CN117279911A - Heterocyclic compound and application thereof - Google Patents
Heterocyclic compound and application thereof Download PDFInfo
- Publication number
- CN117279911A CN117279911A CN202280032814.6A CN202280032814A CN117279911A CN 117279911 A CN117279911 A CN 117279911A CN 202280032814 A CN202280032814 A CN 202280032814A CN 117279911 A CN117279911 A CN 117279911A
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- CN
- China
- Prior art keywords
- alkyl
- unsubstituted
- oxy
- phenyl
- pyrrolo
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 28
- 239000005495 thyroid hormone Substances 0.000 claims abstract description 38
- 229940036555 thyroid hormone Drugs 0.000 claims abstract description 38
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 17
- -1 2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile Chemical compound 0.000 claims description 97
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 12
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 208000003532 hypothyroidism Diseases 0.000 claims description 9
- 230000002989 hypothyroidism Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 9
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 102000012740 beta Adrenergic Receptors Human genes 0.000 claims description 6
- 108010079452 beta Adrenergic Receptors Proteins 0.000 claims description 6
- 208000030159 metabolic disease Diseases 0.000 claims description 6
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- 229940044601 receptor agonist Drugs 0.000 claims description 6
- 239000000018 receptor agonist Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
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- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- JLLONZUUHHDCJN-UHFFFAOYSA-N CC(C)N1C2=NC=NC(OC(C(Cl)=CC(N(C(NC3=O)=O)N=C3C#N)=C3)=C3Cl)=C2N=C1 Chemical compound CC(C)N1C2=NC=NC(OC(C(Cl)=CC(N(C(NC3=O)=O)N=C3C#N)=C3)=C3Cl)=C2N=C1 JLLONZUUHHDCJN-UHFFFAOYSA-N 0.000 claims description 3
- FASNGRUGXZDCGL-UHFFFAOYSA-N N#CC(C(N1)=O)=NN(C(C=C2Cl)=CC(Cl)=C2OC2=C3N=CN(C4CC4)C3=NC=N2)C1=O Chemical compound N#CC(C(N1)=O)=NN(C(C=C2Cl)=CC(Cl)=C2OC2=C3N=CN(C4CC4)C3=NC=N2)C1=O FASNGRUGXZDCGL-UHFFFAOYSA-N 0.000 claims description 3
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- BYFRUBIZFMDGIV-UHFFFAOYSA-N CN1C2=NC=NC(OC(C(Cl)=CC(N(C(NC3=O)=O)N=C3C#N)=C3)=C3Cl)=C2N=C1 Chemical compound CN1C2=NC=NC(OC(C(Cl)=CC(N(C(NC3=O)=O)N=C3C#N)=C3)=C3Cl)=C2N=C1 BYFRUBIZFMDGIV-UHFFFAOYSA-N 0.000 claims description 2
- OIPQQVBOQLZSML-UHFFFAOYSA-N N#CC(C(N1)=O)=NN(C(C=C2Cl)=CC(Cl)=C2OC2=NC=NC3=C2C=CN3CC(F)F)C1=O Chemical compound N#CC(C(N1)=O)=NN(C(C=C2Cl)=CC(Cl)=C2OC2=NC=NC3=C2C=CN3CC(F)F)C1=O OIPQQVBOQLZSML-UHFFFAOYSA-N 0.000 claims description 2
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- 230000004048 modification Effects 0.000 abstract description 5
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 238000006243 chemical reaction Methods 0.000 description 87
- 238000002360 preparation method Methods 0.000 description 59
- 239000007787 solid Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 27
- 238000001914 filtration Methods 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 238000010438 heat treatment Methods 0.000 description 22
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 230000001270 agonistic effect Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 description 12
- 239000012954 diazonium Substances 0.000 description 12
- HSOGVWWWGVFXGF-UHFFFAOYSA-N ethyl n-(2-cyanoacetyl)carbamate Chemical compound CCOC(=O)NC(=O)CC#N HSOGVWWWGVFXGF-UHFFFAOYSA-N 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 239000010413 mother solution Substances 0.000 description 12
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 150000001989 diazonium salts Chemical class 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 230000001376 precipitating effect Effects 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 239000001632 sodium acetate Substances 0.000 description 11
- 235000017281 sodium acetate Nutrition 0.000 description 11
- 235000010288 sodium nitrite Nutrition 0.000 description 11
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000012452 mother liquor Substances 0.000 description 10
- KGEXISHTCZHGFT-UHFFFAOYSA-N 4-azaniumyl-2,6-dichlorophenolate Chemical compound NC1=CC(Cl)=C(O)C(Cl)=C1 KGEXISHTCZHGFT-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000004224 protection Effects 0.000 description 7
- 108090000721 thyroid hormone receptors Proteins 0.000 description 7
- 102000004217 thyroid hormone receptors Human genes 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- DDSQNRDEAZAVDK-UHFFFAOYSA-N 4-chloro-7-ethylpyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2N(CC)C=CC2=C1Cl DDSQNRDEAZAVDK-UHFFFAOYSA-N 0.000 description 4
- OISMAEWRUUQMSY-UHFFFAOYSA-N 4-chloro-7-propan-2-ylpyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2N(C(C)C)C=CC2=C1Cl OISMAEWRUUQMSY-UHFFFAOYSA-N 0.000 description 4
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- 210000004027 cell Anatomy 0.000 description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
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- 208000024891 symptom Diseases 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 3
- HFYPXERYZGFDBD-UHFFFAOYSA-N 4-amino-2,6-dibromophenol Chemical compound NC1=CC(Br)=C(O)C(Br)=C1 HFYPXERYZGFDBD-UHFFFAOYSA-N 0.000 description 3
- BJGDLOLPALCTJQ-UHFFFAOYSA-N 4-chloro-7-methylpyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2N(C)C=CC2=C1Cl BJGDLOLPALCTJQ-UHFFFAOYSA-N 0.000 description 3
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- LJYONJXHRYYZGR-UHFFFAOYSA-N 3,5-dichloro-4-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)oxyaniline Chemical compound CN1C=CC2=C1N=CN=C2OC3=C(C=C(C=C3Cl)N)Cl LJYONJXHRYYZGR-UHFFFAOYSA-N 0.000 description 2
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- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
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- 238000002425 crystallisation Methods 0.000 description 2
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- 125000002950 monocyclic group Chemical group 0.000 description 2
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- VMFCTZUYOILUMY-UHFFFAOYSA-N 1,1-difluoro-2-iodoethane Chemical compound FC(F)CI VMFCTZUYOILUMY-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
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- KTDZIAFYODCVSW-UHFFFAOYSA-N 2-[3,5-dibromo-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile Chemical compound BrC=1C=C(C=C(C1OC=1C2=C(N=CN1)NC=C2)Br)N2N=C(C(NC2=O)=O)C#N KTDZIAFYODCVSW-UHFFFAOYSA-N 0.000 description 1
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- UEZNSCCMEMUEMO-UHFFFAOYSA-N 6-chloro-9-methylpurine Chemical compound N1=CN=C2N(C)C=NC2=C1Cl UEZNSCCMEMUEMO-UHFFFAOYSA-N 0.000 description 1
- RZIIMNOJHLWYNA-UHFFFAOYSA-N 6-chloro-9-propan-2-ylpurine Chemical compound N1=CN=C2N(C(C)C)C=NC2=C1Cl RZIIMNOJHLWYNA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
A heterocyclic compound having a structure represented by formula (I) is provided. Experimental results show that by selecting specific modification groups, the heterocyclic compound has significantly improved activity and higher TR beta selectivity as compared with the prior art, can be used for treating and/or preventing diseases caused by thyroid hormone regulation, and has lower side effects.
Description
The present application is based on and claims priority from CN application number 202110557323.0, application day 2021, 5, 21, the disclosure of which is incorporated herein by reference in its entirety.
The invention relates to the technical field of pharmaceutical chemistry, in particular to a heterocyclic compound and application thereof.
Thyroid Hormone (TH) has a key role in normal growth and development and in maintaining metabolic balance (Paul M Yen, physiological comment (physiological reviews)), volume 81 (3): 1097-1126 (2001)). TH can promote lipid hydrolysis and increase fatty acid availability, thereby providing energy for the body, and finally reducing lipid and weight. Studies have shown that TH levels in obese patients vary greatly from normal. TH is mainly in two forms: 3,5,3',5' -tetraiodo-L-thyronine (T4) and 3,5,3', -tetraiodo-L-thyronine (T3). While T4 is the predominant form of thyroid secretion, T3 is the more physiologically active form. T4 is converted to T3 by a tissue-specific deiodinase that is present in all tissues but primarily in the liver and kidneys. Related studies have shown that T3 or T3 analogues are effective in the treatment of obesity, especially after simultaneous intervention with low calorie foods. Thus, controlling the level of TH can effectively regulate energy balance. It has been observed clinically that hypothyroidism (hypothyroidism) reduces cholesterol excretion, reduces the number of low density lipoprotein-cholesterol (LDL-C) receptors on the liver surface, and thus reduces LDL-C breakdown, and thus patients often experience elevated levels of total cholesterol and LDL-C, leading to metabolic syndromes such as hyperlipidemia, atherosclerosis, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and the like.
From a pathophysiological point of view, tachycardia, arrhythmia, heart failure, and phenomena such as fatigue, shortness of breath and skeletal muscle loss, osteoporosis, etc. are observed in hyperthyroidism (physiological comment (Physiology Review), volume 81: page 1097 (2001)). In contrast, phenomena beneficial for the treatment of metabolic diseases such as lowering of cholesterol in blood and increase of basal metabolism are also observed. Conversely, heart rate decline, increase in blood cholesterol, and weight gain are observed in hypothyroidism (hypothyroidism) caused by pituitary disorders and congenital disorders, etc. This is also why the presence of cardiotoxicity in naturally occurring thyroid hormones limits their therapeutic use.
From a molecular biological perspective, the biological activity of TH is mediated by the nuclear receptor, thyroid hormone receptor (TRs) (M.A.Lazar, critic endocrine (Endocrine Reviews), vol.14:348-399 (1993)). TRs form heterodimers with retinoid receptors that act as ligand-induced transcription factors. TRs have ligand binding domains, DNA binding domains and amino-terminal domains, and regulate gene expression by interaction with corresponding elements of NDA and with various nuclear co-activators and co-repressors. TRs are encoded by different genes α and β located on human chromosomes 17 and 3, respectively, and produce different protein subtypes by selective cleavage of primary transcripts, each gene producing two subtypes: α1, α2, β1, and β2.Trα1, trβ1, and trβ2 can bind to T3, and trα2 does not bind to TH. Studies have shown that thyroid hormone receptor subtypes may differ in their contribution to a particular physiological response. Trβ1 is present in most tissues, particularly the liver. The distribution of trα1 is also broader and TH is similarly active when bound to trα1 and trβ1, but its distribution range is smaller than trβ1, and studies have shown that most TH effects on the heart, particularly heart rhythm and heart rate, are predominantly achieved through trα1 subtypes.
Since TH maintains metabolic balance mainly by receptor regulation of gene expression on target organs (liver), including maintenance of lipid balance of liver and adipose tissue. Thus, the exertion of beneficial aspects of TH and its analogues, such as cholesterol lowering or basal metabolism increase, in particular, while avoiding the above-mentioned adverse events, and the particular accumulation in the liver, would be of clinical significance, opening new approaches to the treatment of patients with: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other diseases such as hepatic steatosis and nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, etc. Therefore, it would be of great interest to provide thyroid hormone beta receptor agonists for the treatment and/or prevention of diseases modulated by thyroid hormone.
Applicant's prior chinese patent application CN112300133a has disclosed a heterocyclic compound structure having agonistic activity on thyroid hormone receptor β. On this basis, the applicant further optimizes and modifies the series of TR beta agonists in order to obtain pharmaceutically acceptable compounds with higher selectivity for TR beta and higher agonistic activity.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a heterocyclic compound which has more excellent TR beta agonistic activity and TR beta selectivity compared with the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
a heterocyclic compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein:
x is selected from N or CH;
R 1 and R is 2 Independently selected from F, cl, br, I or substituted or unsubstituted C 1 ～C 6 Alkyl group；
Preferably, R 1 And R is 2 Independently selected from Cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 1 And R is 2 Independently selected from Cl or Br;
preferably, R 1 And R is 2 Are the same groups;
R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group; wherein R is 1 And R is 2 When Cl and X are CH, R 3 Is not methyl;
preferably, R 3 Selected from C 1 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl; preferably, C 1 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
preferably, R 3 Substituents selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, are independently selected from one or more of the following groups: F. cl or Br.
In some embodiments, R 1 And R is 2 All are Cl.
In some embodiments, R 1 And R is 2 Are all Br.
In some embodiments, X is CH;
R 1 and R is 2 Are all Br;
R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 3 Selected from C 1 -C 6 Alkyl, said C 1 -C 6 Alkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 3 Selected from C 1 ～C 4 An alkyl group;
preferably, R 3 Selected from methyl, ethyl, propyl and isopropyl.
In some embodiments, X is CH;
R 1 and R is 2 All are Cl;
R 3 selected from C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 3 Selected from C 2 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl group, the C 2 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
preferably, R 3 Selected from ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, said Methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or independently substituted by one or more of the following substituents: F. cl or Br;
preferably, R 3 Selected from ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl and cyclobutyl;
preferably, R 3 Selected from ethyl, isopropyl and cyclobutyl.
In some embodiments, X is N;
R 1 and R is 2 Independently selected from F, cl, br, I or substituted or unsubstituted C 1 ～C 6 An alkyl group;
R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group.
In some embodiments, X is N;
R 1 and R is 2 All are Cl;
R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 3 Selected from C 1 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl group, the C 1 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
preferably, R 3 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, which is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
Preferably, R 3 Selected from methyl, isopropyl and cyclopropyl.
In some embodiments, X is selected from N or CH;
R 1 and R is 2 All are Cl;
R 3 selected from C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;
preferably, R 3 Selected from C 2 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl group, the C 2 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
preferably, R 3 Selected from ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;
preferably, R 3 Selected from ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl, cyclopropyl or cyclobutyl.
In some embodiments, the heterocyclic compound is a specific compound selected from the group consisting of:
the preparation method comprises the following steps:
the invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and methods of the present invention. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to literature (as provided by scibinder) or purchased.
The compounds of the general formula (I) according to the invention can be synthesized according to the route described by the following method: 1) Alkalizing the initial material A in low temperature organic solvent, and mixing with R 3 The haloalkane (compound 1) undergoes condensation reaction under normal temperature to obtain an intermediate A1; 2) Intermediate A1 and R-containing 1 、R 2 The substituted para-aminophenol (compound 2) undergoes substitution reaction to obtain an intermediate A2; 3) Intermediate A2 is diazonium salified and then is subjected to substitution reaction with N-cyano-acetyl urethane (compound 3) to generate intermediate A3; 4) The intermediate A3 is subjected to intramolecular degreasing condensation to obtain a target compound shown as the formula I.
Wherein R is 1 、R 2 、R 3 Is defined as before.
Pharmaceutical composition:
it is also an object of the present invention to provide a pharmaceutical composition. The pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of heterocyclic compound shown as the formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and optionally pharmaceutically acceptable medicinal carriers and/or excipients and/or diluents.
Methods of preparing various pharmaceutical compositions containing certain amounts of the active ingredient are known or will be apparent to those of skill in the art in light of the present disclosure. Methods of preparing the pharmaceutical compositions include incorporation of suitable pharmaceutical excipients, carriers, diluents, and the like, as described in REMINGTON' S PHARMACEUTICAL SCIENCES, martin, e.w., ed., mack Publishing Company,19th ed. (1995).
The medical application comprises the following steps:
in another aspect, the invention also provides the use of said compound or a pharmaceutically acceptable salt/stereoisomer thereof, or said pharmaceutical composition for the preparation of an agonist for agonizing thyroid hormone.
In another aspect, the invention also provides the application of the compound or pharmaceutically acceptable salt/stereoisomer thereof or the pharmaceutical composition in preparing medicaments for treating and/or preventing thyroid hormone related diseases.
In another aspect, the invention also provides the use of said compounds or pharmaceutically acceptable salts/stereoisomers thereof, or said pharmaceutical compositions, in the treatment and/or prophylaxis of thyroid hormone related disorders.
It is a further object of the present invention to provide a method for treating and/or preventing thyroid hormone related disorders comprising administering to an individual in need thereof a therapeutically and/or prophylactically effective amount of: the compound or pharmaceutically acceptable salt/stereoisomer thereof, or the pharmaceutical composition.
In another aspect, the invention also provides the use of the compound or a pharmaceutically acceptable salt/stereoisomer thereof, or the pharmaceutical composition, in the preparation of a thyroid hormone receptor agonist, particularly a thyroid hormone beta receptor agonist (e.g., a thyroid hormone beta 1 receptor agonist).
In another aspect, the invention also provides the use of the compound or a pharmaceutically acceptable salt/stereoisomer thereof, or the pharmaceutical composition in the preparation of a medicament for treating and/or preventing thyroid hormone-related diseases.
In another aspect, the invention also provides said compounds or pharmaceutically acceptable salts/stereoisomers thereof, or said pharmaceutical compositions, for use in the treatment and/or prophylaxis of thyroid hormone related diseases.
In another aspect, the present invention also provides a method for treating and/or preventing thyroid hormone related disorders comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the compound or a pharmaceutically acceptable salt/stereoisomer thereof, or the pharmaceutical composition.
In some embodiments, the thyroid hormone-related disease is a metabolic disease, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.
In the present invention, "treatment" generally means obtaining a desired pharmacological and/or physiological effect, covering any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
In the present invention, "individual" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.
In the present invention, an "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosages and times. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the substance/molecule to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the substance/molecule that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow, preferably stop to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow, preferably stop to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with cancer.
Terminology and definition:
it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.
As used herein, examples of the term "pharmaceutically acceptable salts of compounds of formula (I)" are organic acid addition salts formed from organic acids forming pharmaceutically acceptable anions, including, but not limited to, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α -ketoglutarate, α -glycerophosphate, alkylsulfonate, or arylsulfonate; preferably, the alkyl sulfonate is methyl sulfonate or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate. Suitable inorganic salts may also be formed, including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, and carbonate, sulfate or phosphate, and the like. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of the basic compound with a suitable acid to provide a pharmaceutically acceptable anion.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 Alkyl, or independently disclosed "C 2-6 Alkyl ", or independently disclosed" C 1-4 Alkyl ", or independently disclosed" C 1-3 An alkyl group.
The term "alkyl" means a straight or branched chain saturated hydrocarbon group. For example C 1 To C 6 Alkyl groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert-butyl) and the like are specific.
The term "alkenyl" refers to a hydrocarbon chain comprising a straight or branched configuration and having one or more carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C 2-6 Alkenyl "includes C 2 、C 3 、C 4 、C 5 And C 6 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
The term "alkynyl" refers to a hydrocarbon group comprising a straight or branched configuration and having one or more carbon-carbon triple bonds that may be present at any stable point along the chain. For example "C 2-6 Alkynyl "includes C 2 、C 3 、C 4 、C 5 And C 6 Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
Alkyl and cycloalkyl groups may be substituted or unsubstituted. In the case of substitution, there are generally, for example, from 1 to 4 substituents, preferably from 2 to 3 substituents. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, aralkyl (e.g., substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g., trifluoromethyl); oxygen-containing groups such as alcohols (hydroxy, hydroxyalkyl, aryl (hydroxy) alkyl), ethers (e.g., alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g., formaldehyde), ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl), acids (e.g., carboxylic acid, carboxyalkyl), acid derivatives such as esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl), amides (e.g., aminocarbonyl, mono-or di-alkylaminocarbonyl, aminocarbonylalkyl, mono-or di-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g., alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (amino, mono-or di-alkylamino, aminoalkyl, mono-or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, sulfides, sulfoxides, and sulfones (e.g., alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthio alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl).
The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group are replaced with a selection from the designated group, provided that the designated atom's normal valence is not exceeded.
The term "cycloalkyl" refers to a cyclized alkyl group and includes monocyclic, bicyclic, or polycyclic ring systems. C (C) 3-7 Cycloalkyl is meant to include C 3 、C 4 、C 5 、C 6 And C 7 Cycloalkyl radicals, e.g. C 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "aryl" refers to aromatic hydrocarbon groups having a single ring or a fused ring, such as single or bicyclic aromatic hydrocarbon groups having 6 to 12 ring-forming carbon atoms, such as phenyl and naphthyl.
The terms "heterocycle", "heterocycloalkyl", "heterocyclic" or "heterocyclyl" are used interchangeably and include 3-to 7-membered monocyclic, 7-to 11-membered bicyclic and 10-to 15-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the radical may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bi-and tri-cyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclic group may be attached at any available nitrogen or carbon atom.
Compared with the prior art, the invention provides a heterocyclic compound with a structure shown in a formula (I): by selecting specific modification groups, experimental results show that the heterocyclic compound provided by the invention has better activity and/or selectivity as a thyroid hormone beta receptor agonist compared with the prior art, and can be used for treating and/or preventing diseases caused by thyroid hormone regulation.
The invention provides a heterocyclic compound and application thereof, and a person skilled in the art can appropriately improve the structure and the realization of groups by referring to the content of the text. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and they are intended to be within the scope of the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration and combination of the methods and applications herein without departing from the spirit and scope of the invention.
In order to further illustrate the present invention, a heterocyclic compound and its application provided in the present invention are described in detail below with reference to examples.
Example 1
Preparation of 2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (307 mg,2 mmol) is dissolved in tetrahydrofuran (5 ml), nitrogen is used for protection, the temperature is reduced to 0-5 ℃, sodium hydride (144 mg,6 mmol) is added in batches, the reaction is carried out for 30 minutes after the addition is completed, methyl iodide (570 mg,4 mmol) is added, the temperature is raised to room temperature, and the stirring reaction is continued for 2 hours. After the reaction, water (20 ml) was slowly added dropwise thereto, followed by extraction with ethyl acetate, washing of the organic phase with saturated brine, drying of the organic phase, filtration, distillation under reduced pressure to give a residue, finally addition of petroleum ether, stirring for crystallization, filtration, and drying of the residue to give the objective 4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (310 mg,92.5% yield), LC-MS (M/z) 168.6 (M+1).
Step 2: preparation of 3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dibromo-4-aminophenol (320 mg,1.2 mmol) and 4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (168 mg,1 mmol) were dissolved in N, N-dimethylformamide (10 ml), followed by the addition of cesium carbonate (815 mg,2.5 mmol). After the addition, the reaction system is protected by nitrogen replacement, heated, stirred and heated to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirred and filtered, saturated brine is added into the filtrate, the mixture is extracted, an organic phase is dried, filtered and distilled under reduced pressure to obtain a residue, and finally, the residue is separated by column chromatography (ethyl acetate/petroleum ether=1/3). To give the target 3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (63 mg,15.8% yield), LC-MS (M/z) 399.2 (M+1).
Step 3: preparation of (2-cyano-2- (2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dibromo-4- ((7-methyl-7H-pyrrole [2,3-d ] pyrimidine-4-yl) oxy) aniline (63 mg,0.16 mmol) is dissolved in a solution of hydrochloric acid (2 ml) and water (2 ml), cooled to 0-5 ℃, then aqueous solution of sodium nitrite (14 mg,0.19 mmol) is added dropwise, and the reaction is carried out for 30 minutes while keeping the temperature, thus obtaining reaction mother liquor. N-cyanoacetyl urethane (27 mg,0.17 mmol) was dissolved in a solution of pyridine (2 ml) and water (2 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became pale brown to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (74 mg,82.8% yield), LC-MS (M/z) 566.2 (M+1).
Step 4: preparation of 2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (74 mg,0.13 mmol) of (2-cyano-2- (2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (74 mg,0.13 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (54 mg,0.65 mmol) was added thereto, and the reaction was stirred at 100℃for 5 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (51 mg,74.7% yieldd), LC-MS (M/z) 520.1 (m+1). 1H NMR (400 MHz, DMSO-d 6) δ8.36 (s, 1H), 7.95 (s, 3H), 7.62 (d, J=3.5 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 3.86 (s, 4H).
Example 22 preparation of- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 4-chloro-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidine
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (292 mg,6 mmol) was dissolved in N, N-dimethylformamide (10 ml), potassium hydroxide (67 mg,12 mmol) was added at room temperature under nitrogen protection, cooled in an ice water bath, vigorously stirred, and bromoethane (785 mg,7.2 mmol) was added thereto, and the reaction was continued while stirring at room temperature for 1 hour. After the completion of the reaction, water (20 ml) was added dropwise, followed by extraction with ethyl acetate, the organic phase was washed with saturated brine, dried, filtered, distilled under reduced pressure to give a residue, and finally separated by column chromatography (ethyl acetate/petroleum ether=1/5). The target 4-chloro-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidine (955 mg,87.7% yield), LC-MS (M/z) 182.6 (M+1) was obtained.
Step 2: preparation of 3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (214 mg,1.2 mmol) and 4-chloro-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidine (182 mg,1 mmol) were dissolved in N, N-dimethylformamide (10 ml), and cesium carbonate (815 mg,2.5 mmol) was added. After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/3). To give the target 3, 5-dichloro-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (225 mg,69.5% yield), LC-MS (M/z) 324.2 (M+1).
Step 3: preparation of (2-cyano-2- (2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (225 mg,0.7 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, then an aqueous solution of sodium nitrite (58 mg,0.85 mmol) is added dropwise, and the reaction is carried out for 30 minutes while keeping the temperature, thus obtaining a reaction mother liquor. N-cyanoacetyl urethane (116 mg,0.74 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (248 mg,72.7% yield), LC-MS (M/z) 491.3 (m+1).
Step 4: preparation of 2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (248 mg,0.5 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (205 mg,2.5 mmol) was added thereto, and the reaction was stirred at 100℃for 5 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (152 mg,68.5% yieldd), LC-MS (M/z) 445.2 (m+1). 1H NMR (400 MHz, DMSO-d 6) δ8.35 (s, 1H), 7.81 (s, 2H), 7.69 (d, J=3.5 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Example 32 preparation of- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 4-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (922 mg,6 mmol) was dissolved in N, N-dimethylformamide (10 ml), potassium hydroxide (672 mg,12 mmol) was added at room temperature under nitrogen protection, stirring vigorously, and further iodoisopropyl (1.23 g,7.2 mmol) was added, and stirring reaction was continued at room temperature for 8 hours. After the completion of the reaction, water (20 ml) was added dropwise, followed by extraction with ethyl acetate, the organic phase was washed with saturated brine, dried, filtered, distilled under reduced pressure to give a residue, and finally separated by column chromatography (ethyl acetate/petroleum ether=1/6). The target preparation of 4-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (255 mg,77.1% yield) was obtained, LC-MS (M/z) 196.6 (M+1).
Step 2: preparation of 3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (214 mg,1.2 mmol) and 4-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (196 mg,1 mmol) were dissolved in N, N-dimethylformamide (10 ml), and cesium carbonate (815 mg,2.5 mmol) was added. After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/3). To give the target 3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (223 mg,66.0% yield), LC-MS (M/z) 338.2 (M+1).
Step 3: preparation of (2-cyano-2- (2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (222 mg,0.65 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, then an aqueous solution of sodium nitrite (54 mg,0.78 mmol) is added dropwise, and the reaction is carried out for 30 minutes while keeping the temperature, thus obtaining a reaction mother liquor. N-cyanoacetyl urethane (106 mg,0.68 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target (2-cyano-2- (2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester (239 mg,71.8% yield), LC-MS (M/z) 505.3 (m+1).
Step 4: preparation of 2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (239 mg,0.47 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (189 mg,2.3 mmol) was added thereto, and the reaction was stirred at 100℃for 5 hours, and the heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (101 mg,46.6% yieldd). LC-MS (M/z) 459.3 (M+1). 1H NMR (400 MHz, DMSO-d 6) delta 8.35 (s, 1H), 7.87-7.71 (m, 3H), 6.76 (d, J=3.6 Hz, 1H), 5.05 (p, J=6.8 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H).
Example 42 preparation of- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dibromo-4-aminophenol (616 mg,2.4 mmol) and 4-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (390 mg,2 mmol) were dissolved in N, N-dimethylformamide (15 ml), followed by the addition of cesium carbonate (1.6 g,5 mmol). After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/2). To give the target 3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (123 mg,14.5% yield), LC-MS (M/z) 427.1 (M+1).
Step 2: preparation of (2-cyano-2- (2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dibromo-4- ((7-isopropyl-7H-pyrrole [2,3-d ] pyrimidine-4-yl) oxy) aniline (123 mg,0.29 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, then added with an aqueous solution of sodium nitrite (24 mg,0.35 mmol) dropwise, and reacted for 30 minutes under heat preservation to prepare reaction mother liquor. N-cyanoacetyl urethane (48 mg,0.31 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, and after the dropwise addition was completed, the solution became brown to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target (2-cyano-2- (2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester (126 mg,86.5% yield), LC-MS (M/z) 505.3 (M+1).
Step 3: preparation of 2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (126 mg,0.25 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (103 mg,1.25 mmol) was added thereto, and the reaction was stirred at 100℃for 4 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (53 mg,46.3% yieldd). LC-MS (M/z) 459.3 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ8.34 (s, 1H), 7.94 (d, J=0.8 Hz, 2H), 7.79 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 5.04 (q, J=6.7 Hz, 1H), 1.51 (d, J=6.7 Hz, 8H).
Example 5 2 preparation of- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 4-chloro-7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidine
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (922 mg,6 mmol) was dissolved in N, N-dimethylformamide (10 ml), potassium hydroxide (672 mg,12 mmol) was added at room temperature under nitrogen protection, stirring vigorously, and cyclobutyl bromide (972 mg,7.2 mmol) was added and the reaction was continued at room temperature with stirring for 48 hours. The reaction was incomplete, water (20 ml) was added dropwise, ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried, filtered, distilled under reduced pressure to give a residue, and finally separated by column chromatography (ethyl acetate/petroleum ether=1/6). The target 4-chloro-7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidine (211 mg,16.9% yield), LC-MS (M/z) 208.7 (M+1).
Step 2: preparation of 3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (215 mg,1.2 mmol) and 4-chloro-7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidine (211 mg,1 mmol) were dissolved in N, N-dimethylformamide (10 ml), and cesium carbonate (815 mg,2.5 mmol) was added. After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/3). To give the target 3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (219 mg,61.7% yield), LC-MS (M/z) 350.2 (M+1).
Step 3: preparation of (2-cyano-2- (2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidine-4-yl) oxy) aniline (219 mg,0.63 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, then added dropwise with an aqueous solution of sodium nitrite (53 mg,0.76 mmol) for reaction for 30 minutes under heat preservation, and reaction mother liquor is prepared. N-cyanoacetyl urethane (103 mg,0.66 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml), cooled down to 0-5 ℃, then the diazonium salt reaction mother solution prepared above was added dropwise into the system, and after the dropwise addition was completed, the solution became orange-red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target (2-cyano-2- (2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester (237 mg,73.2% yield), LC-MS (M/z) 517.3 (M+1).
Step 4: preparation of 2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (237 mg,0.46 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (188 mg,2.3 mmol) was added thereto, and the reaction was stirred at 100℃for 4 hours, and the heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (99 mg,45.8% yield), LC-MS (M/z) 471.3 (m+1). 1H NMR (400 MHz, DMSO-d 6) delta 8.35 (s, 1H), 7.93 (d, J=3.7 Hz, 1H), 7.82 (s, 2H), 6.80 (d, J=3.6 Hz, 1H), 5.26 (q, J=8.7 Hz, 1H), 2.61 (p, J=10.3, 9.9Hz, 2H), 2.49-2.38 (m, 4H), 1.88 (dt, J=13.3, 6.5Hz, 2H).
Example 6 2 preparation of- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dibromo-4-aminophenol (616 mg,2.4 mmol) and 4-chloro-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidine (284 mg,2 mmol) were dissolved in N, N-dimethylformamide (15 ml), followed by the addition of cesium carbonate (1.6 g,5 mmol). After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/2). To give the target 3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (114 mg,13.4% yield), LC-MS (M/z) 413.1 (M+1).
Step 2: preparation of (2-cyano-2- (2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dibromo-4- ((7-ethyl-7H-pyrrole [2,3-d ] pyrimidine-4-yl) oxy) aniline (114 mg,0.27 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, then added with an aqueous solution of sodium nitrite (23 mg,0.33 mmol) dropwise, and reacted for 30 minutes under heat preservation to prepare reaction mother liquor. N-cyanoacetyl urethane (44 mg,0.28 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, and after the dropwise addition was completed, the solution became brown to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (135 mg, 84.4% yield), LC-MS (M/z) 580.3 (M+1).
Step 3: preparation of 2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (135 mg,0.23 mmol) was dissolved in 5ml of acetic acid at room temperature, sodium acetate (95 mg,1.15 mmol) was added thereto, and the reaction was stirred at 100℃for 4 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding EA for dissolving, drying and concentrating to obtain a red solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded the target compound 2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile (47 mg,37.8% yieldd), LC-MS (M/z) 534.1 (m+1). 1H NMR (400 MHz, DMSO-d 6) δ8.35 (s, 1H), 7.94 (d, J=0.7 Hz, 2H), 7.70 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Example 7 2 preparation of- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of 4-chloro-7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidine
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (616 mg,4 mmol) was dissolved in N, N-dimethylformamide (10 ml), potassium hydroxide (447 mg,8 mmol) was added at room temperature under nitrogen protection, stirring vigorously, and 1, 1-difluoro-2-iodoethane (922 mg,4.8 mmol) was added and the reaction stirred at room temperature for 16 hours. After the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure to give a residue, and finally separated by column chromatography (ethyl acetate/petroleum ether=1/4). The target 4-chloro-7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidine (279 mg,32.1% yield) LC-MS (M/z) 218.6 (M+1).
Step 2: preparation of 3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (215 mg,1.2 mmol) and 4-chloro-7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidine (218 mg,1 mmol) were dissolved in N, N-dimethylformamide (10 ml), and cesium carbonate (815 mg,2.5 mmol) was added. After the addition, the reaction system was protected by nitrogen replacement, heated and stirred to 120 ℃ for 1 hour, the heating was stopped, ethyl acetate was added to the reaction system, stirred and filtered, saturated brine was added to the filtrate, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and distillation under reduced pressure was performed to obtain a residue, which was subjected to column chromatography separation (ethyl acetate/petroleum ether=1/2). To give the target 3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (319 mg,72.1% yield), LC-MS (M/z) 360.2 (M+1).
Step 3: preparation of ((2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrole [2,3-d ] pyrimidine-4-yl) oxy) aniline (319 mg,0.72 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, added dropwise with an aqueous solution of sodium nitrite (60 mg,0.87 mmol) and reacted at 0-5 ℃ for 30 minutes to prepare a reaction mother liquor. N-cyanoacetyl urethane (118 mg,0.76 mmol) was dissolved in a solution of pyridine (3 ml) and water (6 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became orange-red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give ethyl (279 mg,73.6% yield) target (2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (279 mg, LC-MS (M/z) 527.2 (M+1).
Step 4: preparation of 2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
(2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrole) 2, 3-d) at room temperature]Pyrimidine-4-yl-oxy) phenyl hydrazono) acetyl ethyl carbamate (263 mg,0.5 mmol) was dissolved in 10ml acetic acid, sodium acetate (205 mg,2.5 mmol) was added thereto, and the reaction was stirred at 100℃for 3 hours, and the heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding ethyl acetate for dissolution, drying and concentrating to obtain an orange solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded 2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrole [2, 3-d) as a pale yellow solid]Pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4]Triazine-6-carbonitrile (67 mg,28.0% yield), LC-MS (M/z) 481.2 (M+1). 1 H NMR(400MHz,DMSO-d 6 )δ8.41(s,1H),7.83(s,2H),7.68(d,J＝3.7Hz,1H),6.87(d,J＝3.6Hz,1H),6.49(t,J＝54.6Hz,1H),4.92–4.71(m,2H).
Example 8 2 preparation of- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of (4-chloro- (7- (2, 2-trifluoroethyl) -7H-pyrrole [2,3-d ] pyrimidine)
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (616 mg,4 mmol) was dissolved in N, N-dimethylformamide (10 ml), cesium carbonate (3.25 g,10 mmol) was added at room temperature, 2-trifluoroethyl trifluoromethane sulfonate (1.11 g,4.8 mmol) was further added thereto, nitrogen substitution protection was performed, and the temperature was raised to 60℃and the reaction was stirred for 10 hours. After the reaction, the reaction was cooled, filtered, the filter cake was further stirred with ethyl acetate, the organic phase was extracted by washing with saturated brine, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure to give a residue, and finally separated by column chromatography (ethyl acetate/petroleum ether=1/4). The target 4-chloro- (7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidine (413 mg,43.9% yield), LC-MS (M/z) 236.6 (M+1) was obtained.
Step 2: preparation of (4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (356 mg,2.0 mmol) and 4-chloro- (7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidine (400 mg,1.7 mmol) were dissolved in N, N-dimethylformamide (10 ml), cesium carbonate (1.37 g,4.2 mmol) was added after the addition was completed, the reaction system was nitrogen-substituted for protection, heated and stirred to 120 ℃ for 1 hour, heating was stopped, ethyl acetate was added to the reaction system and stirred for filtration, saturated brine was added to the filtrate, the extract was dried over anhydrous sodium sulfate, and filtered, distilled under reduced pressure to give a residue, which was subjected to column chromatography separation (ethyl acetate/petroleum ether=1/2) to give the objective 4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) aniline (238 mg,37.1% yie), LC-MS (m+1) 378.2 (m+1).
Step 3: preparation of ((2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
4- ((7- (2, 2-trifluoroethyl) -7H-pyrrole [2,3-d ] pyrimidine-4-yl) oxy) aniline (238 mg,0.63 mmol) is dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml), cooled to 0-5 ℃, and then an aqueous solution of sodium nitrite (52 mg,0.76 mmol) is added dropwise for reaction at 0-5 ℃ for 30 minutes to prepare a reaction mother liquor. N-cyanoacetyl urethane (103 mg,0.66 mmol) was dissolved in a solution of pyridine (3 ml) and water (6 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became orange-red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) hydrazono) acetyl) carbamate (277 mg,80.8% yield), LC-MS (M/z) 545.3 (M+1).
Step 4: preparation of 2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
(2-cyano-2- (2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrole) 2, 3-d) at room temperature]Pyrimidine-4-yl-oxy) phenyl hydrazono) acetyl ethyl carbamate (277 mg,0.5 mmol) was dissolved in 10ml acetic acid, sodium acetate (205 mg,2.5 mmol) was added thereto, and the reaction was stirred at 100℃for 3 hours, and the heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding ethyl acetate for dissolution, drying and concentrating to obtain an orange solid crude product. Column chromatography (methanol/dichloromethane=1/20) afforded 2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrole [2, 3-d) as a pale yellow solid]Pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4]Triazine-6-carbonitrile (85 mg,34.1% yield), LC-MS (M/z) 499.2 (M+1). 1 H NMR(400MHz,DMSO-d 6 )δ8.45(s,1H),7.84(s,2H),7.73(d,J＝3.7Hz,1H),6.93(d,J＝3.7Hz,1H),5.27(q,J＝9.2Hz,2H).
Example 9 2 preparation of- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (427 mg,2.4 mmol) and 6-chloro-9-methylpurine (337 mg,2 mmol) were dissolved in N, N-dimethylformamide (15 ml), and cesium carbonate (1.63 g,5 mmol) was added. After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/1). The target 3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) aniline (3838 mg,62.6% yield) was obtained, LC-MS (M/z) 311.1 (M+1).
Step 2: preparation of ((2-cyano-2- (2- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) aniline (3838 mg,1.25 mmol) is dissolved in a solution of hydrochloric acid (4 ml) and water (5 ml), cooled down to 0-5 ℃, then added dropwise with an aqueous solution of sodium nitrite (104 mg,1.5 mmol) for reaction for 30 minutes, and reaction mother liquor is prepared. N-cyanoacetyl urethane (205 mg,1.3 mmol) was dissolved in a solution of pyridine (4 ml) and water (8 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target (2-cyano-2- (2- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester (414 mg,69.4% yield), LC-MS (M/z) 478.3 (M+1).
Step 3: preparation of 2- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate (414 mg,0.87 mmol) was dissolved in 5ml acetic acid at room temperature, sodium acetate (360 mg,4.4 mmol) was added thereto, and the reaction was stirred at 100℃for 3 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding tetrahydrofuran for dissolving, drying and concentrating to obtain red solid crude product. Column chromatography (methanol/dichloromethane=1/15) gave 2- (3, 5-dichloro-4- ((9-methyl) as an orange solid phenyl-9H-purin-6-yl) oxy) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4]Triazine-6-carbonitrile (185 mg,49.3% yield), LC-MS (M/z) 432.2 (M+1). 1 H NMR(400MHz,DMSO-d 6 )δ8.54(d,J＝21.8Hz,1H),7.84(s,1H),3.88(s,2H).
Example 10 preparation of 2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (427 mg,2.4 mmol) and 6-chloro-9-isopropylpurine (393 mg,2 mmol) were dissolved in N, N-dimethylformamide (15 ml), and cesium carbonate (1.63 g,5 mmol) was added. After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/1). The target 3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) aniline (431 mg,63.8% yield) was obtained as LC-MS (M/z) 339.2 (M+1).
Step 2: preparation of ((2-cyano-2- (2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) aniline (431 mg,1.27 mmol) is dissolved in a solution of hydrochloric acid (4 ml) and water (5 ml), cooled to 0-5 ℃, added dropwise with an aqueous solution of sodium nitrite (104 mg,1.5 mmol) and reacted for 30 minutes under heat preservation to prepare a reaction mother solution. N-cyanoacetyl urethane (205 mg,1.3 mmol) was dissolved in a solution of pyridine (4 ml) and water (8 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate (470 mg,73.6% yield), LC-MS (M/z) 506.3 (M+1).
Step 3: preparation of 2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate (470 mg,0.93 mmol) was dissolved in 10ml of acetic acid at room temperature, sodium acetate (385 mg,4.7 mmol) was added thereto, and the reaction was stirred at 100℃for 5 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding tetrahydrofuran for dissolving, drying and concentrating to obtain red solid crude product. Column chromatography (methanol/dichloromethane=1/15) afforded 2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4, as an orange solid ]Triazine-6-carbonitrile (204 mg,47.8% yield), LC-MS (M/z) 460.3 (M+1). 1 H NMR(400MHz,DMSO-d 6 ) δ8.73(s,1H),8.50(s,1H),7.84(d,J＝0.8Hz,2H),5.03–4.80(m,1H),1.60(d,J＝6.8Hz,7H).
Example 11 preparation of 2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: preparation of (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) aniline
2, 6-dichloro-4-aminophenol (321 mg,1.8 mmol) and 6-chloro-9-cyclopropylpurine (292 mg,1.5 mmol) were dissolved in N, N-dimethylformamide (10 ml), followed by addition of cesium carbonate (1.24 g,3.8 mmol). After the addition, the reaction system is protected by nitrogen replacement, the mixture is heated, stirred and warmed to 120 ℃ for 1 hour, the heating is stopped, ethyl acetate is added into the reaction system, stirring and filtering are carried out, saturated brine is added into the filtrate, extraction is carried out, an organic phase is dried and filtered, the residue is obtained by reduced pressure distillation, and finally, column chromatography separation is carried out (ethyl acetate/petroleum ether=1/2). The target 3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) aniline (349mg, 67.8% yield), LC-MS (M/z) 337.2 (M+1) was obtained.
Step 2: preparation of ((2-cyano-2- (2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamic acid ethyl ester
3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) aniline (340 mg,1 mmol) is dissolved in a solution of hydrochloric acid (4 ml) and water (5 ml), cooled to 0-5 ℃, then added dropwise with an aqueous solution of sodium nitrite (83 mg,1.2 mmol) for reaction for 30 minutes, and reaction mother liquor is prepared. N-cyanoacetyl urethane (164 mg,1.05 mmol) was dissolved in a solution of pyridine (4 ml) and water (8 ml), cooled down to 0-5 ℃, and then the diazonium salt reaction mother solution prepared above was added dropwise into the system, after the dropwise addition was completed, the solution became red to precipitate a solid, and the reaction was continued for 1 hour at a constant temperature. A small amount of water was added to the reaction mixture, stirred, suction-filtered, and the residue was washed with water. The solid was dried to give the target ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate (387 mg,76.9% yield), LC-MS (M/z) 504.3 (m+1).
Step 3: preparation of 2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate (387 mg,0.77 mmol) was dissolved in 10ml acetic acid at room temperature, sodium acetate (316 mg,3.85 mmol) was added thereto, and the reaction was stirred at 100℃for 3 hours while heating was stopped. Cooling to room temperature, adding ice water, precipitating solid, filtering, adding tetrahydrofuran for dissolving, drying and concentrating to obtain red solid crude product. Column chromatography (methanol/dichloromethane=1/15) afforded 2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4, as an orange solid]Triazine-6-carbonitrile (138 mg,39.2% yield), LC-MS (m/z) 458.3(M+1)。 1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),8.51(s,1H),7.83(s,2H),5.76(s,1H),1.16(dd,J＝30.9,5.4Hz,4H).
Comparative example:
comparative example 1:2- (3, 5-dichloro-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) -phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile.
See example 1 of CN112300133a for structure and method of preparation.
Comparative example 2:
2- (3, 5-dichloro-4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) -phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
See example 4 of CN112300133a for structure and method of preparation.
Comparative example 3:
2- (3, 5-dibromo-4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) -phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
See example 6 of CN112300133a for structure and method of preparation.
Example 12 transcriptional activation experiments on human thyroid hormone receptors α1 (TR α1) and β1 (TR β1)
The pcDNA3.1 vector (manufactured by Invitrogen) of TRα1 or TRβ1 cloned from cells of human liver and the firefly luciferase vector pTA-TRE-Luc (manufactured by Promega) having a thyroid hormone response sequence were transfected into CV-1 cells cultured in Dulbecco's modified Eagle medium, DMEM using X-tremeGENE HP DNA Transfection Reagent (manufactured by Roche). 16 hours after transfection, compounds diluted with dimethylsulfoxide solution were added and luciferase activity after 24 hours was measured.
3,3', 5-triiodo-L-thyroxine (T) 3 ) As a positive control, the transcriptional activation of the compounds on TR. Alpha.1 and TR. Beta.1 is achieved by comparison with T 3 Each EC having a maximum luciferase activity value of 100% 50 Values and maximum luciferase activity values show that the compounds of the invention EC 50 And selectivities, approximately 50% of the active dose, as well as the maximum agonistic activity and its concentration are shown in tables 1-3 below. Wherein the selectivity (alpha/beta) is TR alpha EC 50 /TRβ1EC 50 。
TABLE 1 Compounds of the invention EC 50 And selectivity(s)
| Examples | TRβ1EC 50 (μM) | Selectivity (alpha/beta) | Examples | TRβ1EC 50 (μM) | Selectivity (alpha/beta) |
| Example 1 | 0.8862 | ＞11.28 | Example 2 | 0.4615 | ＞21.67 |
| Example 3 | 0.2442 | ＞40.95 | Example 4 | 0.1373 | ＞72.83 |
| Example 5 | 0.08098 | ＞123.49 | Example 6 | ＜0.3 | ＞33.33 |
| Example 7 | 0.763 | 58.23 | Example 8 | 0.959 | 21.88 |
| Comparative example 1 | 2.717 | 3.31 | Comparative example 2 | 3.393 | / |
| Comparative example 3 | 3.602 | / |
According to the transcription activation experimental results shown in Table 1, the compound of the embodiment of the invention can realize the agonistic activity to thyroid hormone receptor beta; and the compounds of the examples of the present invention unexpectedly significantly increased agonistic activity to trβ compared to comparative examples 1, 2, 3; while the examples of the present invention also show a very high selectivity for trβ1, an unexpected effect compared to comparative example 1.
TABLE 2 near 50% active dose of the compounds of the invention
Near 50% of the active dose refers to the concentration of the compound at which the activity of agonizing the alpha subtype and the beta subtype, respectively, reaches 50% of 100% at T3 agonizing. This data may show the agonistic activity of the compounds on TR alpha and TR beta.
As is clear from the above data in Table 2, comparative example 1 had an agonistic activity of 50% at 10. Mu.m, whereas examples 1 to 3 did not measure values (measured values) around 50% of agonistic activity even at 30. Mu.m. At a concentration of 1 μm, example 1 showed a stronger agonistic activity against β than comparative example 1, and examples 2 and 3 reached approximately 50% at 0.3 μm. This effect is unexpected.
TABLE 3 maximum agonistic activity of the compounds of the invention and their concentrations
| Examples | max％(α) | Cmax(α) | max％(β) | Cmax(β) |
| Comparative example 1 | 49.36 | 10 | 57.35 | 3 |
| Example 1 | 33.91 | 10 | 59.25 | 1 |
| Example 2 | 39.29 | 10 | 70.80 | 3 |
| Example 3 | 39.58 | 3 | 73.84 | 1 |
max% is the maximum agonistic activity of the compound (100% at T3 agonism) and Cmax is the concentration of the compound corresponding to max%.
From the above data in Table 3, comparative example 1 shows that the% max for the alpha subtype is significantly higher than examples 1-3 and the% max for the beta subtype is significantly lower than examples 1-3, indicating that the compounds of the present invention have strong agonistic activity against the beta subtype and weak agonistic activity against the alpha subtype compared to comparative example 1, exhibit better beta agonistic activity while having better selectivity, which effect is unexpected.
Industrial applicability
The heterocyclic compound of the invention has good thyroid hormone beta receptor agonistic activity and can be used as a medicament for treating or preventing diseases related to the action.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (13)
- A heterocyclic compound having a structure represented by formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:Wherein:x is selected from N or CH;R 1 and R is 2 Independently selected from F, cl, br, I or substituted or unsubstituted C 1 ～C 6 An alkyl group;R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;wherein R is 1 And R is 2 When Cl and X are CH, R 3 Is not methyl.
- According to claim 1Or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 And R is 2 Independently selected from Cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 1 And R is 2 Independently selected from Cl or Br;preferably, R 1 And R is 2 All are Cl;preferably, R 1 And R is 2 Are all Br.
- The heterocyclic compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 Selected from C 1 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl; preferably, C 1 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;preferably, R 3 Substituents selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, are independently selected from one or more of the following groups: F. cl or Br.
- A heterocyclic compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH;R 1 and R is 2 Are all Br;R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl radicals being unsubstituted or independently substituted by one or more of the following radicalsGroup substitution: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 3 Selected from C 1 -C 6 Alkyl, said C 1 -C 6 Alkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 3 Selected from C 1 ～C 4 An alkyl group;preferably, R 3 Selected from methyl, ethyl, propyl and isopropyl.
- A heterocyclic compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH;R 1 and R is 2 All are Cl;R 3 selected from C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 3 Selected from C 2 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl group, the C 2 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;Preferably, R 3 Selected from ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, which is unsubstituted or independentlySubstituted with one or more of the following substituents: F. cl or Br;preferably, R 3 Selected from ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl and cyclobutyl;preferably, R 3 Selected from ethyl, isopropyl and cyclobutyl.
- A heterocyclic compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N;R 1 and R is 2 Independently selected from F, cl, br, I or substituted or unsubstituted C 1 ～C 6 An alkyl group;R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group.
- The heterocyclic compound according to any one of claims 1-3 or 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N;R 1 and R is 2 All are Cl;R 3 selected from C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 3 Selected from C 1 ～C 4 Alkyl orC 3 ～C 6 Cycloalkyl group, the C 1 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;preferably, R 3 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, which is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;preferably, R 3 Selected from methyl, isopropyl and cyclopropyl.
- The heterocyclic compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is selected from N or CH;R 1 and R is 2 All are Cl;R 3 selected from C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl group, the C 2 -C 6 Alkyl or C 3 -C 8 Cycloalkyl is unsubstituted or independently substituted with one or more of the following groups: D. f, cl, br or substituted or unsubstituted C 1 ～C 3 An alkyl group;preferably, R 3 Selected from C 2 ～C 4 Alkyl or C 3 ～C 6 Cycloalkyl group, the C 2 -C 4 Alkyl or C 3 -C 6 Cycloalkyl is unsubstituted or independently substituted with one or more of the following substituents: F. cl or Br;preferably, R 3 Selected from ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, unsubstituted or independently substituted with one or more of the following substituents: F. cl or B r；Preferably, R 3 Selected from ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl, cyclopropyl or cyclobutyl.
- The heterocyclic compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the heterocyclic compound is a specific compound selected from the following:2- (3, 5-dibromo-4- ((7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dibromo-4- ((7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dibromo-4- ((7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((7- (2, 2-difluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((9-methyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((9-isopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile;2- (3, 5-dichloro-4- ((9-cyclopropyl-9H-purin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile.
- A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the heterocyclic compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally a pharmaceutically acceptable carrier and/or excipient and/or diluent.
- Use of the heterocyclic compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 10, for the manufacture of a thyroid hormone receptor agonist, in particular a thyroid hormone beta receptor agonist (e.g. a thyroid hormone beta 1 receptor agonist), and/or for the manufacture of a medicament for the treatment and/or prophylaxis of a thyroid hormone related disorder;Preferably, the thyroid hormone-related disorder is a metabolic disorder such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism or thyroid cancer.
- The heterocyclic compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof or the pharmaceutical composition according to claim 10, for use in the treatment and/or prevention of thyroid hormone-related diseases;preferably, the thyroid hormone-related disorder is a metabolic disorder such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism or thyroid cancer.
- A method of treating and/or preventing a thyroid hormone β receptor associated disease comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the heterocyclic compound of any one of claims 1-9, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 10;preferably, the thyroid hormone-related disorder is a metabolic disorder such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism or thyroid cancer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021105573230 | 2021-05-21 | ||
| CN202110557323 | 2021-05-21 | ||
| PCT/CN2022/094094 WO2022242743A1 (en) | 2021-05-21 | 2022-05-20 | Heterocyclic compound and application thereof |
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| Publication Number | Publication Date |
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| CN117279911A true CN117279911A (en) | 2023-12-22 |
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| CN (1) | CN117279911A (en) |
| TW (1) | TW202313615A (en) |
| WO (1) | WO2022242743A1 (en) |
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| JP7445996B2 (en) * | 2019-02-21 | 2024-03-08 | ナンジン・ルイジェ・ファーマ・カンパニー・リミテッド | Novel compounds and their use as thyroid hormone receptor agonists |
| CA3139101A1 (en) * | 2019-05-08 | 2020-11-12 | Aligos Therapeutics, Inc. | Modulators of thr-s and methods of use thereof |
| TW202115029A (en) * | 2019-07-31 | 2021-04-16 | 大陸商深圳微芯生物科技股份有限公司 | Heterocyclic compound and use thereof |
| US20220281849A1 (en) * | 2019-08-23 | 2022-09-08 | Terns Pharmaceuticals, Inc. | Thyroid hormone receptor beta agonist compounds |
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| WO2022242743A1 (en) | 2022-11-24 |
| TW202313615A (en) | 2023-04-01 |
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