3And B4It is each independently selected from CR6；
L1Selected from O；
R1And R24~8 circle heterocycles bases, preferably 5~7 yuan are formed together with N the or C atoms being connected；Wherein described heterocyclic radical
It is interior to contain one or more N, O, S (O)mAtom, and described heterocyclic radical optionally further replaces by one or more halogens；
Preferably F, Cl or Br, more preferably F；
R3Selected from alkyl, wherein described alkyl optionally further by it is one or more selected from halogen, hydroxyl, cyano group, nitro,
Cycloalkyl, heterocyclic radical or-NR7R8Substituent replaced；
R4Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen by one or more
Element, hydroxyl, cyano group, nitro, alkoxy ,-NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9Or-NR7C(O)R8
Substituent replaced, wherein described alkyl or alkoxy are optionally further replaced by one or more halogens；
R5Hydrogen atom, alkyl or halogen are each independently selected from, wherein described alkyl is optionally further by one or more halogens
Replaced；
R6Hydrogen atom, alkyl or halogen are each independently selected from, wherein described alkyl is optionally further by one or more halogens
Replaced；And
R7~R9Definition with n is as described in the appended claim 1.
11. compound or its stereoisomer, dynamic isomer according to any one of claim 1~10 or its is pharmaceutically useful
Salt, wherein described compound is selected from：
12. the preparation method of a kind of logical formula (I) compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, the party
Method includes：
Formula (Ib) compound or its salt carries out condensation reaction with formula (Ic) compound or its salt in the presence of condensation reagent,
Obtain formula (Id) compound；
Formula (Id) compound carries out Mistunobu reactions with formula (Ie) compound,
Obtain formula (IA) compound；
Formula (IA) compound is hydrolyzed in the basic conditions, obtains logical formula (I) compound；
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in the appended claim 1.
13. the preparation method of a kind of logical formula (II) compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, the party
Method includes：
Formula (IIb) compound or its salt carries out condensation reaction with formula (Ic) compound or its salt in the presence of condensation reagent,
Obtain formula (IIc) compound；
Formula (IIc) compound carries out Mistunobu reactions with formula (Ie) compound,
Obtain formula (IIA) compound；
Formula (IIA) compound is hydrolyzed in the basic conditions, obtains logical formula (II) compound；
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in the appended claim 1.
14. the preparation method of a kind of logical formula (III) compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, should
Method includes：
Formula (IIIb) compound carries out Mistunobu reactions with formula (Ie) compound,
Obtain formula (IIIA) compound；
Formula (IIIA) compound is hydrolyzed in the basic conditions, obtains logical formula (III) compound；
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1For O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in the appended claim 1.
15. the preparation method of a kind of logical formula (IV) compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, should
Method includes：
Formula (IVa) compound carries out Mistunobu reactions with formula (Ie) compound,
Obtain formula (IVA) compound；
Formula (IVA) compound is hydrolyzed in the basic conditions, obtains logical formula (IV) compound；
Wherein：
RbFor alkyl, wherein described alkyl is optionally further replaced by one or more halogens；
L1Selected from O；And
A1~A4、B1~B4、R1~R4Definition with n is as described in the appended claim 1.
16. compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt shown in a kind of formula (IA)~(IVA)：
Wherein：
RbFor alkyl, wherein described alkyl is optionally replaced by one or more halogens；
A1~A4、B1~B4、L1、R1~R4Definition with n is as described in the appended claim 1.
17. compound or its stereoisomer, dynamic isomer according to claim 16 formula (IA)~(IVA) or its can
Medicinal salt, wherein the compound is selected from：
18. a kind of pharmaceutical composition, described pharmaceutical composition contain effective dose according to any one in claim 1~11
Described compound or its stereoisomer, dynamic isomer or its pharmaceutically useful salt, and pharmaceutically useful carrier, excipient or it
Combination.
19. compound or its stereoisomer, dynamic isomer according to any one of claim 1~11 or its can
Medicinal salt, or pharmaceutical composition according to claim 18 prepare type i diabetes, type ii diabetes, hyperglycemia,
Purposes in the medicine of obesity or insulin resistance.
20. compound or its stereoisomer, dynamic isomer according to any one of claim 1~11 or its can
Medicinal salt, or pharmaceutical composition according to claim 18 are preparing glucagon receptor antagonist or inverse agonist
In purposes.
21. compound or its stereoisomer, dynamic isomer according to any one of claim 1~11 or its can
Medicinal salt, or pharmaceutical composition according to claim 18 are preparing treatment hyperlipidemia, dyslipidemia, cholesterolemia
Purposes in excessive disease, atherosclerosis, the medicine of metabolic syndrome.
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| CN114957132A (en) * | 2021-02-20 | 2022-08-30 | 中国科学院上海药物研究所 | S-configuration-containing aminobenzamide pyridazinone compound, preparation method thereof, pharmaceutical composition and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103370306A (en) * | 2011-02-08 | 2013-10-23 | 辉瑞大药厂 | Glucagon receptor modulator |
| CN104350040A (en) * | 2012-03-29 | 2015-02-11 | 武田药品工业株式会社 | Aromatic ring compound |
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2016
- 2016-03-29 CN CN201610187531.5A patent/CN107235960B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103370306A (en) * | 2011-02-08 | 2013-10-23 | 辉瑞大药厂 | Glucagon receptor modulator |
| CN104350040A (en) * | 2012-03-29 | 2015-02-11 | 武田药品工业株式会社 | Aromatic ring compound |
Non-Patent Citations (2)
| Title |
|---|
| ANGEL GUZMAN-PEREZ 等: "《The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus》", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957132A (en) * | 2021-02-20 | 2022-08-30 | 中国科学院上海药物研究所 | S-configuration-containing aminobenzamide pyridazinone compound, preparation method thereof, pharmaceutical composition and application |
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Effective date of registration: 20210825 Address after: Jiaojiang District of Taizhou City, Zhejiang province 318000 road outside No. 46 Patentee after: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai Angrui Pharmaceutical Technology Co.,Ltd. Address before: Jiaojiang District of Taizhou City, Zhejiang province 318000 road outside No. 46 Patentee before: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. |