WO2020151636A1 - Pde9抑制剂及其用途 - Google Patents
Pde9抑制剂及其用途 Download PDFInfo
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- WO2020151636A1 WO2020151636A1 PCT/CN2020/073128 CN2020073128W WO2020151636A1 WO 2020151636 A1 WO2020151636 A1 WO 2020151636A1 CN 2020073128 W CN2020073128 W CN 2020073128W WO 2020151636 A1 WO2020151636 A1 WO 2020151636A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkoxy
- membered
- amino
- halogenated
- Prior art date
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- 229940076380 PDE9 inhibitor Drugs 0.000 title claims abstract description 7
- RVEJWGYZBXCGGM-DNVCBOLYSA-N chembl2179094 Chemical compound C([C@H]([C@@H](C1)C=2NC(=O)C=3C=NN(C=3N=2)C2CCOCC2)C)N1CC1=CC=CC=C1 RVEJWGYZBXCGGM-DNVCBOLYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 193
- -1 PDE9 inhibitor compound Chemical class 0.000 claims abstract description 139
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000002207 metabolite Chemical class 0.000 claims abstract description 34
- 239000000651 prodrug Chemical class 0.000 claims abstract description 34
- 229940002612 prodrug Drugs 0.000 claims abstract description 34
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
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- 125000000217 alkyl group Chemical group 0.000 claims description 330
- 125000003545 alkoxy group Chemical group 0.000 claims description 197
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 87
- 125000000623 heterocyclic group Chemical group 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 73
- 229910052736 halogen Inorganic materials 0.000 claims description 70
- 150000002367 halogens Chemical class 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 64
- 125000000304 alkynyl group Chemical group 0.000 claims description 61
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 61
- 125000003342 alkenyl group Chemical group 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 59
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 58
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 58
- 150000002431 hydrogen Chemical class 0.000 claims description 56
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 47
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 39
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 39
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 39
- 229910052805 deuterium Inorganic materials 0.000 claims description 38
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 37
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 34
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 33
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 33
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 33
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000003282 alkyl amino group Chemical group 0.000 claims description 29
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 23
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 20
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 19
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
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- 238000006467 substitution reaction Methods 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 15
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 13
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 12
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- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
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- 239000003112 inhibitor Substances 0.000 claims description 8
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- 239000013543 active substance Substances 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
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- 230000002401 inhibitory effect Effects 0.000 claims description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 4
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- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 2
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- 108010005551 GABA Receptors Proteins 0.000 claims description 2
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
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- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 2
- 229940125681 anticonvulsant agent Drugs 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 claims description 2
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- MJHRQNOSSYGZGK-UHFFFAOYSA-N trichloro phosphite Chemical compound ClOP(OCl)OCl MJHRQNOSSYGZGK-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the present invention belongs to the technical field of medicine, and relates to a phosphodiesterase 9 inhibitor represented by formula (I), or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs and applications thereof.
- Phosphodiesterase is a class of proteases that can selectively degrade the important second messengers cGMP (cyclic guanosine phosphate) and cAMP (cyclic adenosine phosphate) in the body, thereby participating in important physiological processes in the body.
- cGMP cyclic guanosine phosphate
- cAMP cyclic adenosine phosphate
- PDEs can be divided into 11 members (PDE1 ⁇ PDE11).
- PDE9A is an important member of the PDE family, and it is widely expressed in the testis, brain, small intestine, skeletal muscle, heart, lung, thymus and pancreas.
- PDE9A inhibitors are used to treat cognitive impairment diseases caused by central nervous system disorders, such as Alzheimer’s and schizophrenia, and brain
- the two nucleotides cAMP and cGMP are important second messengers and play a central role in the process of cell signal transduction; they mainly activate protein kinases: protein kinase A (PKA) activated by cAMP, and activated by cGMP It is called protein kinase G (PKG).
- PKA protein kinase A
- PKG protein kinase G
- the activated PKA and PKG can phosphorylate many cellular effectors, such as ion channels, G-protein coupled receptors, structural proteins, and conductance factors.
- cAMP and cGMP may control most physiological processes in many organs in this way.
- cAMP and cGMP can also directly act on effector proteins, thus playing the same role as mentioned above.
- cGMP can directly act on ion receptors, thereby affecting the ion concentration in cells.
- Phosphodiesterase (PDEs) hydrolyze cyclic monophosphate cAMP and cGMP, and convert them into inactivated monophosphate AMP and GMP.
- Human PDE9 was first cloned and sequenced in 1998 and is the most selective PDE for cGMP reported so far.
- the binding constant (Km) of PDE9 and cGMP is 170 nM, and the binding constant for cAMP is as high as 230,000 nM, and the selectivity is more than 1000 times.
- Km binding constant
- PDE9 inhibitors may increase the baseline cGMP concentration.
- Pfizer s PF-04447943 (WO2008139293A1, Example 111) and BI’s BI-409306 (WO2009121919A1, Exp.51).
- the two compounds are in the clinical research phase.
- An object of the invention is to provide a class of compounds used as PDE9 protease inhibitors, or pharmaceutically acceptable salts, isomers and deuterated compounds thereof.
- the compounds of the present invention have good PDE9 protease inhibitory activity, selectivity and druggability (Such as good in vivo and in vitro pharmacokinetic properties, high liver microsomal stability), can treat or prevent related diseases mediated by PDE9, and can be used in the treatment of diseases of cognitive impairment caused by central nervous system disorders Play an important role.
- X 1 , X 2 , X 4 are independently selected from CR' or N
- X 3 is selected from CR 3 or N
- X 1 , X 2 , X 3 , X 4 are
- At least one of the N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkane Carbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein said C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamin
- the above-mentioned 4-6 membered heterocyclic group optionally substituted by one or more independent substituents, and the substituent of the heteroaryl group optionally substituted by one or more independent substituents are selected from hydroxyl, amino, carboxyl, cyano, Nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy;
- Y is selected from metal ions or organic ammonium ions; preferably Na + , K + , NH 4 + ;
- L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
- Ring A is a 3-12 membered heterocyclic group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, wherein the heteroatom of the 3-12 membered heterocyclic group is selected from One of O, S, and N or any combination thereof, S atoms can be optionally oxidized to S(O) or S(O) 2 , C atoms can be optionally oxidized to C(O), and N heteroatoms can be Is optionally oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- n 0, 1, 2 or 3;
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- X 2 is N
- X 1 is CH
- X 3 is CR 3
- X 4 is CH
- R 3 is selected from isopropyl, cyclopropyl, hydroxymethyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, is Substituted C 1-6 alkyl, C 3-6 cycloalkylcarbonyloxy C 1-6 alkyl, deuterated C 1-6 alkyl;
- X 2 is N
- X 1 is CH
- X 3 is CR 3
- X 4 is CH
- ring A is
- X 2 is N
- X 1 and X 4 are each independently CR'
- X 3 is CR 3 .
- X 4 is N
- X 1 and X 2 are each independently CR'
- X 3 is CR 3 .
- X 2 and X 4 are each independently N, X 1 is CR', and X 3 is CR 3 .
- Some embodiments of the present invention relate to compounds represented by formula (II) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- X 1 and X 2 are independently selected from CR' or N
- X 3 is selected from CR 3 or N
- N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkane Carbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein said C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamin
- the above-mentioned 4-6 membered heterocyclic group optionally substituted by one or more independent substituents, and the substituent of the heteroaryl group optionally substituted by one or more independent substituents are selected from hydroxyl, amino, carboxyl, cyano, Nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy;
- L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
- Ring A is a 3-12 membered heterocyclic group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, wherein the heteroatom of the 3-12 membered heterocyclic group is selected from One of O, S, and N or any combination thereof, S atoms can be optionally oxidized to S(O) or S(O) 2 , C atoms can be optionally oxidized to C(O), and N heteroatoms can be Optionally oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- n 0, 1, 2 or 3;
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- X 1 and X 2 are each independently CR', and X 3 is CR 3 .
- X 2 is N
- X 1 is CR'
- X 3 is CR 3 .
- Some embodiments of the present invention relate to compounds represented by general formula (III) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkane Carbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein said C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamin
- the above-mentioned 4-6 membered heterocyclic group optionally substituted by one or more independent substituents, and the substituent of the heteroaryl group optionally substituted by one or more independent substituents are selected from hydroxyl, amino, carboxyl, cyano, Nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy;
- Ring A is a 3-12 membered heterocyclic group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, and the heteroatom of the 3-12 membered heterocyclic group is selected from O , S, N or any combination thereof, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O), N heteroatom can be any Choose to be oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- n 0, 1, 2 or 3;
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- X 1 and X 2 are each independently CR'.
- Some embodiments of the present invention relate to compounds represented by formulas (I), (II), (III) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- X 1 and X 2 are independently selected from CR' or N, and N heteroatoms can be optionally oxidized to
- Ring A is a 4-7 membered monocyclic group, and the heteroatom of the 4-7 membered monocyclic group is selected from one or a combination of O, S, and N, and contains at least one N, ring A
- N atom By connecting N atom to L, S atom can be optionally oxidized to S(O) 2 , C atom can be optionally oxidized to C(O), and N heteroatom can be optionally oxidized to
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- X 1 and X 2 are each independently CR'.
- X 2 is N and X 1 is CR'.
- X 1 and X 2 are independently selected from CR' or N, and N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, aryl, C 1- 4 alkoxy, C 2-6 alkenyl, C 1-4 alkylaminocarbonyl, C 1-4 alkylcarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, and aminocarbonyl, wherein the C 1-4 alkyl Group, C 3-6 cycloalkyl, 5-6 membered heteroaryl, aryl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylaminocarbonyl, C 1-4 alkylcarbonyl , (C 1-4 alkyl) 2 aminocarbonyl and aminocarbonyl are unsubstituted or optionally one or more independently selected from hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3- 6 cycloalkyl, C 1-6 alkylcarbonyloxy, C
- Each R 1 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 1-4 alkoxy;
- n 0, 1 or 2;
- R 2 is selected from hydrogen, C 1-4 alkyl.
- X 1 and X 2 are each independently CR'.
- X 2 is N and X 1 is CR'.
- Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- X 2 is N
- X 3 is CR 3
- X 1 and X 4 are each independently CR'
- N heteroatoms can be optionally oxidized to
- R 3 is selected from isopropyl, cyclopropyl, hydroxymethyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, is Substituted C 1-6 alkyl, C 3-6 cycloalkylcarbonyloxy C 1-6 alkyl, deuterated C 1-6 alkyl;
- R 2 is selected from hydrogen, C 1-4 alkyl
- n 0, 1, or 2.
- X 2 is N
- X 3 is CR 3
- X 1 and X 4 are each independently CR'
- N heteroatoms can be optionally oxidized to
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, and C 1-4 alkyl;
- R 2 is selected from hydrogen, C 1-4 alkyl
- n 0, 1, or 2.
- Some embodiments of the present invention relate to compounds represented by formulas (I), (II), (III) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- R'and R 3 is independently selected from hydrogen, deuterium, amino, carboxyl, cyano, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , (C 1-4 alkyl) 2 amino, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 3-6 cycloalkane Group, 4-6 membered nitrogen-containing heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl and Aminocarbonyl group, wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, (C 1-4 alkyl) 2 amino group, C 2-6 alkenyl group, C 2- 6- alkynyl, C 1-4 alkylsul
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- X 1 and X 2 are independently selected from CR' or N, and N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1 at each occurrence.
- Ring A is a 7-12 membered spiro heterocyclic group.
- the heteroatom of the spiro heterocyclic group is selected from one or a combination of O, S and N, and contains at least one N.
- Ring A is connected to L phase is connected, S atom can be optionally oxidized to S(O) 2 , C atom can be optionally oxidized to C(O), N heteroatom can be optionally oxidized to
- the 7-12 membered spiro heterocyclic group is a 7-12 membered nitrogen-containing saturated spiro heterocyclic group; more preferably, the 7-12 membered nitrogen-containing saturated spiro heterocyclic group is selected from the following groups:
- ring A is selected from
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkyl Sulfonyl, C 1-4 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C
- n 0, 1 or 2;
- X 1 and X 2 are each independently CR'.
- X 2 is N and X 1 is CR'.
- Some embodiments of the present invention relate to compounds represented by formulas (I), (II), (III) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- X 2 and X 4 are each independently CR' or N, X 3 is selected from CR 3 or N, and N heteroatoms can be optionally oxidized to
- R 2 is selected from hydrogen, C 1-4 alkyl
- n 0, 1 or 2;
- X 1 and X 2 are each independently CR'.
- X 2 is N and X 1 is CR'.
- Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- X 1 , X 2 , X 4 are each independently selected from CR' or N, X 3 is selected from CR 3 or N, and X 1 , X 2 , X 3 , X 4
- N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkane Carbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein said C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamin
- the above-mentioned 4-6 membered heterocyclic group optionally substituted by one or more independent substituents, and the substituent of the heteroaryl group optionally substituted by one or more independent substituents are selected from hydroxyl, amino, carboxyl, cyano, Nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy;
- L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- n 0, 1 or 2;
- Ring A is selected from the following groups:
- R 3 is selected from isopropyl, cyclopropyl, hydroxymethyl
- R 1 is independently hydrogen, methyl and hydroxyl, R 3 is not H;
- X 2 is N
- X 1 and X 4 are each independently CR'
- X 3 is CR 3 .
- X 4 is N
- X 1 and X 2 are each independently CR'
- X 3 is CR 3 .
- X 2 and X 4 are each independently N, X 1 is CR', and X 3 is CR 3 .
- Some embodiments of the present invention relate to compounds represented by formula (IV) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof,
- R 3 is selected from hydrogen, deuterium, amino, carboxyl, cyano, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino , C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 3-6 cycloalkyl, 4-6 membered nitrogen-containing heterocyclic group , 5-6 membered heteroaryl, aryl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl Group, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylsulfonyl Acyl, C 1-4 alkyl
- L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
- Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
- R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogenated C 1-6 alkyl;
- R 3 when for When R 3 is selected from isopropyl, cyclopropyl, hydroxymethyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, is Substituted C 1-6 alkyl, C 3-6 cycloalkylcarbonyloxy C 1-6 alkyl, deuterated C 1-6 alkyl;
- ring A is
- X 1 , X 2 , X 4 are each independently selected from CR' or N, X 3 is selected from CR 3 or N, and X 1 , X 2 , X 3 , X 4
- N heteroatoms can be optionally oxidized to
- R'and R 3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkane Carbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein said C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamin
- the above-mentioned 4-6 membered heterocyclic group optionally substituted by one or more independent substituents, and the substituent of the heteroaryl group optionally substituted by one or more independent substituents are selected from hydroxyl, amino, carboxyl, cyano, Nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy; L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
- Ring A is a 5-10 membered heteroaryl group, and the heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
- n 0, 1, 2 or 3;
- ring A is selected from
- the tautomer is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the hydrogen atom in the structure can be arbitrarily deuterated by one or more deuterium atoms.
- the present invention also provides compounds containing the aforementioned formulas (I), (II), (III), (IV) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites and prodrugs thereof, And a pharmaceutical composition of one or more second therapeutically active agents.
- the composition may be a "therapeutically effective amount" of the compound represented by the aforementioned formula (I), (II), (III), (IV) or its pharmaceutically acceptable
- the salts, isomers, deuterated compounds, metabolites and prodrugs of, and one or more second therapeutically active agents are used in a combined manner of administration, such as sequential administration, simultaneous administration, or the present invention provides
- the compound or its pharmaceutically acceptable salt, isomer, deuterated compound and the second therapeutically active agent are administered as a compound preparation.
- the present invention also provides drugs containing the compounds represented by the aforementioned formulas (I), (II), (III), (IV) or pharmaceutically acceptable salts, isomers, deuterated compound metabolites and prodrugs preparation.
- the pharmaceutical formulation may include one or more pharmaceutical carriers.
- the pharmaceutical carrier of the present invention can be one or more solid or liquid fillers or gel substances suitable for human use.
- the pharmaceutical carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the compound provided by the present invention or its pharmaceutically acceptable salt or isomer without significantly reducing its efficacy.
- the pharmaceutical carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent or a non-aqueous solvent, and the like.
- the present invention also provides the compounds represented by the aforementioned formulas (I), (II), (III), (IV) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites, prodrugs, the foregoing Use of the pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a medicine for the treatment or prevention of related diseases mediated by PDE9; specifically, the related diseases mediated by PDE9 are cognitive impairment caused by central nervous system disorders; More specifically, the cognitive impairment includes: perception, attention, memory and learning impairment; including but not limited to Alzheimer’s disease, schizophrenia, age-related memory loss, vascular dementia, traumatic brain injury, stroke, Dementia after a stroke, post-traumatic dementia, general attention deficit, childhood attention deficit with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontal lobe degeneration, cortical basal ganglia degeneration, muscular atrophy Lateral sclerosis, Huntington’s disease, multiple sclerosis, thalamic degeneration, Kuga’s dementia, HIV dementia, schizophrenia, Kor
- the present invention also provides the compounds represented by the aforementioned formulas (I), (II), (III), (IV) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites, prodrugs, the foregoing
- pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment or prevention of diseases.
- the present invention also provides the compounds represented by the aforementioned formulas (I), (II), (III), (IV) or pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites, prodrugs, the foregoing
- the use of the pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment or prevention of related diseases mediated by PDE9; specifically, the related diseases mediated by PDE9 are cognitive impairment caused by central nervous system disorders; more specifically In particular, the cognitive impairment includes: perception, attention, memory and learning impairment; including but not limited to Alzheimer’s, schizophrenia, age-related memory loss, vascular dementia, head injury, stroke, and post-stroke Dementia, post-traumatic dementia, general attention deficit, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontal lobe dementia, cortical basal ganglia degeneration, amyotrophic lateral spinal cord Sclerosis, Huntington’s disease, multiple sclerosis, thalamic degeneration, Kuga’s dementia, HIV dementia, schizophrenia, Korsa
- the present invention also provides a method for treating or preventing diseases, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by the aforementioned formula (I), (II), (III), (IV) or The pharmaceutically acceptable salts, isomers, deuterated compounds, metabolites, prodrugs, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions thereof; the disease is a related disease mediated by PDE9; specifically, the PDE9
- the related diseases mediated are cognitive impairment caused by central nervous system disorders; more specifically, the cognitive impairment includes: perception, attention, memory, and learning impairment; including but not limited to Alzheimer’s disease and schizophrenia , Age-related memory loss, vascular dementia, traumatic brain injury, stroke, dementia after stroke, post-traumatic dementia, general attention deficit, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy Body dementia, frontal lobe degeneration, cortical basal ganglia degeneration, amyotrophic lateral sclerosis, Huntington's disease, multiple
- halogen in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.
- halo in the present invention means that any hydrogen atom in the substituent can be replaced by one or more halogen atoms which are the same or different.
- Halogen is as defined above.
- C 1-6 alkyl group in the present invention refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl Base, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl
- C 2-8 alkenyl group in the present invention refers to a linear or branched or cyclic alkene group derived from an alkene group of 2-8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as vinyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hexadienyl.
- C 1-6 alkoxy refers to the present invention as hereinbefore defined "C 1-6 alkyl” group linked to the parent molecule through an oxygen atom, i.e., "C 1-6 alkyl -O- "Groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentyloxy and n-hexoxy, etc.
- the "C 1-4 alkoxy” refers to the above-mentioned examples containing 1-4 carbon atoms, that is, the "C 1-4 alkyl-O-" group.
- C 1-6 alkylamino "(C 1-6 alkyl) 2 amino", “C 1-6 alkylcarbonylamino”, “C 1-6 alkylsulfonylamino”, “C 1-6 alkylaminocarbonyl”, “(C 1-6 alkyl) 2 amino-carbonyl”, “C 1-6 alkoxy-carbonyl”, “C 1-6 alkylsulfonyl”, “ C 1-6 alkylthio" and “C 1-6 alkylcarbonyl” respectively refer to C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N- , C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -NH 2 -, C 1-6 alkyl-NH-C(O)-, (C 1-6 alkyl) (C 1-6 alkyl) NC(O)-, C 1-6 alkyl-OC(O)-, C 1-6 alkyl
- the "fused ring" in the present invention refers to a multi-ring system structure formed by two or more cyclic structures connected in a union, spiro, or bridge connection.
- the combined ring refers to a condensed ring structure formed by two or more ring structures sharing two adjacent ring atoms (that is, sharing a bond).
- the bridged ring refers to a condensed ring structure formed by two or more ring-mounted structures sharing two non-adjacent ring atoms.
- the spiro ring refers to a condensed ring structure formed by two or more ring structures sharing one ring atom with each other.
- the cycloalkyl group described in the present invention includes all possible monocyclic, condensed rings (including condensed in the form of union, spiro, and bridge); for example, "3-12 membered cycloalkyl" can be monocyclic, Bicyclic or polycyclic cycloalkyl system (also called fused ring system). Unless otherwise specified, a monocyclic ring system is a cyclic hydrocarbon group containing 3-8 carbon atoms. Examples of 3-8 membered cycloalkyl groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl and the like.
- the fused-ring cycloalkyl group includes a bicyclic cycloalkyl group, a bridged cycloalkyl group, and a spirocycloalkyl group.
- the bicyclic cycloalkyl group can be a 6-11 membered bicyclic cycloalkyl group, a 7-10 membered bicyclic cycloalkyl group, and representative examples thereof include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1 ]Heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
- the spiro ring group can be a 7-12 membered spiro ring group or a 7-11 membered spiro ring group, examples of which include but are not limited to:
- the bridging ring group may be 6-11 membered bridging ring group, 7-10 membered bridging ring group, examples of which include but are not limited to:
- heterocyclic group in the present invention refers to a non-aromatic cyclic group in which at least one ring carbon atom of 3-12 members is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms. Atoms, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo.
- 3-12 membered heterocyclic group refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system (also called a fused ring system), including saturated and partially saturated heterocyclic groups, but Does not include aromatic rings. Unless otherwise specified, it includes all possible monocyclic, condensed rings (including condensed in the form of union, spiro and bridge), saturated and partially saturated conditions.
- the single heterocyclic group can be 3-8 membered heterocyclic group, 3-8 membered saturated heterocyclic group, 3-6 membered heterocyclic group, 4-7 membered heterocyclic group, 5-7 membered heterocyclic group, 5- 6-membered heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 3-8 membered nitrogen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered saturated heterocyclic group, etc.
- "3-8" membered saturated heterocyclic group examples of which include but are not limited to aziridinyl, oxetanyl, thiiridine, azetidinyl, oxetanyl, sulfur Etanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazole Alkyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl Alkyl, 1,4-oxathiolanyl; "3-8" membered partially saturated heterocyclic group, examples of which include but are not limited to 4,5-dihydroisoxazoly
- the fused heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, which may be saturated, partially saturated or unsaturated, but not aromatic.
- the fused heterocyclic group is fused to a benzene ring, 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic cycloalkenyl, 5-6 membered monocyclic heterocyclic group or 5-6 membered monocyclic heteroaromatic 5-6 membered monocyclic heterocyclyl ring.
- the heterocyclic group may be a 6-12 membered cyclic group, a 7-10 membered cyclic group, a 6-10 membered cyclic group, a 6-12 membered saturated cyclic group, and representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-Diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzo
- the spiro heterocyclic group may be 6-12 membered spiro heterocyclic group, 7-11 membered spiro heterocyclic group, 6-12 membered saturated spiro heterocyclic group, examples of which include but are not limited to:
- the bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, a 6-12 membered saturated bridged ring group, and examples thereof include but are not limited to:
- aryl group in the present invention refers to a cyclic aromatic group containing 6-14 carbon atoms, including phenyl, naphthalene, phenanthrene and the like.
- heteroaryl group described in the present invention includes all possible monocyclic rings, condensed rings, all aromatics, and partial aromatics.
- "5-10 membered heteroaryl” refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, including carbon atoms.
- Sulfur atom is replaced by oxo, for example, carbon atom is replaced by C(O), sulfur atom is replaced by S(O), S(O) 2 , nitrogen atom Can be Substitute.
- Heteroaryl groups include mono-heteroaryl groups and condensed heteroaryl groups.
- mono-heteroaryl groups can be 5-7 membered heteroaryl groups, 5-6 membered heteroaryl groups, examples of which include but are not limited to Furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazole Group, thiadiazolyl, thienyl, triazolyl and triazinyl.
- Examples include but are not limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, and benzothiadiyl Azolyl, benzothiazolyl, cinolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridyl, indazolyl, indole Group, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydro Quinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridyl, 4,5,6, 7-tetrahydro[c][1,2,
- the "pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid and base addition salts or solvates thereof.
- Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid , Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 )n-COOH (where n is 0-4)), etc.
- Alkaline salts sodium salt, potassium salt, calcium salt, ammonium salt, etc. Those skilled in the art know a variety of non-toxic pharmaceutically acceptable addition salts.
- the "isomers" in the present invention refer to stereoisomers and tautomers.
- Stereoisomers means that when a compound has an asymmetric atom, it will produce an enantiomer; when a compound has a double bond or a cyclic structure, it will produce a cis-trans isomer; all the enantiomers of the compound of formula (I) Isomers, diastereomers, racemic isomers, cis-trans isomers, geometric isomers, epimers and mixtures thereof are all included in the scope of the present invention.
- Tautomers refer to functional group isomers produced by the rapid movement of an atom in two positions in a molecule. Tautomers are a special functional group isomer. Such as the tautomerism of carbonyl compounds containing ⁇ -H, such as Such as other proton migration tautomerism, such as phenol-ketone tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.
- T, T1, and T2 are each independently any group that conforms to the bonding law of the compound.
- the compound of the present invention contains a lactam structure and exists Tautomerism, when referring to a compound of the present invention, means that the tautomer of the compound is also mentioned.
- the synthesis embodiment of the present invention synthesizes any type of tautomer, which means that another tautomer configuration is obtained at the same time, which can be converted to each other quickly and is in dynamic equilibrium.
- deuterated in the present invention refers to the replacement of one or more hydrogens in a compound or group with deuterium.
- the “therapeutically effective amount” in the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salt, isomer, composition or pharmaceutical preparation that can at least alleviate the symptoms of the patient's disease when administered to the patient.
- the actual amount including the “therapeutically effective amount” will vary according to various conditions, including but not limited to the specific condition being treated, the severity of the condition, the physical and health status of the patient, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.
- N atom in the present invention can be Replacement; "C atom” can be replaced by C(O); “S atom” can be replaced by S(O), S(O) 2 .
- the compounds of the present invention can be prepared by various methods including standard chemical methods. Unless otherwise indicated, any previously defined variables will continue to have the previously defined meaning. Exemplary general synthetic methods are illustrated in the following schemes, and can be easily modified to prepare other compounds of the invention. The specific compounds of the invention are prepared in the example section.
- the compound of formula (I) can be prepared by reacting the compound of formula (I-d) with the compound of formula (I-e) through metal-catalyzed coupling or aromatic nucleophilic substitution.
- the compound of formula (I-d) can be prepared by the action of the compound of formula (I-c) with a halogenating reagent, substituted or unsubstituted sulfonyl chloride or sulfonic anhydride.
- the compound of formula (I-c) can be prepared by ring closure of the compound of formula (I-b) under the action of a suitable base.
- the compound of formula (I-b) can be prepared by reacting the compound of formula (I-a) with cyanoacetic acid under the action of a suitable peptide coupling agent.
- X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , A, L and m are as defined above, Ra 1 is selected from C 1-6 alkyl, and LG is selected from halogen, substituted Or unsubstituted benzene sulfonate, C 1-6 alkyl sulfonate, triflate, etc.
- the compound of formula (I) can be coupled by a metal-catalyzed coupling reaction between a compound of formula (I-f2) and a suitable R 2 group-containing reagent, or a compound of formula (I-f2)
- a metal-catalyzed coupling reaction between a compound of formula (I-f2) and a suitable R 2 group-containing reagent, or a compound of formula (I-f2)
- Appropriate reagents are prepared through metal-catalyzed coupling reactions and then through one or more conventional chemical reaction transformations (such as oxidation, reduction, addition, substitution, hydrogenation, chlorination, amination, etc.).
- the compound of formula (I-f2) can be prepared by reacting the compound of formula (I-d2) with the compound of formula (I-e) through aromatic nucleophilic substitution and the like.
- the compound of formula (I-d2) can be prepared by the reaction of the compound of formula (I-c2) with a halogenating reagent, substituted or unsubstituted sulfonyl chloride or sulfonic anhydride.
- the compound of formula (I-c2) can be prepared by ring closure of the compound of formula (I-b2) under the action of a suitable base.
- the compound of formula (I-b2) can be prepared by reacting the compound of formula (I-a2) with cyanoacetic acid under the action of a suitable peptide coupling agent.
- X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , A, L and m are as defined above, Ra 1 is selected from C 1-6 alkyl, and LG is selected from halogen, substituted Or unsubstituted benzene sulfonate, C 1-6 alkyl sulfonate, triflate, etc.
- X 5 , X 6 , X 7 , and X 8 are independently selected from N or C-Xa, wherein Xa is bromine or iodine, and at least one of X 5 , X 6 , X 7 , and X 8 is N.
- Halogenated reagents refer to reagents used in halogenation reactions, including but not limited to N-bromosuccinimide, N- chlorosuccinimide , N-iodosuccinimide, and dibromosuccinimide Because, phosphorus tribromide, phosphine trichloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxybromide.
- Suitable bases include organic bases and inorganic bases.
- organic bases include but are not limited to sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, LiHMDS, N,N-diisopropylethylamine, triethylamine, lithium diisopropylamine, etc.
- inorganic bases include but are not limited to sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide and the like.
- the substituted or unsubstituted sulfonyl chloride refers to Ra 2 -SO 2 Cl.
- the substituted or unsubstituted sulfonic acid anhydride refers to (Ra 2 -SO 2 ) 2 -O.
- Ra 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, substituted or unsubstituted aryl and the like.
- Peptide coupling agent refers to a reagent that can activate carboxylic acid and amine to form an amide, including but not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-( 7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, N,N '-Carbonyl diimidazole, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, propyl phosphoric anhydride, carbodiimide, etc.
- DIPEA N,N-diisopropylethylamine
- EA ethyl acetate
- PE petroleum ether
- DCM dichloromethane
- THF tetrahydrofuran
- Step 1 Synthesis of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate
- Step 2 Synthesis of tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate
- Step 1 Synthesis of methyl 6-ethyl-3-(cyanoacetamido)-1-pyridine-4-carboxylate
- Step 3 6-Ethyl-4chloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile and 2,4-dichloro-6-ethyl-1 Synthesis of ,7-Naphthalazine-3-carbonitrile
- Triethylamine (35.182g, 0.3478mol, 2eq) and ethyl cyanoacetate (19.665g, 0.1738mol) were added to the above reaction solution, reacted at 150°C for 3h, LC-MS monitored the reaction to be complete, and the reaction solution was cooled to room temperature. Concentrate by pressure, add water (200mL), adjust the pH to 1 with hydrochloric acid (1mol/L), stir for 15 minutes, filter with suction, wash the filter cake twice with EA, and dry at 40°C to obtain a light brick red solid product (25.655) g, yield: 66%).
- Step 4 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
- Step 5 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-(prop-1-en-2-yl)-1,2-dihydro- Synthesis of 1,7-naphthalene-3-carbonitrile
- Step 6 6-isopropyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene Synthesis of -3-carbonitrile
- Step 1 Synthesis of ethyl 2-chloro-5-nitroisonicotinate
- Step 2 Synthesis of ethyl 2-cyclopropyl-5-nitroisonicotinate
- Step 3 Synthesis of ethyl 5-amino-2-cyclopropylisonicotinate
- Step 4 Synthesis of ethyl 5-(2-cyanoacetamido)-2-cyclopropylisonicotinate
- TLC monitors that there is no raw material add dichloromethane (40mL), wash with water (50mL ⁇ 2), wash the organic phase with saturated aqueous sodium carbonate (50mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (5.6g , Yield: 100%), put into the next step according to the theoretical amount.
- Step 7 Synthesis of 2-chloro-6-cyclopropyl-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile
- reaction solution was cooled to room temperature, poured into ice water (20mL), extracted with ethyl acetate (50mL ⁇ 3), the organic phases were combined, and water (50mL ⁇ 2) Washed, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was slurried with methyl tert-butyl ether (5 mL) for 1 h, filtered with suction, and the filter cake was dried to obtain the product (182 mg, yield: 66%).
- Step 6 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthalene-3-carbonitrile synthesis
- Step 1 Synthesis of ethyl 3-aminopicolinate
- Step 3 Synthesis of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate
- the intermediate 2,4,6-trichloro-1,5-naphthalene-3-carbonitrile obtained in the previous step was dissolved in a mixed solvent of trifluoroacetic acid (22mL) and water (5.5mL) and heated to 90 Reacted at °C for 2h, LC-MS detected no raw material. The temperature was lowered to room temperature. The reaction solution was poured into ice water (50mL). A yellow solid precipitated out. Filtered. Add methanol (20mL) to the filter cake. Heat to reflux for 1h. Filter while hot. Concentrate under reduced pressure, beat with ethyl acetate (20 mL) for 1 h, filter, and dry the filter cake to obtain the product (311 mg, yield: 15%).
- Step 7 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthalene-3 -Synthesis of formonitrile
- Step 8 4-(4-Methoxy-4-methylpiperidin-1-yl)-6-methyl-2-oxo-1,2-dihydro-1,5-naphthalene- Synthesis of 3-carbonitrile
- Step 1 Synthesis of ethyl 3-aminopicolinate
- Step 3 Synthesis of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate
- TLC detects that there is no raw material remaining, concentrate under reduced pressure, add water (100mL), heat to 50°C to dissolve, adjust the pH to 2 ⁇ 3 with concentrated hydrochloric acid, precipitate solid, filter, the filter cake is rinsed with water and acetone successively, and the filter cake is dried
- the product (6.4g crude product) is obtained, and the theoretical amount is put into the next step.
- the intermediate 2,4,6-trichloro-1,5-naphthalene-3-carbonitrile (3.0g crude) was dissolved in a mixed solvent of trifluoroacetic acid (30mL) and water (7.5mL), and heated React at 60°C for 3h, LC-MS detects no raw materials, cool to room temperature, pour the reaction solution into ice water (100mL), precipitate a yellow solid, filter, the filter cake is rinsed with water and acetone successively, and the filter cake is dried to obtain the product (1.9g, three-step yield: 76%).
- Step 7 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthalene-3 -Synthesis of formonitrile
- Step 8 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydro-1,5-naphthalene- Synthesis of 3-carbonitrile
- Step 1 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
- Example 1 step 3 The product 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile (2.0g, 8.33mmol, 1.0eq) of Example 1 step 3 was dissolved In DMF (10mL), add DIPEA (6.45g, 50mmol, 6.0eq) and 4-methoxy-4-methylpiperidine trifluoroacetate (2.2g, 9.16mmol, 1.1eq), 80°C reaction 2 hour.
- Step 1 (3-cyano-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-6 -The synthesis of methyl acetate
- Step 1 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
- Example 1 step 3 The product 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile (2.0g, 8.33mmol, 1.0eq) of Example 1 step 3 was dissolved In DMF (10mL), add DIPEA (6.45g, 50mmol, 6.0eq) and 4-methoxy-4-methylpiperidine trifluoroacetate (2.2g, 9.16mmol, 1.1eq), 80°C reaction 2 hour.
- Step 2 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydro-1,7-naphthalene- Synthesis of 3-carbonitrile
- Step 5 6-Ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene- Synthesis of 3-carbonitrile-7-nitrogen oxide
- reaction solution was cooled to 10-15°C, filtered with suction, the filtrate was concentrated to dryness, and recrystallized with PE and EA to obtain the product 6-(1-bromoethyl)-2,4-dichloro-1,7-diazepine Naphthalene-3-carbonitrile 35g.
- Step 2 6-(1-Bromoethyl)-2-chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-methyl Synthesis of Nitriles
- the crude product is first beaten with EA and then recrystallized with ethanol to obtain the product 2-hydroxy-6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)- 1,7-Naphthalene-3-carbonitrile 6g.
- Step 4 Synthesis of 6-acetyl-2-hydroxy-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile
- Step 1 Synthesis of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate
- Step 2 Synthesis of tert-butyl 4-(methoxy-d 3 )-4-methylpiperidine-1-carboxylate
- Step 4 6-Ethyl-2-hydroxy-4-(4-(methoxy-d 3 )-4-methylpiperidin-1-yl)-1,7-naphthalene-3-methyl Synthesis of Nitriles
- Step 1 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
- Example 1 step 3 The product 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile (2.0g, 8.33mmol, 1.0eq) of Example 1 step 3 was dissolved In DMF (10mL), add DIPEA (6.45g, 50mmol, 6.0eq) and 4-methoxy-4-methylpiperidine trifluoroacetate (2.2g, 9.16mmol, 1.1eq), 80°C reaction 2 hour.
- Step 2 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydro-1,7-naphthalene- Synthesis of 3-carbonitrile
- Step 3 6-(1,2-Dihydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1 Synthesis of ,7-Naphthalazine-3-carbonitrile
- Step 5 6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7- Synthesis of naphthalene-3-carbonitrile
- Step 2 6-Ethyl-4-(4-hydroxy-4-(deuterated methyl)piperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazepine Synthesis of naphthalene-3-carbonitrile
- Step 2 Synthesis of tert-butyl 4-methoxy-4-(deuterated methyl)piperidine-1-carboxylate
- Step 4 6-(1-Bromoethyl)-2-chloro-4-(4-methoxy-4-(deuterated methyl)piperidin-1-yl)-1,7-naphthalene Synthesis of -3-carbonitrile
- 6-(1-bromoethyl)-2,4-dichloro-1,7-naphthalene-3-carbonitrile (6.00g, 18.12mmol, 1.0eq), 4-methoxy-4- (Deuterated methyl)piperidine hydrochloride (3.36g, 19.9mmol, 1.1eq) and triethylamine (4.03g, 39.9mmol, 2.2eq) were added with ethanol (60mL) and reacted at 90°C for 2 hours.
- Step 5 6-(1-hydroxyethyl)-4-(4-methoxy-4-(deuterated methyl)piperidin-1-yl)-2-oxo-1,2-dihydro- Synthesis of 1,7-naphthalene-3-carbonitrile
- Step 1 6-Acetyl-4-(4-methoxy-4-(deuterated methyl)piperidin-1-yl)-2-oxo-1,2-dihydro-1,7-di Synthesis of Azone-3-carbonitrile
- Example 12 Step 5 product 6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro- 1,7-Naphthalene-3-carbonitrile (200mg, 0.58mmol, 1.0eq) was dissolved in DCM (5mL), DMAP (7.08g, 0.058mmol, 0.1eq) and triethylamine (175.9mg, 1.74mmol, 3.0eq), cooled in an ice-water bath, dropwise add 2,2-dimethylbutyryl chloride (86.5mg, 0.64mmol, 1.1eq), after dripping, react for 2h, TCL detects about 40% of the raw materials, add 2,2-Dimethylbutyryl chloride (39mg, 0.29mmol, 0.5eq), react for 1h, add water (20mL), extract with DCM (20mL ⁇ 3), combine the organic phases, dry with anhydrous magnesium sulfate, filter, and filtrate
- Step 2 6-(1-bromoethyl)-2-chloro-4-(4-hydroxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile synthesis
- Step 3 1-(3-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-6 -The synthesis of ethyl acetate
- Step 4 4-(4-hydroxy-4-methylpiperidin-1-yl)-6-(1-hydroxyethyl)-2-oxo-1,2-dihydro-1,7-diazepine Synthesis of phthalazin-3-carbonitrile
- Example 12 Step 5 product 6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro- 1,7-Naphthalene-3-carbonitrile (330mg, 0.96mmol, 1.0eq) was dissolved in DCM (5mL), DMAP (11.7mg, 0.096mmol, 0.1eq) and triethylamine (291.2mg, 2.88mmol, 3.0eq), cooled in an ice water bath, added cyclopropanecarbonyl chloride (130.6mg, 1.25mmol, 1.3eq) dropwise, reacted for 2h, TCL detected a small amount of raw material remaining, add water (20mL), use DCM (20mL ⁇ 3 ) Extract, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure.
- the crude product is purified by preparative thin-layer chromatography (MeOH:D
- Step 1 Dibenzyl (1-(3-cyano-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1, Synthesis of 7-naphthyridin-6-yl)ethyl)phosphate
- Example 12 Step 5 product 6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro- 1,7-Naphthalene-3-carbonitrile (675mg, 1.97mmol, 1.0eq) and 1H-tetrazole (276.2mg, 3.94 mmol, 2.0eq) were dissolved in DCM (10mL) under nitrogen protection, The temperature was lowered to 0°C, and dibenzyl diisopropyl phosphoramidite (1g, 2.96mmol, 1.5eq) was added dropwise.
- Step 2 1-(3-cyano-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine -6-yl) synthesis of potassium phosphate
- Test substance The compound of the present invention, prepared by the corresponding example of the present invention and compound I-11 of patent WO2017019723A1 (prepared with reference to the synthesis example in WO2017019723A1), its structural formula is as follows:
- PDE9A2 enzyme (BPS, Cat.No.60090)
- Dosing and incubation Use a very small amount of liquid pipetting system Echo to transfer the compound dilution mother solution to a 384-well plate; add 200 nL of the compound dilution mother solution and 10 ⁇ L PDE9A2 enzyme solution to each compound well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min. Then add 10 ⁇ L of the substrate mixture, centrifuge at 1000 rpm for 1 min, and incubate with shaking at room temperature for 30 min. Finally, stop the reaction system by adding stop solution, and incubate with shaking at room temperature for 60 minutes. In the maximum reading hole (Max), replace the compound with solvent; in the minimum reading hole (Min), replace the compound and enzyme solution with solvent.
- Max maximum reading hole
- Min replace the compound and enzyme solution with solvent.
- Detection Use a microplate reader to detect the fluorescence reading (F) at 480nm/535nm.
- Test object PDE9A2 IC 50 (nM) Compound I-11 70 Compound 163 50 Compound 164 25 Compound 165 twenty four Compound 166 19 Compound 167 11 Compound 177 15 Compound 183 48 Compound 184 19 Compound A 61 Compound B 3 Compound 191 5 Compound 192 64 Compound 194 37
- Example 2 Evaluation of the stability of canine liver microsomes of the compound of the present invention
- Test substance the compound of the present invention and the compound I-8 of patent WO2017019723A1 (prepared with reference to the synthesis example in WO2017019723A1), the structural formula is as follows:
- composition of the incubation system is the composition of the incubation system:
- liver microsomes (20mg protein/mL) from the -80°C refrigerator, pre-incubate them on a 37°C water bath constant temperature shaker for 3 minutes, and melt them for use.
- Control group (without ⁇ -NADPH): Take 30 ⁇ L of water and 30 ⁇ L of compound working solution (10 ⁇ M) and add them to 240 ⁇ L of the incubation system mixture described in step (2), vortex for 30s, and mix well. The volume is 300 ⁇ L, and 2 copies are sampled in parallel. Put it into 37°C water bath constant temperature shaker for incubation, and start timing, sampling time points are 0min and 60min.
- Sample group Take 70 ⁇ L of ⁇ -NADPH solution (10mM) and 70 ⁇ L of compound working solution (10 ⁇ M) respectively and add 560 ⁇ L of the mixed solution described in step (2), the total volume of the reaction is 700 ⁇ L, vortex for 30s, mix, parallel sample 2 Copies. Put it into 37°C water bath constant temperature shaker for incubation, and start timing, sampling time point is 0min, 5min, 10min, 20min, 30min, 60min after timing.
- k is the slope of the plot of the logarithm of the remaining amount of the compound versus time
- V d is the apparent volume of distribution
- C 0 is the drug concentration at 0 h.
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Abstract
本发明属于医药技术领域,具体涉及式(I)所示的PDE9抑制剂化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,本发明还涉及这些化合物的药物制剂、药物组合物及其应用。X 1、X 2、X 3、X 4、R 1、R 2、环A、L和m如说明书中所定义。本发明化合物可用于制备治疗或者预防由PDE9介导的相关疾病的药物。(I)
Description
本发明属于医药技术领域,涉及式(I)所示的磷酸二酯酶9抑制剂,或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药及其应用。
磷酸二酯酶(phosphodiesterase,PDEs)是一类蛋白酶,能选择性的降解体内重要的第二信使cGMP(环磷酸鸟苷)和cAMP(环磷酸腺苷),从而参与体内重要的生理过程。依据基因的序列同源性和对cGMP或cAMP的选择性,PDEs可分为(PDE1~PDE11)11个成员。其中,PDE9A是PDE家族中的重要一员,其广泛表达于睾丸、大脑、小肠、骨肌、心脏、肺、胸腺和胰脏。随着近几年的研究深入,已有多篇文献报道和临床数据证明,PDE9A抑制剂用于治疗由于中枢神经系统紊乱导致的认知损害方面的疾病,比如老年痴呆症和精神分裂症、大脑的神经变性过程疾病。cAMP和cGMP这两种核苷酸是重要的第二信使,在细胞信号传导过程中起着核心作用;它们主要活化蛋白激酶:由cAMP激活的称作蛋白激酶A(PKA),由cGMP激活的称作蛋白激酶G(PKG)。被激活的PKA和PKG可以磷酸化许多细胞效应蛋白,比如离子通道、G-蛋白耦联受体、结构蛋白、传导因子。因此,cAMP和cGMP通过这种方式可能控制许多器官中的大多数生理过程。同时,cAMP和cGMP也可以直接作用于效应蛋白,从而起到上述相同的作用。众所周知,cGMP可以直接作用于离子受体,从而影响细胞中的离子浓度。磷酸二酯酶(PDEs)水解环状单磷酸酯cAMP和cGMP,将其转化为失活的单磷酸酯AMP和GMP。
人类的PDE9最早在1998年被克隆和测序,是迄今为止报道的对cGMP选择性最高的PDE。PDE9与cGMP的结合常数(Km)为170nM,而对cAMP的结合常数值高达230000nM,选择性超过1000倍。和PDE2A及PDE5A比较,由于PDE9没有cGMP的结合区域,因此PDE9的催化活性并不会被cGMP增强,所以PDE9抑制剂可能提高基线cGMP浓度。
传统的PDE抑制剂不能抑制人类PDE9,因此,药物IBMX、dipyridamole、SKF94120、rolipram和vinpocetine对PDE9没有抑制活性或者很低。
目前市场上没有PDE9抑制剂药物,只有一些正在处于临床研发阶段的抑制剂,例如Pfizer公司的PF-04447943(WO2008139293A1,实施例111)和BI公司的BI-409306(WO2009121919A1,Exp.51),目前两个化合物正处于临床研究阶段。
另外,Merck也在专利WO2017019723A1、WO2017019726A1和WO2017019724A1中报道了一些具有PDE9抑制作用的化合物。如专利WO2017019723A1中的化合物I-8,其结构如下:
发明内容
发明的一个目的是提供一类用作PDE9蛋白酶抑制剂的化合物,或其药学上可接受的盐、异构体和氘代化合物,本发明化合物具有良好的PDE9蛋白酶抑制活性、选择性和成药性(如良好的体内外药代动力学性质、较高的肝微粒体稳定性),能够治疗或者预防由PDE9介导的相关疾病,可在中枢神经系统紊乱导致的认知损害方面的疾病的治疗方面发挥重要的作用。
本发明的技术方案如下:
通式(I)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药:
其中,X
1、X
2、X
4分别独立地选自CR’或N,X
3选自CR
3或N,且X
1、X
2、X
3、X
4中
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、C
2-8烯基、卤代C
1-6烷氧基、
未被取代或任选被一至多个独立的取代基取代的4-6元杂环基、未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;
Y选自金属离子或有机铵离子;优选为Na
+、K
+、NH
4
+;
L为键、-NH-(CH
2)t-,t为0、1、2或3;
环A为3-12元杂环基、5-10元杂芳基、3-12元环烷基、3-12元环烯基,其中所 述3-12元杂环基的杂原子选自O、S、N中的一种或其任意组合,S原子可任选被氧化为S(O)或S(O)
2,C原子可任选被氧化为C(O),N杂原子可以被任选氧化为
所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
m为0、1、2或3;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
条件是,
优选地,当X
2为N,X
1为CH,X
3为CR
3,X
4为CH,
为
时,R
3选自异丙基、环丙基、羟甲基、
C
1-6烷基羰基,C
1-6烷基羰氧基C
1-6烷基,被
取代的C
1-6烷基,C
3-6环烷基羰氧基C
1-6烷基,氘代C
1-6烷基;
在一优选例中,X
2为N,X
1、X
4分别独立地为CR’,X
3为CR
3。
在另一优选例中,X
4为N,X
1、X
2分别独立地为CR’,X
3为CR
3。
在另一优选例中,X
2和X
4分别独立地为N,X
1为CR’,X
3为CR
3。
本发明的一些实施方式涉及式(II)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、C
2-8烯基、卤代C
1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基、未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;
L为键、-NH-(CH
2)t-,t为0、1、2或3;
环A为3-12元杂环基、5-10元杂芳基、3-12元环烷基、3-12元环烯基,其中所述3-12元杂环基的杂原子选自O、S、N中的一种或其任意组合,S原子可任选被氧化为S(O)或S(O)
2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为
所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳 基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
m为0、1、2或3;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
条件是
在另一优选例中,X
1、X
2分别独立地为CR’,X
3为CR
3。
在另一优选例中,X
2地为N,X
1为CR’,X
3为CR
3。
本发明的一些实施方式涉及通式(III)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基 羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、C
2-8烯基、卤代C
1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基、未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;
L为键、-NH-(CH
2)t-,t为0、1、2或3;
环A为3-12元杂环基、5-10元杂芳基、3-12元环烷基、3-12元环烯基,所述3-12元杂环基的杂原子选自O、S、N中的一种或其任意组合,S原子可任选被氧化为S(O)或S(O)
2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为
所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
m为0、1、2或3;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
条件是
在另一优选例中,X
1、X
2分别独立地为CR’。
在另一优选例中,X
2地为N,X
1为CR’。
本发明的一些实施方式涉及式(I)、(II)、(III)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代 C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、C
2-8烯基、卤代C
1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;
L为键;
环A为4-7元单杂环基,所述4-7元单杂环基的杂原子选自O、S、N中的一种或两种的组合,且至少含有一个N,环A通过N原子与L相连接,S原子可任选被氧化为S(O)
2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为
优选地,环A为4-7元含氮饱和单杂环基,进一步优选为:
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
m为0、1或2;
条件是,
在另一优选例中,X
1、X
2分别独立地为CR’。
在另一优选例中,X
2地为N,X
1为CR’。
本发明的一些实施方式涉及式(I)、(II)、(III)所示的化合物或其药学上可接受的盐、异构体和氘代化合物,
R’、R
3在每次出现时分别独立地选自氢、氘、卤素、C
1-4烷基、C
3-6环烷基、5-6元杂芳基、芳基、C
1-4烷氧基、C
2-6烯基、C
1-4烷氨羰基、C
1-4烷羰基、(C
1-4烷基)
2氨基羰基和氨基羰基,其中所述C
1-4烷基、C
3-6环烷基、5-6元杂芳基、芳基、C
1-4烷氧基、C
2-6烯基、C
1-4烷氨羰基、C
1-4烷羰基、(C
1-4烷基)
2氨基羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
1-6烷羰氧基、C
3-6环烷基羰氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基和未被取代或被C
1-4烷基取代的4-6元杂环基的基团取代;
L为键;
每个R
1分别独立地选自氢、氘、C
1-4烷基和C
1-4烷氧基;
m为0、1或2;
R
2选自氢、C
1-4烷基。
在另一优选例中,X
1、X
2分别独立地为CR’。
在另一优选例中,X
2地为N,X
1为CR’。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’选自氢、氘、C
1-4烷基;
L为键;
每个R
1分别独立地选自氢、氘、C
1-4烷基和C
1-4烷氧基;
R
2选自氢、C
1-4烷基;
m为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’选自氢、氘、C
1-4烷基;
R
3选自C
1-4烷基,优选地,R
3选自甲基、乙基;
L为键;
每个R
1分别独立地选自氢、氘、羟基、C
1-4烷基;
R
2选自氢、C
1-4烷基;
m为0、1或2。
本发明的一些实施方式涉及式(I)、(II)、(III)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R’、R
3在每次出现时分别独立地选自氢、氘、氨基、羧基、氰基、卤素、C
1-6烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
2-4烯基、C
2-4炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基和氨基羰基,其中所述C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷羰氧基、C
3-6环烷基羰氧基、C
3-6环烷基和未被取代或被一至多个独立的C
1-4烷基取代的4-6元杂环基的基团取代;
L为键;
R
2选自氢、C
1-4烷基;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6 烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
本发明的一些实施方式涉及式(I)、(II)、(III)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
L为键;
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、氨基羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、氨基羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷氧C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷基羰基氨基、C
1-4烷基磺酰氨基、C
1-4烷羰氧基、C
3-6环烷基羰氧基、C
3-6环烷基、C
2-6炔基、卤代C
1-4烷基、C
2-6烯基、卤代C
1-4烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基和C
1-4烷氧基;
环A为7-12元螺杂环基,所述螺杂环基的杂原子选自O、S、N中的一种或两种的组合,且至少含有一个N,环A通过N原子与L相连接,S原子可任选被氧化为S(O)
2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为
优选地,7-12元螺杂环基为7-12元含氮饱和螺杂环基;更优选地,7-12元含氮饱和螺杂环基选自如下基团:
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷氧C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷基羰基氨基和C
1-4烷基磺酰氨基的基团取代;
R
2选自氢、C
1-4烷基、C
2-6烯基、C
2-6炔基、卤代C
1-4烷基;
m为0、1或2;
条件是
在另一优选例中,X
1、X
2分别独立地为CR’。
在另一优选例中,X
2地为N,X
1为CR’。
本发明的一些实施方式涉及式(I)、(II)、(III)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
其中,
R’、R
3在每次出现时分别独立地选自氢、氘、氰基、氨基、卤素、羧基、C
1-4烷基、C
1-4烷氧基、C
2-6烯基、C
1-4烷羰基、C
2-6炔基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷氨羰基、C
1-4烷基羰基、C
1-4烷基硫基、C
1-4烷基磺酰基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基,其中所述C
1-4烷基、C
1-4烷氧基、C
2-6烯基、C
1-4烷羰基、C
2-6炔基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷氨羰基、C
1-4烷基硫基、C
1-4烷基磺酰基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
3-6环烷基、C
1-6烷羰氧基、C
3-6环烷基羰氧基、C
1-4烷羰氧基的基团取代;
L为键;
R
2选自氢、C
1-4烷基;
m为0、1或2;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、卤代C
1-4烷基、卤代C
1-4烷氧基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷氧C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷基羰基氨基和C
1-4烷基磺酰氨基的基团取代;
条件是
在另一优选例中,X
1、X
2分别独立地为CR’。
在另一优选例中,X
2地为N,X
1为CR’。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构 体、氘代化合物、代谢产物和前药,
其中,
X
1、X
2、X
4分别独立地选自CR’或N,X
3选自CR
3或N,且X
1、X
2、X
3、X
4
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、
C
2-8烯基、卤代C
1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;
Y选自金属离子或有机铵离子;优选为Na
+、K
+、NH
4
+;
L为键、-NH-(CH
2)t-,t为0、1、2或3;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
m为0、1或2;
环A选自如下基团:
条件是,
(ii)当R
1独立地为氢、甲基和羟基时,R
3不为H;
(4)当X
1为N,X
2、X
4为CR’,X
3为CR
3,且环A为吡咯烷基,m为0时,R
2不为C
1-6烷基。
在一优选例中,X
2为N,X
1、X
4分别独立地为CR’,X
3为CR
3。
在另一优选例中,X
4为N,X
1、X
2分别独立地为CR’,X
3为CR
3。
在另一优选例中,X
2和X
4分别独立地为N,X
1为CR’,X
3为CR
3。
本发明的一些实施方式涉及式(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,
R
3选自氢、氘、氨基、羧基、氰基、卤素、C
1-6烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
2-6烯基、C
2-6炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基和氨基羰基,其中所述C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
2-4烯基、C
2-4炔基、C
1-4烷基磺酰基、C
1-4烷基硫基、C
3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C
1-4烷羰基、C
1-4烷氨羰基、(C
1-4烷基)
2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、(C
1-4烷基)
2氨基、C
1-4烷羰氧基、
C
3-6环烷基羰氧基、C
3-6环烷基和未被取代或被一至多个独立的C
1-4烷基取代的4-6元杂环基的基团取代;
L为键、-NH-(CH
2)t-,t为0、1、2或3;
m为0、1或2;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
条件是,
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构 体、氘代化合物、代谢产物和前药,
其中,
X
1、X
2、X
4分别独立地选自CR’或N,X
3选自CR
3或N,且X
1、X
2、X
3、X
4
R’、R
3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C
1-6烷羰基、氨基羰基、C
1-6烷氨羰基、(C
1-6烷基)
2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰氨基、C
1-6烷羰氧基、C
3-6环烷基、C
3-6环烷基羰氧基、C
2-8炔基、卤代C
1-6烷基、C
2-8烯基、卤代C
1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基、未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;
上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基和C
1-6烷氧基;L为键、-NH-(CH
2)t-,t为0、1、2或3;
环A为5-10元杂芳基,所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合;
每个R
1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C
1-6烷基、C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、卤代C
1-6烷基、卤代C
1-6烷氧基、C
2-8烯基、C
2-8炔基、C
1-6烷基磺酰基、C
1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧C
1-6烷氧基、C
1-6烷基氨基、(C
1-6烷基)
2氨基、C
1-6烷基羰基氨基和C
1-6烷基磺酰氨基的基团取代;
m为0、1、2或3;
R
2选自氢、C
1-6烷基、C
2-8烯基、C
2-8炔基、卤代C
1-6烷基;
更优选地,环A为9-10元含氮杂芳基。
本发明的一个实施方式,通式(I)、(II)、(III)、(IV)所示的化合物的异构体是指立体异构体和互变异构体。
本发明的一个实施方式,通式(I)所示的结构R
2为氢时,具有通式(I’)所示的互变异构体
在本发明的一种实施方式中,如前述式(I)、(II)、(III)、(IV)所示的化合物、其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药见表1:
表1
在本发明的一种实施方式中,通式(I)所示的化合物的氘代化合物,其结构上的氢原子可任意被一至多个氘原子所氘代。
在本发明的一种实施方式中,前述式(I)、(II)、(III)、(IV)所示的化合物的氘代化合物选自以下结构:
本发明还提供了含有前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,及一种或多种第二治疗活性剂的药物组合物。
所述第二治疗活性剂为乙酰胆碱酯酶抑制剂、淀粉样蛋白-β(或其片段)、淀粉样蛋白-β(或其片段)的抗体、淀粉样蛋白的降低或抑制试剂、α-肾上腺素受体拮抗剂、β-肾上腺素受体阻断剂、抗胆碱能药、抗惊厥药、安定药、钙通道阻断剂、儿茶酚-O转甲基酶抑制剂、中枢神经系统刺激剂、皮质类固醇、多巴胺受体激动剂、多巴胺受体拮抗剂、多巴胺再摄入抑制剂、γ-氨基丁酸受体激动剂、免疫调节剂、免疫抑制剂、干扰素、左旋多巴、N-甲基-D天冬氨酸受体拮抗剂、单胺氧化酶抑制剂、毒蕈碱受体激动剂、烟碱受体激动剂、神经保护药物、降肾上腺素(去甲肾上腺素)再摄入抑制剂、其他PDE9抑制剂、其他磷酸二酯酶抑制剂、β-分泌酶抑制剂、γ-分泌酶抑制剂、血清素(5-羟色胺)1A(5-HT
1A)受体拮抗剂、血清素(5-羟色胺)6(5-HT
6)受体拮抗剂、血清素(5-HT)再摄入抑制剂和营养因子。
在本发明的一种具体实施方式中,该组合物可以是将“治疗有效量”的前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,与一种或多种第二治疗活性剂采用联合给药的方式使用,例如先后给药,同时给药,或将本发明提供的化合物或其药学上可接受的盐、异构体、氘代化合物与第二治疗活性剂做成复方制剂给药。
本发明还提供了含有前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物代谢产物和前药的药物制剂。
在发明的一些实施方式中,药物制剂可以包含一种或多种药用载体。
本发明所述的药用载体可以是一种或多种适合于人使用的固体或液体填料或凝胶物质。所述药用载体优选具有足够的纯度和足够低的毒性,并且与本发明提供的化合物或其药学上可接受的盐、异构体具有相容性且不明显减低其药效。例如,药用载体可以填充剂、粘合剂、崩解剂、润滑剂、水性溶剂或非水性溶剂等。
本发明所述的药物制剂,可以制成药学上可接受的任意剂型,以任何合适的给药方式,例如通过口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,可以制成片剂、胶囊剂、丸剂、颗粒剂等。用于肠胃外给药时,可以制成注射液、注射用无菌粉末等。
本发明还提供了前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物、前药、前述的药物制剂或前述的药物组合物在制备治疗或者预防由PDE9介导的相关疾病的药物中的用途;具体地,所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害;更为具体地,所述认知损害包括:知觉、注意力、记忆力及学习损害;包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
本发明还提供了前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物、前药、前述的药物制剂或前述的药物组合物在治疗或者预防疾病中的用途。
本发明还提供了前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物、前药、前述的药物制剂或前述的药物组合物在治疗或者预防由PDE9介导的相关疾病中的用途;具体地,所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害;更为具体地,所述认知损害包括:知觉、注意力、记忆力及学习损害;包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
本发明还提供了一种治疗或预防疾病的方法,该方法包括向有需要的患者给药治疗有效量的前述式(I)、(II)、(III)、(IV)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物、前药、前述的药物制剂或前述的药物组合物;所述疾病为PDE9介导的相关疾病;具体地,所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害;更为具体地,所述认知损害包括:知觉、注意力、记忆力及学习损害;包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
发明详述
本发明所述的“卤素”是指氟、氯、溴、碘等,优选氟,氯。
本发明所述的“卤代”是指取代基中的任一氢原子可被一个或多个相同或不同的卤素原子取代。“卤素”如前文所定义。
本发明所述的“C
1-6烷基”指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。所述“C
1-4烷基”指含有1-4个碳原子的上述实例。
本发明所述的“C
2-8烯基”指含有碳碳双键的2~8个碳原子的烯烃部分去除一个氢原子衍生的直链或支链或环状的烯烃基,如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、1,4-己二烯基。
本发明所述的“C
2-8炔基”指含有碳碳叁键的2~8个碳原子的炔烃部分去除一个氢原子衍生的直链或支链的炔烃基,如乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基等。
本发明所述的“C
1-6烷氧基”是指前文所定义的“C
1-6烷基”通过氧原子与母体分子连接的基团,即“C
1-6烷基-O-”基团,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述的“C
1-4烷氧基”指含有1-4个碳原子的上述实例,即“C
1-4烷基-O-”基团。
发明所述的“C
1-6烷基氨基”、“(C
1-6烷基)
2氨基”、“C
1-6烷基羰基氨基”、“C
1-6烷基磺酰氨基”、“C
1-6烷基氨基羰基”、“(C
1-6烷基)
2氨基-羰基”、“C
1-6烷氧基-羰基”、“C
1-6烷基磺酰基”、“C
1-6烷基硫基”、“C
1-6烷基羰基”、分别指C
1-6烷基-NH-、(C
1-6烷基)(C
1-6烷基)N-、C
1-6烷基-C(O)-NH-、C
1-6烷基-S(O)
2-NH
2-、C
1-6烷基-NH-C(O)-、(C
1-6烷基)(C
1-6烷基)N-C(O)-、C
1-6烷基-O-C(O)-、C
1-6烷基-S(O)
2-、C
1-6烷基-S-、C
1-6烷基-C(O)-;所述“C
1-6烷基”如前文所定义,优选为“C
1-4烷基”。
本发明所述的“稠环”是指由两个或两个以上环状结构以并、螺、桥的连接方式所形成的多环系结构。所述的并环是指由两个或两个以上环状结构彼此公用两个相邻的环原子(即共用一个键)所形成的稠环结构。所述的桥环是指有两个或两个以上环装结构彼此共用两个非相邻的环原子所形成的稠环结构。所述的螺环是指由两个或两个以上环状结构彼此共用一个环原子所形成的稠环结构。
本发明所述的“3-12元环烯基”,在不特别指明的情况下,包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形,例如3-8元单环烯、7-11元螺环烯、7-11元并环烯、6-11元桥环烯等。
本发明所述的环烷基包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形;例如“3-12元环烷基”,可以是单环、双环、或者多环环烷基系统(也称为稠环系统)。在不特别指明的情况下,单环系统是含3-8个碳原子的环烃基基团。3-8元环烷基实例包括但不限于:环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。稠环环烷基包括并环环烷基、桥环烷基、螺环烷基。并环环烷基可以为6-11元并环环烷基、7-10元并环环烷基,其的代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷。所述的螺环基可以为7-12元螺环基、7-11元螺环基,其实例包括但不限于:
所述的桥环基可以为6-11元桥环基、7-10元桥环基,其实例包括但不限于:
本发明所述的“杂环基”是指3-12元的至少一个环碳原子被选自O、S、N的杂原子替代的非芳香性的环状基团,优选1-3个杂原子,同时包括碳原子、氮原子和硫原子可以被氧代。
“3-12元杂环基”,是指单环杂环基、双环杂环基系统或多环杂环基系统(也称为稠环系统),包括饱和、部分饱和的杂环基,但不包括芳环。在不特别指明的情况下,包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)、饱和、部分饱和的情形。
单杂环基可以为3-8元杂环基、3-8元饱和杂环基、3-6元杂环基、4-7元元杂环基、5-7元杂环基、5-6元杂环基、5-6元含氧杂环基、3-8元含氮杂环基、5-6元含氮杂环基、5-6元饱和杂环基等。“3-8”元饱和杂环基,其实例包括但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、四氢噻吩基、咪唑烷基、吡唑烷基、1,2-噁唑烷基、1,3-噁唑烷基、1,2-噻唑烷基、1,3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1,4-二氧杂环己烷基、1,4-氧硫杂环己烷基;“3-8”元部分饱和杂环基,其实例包括但不限于4,5-二氢异噁唑基、4,5-二氢噁唑基、2,5-二氢噁唑基、2,3-二氢噁唑基、3,4-二氢-2H-吡咯基、2,3-二氢-1H-吡咯基、2,5-二氢-1H-咪唑基、4,5-二氢-1H-咪唑基、4,5-二氢-1H-吡唑基、4,5-二氢-3H-吡唑基、4,5-二氢噻唑基、2,5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2,3,4,5-四氢吡啶基、1,2-异噁嗪基、1,4-异噁嗪基或6H-1,3-噁嗪基等。稠杂环包括并杂环基、螺杂环基、桥杂环基,可以是饱和的、部分饱和的或不饱和的,但不是芳香性的。稠杂环基是稠合到苯环、5-6元的单环环烷基、5-6元单环环烯基、5-6元单环杂环基或5-6元单环杂芳基的5-6元单环杂环基环。所述的并杂环基可以为6-12元并环基、7-10元并环基、6-10元并环基、6-12元饱和并环基,代表性实例包括但不限于:3-氮杂双环[3.1.0]己烷基、3,6-二氮杂双环[3.2.0]庚烷基、3,8-二氮杂双环[4.2.0]辛烷基、3,7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3,4-c]吡咯基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,4-b][1,4]噁嗪基、八氢-1H-吡咯并[3,4-c]吡啶基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2,3-二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基。所述的螺杂环基可以为6-12元螺杂环基、7-11元螺杂环基、6-12元饱和螺环基,其实例包括但不限于:
本发明所述“芳基”,是指含有6-14个碳原子的环状芳香性基团,包括,苯基、萘、菲等。
本发明所述的杂芳基,包括可能形成的所有单环、稠环、全部芳香、部分芳香的情形。例如“5-10元杂芳基”是指至少一个环碳原子被选自O、S、N的杂原子替代的芳香性的环状基团,优选1-3个杂原子,同时包括碳原子、硫原子被氧代的情况,例如碳原子被C(O)替代,硫原子被S(O)、S(O)
2替代,氮原子
可被
替代。杂芳基包括单杂芳基和稠杂芳基,在不特别指明的情况下,单杂芳基可以为5-7元杂芳基、5-6元杂芳基,其实例包括但不仅限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻吩基、三唑基和三嗪基。在某些实施例中,稠杂芳基是指单环杂芳环稠合到苯基、环烯基、杂芳基、环烷基、杂环基所形成的基团,稠杂芳基可以为8-12元并杂芳基、9-10元并杂芳基,例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢异喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基和6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐或其溶剂化物。这样的可药用盐包括诸如以下的酸的盐:盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH
2)n-COOH(其中n是0~4))等。碱的盐:钠盐、钾盐、钙盐、铵盐等。本领域技术人员知晓多种无毒的可药用加成盐。
本发明所述“异构体”是指立体异构体和互变异构体。
立体异构体是指当化合物存在不对称原子时,会产生对映异构体;当化合物存在双键或环状结构时,会产生顺反异构体;所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、几何异构体、差向异构体及其混合物,均包括在本发 明范围中。
“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体,互变异构体是一种特殊的官能团异构体。如含有α-H的羰基化合物的互变异构,具体如
如其他质子迁移互变异构,具体如酚-酮互变异构、亚硝基-肟互变异构、亚胺-烯胺互变异构。
T、T1、T2分别独立地为任意符合化合物成键规律的基团。
本发明化合物含有内酰胺结构,存在
互变异构,当提到本发明化合物时,意味着该化合物的互变异构体也同时提及。本发明合成实施例合成得到任意一种互变异构体的类型,意味着同时得到另一种互变异构构型,其能迅速地相互转换,且处于动态平衡中。
本发明所述的“氘代”指化合物或基团中的一个或多个氢被氘所取代。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物或其药学上可接受的盐、异构体、组合物或药物制剂的量。包含“治疗有效量”的实际量会根据多种情况而变化,多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
化合物制备
通过标准化学方法在内的多种方法,可以制备本发明的化合物。除非另外指出,否则任何前面定义的变量将继续具有前面定义的含义。示例性的一般合成方法阐述在下述方案中,并且可以很容易的改进以制备本发明的其他化合物。在实施例部分中制备本发明的具体化合物。
在一些实施例中,式(I)的化合物可以通过式(I-d)的化合物与式(I-e)的化合物通过金属催化的偶联或芳香亲核取代等反应来制备。
在一些实施例中,式(I-d)的化合物可以通过式(I-c)的化合物与卤代试剂、 取代或未取代的磺酰氯或磺酸酐的作用来制备。
在一些实施例中,式(I-c)化合物可通过式(I-b)的化合物在合适的碱的作用下,关环来制备。
在一些实施例中,式(I-b)化合物可以通过式(I-a)的化合物与氰基乙酸在合适的肽偶联剂作用下反应来制备。
上述实施方式中,X
1、X
2、X
3、X
4、R
1、R
2、A、L和m如上文中所定义,Ra
1选自C
1-6烷基,LG选自卤素、取代或未取代苯磺酸酯、C
1-6烷基磺酸酯、三氟甲磺酸酯等。
在一些实施例中,式(I)的化合物可以通过式(I-f2)的化合物与合适的含有R
2基团的试剂通过金属催化的偶联反应,或者式(I-f2)的化合物与合适的试剂通过金属催化的偶联反应后,再经过一步或多步常规的化学反应转化(如氧化、还原、加成、取代、氢化、氯代、氨化等)来制备。
在一些实施例中,式(I-f2)的化合物可以通过式(I-d2)的化合物与式(I-e)的化合物通过芳香亲核取代等反应来制备。
在一些实施例中,式(I-d2)的化合物可以通过式(I-c2)的化合物与卤代试剂、取代或未取代的磺酰氯或磺酸酐的作用来制备。
在一些实施例中,式(I-c2)的化合物可以通过式(I-b2)的化合物在合适的碱的作用下,关环来制备。
在一些实施例中,式(I-b2)的化合物可以通过式(I-a2)的化合物与氰基乙酸 在合适的肽偶联剂作用下反应来制备。
上述实施方式中,X
1、X
2、X
3、X
4、R
1、R
2、A、L和m如上文中所定义,Ra
1选自C
1-6烷基,LG选自卤素、取代或未取代苯磺酸酯、C
1-6烷基磺酸酯、三氟甲磺酸酯等。X
5、X
6、X
7、X
8独立的选自N或C-Xa,其中Xa为溴或碘,X
5、X
6、X
7、X
8中至少有一个为N。
卤代试剂,是指用于卤化反应的试剂,包括但不限制于N-溴代琥珀酰亚胺、
N-
氯代丁二酰亚胺、N-碘代丁二酰亚胺、二溴海因、三溴化磷、三氯化膦、氯化亚砜、三氯氧磷、五氯化磷或三溴氧磷。
合适的碱,是指包括有机碱和无机碱。其中,有机碱包括但不限制于叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、LiHMDS、N,N-二异丙基乙胺、三乙胺、二异丙基胺基锂等。无机碱包括但不限制于氢化钠,碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钾、氢氧化钠、氢氧化镁、氢氧化钙等。
取代或未取代的磺酰氯是指Ra
2-SO
2Cl。
取代或未取代的磺酸酐是指(Ra
2-SO
2)
2-O。
其中,Ra
2选自C
1-6烷基、C
1-6卤代烷基、取代或未取代的芳基等。
肽偶联剂,是指能够活化羧酸与胺形成酰胺的试剂,包括但不限制于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,O-苯并三氮唑-四甲基脲六氟磷酸酯,N,N'-羰基二咪唑,苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐,丙基磷酸酐,碳化二亚胺等。
本文中使用的缩写,“DIPEA”是指N,N-二异丙基乙胺;“EA”是指乙酸乙酯;“PE”是指石油醚;“DCM”是指二氯甲烷;“THF”是指四氢呋喃。
制备例1:中间体4-甲氧基-4-甲基哌啶-三氟乙酸盐的合成
步骤1:4-羟基-4-甲基哌啶-1-羧酸叔丁酯的合成
将原料4-氧代哌啶-1-羧酸叔丁酯(5.0g,0.025mol,1.0eq)溶于四氢呋喃(25ml),氮气保护0℃下加入甲基氯化镁试剂(9mL,0.0055mol,1.1eq)。反应两个小时后TLC检测反应完,加入稀盐酸调节PH=4,再加入水(30mL),乙酸乙酯(30mL×3)萃取,有机相干燥过滤减压浓缩,粗品经硅胶柱层析(PE:EA=5:1)得黄色液体4-羟基-4-甲基哌 啶-1-羧酸叔丁酯(5.2g,收率:96%)。
步骤2:4-甲氧基-4-甲基哌啶-1-羧酸叔丁酯的合成
将原料4-羟基-4-甲基哌啶-1-羧酸叔丁酯(500mg,2.32mmol,1.0eq)溶于四氢呋喃(5mL),加入钠氢(186mg,4.64mmol,2.0eq),反应1h后加入碘甲烷(659mg,4.64mmol,2.0eq),反应8h后TLC检测反应完。向反应瓶中加10mL水,乙酸乙酯萃取(20mL×3),有机相干燥过滤减压浓缩,粗品经硅胶柱层析(PE:EA=20:1)得黄色液体4-甲氧基-4-甲基哌啶-1-羧酸叔丁酯(306mg,收率:57%)。
步骤3:4-甲氧基-4-甲基哌啶-三氟乙酸盐的合成
将原料4-甲氧基-4-甲基哌啶-1-羧酸叔丁酯(500mg,2.18mmol,1.0eq)溶于二氯甲烷(4mL),在0℃下加入三氟乙酸(3mL),反应1h后TLC检测反应完。直接减压浓缩得黄色液体4-甲氧基-4-甲基哌啶-三氟乙酸盐(530mg,收率:100%)
制备例2:中间体4-羟基-4-(氘代甲基)哌啶-1-羧酸叔丁酯的合成
向反应瓶中加入Mg(4.40g,181.1mmol,1.9eq)、I
2(0.20g,0.79mmol)和Et
2O(200mL),氮气保护下滴加CD
3I(26.19g,180.7mmol,1.8eq),室温下反应2.5小时。将4-氧代哌啶酮-1-甲酸叔丁酯(20.0g,100.38mmol,1.0eq)加入2-甲基四氢呋喃(160mL),降温至-30~-40℃,将制好的格式试剂滴加到溶液中,控温-30℃以下,滴完后室温反应18小时。TLC检测反应完全,向反应液中加入饱和氯化铵溶液(400mL)和乙酸乙酯(400mL),分液,水相用乙酸乙酯(2×300mL)萃取,有机相合并,无水硫酸钠干燥,抽滤,滤液浓缩,粗品经硅胶柱层析纯化(PE:EA=3:1)得产品(16g,收率:73%)。
制备例2:中间体6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈和2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈的合成
步骤1:6-乙基-3-(氰基乙酰胺基)-1-吡啶-4-甲酸甲酯的合成
将中间体6-乙基-3-氨基-1-吡啶-4-甲酸甲酯(131g,727.13mmol,1.0eq)溶于二氯甲烷(1.31L),在冰浴条件下加入氰基乙酸(74.22g,872.56mmol,1.2eq),分批加入EDCI(209.07g,1090.70mmol,1.5eq),25℃反应2小时,LC-MS检测反应完全。向反应液中加入H
2O(1.5L),分液,有机相用H
2O(2×800mL)洗,无水硫酸钠干燥,抽滤,滤液浓缩,粗品经甲基叔丁基醚(500mL)打浆得到产品(165g,收率:91.78%)。
步骤2:6-乙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-乙基-3-(氰基乙酰胺基)-1-吡啶-4-甲酸甲酯(165g,667.34mmol,1.0eq)溶于乙醇(1.65L)中,冰浴条件下分批加入乙醇钠(136.24g,2002.62mmol,3.0eq),加完25℃反应2小时,LC-MS检测反应完全。浓缩,加H
2O(1.5L),在冰浴条件下用浓盐酸调pH值至4以下,析出大量淡黄色固体,抽滤,滤饼干燥得到产品(138g,收率:96.09%)。
步骤3:6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈和2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈的合成
将中间体6-乙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(605g,2.81mol,1.0eq)溶于乙腈(3L),冰浴下加入三氯氧膦(1723g,11.24mol,4.0eq),100℃反应2小时。将反应液降温,浓缩,加入乙腈分散(1L),倒入冰水中,用饱和氢氧化钠溶液调pH值至5-6左右,有大量黄色固体析出,抽滤,烘干得粗品,粗品用正庚烷/乙酸乙酯(3L/0.6L)打浆,抽滤得到6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(510g,收率:78%)。
滤液浓缩,粗品经硅胶柱层析纯化(PE:EA=10:1)得到2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(50g,收率:7%)。
实施例1:6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物163)
步骤1:6-氯-2H-吡啶并[3,4-d][1,3]恶嗪-2,4(1H)-二酮的合成
将5-氨基-2-氯异烟酸(30g,0.1738mol,1.0eq),溶于N,N-二甲基甲酰胺(300mL)中,0℃下分批加入N,N’-羰基二咪唑(48g,0.2955mol,1.7eq),缓慢升至室温过夜。LC-MS显示反应完全,冷却至室温,不经处理直接进行下一步。
步骤2:6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
向上述反应液中加入三乙胺(35.182g,0.3478mol,2eq)和氰乙酸乙酯(19.665g,0.1738mol),150℃反应3h,LC-MS监测反应完全,反应液冷却至室温,减压浓缩,加入水(200mL),用盐酸(1mol/L)调节pH值至1,搅拌15分钟,抽滤,滤饼用EA洗涤两次,40℃烘干得浅砖红色固体状产物(25.655g,产率:66%)。
步骤3:4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(5.0g,0.0226mol,1eq)和三氯氧磷(15mL)加入反应瓶,将反应瓶放入已经加热至100℃的油浴中,反应约6min,固体开始慢慢溶解,颜色由淡黄色开始加慢慢加深。TLC检测反应完全,冷却至室温,向瓶中加入适量DCM,倒入冰水(100mL)中,搅拌10min,抽滤,滤饼用甲基叔丁基醚洗,抽干,40℃真空干燥得淡黄色固体状产品。分五批投料,共投料6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈25.655g(0.1157mol)得到产品19.486g(产率:70.1%)。
步骤4:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL),加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq),80℃反应2小时。LC-MS检测反应完全,加入水(10mL),二氯甲烷(10mL×3)萃取,有机相用水洗(10mL×3),无水硫酸钠干燥,过滤,减压浓缩得到黄色固体状产物(2.7g粗品)。
步骤5:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-(丙-1-烯-2-基)-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(500mg,1.5mmol,1.0eq)溶于1,4-二氧六环(5mL)和H
2O(1mL)中,加入三氟(丙-1-烯-2-基)硼酸钾(668mg,4.5mmol,3.0eq)和碳酸铯(1.466g,4.5mmol,3.0eq),氮气保护下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg,0.15mmol,0.1eq),100℃反应12小时,LC-MS检测反应完全。加入水(20mL),乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=50:1)得到产品(390mg,收率:76.9%)。
步骤6:6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-(丙-1-烯-2-基)-1,2-二氢-1,7-二氮杂萘-3-甲腈(390mg,1.15mmol,1.0eq)溶于甲醇(10mL),加入Pd/C(100mg),氢气条件下反应12小时,LC-MS检测反应完全。抽滤,滤液减压浓缩,粗品用甲基叔丁醚打浆,抽滤,粗品再经制备薄层层析分离(DCM:MeOH=15:1)得到产品(100mg,收率:25.6%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.82(s,1H),8.61(s,1H),7.38(s,1H),3.60-3.61(m,4H),3.19(s,3H),3.06-3.13(m,1H),1.90-1.93(m,2H),1.75-1.82(d,2H),1.26(s,9H).
分子式:C
19H
24N
4O
2分子量:340.43 LC-MS(Pos,m/z)=341.19[M+H]
+.
实施例2:6-环丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物164)
步骤1:2-氯-5-硝基异烟酸乙酯的合成
将2-氯-5-硝基异烟酸(20.0g,98.74mmol,1.0eq)溶于原甲酸三乙酯(43.9g,296.20mmol,3.0eq),120℃反应3h,TLC检测无原料,减压浓缩,得到黄色油状液体,加石油醚(150mL),搅拌12h,过滤,滤饼室温烘干得到产品(11.0g,收率:51.6%)。
步骤2:2-环丙基-5-硝基异烟酸乙酯的合成
将2-氯-5-硝基异烟酸乙酯(11.0g,47.70mmol,1.0eq)、环丙基硼酸(10.2g,119.25mmol,2.5eq)和磷酸钾(35.4g,166.95mmol,3.5eq)溶于水(27.5mL)和甲苯(275mL)的混合溶剂中,氮气保护下加三苯基膦(2.5g,9.54mmol,0.2eq)和醋酸钯(1.1g,4.77mmol,0.1eq),氮气置换三次,回流反应24h,TLC检测反应完全,减压浓缩,粗品经硅胶柱层析(EA:PE=1:30)纯化得到产品(6.18g,收率:55%)。
步骤3:5-氨基-2-环丙基异烟酸乙酯的合成
将中间体2-环丙基-5-硝基异烟酸乙酯(6.18g,26.16mmol,1.0eq)溶于无水乙醇(60mL),加入铁粉(5.86g,104.64mmol,4.0eq),升温至回流,滴加乙酸(9.4g,156.96mmol,6.0eq),回流反应3h,TLC检测反应完全,向反应液中加入乙酸乙酯(100mL),趁热过滤,滤饼用乙酸乙酯淋洗,滤液减压浓缩,加水(50mL)和乙酸乙酯(100mL),冰水浴降温,加碳酸氢钠固体调pH值至8左右,分液,水相用乙酸乙酯(50mL×3)萃取,有机相合并,用无水硫酸镁干燥,过滤,滤液减压浓缩得到产品(4.77g,收率:90%)。
步骤4:5-(2-氰基乙酰胺基)-2-环丙基异烟酸乙酯的合成
将中间体5-氨基-2-环丙基异烟酸乙酯(4.77g,23.13mmol,1.0eq)溶于二氯甲烷(60mL),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(8.7g,46.25mmol,2.0eq)和氰基乙酸(3g,34.69mmol,1.5eq),室温搅拌16h。TLC监测无原料,加二氯甲烷(40mL),用水(50mL×2)洗涤,有机相用饱和碳酸钠水溶液(50mL)洗涤,无水硫酸镁干燥,过滤,滤液减压浓缩得到产品(5.6g,收率:100%),按理论量投入下一步。
步骤4:6-环丙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体5-(2-氰基乙酰胺基)-2-环丙基异烟酸乙酯(5.6g,20.51mmol,1.0eq)溶于无水乙醇(100mL),搅拌10min,加乙醇钠(4.7g,69.39mmol,3.0eq),室温搅拌1h。TLC检测有原料剩余,补加乙醇钠(4.7g,69.39mmol,3.0eq),室温搅拌2h。TLC检测无原料,减压浓缩,加水(200mL),用甲基叔丁基醚(100mL×2)萃取,水相冰水降温,用浓盐酸调pH值至1~2,析出固体,过滤,滤饼用水淋洗,滤饼烘干得到产品(3.95g,收率:84.84%)。
步骤5:2,4-二氯-6-环丙基-1,7-二氮杂萘-3-甲腈的合成
将中间体6-环丙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(1g,4.4mmol,1.0eq)溶于无水乙腈(15mL),加三氯氧磷(1.35g,8.8mmol,2.0eq),升温至80℃反应1h。TLC检测剩余大部分原料,补加三氯氧磷(1.35g,8.8mmol,2.0eq),加热至90℃,LC-MS检测反应完全,降至室温,减压浓缩,加乙腈(10mL),冰水降温,用氢氧化钠溶液调pH值至8~9,析出黄色固体,过滤,滤饼用水淋洗得到产品(1.5g粗品),按理论量投入下一步。
步骤6:4-氯-6-环丙基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体2,4-二氯-6-环丙基-1,7-二氮杂萘-3-甲腈(1.16g粗品,4.40mmol,1.0eq)溶于三氟乙酸(10mL)和水(2.5mL)的混合溶剂中,加热至60℃反应18h,降温0℃,加水(20mL),用氢氧化钠固体调pH值至8~9,析出黄色固体,过滤,滤饼用水淋洗,烘干,加乙酸乙酯(10mL),加热至60℃搅拌1h,趁热过滤,滤饼烘干得到产品(660mg,两步收率:61%)。
步骤7:2-氯-6-环丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
将中间体4-氯-6-环丙基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(200mg,0.81mmol,1.0eq)溶于N,N-二甲基乙酰胺(2mL),加DIPEA(420.5mg,3.26mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(188.8mg,1.14mmol,1.4eq),升温至80℃反应1h,TLC检测无原料,将反应液降至室温,倒入冰水(20mL)中,用乙酸乙酯(50mL×3)萃取,有机相合并,用水(50mL×2)洗涤,无水硫酸镁干燥,过滤,滤液减压浓缩,粗品用甲基叔丁基醚(5mL)打浆1h,抽滤,滤饼烘干得到产品(182mg,收率:66%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.85(s,1H),8.51(d,1H),7.45(s,1H),3.61-3.60(d,4H),3.19(s,3H),2.27-2.21(m,1H),1.93-1.90(m,2H),1.84-1.80(m,2H),1.22(s,3H),0.95(m,2H),0.85(m,2H).
分子式:C
19H
22N
4O
2 分子量:338.17 LC-MS(Pos,m/z)=339.13[M+H]
+.
实施例3:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成(化合物165)
步骤1:3-氨基吡啶甲酸甲酯的合成
将3-氨基吡啶甲酸(10.0g,72.39mmol,1.0eq)溶于无水甲醇(100mL),滴加硫酸(10mL),加毕,升温至80℃反应144h,LC-MS检测20%原料剩余,减压浓缩,加乙酸乙酯(100mL),用饱和碳酸钠水溶液调pH=9左右,分液,水相用乙酸乙酯(100mL×3)萃取,有机相合并,用无水硫酸钠干燥,过滤,减压浓缩得到产品(5.3g,收率:48%)。
步骤2:3-(2-氰基乙酰胺基)吡啶甲酸甲酯的合成
将中间体3-氨基吡啶甲酸甲酯(5.3g,34.83mmol,1.0eq)溶于二氯甲烷(60mL),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(10g,52.25mmol,1.5eq)和氰基乙酸(3.6g,41.79mmol,1.2eq),加毕,室温搅拌1h。TLC显示无原料,加二氯甲烷(100mL)和水(50mL),搅拌10min,析出固体,过滤,滤饼收集,干燥得部分产品(3.3g),滤液分液,水相用二氯甲烷(50mL)萃取,有机相合并,无水硫酸镁干燥,过滤,滤液减压浓缩,粗品用甲基叔丁基醚打浆,过滤,烘干得另一部分产品(2.68g),合并得到产品(6.0g,收率:78.9%)。
步骤3:4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体3-(2-氰基乙酰胺基)吡啶甲酸甲酯(2.68g,12.23mmol,1.0eq)溶于无水乙醇(100mL),加热至50℃搅拌0.5h,加乙醇钠(2.5g,36.67mmol,3.0eq),加毕,50℃搅拌1h。TLC显示无原料,减压浓缩,加水(50mL),用浓盐酸调pH=2左右,析出固体,过滤,滤饼依次用水和丙酮淋洗,烘干得到产品(2.28g,收率:100%)。
步骤4:2,4-二氯-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(1.5g,8.02mmol,1.0eq)加入三氯氧磷(6.5g,10mL),加毕,升温至110℃反应2h,LC-MS检测无原料,降至室温,倒入冰水(100mL)中,搅拌10min,析出黄色固体,过滤,滤饼用水淋洗,烘干得到产品(1.5g,收率:83.7%)。
步骤5:4-氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体2,4-二氯-1,2-二氢-1,5-二氮杂萘-3-甲腈(1.5g,6.69mmol,1.0eq)溶于三氟乙酸(15mL)和水(4mL)的混合溶剂中,加热至60℃反应16h,LC-MS检测无原料,降至室温,将反应液倒入冰水(50mL)中,析出黄色固体,过滤,滤饼依次用水和丙酮淋洗,烘干得到产品(822mg,收率:60%)。
步骤6:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体4-氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(500mg,2.43mmol,1.0eq)溶于N,N-二甲基乙酰胺(3mL),加DIPEA(1.26g,9.72mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(564mg,3.40mmol,1.4eq),加毕,升温至80℃反应1h,LC-MS检测无原料,将反应液降至室温,倒入冰水(50mL)中,析出固体,用二氯甲烷溶解,无水硫酸镁干燥,过滤,滤液减压浓缩,粗品加乙酸乙酯(10mL)和甲基叔丁基醚(10mL)的混合溶剂中,搅拌48h,抽滤,滤饼烘干得到产品(190mg,收率:26.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.64(s,1H),8.50-8.48(d,1H),7.66-7.63(d,1H),7.59-7.56(d,1H),4.06-4.02(m,2H),3.68-3.61(m,2H),3.19(s,3H),1.91-1.88(m,2H),1.79-1.71(m,2H),1.19(s,3H).
分子式:C
16H
18N
4O
2分子量:298.35 LC-MS(Pos,m/z)=298.98[M+H]
+.
实施例4:4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成(化合物166)
步骤1:3-氨基吡啶甲酸乙酯的合成
将原料3-氨基吡啶甲酸(18.0g,0.13mol,1.0eq)溶于无水乙醇(300mL),滴加硫酸(20mL),升温至80℃反应92h,LC-MS检测还有23%原料,减压浓缩,加乙酸乙酯(100mL)和水(200mL),用碳酸钾水溶液调pH值至9左右,过滤,滤饼用乙酸乙酯淋洗,滤液分液,水相再用乙酸乙酯(100mL×4)萃取,有机相合并,用无水硫酸钠干燥,过滤,减压浓缩得粗品,用甲基叔丁基醚(100mL)和石油醚(100mL)的混合溶剂打浆1h,过滤,滤饼烘干得到产品(9.2g,收率:42.5%)。
步骤2:3-氨基-6-溴吡啶甲酸乙酯的合成
将中间体3-氨基吡啶甲酸乙酯(9.2g,55.36mmol,1.0eq)溶于乙腈(225mL),加NBS(9.8g,53.36mmol,1.0eq),室温反应2~3h,TLC检测反应完全,减压浓缩,粗品经硅胶柱层析(EA:PE=1:3)纯化得到产品(12g,收率:88.8%)。
步骤3:6-溴-3-(2-氰基乙酰胺基)吡啶甲酸乙酯的合成
将中间体3-氨基-6-溴吡啶甲酸乙酯(3.0g,12.24mmol,1.0eq)溶于二氯甲烷(50mL),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(4.7g,24.48mmol,2.0eq)和氰基乙酸(1.56g,18.36mmol,1.5eq),室温搅拌1h。TLC检测无原料,加二氯甲烷(50mL),依次用水(50mL×2)和饱和碳酸钠水溶液(50mL)洗涤,无水硫酸镁干燥,过滤,滤液减压浓缩得到产品(3.2g,收率:84.2%)。
步骤4:6-溴-4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体6-溴-3-(2-氰基乙酰胺基)吡啶甲酸乙酯(3.2g,10.26mmol,1.0eq)溶于无水乙醇(50mL),加热至40℃,加乙醇钠(2.1g,30.79mmol,3.0eq),40℃搅拌1h。TLC检测无原料,减压浓缩,加水(50mL),用浓盐酸调pH值至2~3,析出固体,过滤,滤饼用水淋洗,滤饼烘干得到产品(2.3g,收率:85.1%)。
步骤5:2,4,6-三氯-1,5-二氮杂萘-3-甲腈的合成
将中间体6-溴-4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(2.3g,8.64mmol,1.0eq)、三氯氧磷(6.6g,43.2mmol,5.0eq)和五氯化磷(3.6g,17.28mmol,2.0eq)升温至110℃反应3h,LC-MS检测无原料,减压浓缩,加乙腈(10mL),用氢氧化钠水溶液调pH值至8左右,得到淡黄色固体,过滤,滤饼用水淋洗,得到产品,按理论量投下一步反应。
步骤6:4,6-二氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将上步所得中间体2,4,6-三氯-1,5-二氮杂萘-3-甲腈溶于三氟乙酸(22mL)和水(5.5mL)的混合溶剂中,加热至90℃反应2h,LC-MS检测无原料,降至室温,将反应液倒入冰水(50mL)中,析出黄色固体,过滤,滤饼加甲醇(20mL),加热回流1h,趁热过滤,滤液减压浓缩,用乙酸乙酯(20mL)打浆1h,过滤,滤饼烘干得到产品(311mg,产率:15%)。
步骤7:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体4-氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(310mg,1.29mmol,1.0eq)溶于N,N-二甲基乙酰胺(2mL),加DIPEA(666.4mg,5.16mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(299.5mg,1.81mmol,1.4eq),升温至80℃反应1h,LC-MS检测无原料,将反应液降至室温,倒入冰水(30mL)中,析出固体,过滤,滤饼用水淋洗,烘干得到产品(260mg,收率:60.5%)。
步骤8:4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(260mg,0.78mmol,1.0eq)(质量分数50%)三甲基环三硼氧烷(784.5mg,3.12mmol,4.0eq)和碳酸铯(764.2mg,2.34mmol,3.0eq)溶于1,4-二氧六环(8mL)和水(1.5mL)的混合溶剂中,氮气置换三遍,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(57.0mg,0.078mmol,0.1eq),氮气保护下90℃反应6h,LC-MS检测反应完全。减压浓缩,粗品经硅胶柱层析(DCM:MeOH=80:1)纯化得到黄色固体,用甲基叔丁基醚打浆,过滤,滤饼烘干得到产品(160mg,收率:65.6%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.57(s,1H),7.56-7.53(d,1H),7.47-7.45(d,1H),4.06-4.02(d,2H),3.65-3.60(m,2H),3.19(s,3H),2.52(s,3H),1.91-1.88(m,2H),1.80-1.73(m,2H),1.19(s,3H).
分子式:C
17H
20N
4O
2 分子量:312.37 LC-MS(Pos,m/z)=313.40[M+H]
+.
实施例5:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(化合物167)
步骤1:3-氨基吡啶甲酸乙酯的合成
将原料3-氨基吡啶甲酸(20.0g,0.14mol,1.0eq)溶于无水乙醇(300mL),滴加硫酸(10mL),升温至80℃反应16h,LC-MS检测剩余90%原料,补加无水乙醇(300mL),滴加硫酸(10mL),回流反应24h,LC-MS检测剩余30%原料,减压浓缩,加乙酸乙酯(300mL)和水(200mL),用碳酸钾水溶液调pH值至9左右,过滤,滤饼用乙酸乙酯淋洗,分液,水相再用乙酸乙酯(100mL×3)萃取,有机相合并,用无水硫酸钠干燥,过滤,减压浓缩得到产品(10g,收率:41.8%)。
步骤2:3-氨基-6-溴吡啶甲酸乙酯的合成
将中间体3-氨基吡啶甲酸乙酯(6g,36.11mmol,1.0eq)溶于乙腈(150mL),加NBS(7.1g,39.72mmol,1.1eq),室温反应48h,TLC检测反应完全,减压浓缩,粗品经硅胶柱层析(EA:PE=1:10~1:6)纯化得到产品(6.28g,收率:71.3%)。
步骤3:6-溴-3-(2-氰基乙酰胺基)吡啶甲酸乙酯的合成
将中间体3-氨基-6-溴吡啶甲酸乙酯(6.28g,25.6mmol)溶于二氯甲烷(100mL),加1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(9.8g,51.25mmol,2.0eq)和氰基乙酸(3.3g,38.45mmol,1.5eq),室温搅拌1h。TLC检测无原料,加二氯甲烷(50mL),依 次用水(80mL×2)和饱和碳酸钠水溶液(80mL)洗涤,析出固体,过滤,滤液分液,有机相用无水硫酸镁干燥,过滤,滤液减压浓缩得到产品(7.4g,收率:93.6%)。
步骤4:6-溴-4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体6-溴-3-(2-氰基乙酰胺基)吡啶甲酸乙酯(7.4g,23.71mmol,1.0eq)溶于无水乙醇(150mL),加热至50℃搅拌0.5h,加乙醇钠(4.8g,71.13mmol,3.0eq),50℃搅拌0.5h。TLC检测无原料剩余,减压浓缩,加水(100mL),加热至50℃溶解,用浓盐酸调pH值至2~3,析出固体,过滤,滤饼依次用水和丙酮淋洗,滤饼烘干得到产品(6.4g粗品),按理论量投入下一步。
步骤5:2,4,6-三氯-1,5-二氮杂萘-3-甲腈的合成
将中间体6-溴-4-羟基-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(6.3g粗品,23.71mmol,1.0eq)加入三氯氧磷(29g,189.68mmol,8.0eq),升温至110℃反应4h,LC-MS检测大部分是原料,加五氯化磷(9.8g,47.42mmol,2.0eq),110℃反应3h,LC-MS检测无原料,降至室温,倒入冰水(100mL)中,过滤得到产品(3.0g粗品)。
步骤6:4,6-二氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体2,4,6-三氯-1,5-二氮杂萘-3-甲腈(3.0g粗品)溶于三氟乙酸(30mL)和水(7.5mL)的混合溶剂中,加热至60℃反应3h,LC-MS检测无原料,降至室温,将反应液倒入冰水(100mL)中,析出黄色固体,过滤,滤饼依次用水和丙酮淋洗,滤饼烘干得到产品(1.9g,三步收率:76%)。
步骤7:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体4-氯-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(1.9g,7.92mmol,1.0eq)溶于N,N-二甲基乙酰胺(10mL),加DIPEA(3.5g,26.72mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(1.5g,9.35mmol,1.4eq),升温至80℃反应1h,LC-MS检测无原料,将反应液降至室温,倒入冰水(50mL)中,析出固体,滤饼用水淋洗,滤饼烘干得到产品(561mg,收率:21.3%)。
步骤8:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈(500mg,1.5mmol,1.0eq)溶于1,4-二氧六环(15mL)和H
2O(3mL)的混合溶剂中,加入三氟(丙-1-烯-2-基)硼酸钾(301.9mg,2.25mmol,1.5eq)、碳酸铯(1.5g,4.5mmol,3.0eq),氮气保护下,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(109.8mg,0.15mmol,0.1eq),氮气保护下100℃反应15h,LC-MS检测反应完全。减压浓缩,粗品经硅胶柱层析(DCM:MeOH=80:1)纯化得到产品(206mg,收率:42.3%)。
步骤9:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,5-二氮杂萘-3-甲腈的合成
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,5-二氮杂萘-3-甲腈(206mg,0.64mmol,1.0eq)溶于无水甲醇(20mL),加入Pd/C(200mg),氢气置换三次,氢气条件下反应12小时,LC-MS检测反应完全。抽滤,滤饼用甲醇淋洗,滤液减压浓缩得到类白色固体,用甲基叔丁醚(3mL)打浆,过滤,滤饼烘干得到产品(86.9mg,收率:41.9%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.56(s,1H),7.58-7.56(d,1H),7.49-7.47(d,1H),4.10-4.06(d,2H),3.67-3.62(m,2H),3.19(s,3H),2.85-2.79(m,2H),1.92-1.88(m,2H),1.80-1.75(m,2H),1.28-1.24(m,3H),1.19(s,3H).
分子式:C
18H
22N
4O
2 分子量:326.40 LC-MS(Pos,m/z)=327.41[M+H]
+.
实施例6:3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘7-氧化物的合成(化合物178)
步骤1:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将实施例1步骤3产物4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL),加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq),80℃反应2小时。LC-MS检测反应完全,加入水(10mL),二氯甲烷(10mL×3)萃取,有机相用水洗(10mL×3),无水硫酸钠干燥,过滤,减压浓缩得到黄色固体状产物(2.7g粗品)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):12.11(s,1H),8.45(s,1H),7.61(s,1H),3.61-3.59(m,4H),3.18(s,3H),1.91-1.88(m,2H),1.81-1.76(m,2H),1.21(s,3H).
步骤2:4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(1.3g,3.91mmol,1.0eq)、碳酸铯(3.8g,11.73mmol,3.0eq)和三甲基环三硼氧烷(50%THF溶液,3.9g,15.62mmol,4.0eq)溶于1,4-二氧六环(20mL),加毕,氮气置换三次,在加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(286mg,0.39mmol,0.1eq),加毕,氮气置换三次,加热回流12h,TLC检测还有原料,再补加三甲基环三硼氧烷(50%THF溶液,3.9g,15.62mmol,4.0eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(286mg,0.39mmol,0.1eq),继续回流4h,TLC检测无原料,降至室温,加水(50mL)和二氯甲烷(100mL),搅拌5min,析出固体,过滤,滤饼用二氯甲烷淋洗,分液,水相用二氯甲烷(100mL×3)萃取,合并有机相,用无水硫酸钠干燥,过滤,母液减压浓缩,粗品先经硅胶柱层析(MeOH:DCM=1:100~1:50)纯化得产品(309.9mg,收率:25.4%)。
步骤3:3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘7-氧化物的合成
将4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(3.0g,9.6mmol,1.0eq)溶于二氯甲烷(30mL),冰浴降温至0℃,加入间氯过氧苯甲酸(70%,2.367g,9.6mmol,1.0eq),反应12小时,LC-MS检测反应完全。加入二氯甲烷(30mL)和碳酸钾(2.65g,19.2mmol,2.0eq),搅拌30min,抽滤,滤饼用水(50mL)打浆,过滤,滤液减压浓缩,与滤饼合并,烘干得到产品(2.9g,收率:92%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.69(s,1H),8.19(s,1H),7.66(s,1H),3.54-3.65(m,4H),3.19(s,3H),2.37(s,3H),1.87-1.91(d,2H),1.74-1.82(m,2H),1.21(s,3H).
分子式:C
17H
20N
4O
3 分子量:328.36 LC-MS(Pos,m/z)=329.15[M+H]
+.
实施例7:6-(羟甲基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈合成(化合物177)
步骤1:(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)甲基乙酸酯的合成
将实施例6产物3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘7-氧化物(1.5g,4.56mmol,1.0eq)悬浮于乙酸酐(20mL),140℃反应5小时,LC-MS检测反应完全,减压浓缩,加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=50:1)得到产品(220mg,收率:13%)。
步骤2:6-(羟甲基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)甲基乙酸酯(220mg,0.59mmol,1.0eq)和一水合氢氧化锂(170mg,4.05mmol,6.9eq)溶于甲醇(2mL)和水(2mL),反应12小时,LC-MS检测反应完全。减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=10:1)得到产品(110mg,收率:57%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.97(s,1H),8.57(s,1H),7.66(s,1H),5.55-5.58(m,1H),4.59-4.61(d,2H),3.60-3.61(d,4H),3.19(s,3H),1.91-1.94(d,2H),1.73-1.80(m,2H),1.23(s,3H).
分子式:C
17H
20N
4O
3 分子量:328.37 LC-MS(Pos,m/z)=329.15[M+H]
+.
实施例8:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈-7-氮氧化物的合成(化合物180)
步骤1:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将实施例1步骤3产物4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL),加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq),80℃反应2小时。LC-MS检测反应完全,加入水(10mL),二氯甲烷(10mL×3)萃取,有机相用水洗(10mL×3),无水硫酸钠干燥,过滤,减压浓缩得到黄色固体状产物(2.7g粗品)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):12.11(s,1H),8.45(s,1H),7.61(s,1H),3.61-3.59(m,4H),3.18(s,3H),1.91-1.88(m,2H),1.81-1.76(m,2H),1.21(s,3H).
分子式:C
16H
17N
4O
2Cl 分子量:332.79 LC-MS(Pos,m/z)=333.7[M+H]
+
步骤2:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.7g粗品,8.11mmol,1.0eq)溶于1,4-二氧六环(20mL)和H
2O(5mL),加入乙烯基三氟硼酸钾(1.63g,12.17mmol,1.5eq)、碳酸铯(3.965g,12.17mmol,1.5eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(297mg,0.41mmol,0.05eq),氮气保护下100℃反应 8小时。LC-MS检测反应完全,加入水(20mL),二氯甲烷(30mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析(DCM:MeOH=70:1)纯化得到黄色固体状产品(1.15g,收率:43%)。
步骤3:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈(150mg,0.46mmol,1.0eq)溶于甲醇(5mL),加入Pd/C(100mg),氢气置换三次,氢气氛围下反应1小时,LC-MS检测反应完全。抽滤,滤液减压浓缩得到产品(120mg,收率:80%)。
步骤5:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈-7-氮氧化物的合成
将6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.00g,6.13mmol,1.0eq)溶于二氯甲烷(20.00mL)中,冰浴下加入3-氯过氧苯甲酸(70%,1.66g,6.74mmol,1.1eq),氮气保护下,25℃反应4小时,LC-MS检测反应完全。加入水(20mL),用碳酸钾调节pH值到8-9,有固体析出,抽滤得到产品(1.20g,收率:57.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.77(s,1H),8.18(s,1H),7.51(s,1H),3.52-3.62(m,4H),3.18(s,3H),2.76-2.81(m,2H),1.88-1.91(d,2H),1.73-1.80(m,2H),1.05-1.20(m,6H).
分子式:C
18H
22N
4O
3 分子量:342.40 LC-MS(Pos,m/z)=343.40[M+H]
+.
实施例9:6-乙基-4-(4-羟基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物181)
参照化合物180的合成方法合成。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.88(s,1H),8.58(s,1H),7.39(s,1H),4.57(s,1H),3.58-3.73(m,4H),2.78-2.84(m,2H),1.66-1.83(m,4H),1.10-1.30(m,6H).
分子式:C
17H
20N
4O
2 分子量:312.37 LC-MS(Pos,m/z)=313.37[M+H]
+.
实施例10:6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成(化合物183)
步骤1:6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈的合成
在1L单口瓶中加入四氯化碳(600.00mL),2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(30.00g,119.00mmol,1eq),NBS(42.36g,238.00mmol,2eq)和AIBN(15.00g)。90℃反应2小时。LC-MS显示反应完全。将反应液降温至10-15℃,抽滤,滤液浓缩至干,用PE和EA重结晶得到产品6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈35g。
步骤2:6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
在1L单口瓶中,加入乙醇(400.00mL),6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈(20.00g,60.40mmol,1eq),4-甲氧基-4-甲基哌啶盐酸盐(11.00g,66.44mmol,1.1eq)和三乙胺(13.45g,132.88mmol,2.2eq)。90℃反应2小时。LC-MS显示反应完全,将反应液降温至室温,减压浓缩至干,加入400mL水搅拌1小时,抽滤,滤饼用乙醇重结晶,得到产品6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈20g。
步骤3:2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
在250mL单口瓶中加入乙酸(60.00mL),水(30.00mL),6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(15.00g),100℃反应6小时,LC-MS显示反应完全。降温至室温,反应液减压浓缩至干。加入100mL水,调pH=7-8,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,抽滤,滤液减压浓缩至干得到粗品。粗品先用EA热打浆,再用乙醇重结晶,得到产品2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈6g。
步骤4:6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
在250mL单口瓶中,加入DCM(90.00mL),2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(4.50g,13.15mmol,1eq),戴斯-马丁氧化剂(6.14g,1.1eq,14.47mmol),室温搅拌2小时。LC-MS显示反应完全,加入60mL水,30mL饱和硫代硫酸钠溶液,搅拌1小时,分液,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩至干,得粗品,经柱层析纯化,得到产品6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈0.7g。
1HNMR(400MHz,DMSO)δ(ppm):12.33(s,1H),8.70(s,1H),8.19(s,1H),3.62-3.64(d,4H),3.20(s,3H),2.63(s,3H),1.92-1.96(m,2H),1.76-1.78(m,2H),1.24(s,3H).
分子式:C
18H
20N
4O
3,分子量:340.38,LC-MS(Pos,m/z)=341.21[M+H
+].
实施例11:6-乙基-2-羟基-4-(4-(甲氧基-d
3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成(化合物184的互变异构体)
步骤1:4-羟基-4-甲基哌啶-1-羧酸叔丁酯的合成
将原料4-氧代哌啶-1-羧酸叔丁酯(5.0g,25mmol,1.0eq)溶于四氢呋喃(25mL),氮气保护0℃下加入甲基氯化镁试剂(9mL,27mmol,1.1eq)。反应2小时后TLC检测反应完全,加入稀盐酸调节pH=4,再加入水(30mL),乙酸乙酯(30mL×3)萃取,有机相干燥,过滤,减压浓缩,粗品经硅胶柱层析(PE:EA=5:1)纯化得产品(5.2g,收率:96%)。
步骤2:4-(甲氧基-d
3)-4-甲基哌啶-1-羧酸叔丁酯的合成
在100mL单口瓶中,氮气置换,加入4-羟基-4-甲基哌啶-1-羧酸叔丁酯(2.70g,12.55mmol,1eq),THF(27.00mL),分批加入氢化钠(60%,0.76g,1.5eq),室温反应0.5小时。滴加CD
3I(4.00g,27.62mmol,2.2eq),加完后30℃反应过夜。TLC显示反应完全。将反应液减压浓缩至干,加入100mL EA,分液,有机相水洗后,无水硫酸钠干燥,抽滤,滤液减压浓缩至干,得到产品4-(甲氧基-d
3)-4-甲基哌啶-1-羧酸叔丁酯(4.3g)。
步骤3:4-(甲氧基-d
3)-4-甲基哌啶盐酸盐的合成
在500mL单口瓶中氮气置换,加入4-(甲氧基-d
3)-4-甲基哌啶-1-羧酸叔丁酯(4.30g),加入氯化氢乙醇(8.60mL)和乙醇(8.60mL)。30℃反应2小时。TLC显示反应完全,将反应液减压浓缩至干,加入30mL EA搅拌0.5小时,抽滤,得到产品4-(甲氧基-d
3)-4-甲基哌啶盐酸盐1.20g。
步骤4:6-乙基-2-羟基-4-(4-(甲氧基-d
3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
在100mL单口瓶中加入4-氯-6-乙基-2-羟基-1,7-二氮杂萘-3-甲腈(1.50g,6.47mmol,1eq),4-(甲氧基-d
3)-4-甲基哌啶盐酸盐(1.20g,7.12mmol 1.1eq),乙醇(15.00mL),TEA(1.44g,14.23mmol,2.2eq),90℃反应1小时,LC-MS显示反应完全。降温,反应液减压浓缩至干。加入50mL水,搅拌0.5小时,抽滤,得到粗品。粗品经乙醇重结晶,得到产品6-乙基-2-羟基-4-(4-(甲氧基-d
3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(2.03)。
1HNMR(400MHz,DMSO)δ(ppm):11.91(s,1H),8.58(s,1H),7.40(s,1H),3.60-3.61(d,4H),2.78-2.84(q,2H),1.89-1.92(m,2H),1.77-1.82(m,2H),1.26(s,6H).
分子式:C
18H
19D
3N
4O
2,分子量:329.42,LC-MS(Pos,m/z)=330.21[M+H
+].实施例12:(R)-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈和(S)-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
步骤1:6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将实施例1步骤3产物4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL),加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq),80℃反应2小时。LC-MS检测反应完全,加入水(10mL),二氯甲烷(10mL×3)萃取,有机相用水洗(10mL×3),无水硫酸钠干燥,过滤,减压浓缩得到黄色固体状产物(2.7g粗品)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):12.11(s,1H),8.45(s,1H),7.61(s,1H),3.61-3.59(m,4H),3.18(s,3H),1.91-1.88(m,2H),1.81-1.76(m,2H),1.21(s,3H).
分子式:C
16H
17N
4O
2Cl 分子量:332.79 LC-MS(Pos,m/z)=333.7[M+H]
+
步骤2:4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.7g粗品,8.11mmol,1.0eq)溶于1,4-二氧六环(20mL)和H
2O(5mL),加入乙烯基三氟硼酸钾(1.63g,12.17mmol,1.5eq)、碳酸铯(3.965g,12.17mmol,1.5eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(297mg,0.41mmol,0.05eq),氮气保护下100℃反应8小时。LC-MS检测反应完全,加入水(20mL),二氯甲烷(30mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析(DCM:MeOH=70:1)纯化得到黄色固体状产品(1.15g,收率:43%)。
步骤3:6-(1,2-二羟基乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈(500mg,1.542mmol,1.0eq)溶于叔丁醇(10mL)和水(10mL),加入甲磺酰胺(147mg,1.542mmol,1.0eq)和AD-mix-β(6.0g),常温反应12小时,LC-MS检测反应完全。加入水(10mL),二氯甲烷(30mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到产品(552mg,收率:100%)。
步骤4:6-甲酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-(1,2-二羟基乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(552mg,1.542mmol,1.0eq)溶于四氢呋喃(10mL)和水(2mL),加入高碘酸钠(650mg,3.084mmol,2.0eq),反应4个小时,LC-MS检测反应完全。加入水(10mL),乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=60:1)得到黄色固体状产品(160g,两步收率:32%)。
步骤5:6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将中间体6-甲酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(160mg,0.49mmol,1.0eq)溶于四氢呋喃(5mL),在0℃下滴加甲基氯化镁(1mL),反应1小时,LC-MS检测反应完全。加入水(10mL),乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=40:1)得到产品(108mg,收率:64%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):11.93(s,1H),8.58(s,1H),7.72(s,1H),5.48-5.49(d,1H),4.75-4.81(m,1H),3.56-3.65(m,4H),3.20(s,3H),1.91-1.95(m,2H), 1.73-1.79(m,2H),1.38-1.40(d,3H),1.23(s,3H).
分子式:C
18H
22N
4O
3 分子量:342.40 LC-MS(Pos,m/z)=343.17[M+H]
+.
取0.3925g化合物M用甲醇溶解为浓度为2mg/ml的溶液,采用Shimadzu LC-20AD制备液相进行对映异构体分离,分离条件如下:分别收集6分钟及12分钟相应组分得到的化合物。6分钟相应组分得到的化合物是化合物A,12分钟相应组分得到化合物B。旋转蒸发出去溶剂,分别得到化合物A 0.1814g和化合物B 0.1984g。化合物A和B为对映异构体,二者的结构如下,当化合物A为其中一个结构时,化合物B为另外一个:
实施例13:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙酸乙酯的合成(化合物189)
步骤:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙酸乙酯
将实施例12步骤5产物6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(400mg,1.17mmol,1.0eq)溶于DCM(4mL)中,加入DMAP(3mg,0.023mmol,0.02eq)、三乙胺(590mg,5.84mmol,5.0eq)和乙酸酐(240mg,2.34mmol,2.0eq),加热至35℃反应2h,TCL检测还有少量原料剩余,减压浓缩,加水(20mL),用DCM(20mL×3)萃取,有机相合并,用无水硫酸镁干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(MeOH:DCM=1:15)纯化得到产品(238.8mg,收率:51.3%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):12.02(s,1H),8.63(s,1H),7.57(s,1H),5.88-5.86(m,1H),3.59-3.58(m,4H),3.19(s,3H),2.51-2.50(s,3H),1.94-1.91(m,2H), 1.81-1.76(m,2H),1.54-1.53(d,3H),1.23(s,3H).
分子式:C
20H
24N
4O
4 分子量:384.44 LC-MS(Pos,m/z)=385.01[M+H]
+
实施例14:6-乙基-4-(4-羟基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物190)
步骤1:4-羟基-4-(氘代甲基)哌啶盐酸盐的合成
将4-羟基-4-(氘代甲基)哌啶-1-羧酸叔丁酯(3.80g,17.4mmol)加入乙醇(7.60mL)中,加入乙醇氯化氢溶液(7.60mL),室温下反应17小时。TLC检测反应完全,将反应液浓缩,加入乙醇(10mL)和乙酸乙酯(30mL),室温搅拌1.5小时,抽滤得产品(1.70g,收率:63.3%)。
步骤2:6-乙基-4-(4-羟基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将4-氯-6-乙基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.33g,10mmol)、4-羟基-4-(氘代甲基)哌啶盐酸盐(1.70g,11mmol)和三乙胺(2.23g,22.00mmol)加入乙醇(23.3mL),80℃反应2小时。LC-MS显示反应完全,将反应液降至室温,浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=10:1)得到(1.65g,收率:52.4%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):11.88(s,1H),8.57(s,1H),7.38(s,1H),4.56(s,1H),3.56-3.83(m,4H),2.73-2.84(m,2H),1.69-1.83(m,4H),1.10-1.30(m,3H).
分子式:C
17H
17D
3N
4O
2 分子量:315.18 LC-MS(Pos,m/z)=315.92[M+H]
+.
实施例15:6-(1-羟乙基)-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物191)
步骤1:6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈的合成
将2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(85g,337mmol,1.0eq)、NBS(120g,674mmol,2.0eq)和AIBN(42.5g,5.95mmol,0.5eq)溶于四氯化碳(850mL),90℃反应4小时。LC-MS显示反应完全,将反应液降温至10~15℃,抽滤,滤液浓缩,用PE和EA(5:1,120mL)重结晶得产物(50g,收率:44.8%)。
步骤2:4-甲氧基-4-(氘代甲基)哌啶-1-甲酸叔丁酯的合成
将4-羟基-4-(氘代甲基)哌啶-1-羧酸叔丁酯(16.0g,73.4mmol,1.0eq)加入THF(160mL),氮气保护下,分批加入NaH(质量分数60%,4.40g,110.04mmol,1.5eq),加完室温下反应0.5小时,滴加碘甲烷(22.91g,161.40mmol,2.2eq),加完30℃反应16小时。TLC检测反应完全,将反应液浓缩,加入乙酸乙酯(300mL),水洗(2×100mL),无水硫酸钠干燥,抽滤,滤液浓缩,粗品经硅胶柱层析(PE:EA=10:1)纯化得产品(16.5g,收率:96.9%)。
步骤3:4-甲氧基-4-(氘代甲基)哌啶盐酸盐的合成
将4-甲氧基-4-(氘代甲基)哌啶-1-甲酸叔丁酯(16.5g,71.0mmol,1.0eq)加入乙醇(33mL)中,加入乙醇氯化氢溶液(33mL),30℃反应3小时。TLC检测反应完全,将反应液浓缩,加入乙醇(30mL)和乙酸乙酯(90mL),室温搅拌1小时,抽滤得产品(3.36g,收率:28.0%)
步骤4:6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
将6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈(6.00g,18.12mmol,1.0eq)、4-甲氧基-4-(氘代甲基)哌啶盐酸盐(3.36g,19.9mmol,1.1eq)和三乙胺(4.03g,39.9mmol,2.2eq)加入乙醇(60mL),90℃反应2小时。LC-MS检测显示反应完全,将反应液降温至室温,浓缩,加入水(150mL),搅拌0.5小时,抽滤,滤饼用乙醇(50mL)重结晶得产品(6.20g,收率:80.1%)。
步骤5:6-(1-羟乙基)-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-1,7-二氮杂萘-3-甲腈(6.20g,14.54mmol,1.0eq)和乙酸钠(2.50g,30.53mmol,2.1eq)加入乙酸(24.80mL)和水(12.40mL)中,100℃反应3小时。LC-MS检测显示产物占60%,将反应液降温至室温,浓缩,粗品经硅胶柱层析(DCM:MeOH=10:1)纯化得到产品(3.31g,收率:66.0%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):11.94(s,1H),8.58(s,1H),7.72(s,1H),5.48-5.50(d,1H),4.74-4.82(m,1H),3.55-3.62(m,4H),3.19(s,3H),1.90-1.99(m,2H),1.71-1.80(m,2H),1.38-1.40(d,3H).
分子式:C
18H
19D
3N
4O
3 分子量:345.42 LC-MS(Pos,m/z)=346.40[M+H]
+.
实施例16:6-乙酰基-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物192)
步骤1:6-乙酰基-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
向反应瓶中加入二氯甲烷(40.00mL)、实施例15的产物6-(1-羟乙基)-4-(4-甲氧基-4-(氘代甲基)哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.00g,5.8mmol,1.0eq)和戴斯-马丁氧化剂(2.70g,6.37mmol,1.1eq),22℃反应3小时。LC-MS检测显示反应完全,向反应液中加入水(25mL)和饱和硫代硫酸钠水溶液(15mL),搅拌0.5小时,分液,有机相用无水硫酸钠干燥,抽滤,滤液浓缩得粗品,经乙醇(20mL)重结晶得产品(1.65g,收率:83%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):12.31(s,1H),8.70(s,1H),8.19(s,1H),3.58-3.65(m,4H),3.20(s,3H),2.63(s,3H),1.92-2.01(m,2H),1.71-1.81(m,2H).
分子式:C
18H
17D
3N
4O
3 分子量:343.40 LC-MS(Pos,m/z)=344.35[M+H]
+.
实施例17:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基-2,2-二甲基丁酸酯的合成(化合物193)
步骤:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基-2,2-二甲基丁酸酯的合成
将实施例12步骤5产物6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(200mg,0.58mmol,1.0eq)溶于DCM(5mL)中,加入DMAP(7.08g,0.058mmol,0.1eq)和三乙胺(175.9mg,1.74mmol,3.0eq),冰水浴降温,滴加2,2-二甲基丁酰氯(86.5mg,0.64mmol,1.1eq),滴毕,反应2h,TCL检测还有约40%原料,补加2,2-二甲基丁酰氯(39mg,0.29mmol,0.5eq),反应1h,加水(20mL),用DCM(20mL×3)萃取,合并有机相,用无水硫酸镁干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(MeOH:DCM=1:20)纯化得产品(120mg,收率:46.9%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):12.03(s,1H),8.63(s,1H),7.58(s,1H),5.89-5.84(m,1H),3.60-3.59(m,4H),3.19(s,3H),1.94-1.91(m,2H),1.81-1.79(m,2H),1.77-1.75(m,5H),1.72-1.71(d,3H),1.55-1.53(s,6H),1.51(d,3H).
分子式:C
24H
32N
4O
4 分子量:440.54 LC-MS(Pos,m/z)=441.53[M+H]
+.
实施例18:4-(4-羟基-4-甲基哌啶-1-基)-6-(1-羟乙基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物194)
步骤:
步骤1:6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈的合成
将原料2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(3g,11.9mmol,1.0eq)、NBS(4.23g,23.8mmol,2.0eq)和AIBN(977mg,5.95mmol,0.5eq)溶于四氯化碳(60mL),90℃反应2个小时,LCMS检测反应完全。减压浓缩,粗品经硅胶柱(PE:EA=20:1)得到产品(3.2g,收率:81%)。
步骤2:6-(1-溴乙基)-2-氯-4-(4-羟基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
将6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈(3.2g,9.67mmol,1.0eq)、4-甲基哌啶-4-醇盐酸盐(1.75g,11.6mmol,1.2eq)和DIPEA(3.75g,29.01mmol,3.0eq)溶于乙醇(30mL),90℃反应90min,TLC检测反应完全。减压浓缩,粗品经硅胶柱层析纯化(PE:EA=2:1)得到产品(1.1g,两步收率:27%)。
步骤3:1-(3-氰基-4-(4-羟基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙酸乙酯的合成
将原料6-(1-溴乙基)-2-氯-4-(4-羟基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(1.1g,2.68mmol,1.0eq)和乙酸钠(429mg,5.36mmol,2.0eq)溶于水(2mL)和乙酸(8mL),80℃反应22h,LC-MS检测反应完全,减压浓缩得到产物。
步骤4:4-(4-羟基-4-甲基哌啶-1-基)-6-(1-羟乙基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
将1-(3-氰基-4-(4-羟基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙酸乙酯(994mg,2.68mmol,1.0eq)和碳酸钾(222mg,1.61mmol,0.6eq)溶于水(5mL)和乙醇(5mL),60℃反应2.5h,TLC检测基本反应完全。减压浓缩,粗品经硅胶柱层析纯化(MeOH:DCM=1:20)得到产品(470mg,收率:53%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):11.92(s,1H),8.58(s,1H),7.73(s,1H),5.5(s,1H),4.77-4.79(d,1H),4.61(s,1H),3.58-3.72(m,4H),1.68-1.77(m,4H),1.37-1.40(d,3H),1.25(s,3H).
分子式:C
17H
20N
4O
3 分子量:328.37 LC-MS(Pos,m/z)=329.35[M+H]
+.
实施例19:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基环丙烷羧酸酯的合成(化合物195)
步骤:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基环丙烷羧酸酯的合成
将实施例12步骤5产物6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(330mg,0.96mmol,1.0eq)溶于DCM(5mL)中,加入DMAP(11.7mg,0.096mmol,0.1eq)和三乙胺(291.2mg,2.88mmol,3.0eq),冰水浴降温,滴加环丙烷甲酰氯(130.6mg,1.25mmol,1.3eq),反应2h,TCL检测还有少量原料剩余,加水(20mL),用DCM(20mL×3)萃取,合并有机相,用无水硫酸镁干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(MeOH:DCM=1:20)纯化得到产品(260mg,收率:65.9%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):12.03(s,1H),8.63(s,1H),7.54(s,1H),5.90-5.84(m,1H),3.59-3.58(m,4H),3.19(s,3H),1.95-1.91(m,2H),1.80-1.60(m,3H),1.55-1.53(d,3H),1.23(s,3H),0.97-0.92(m,4H).
分子式:C
22H
26N
4O
4 分子量:410.47 LC-MS(Pos,m/z)=411.13[M+H]
+.
实施例20:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基戊酸酯的合成(化合物196)
步骤:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基戊酸酯的合成
将实施例12步骤5产物6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(330mg,0.96mmol,1.0eq)溶于DCM(5mL)中,加入DMAP(11.7mg,0.096mmol,0.1eq)和三乙胺(291.2mg,2.88mmol,3.0eq),冰水浴降温,滴加戊酰氯(151mg,1.25mmol,1.3eq),反应2h,TCL检测还有少量原料剩余,加水(20mL),用DCM(20mL×3)萃取,合并有机相,用无水硫酸镁干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(MeOH:DCM=1:20)纯化得到产品(246mg,收率:60%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):12.02(s,1H),8.63(s,1H),7.56(s,1H),5.92-5.85(m,1H),3.61-3.59(m,4H),3.19(s,3H),2.39-2.33(m,2H),1.95-1.90(m,2H),1.80-1.77(m,2H),1.58(m,5H),1.54-1.52(m,2H),1.50-1.48(s,3H),1.30(m,3H).
分子式:C
23H
30N
4O
4 分子量:426.52 LC-MS(Pos,m/z)=427.18[M+H]
+.
实施例21:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基磷酸酯二钠盐的合成
步骤:
步骤1:二苄基(1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基)磷酸酯的合成
将实施例12步骤5产物6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(675mg,1.97mmol,1.0eq)和1H-四氮唑(276.2mg,3.94 mmol,2.0eq)溶于DCM(10mL)中,氮气保护下,降温至0℃,滴加二苄基二异丙基亚磷酰胺(1g,2.96mmol,1.5eq)。滴毕,室温反应48h,降温至0℃,滴加质量分数85%mCPBA(510.8mg,2.96mmol,1.5eq)的二氯甲烷(10mL)溶液,0℃反应0.5-1h,加饱和碳酸钠溶液(30mL),搅拌5min,分液,水相用二氯甲烷(30mL×2)萃取,有机相合并,依次用5%亚硫酸钠溶液(30mL)、饱和碳酸钠溶液(30mL)和食盐水(30mL)洗涤,无水硫酸镁干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(MeOH:DCM=1:20)得到产品(148mg,收率:12.5%)。
步骤2:1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)磷酸钾的合成
将二苄基(1-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-基)乙基)磷酸酯(130mg,0.22mmol,1.0eq)溶于DCM(3mL)中,加TFA(3mL)室温反应48h,常温减压浓缩,加甲醇(5mL)和水(5mL),冰水降温,加碳酸钠固体调节pH值至8左右,析出固体,过滤,滤饼溶于水(10mL)中,通过制备HPLC(水+0.1%氨水)纯化,冻干得到淡黄色固体(54.7mg,收率:53.3%)。
1HNMR(300MHz,D
2O)δ(ppm):8.38(s,1H),7.74(s,1H),5.20-5.15(m,1H),3.75(m,4H),3.20(s,3H),1.95-1.79(m,4H),1.42-1.40(d,3H),1.21(s,3H).
分子式:C
18H
21K
2N
4O
6P 分子量:498.56 LC-MS(Pos,m/z)=423.23[M+H]
+.
根据下述实验例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实验例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实验例1:PDE9酶学评价方法
测试物:本发明化合物,由本发明相应的实施例所制备和专利WO2017019723A1的化合物I-11(参照WO2017019723A1中合成实施例制备),其结构式如下:
一、实验材料及仪器
PDE9A2酶(BPS,Cat.No.60090)
384孔板(Perkin Elmer,Cat.No.6007279)
二、试验步骤
准备化合物:用DMSO将化合物配制成10mM化合物储存液长期储存,以DMSO100倍稀释得到100μM化合物工作母液,再以DMSO将化合物工作母液3倍稀释,共得到8-10个浓度梯度的化合物稀释母液(100×)。
加药孵育:使用极微量液体移液系统Echo移取化合物稀释母液至384孔板中;每个化合物孔加入200nL化合物稀释母液以及10μL PDE9A2酶液,1000rpm离心1min后,室温孵育15min。随后加入10μL底物混合液,1000rpm离心1min后,室温振荡孵育30min。最后,加入终止液终止反应体系,室温振荡孵育60min。最大读值孔(Max)中,以溶剂代替化合物;最小读值孔(Min)中,以溶剂代替化合物以及酶液。
检测:使用酶标仪检测480nm/535nm处荧光读值(F)。
计算:抑制率按照如下公式计算,使用GraphPad Prism5.0拟合IC
50:
三、试验结果如下表2所示:
表2
测试物 | PDE9A2 IC 50(nM) |
化合物I-11 | 70 |
化合物163 | 50 |
化合物164 | 25 |
化合物165 | 24 |
化合物166 | 19 |
化合物167 | 11 |
化合物177 | 15 |
化合物183 | 48 |
化合物184 | 19 |
化合物A | 61 |
化合物B | 3 |
化合物191 | 5 |
化合物192 | 64 |
化合物194 | 37 |
由表2可知,本发明化合物具有非常好的PDE9酶学抑制活性,具有潜在的临床应用价值。
实施例2:本发明化合物的犬肝微粒体稳定性评价
测试物:本发明化合物和专利WO2017019723A1的化合物I-8(参照WO2017019723A1中合成实施例制备),其结构式如下:
温孵体系的构成:
化合物配制:
精确称取适量化合物,用DMSO溶解配成5.0mM储备液。将5.0mM的储备液,用DMSO稀释成1.0mM,最后用水稀释成10μM的化合物工作溶液,待用(反应体系中DMSO含量为0.1%,v/v)。
试验步骤:
(1).从-80℃冰箱中取出肝微粒体(20mg蛋白/mL),置于37℃水浴恒温振荡器上预温孵3min,融化待用。
(2).按照上面“实验温孵体系的构成”比例,制备温孵体系混合溶液(不含化合物和β-NADPH),置于37℃水浴恒温振荡器上预孵育2min。
3).对照组(不含β-NADPH):分别取30μL水和30μL化合物工作溶液(10μM)加入到240μL步骤(2)所述温孵体系混合液中,涡旋30s,混匀,反应总体积300μL,平行样2份。放入到37℃水浴恒温振荡器中进行孵育,并开始计时,取样时间点为0min和60min。
4).样品组:分别取70μLβ-NADPH溶液(10mM)和70μL化合物工作溶液(10μM)加入560μL步骤(2)所述混合溶液中,反应总体积700μL,涡旋30s,混匀,平行样2份。放入到37℃水浴恒温振荡器中进行孵育,并开始计时,取样时间点为计时后0min,5min,10min,20min,30min,60min。
(5).涡旋3min后,4000rpm离心10min。
(6).取上清液50μL加入150μL水,涡旋混匀,LC/MS/MS进样分析。
数据分析:
用下列一级动力学公式计算半衰期(t
1/2)和清除率(Cl):
Ct=C
0*e
–kt
t
1/2=ln2/k=0.693/k
Cl
int=V
d*k
Vd=1/肝微粒体中蛋白含量
注:k为化合物剩余量的对数与时间作图的斜率,V
d为表观分布容积,C
0为0h药物浓度。
结果:
表3本发明化合物的犬肝微粒体稳定性实验
CL int(mL/min/mg) | t 1/2(min) | |
化合物I-8 | 0.1158 | 12 |
化合物166 | 0.0034 | 408 |
化合物167 | 0.0100 | 139 |
化合物B | 0.0016 | 866 |
化合物204 | 0.0028 | 495 |
由表3可知,本发明化合物较现有技术化合物在犬肝微粒体具有较低的清除率。
Claims (14)
- 通式(I)所示的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药:R’、R 3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、C 1-6烷羰氧基、C 3-6环烷基、C 3-6环烷基羰氧基、C 2-8炔基、卤代C 1-6烷基、C 2-8烯基、卤代C 1-6烷氧基、 未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基;Y选自金属离子或有机铵离子;优选为Na +、K +、NH 4 +;L为键、-NH-(CH 2)t-,t为0、1、2或3;环A为3-12元杂环基、5-10元杂芳基、3-12元环烷基、3-12元环烯基,其中所述3-12元杂环基的杂原子选自O、S、N中的一种或其任意组合,S原子可任选被氧化为S(O)或S(O) 2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为 所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合;每个R 1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧 基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基和C 1-6烷基磺酰氨基的基团取代;m为0、1、2或3;R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基;条件是,优选地,当X 2为N,X 1为CH,X 3为CR 3,X 4为CH, 为 时,R 3选自异丙基、环丙基、羟甲基、 C 1-6烷基羰基,C 1-6烷基羰氧基C 1-6烷基,被 取代的C 1-6烷基,C 3-6环烷基羰氧基C 1-6烷基,氘代C 1-6烷基;
- 如权利要求3所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,其中,R’、R 3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2 氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、C 1-6烷羰氧基、C 3-6环烷基羰氧基、C 3-6环烷基、C 2-8炔基、卤代C 1-6烷基、C 2-8烯基、卤代C 1-6烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基;L为键、-NH-(CH 2)t-,t为0、1、2或3;环A为4-7元单杂环基,所述4-7元单杂环基的杂原子选自O、S、N中的一种或两种的组合,且至少含有一个N,环A通过N原子与L相连接,S原子可任选被氧化为S(O) 2,C原子可任选被氧化为C(O),N原子可以任选被氧化为每个R 1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基和C 1-6烷基磺酰氨基的基团取代;R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基;m为0、1或2;条件是,
- 如权利要求4所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,其中,R’、R 3在每次出现时分别独立地选自氢、氘、卤素、C 1-4烷基、C 3-6环烷基、5-6 元杂芳基、芳基、C 1-4烷氧基、C 2-6烯基、C 1-4烷氨羰基、C 1-4烷羰基、(C 1-4烷基) 2氨基羰基和氨基羰基,其中所述C 1-4烷基、C 3-6环烷基、5-6元杂芳基、芳基、C 1-4烷氧基、C 2-6烯基、C 1-4烷氨羰基、C 1-4烷羰基、(C 1-4烷基) 2氨基羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 1-4烷基氨基、C 1-6烷羰氧基、C 3-6环烷基羰氧基、(C 1-4烷基) 2氨基和未被取代或被一至多个独立的C 1-4烷基取代的4-6元杂环基的基团取代;L为键;每个R 1分别独立地选自氢、氘、C 1-4烷基和C 1-4烷氧基;R 2选自氢、C 1-4烷基;m为0、1或2。
- 如权利要求3所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,其中,R’、R 3在每次出现时分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 2-6烯基、C 2-6炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-4烷羰基、氨基羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基,其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、卤代C 1-4烷氧基、C 2-6烯基、C 2-6炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、C 3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C 1-4烷羰基、氨基羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、C 1-4烷羰氧基、C 3-6环烷基羰氧基、C 3-6环烷基、C 2-6炔基、卤代C 1-4烷基、C 2-6烯基、卤代C 1-4烷氧基、未被取代或任选被一至多个独立的取代基取代的4-6元杂环基和未被取代或任选被一至多个独立的取代基取代的杂芳基的基团取代;上述任选被一至多个独立的取代基取代的4-6元杂环基、任选被一至多个独立的取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基;L为键;环A为7-12元螺杂环基,所述螺杂环基的杂原子选自O、S、N中的一种或两种的组合,且至少含有一个N,环A通过N原子与L相连接,S原子可任选被氧化为S(O) 2,C原子可任选被氧化为C(O),N杂原子可以任选被氧化为每个R 1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 2-6烯基、C 2-6炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 2-6烯基、C 2-6炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基和C 1-4烷基磺酰氨基的基团取代;R 2选自氢、C 1-4烷基、C 2-6烯基、C 2-6炔基、卤代C 1-4烷基;m为0、1或2;条件是
- 如权利要求1所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药,具有通式(IV)所示结构,其中,R 3选自氢、氘、氨基、羧基、氰基、卤素、C 1-6烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 2-6烯基、C 2-6炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、C 3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷 基) 2氨羰基和氨基羰基,其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 2-4烯基、C 2-4炔基、C 1-4烷基磺酰基、C 1-4烷基硫基、C 3-6环烷基、4-6元含氮杂环基、5-6元杂芳基、芳基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷羰氧基、 C 3-6环烷基羰氧基、C 3-6环烷基和未被取代或被一至多个独立的C 1-4烷基取代的4-6元杂环基的基团取代;L为键、-NH-(CH 2)t-,t为0、1、2或3;m为0、1或2;每个R 1分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基,其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基和C 1-6烷基磺酰氨基的基团取代;R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基;条件是,
- 通式(I)所示的化合物的氘代化合物,其结构上的氢原子可任意被一至多个氘原子所氘代。
- 含有权利要求1-11任一项所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药及一种或多种第二治疗活性剂的药物组合物,所述第二治疗活性剂为乙酰胆碱酯酶抑制剂、淀粉样蛋白-β(或其片段)、淀粉样蛋白-β(或其片段)的抗体、淀粉样蛋白的降低或抑制试剂、α-肾上腺素受体拮抗剂、β-肾上腺素受体阻断剂、抗胆碱能药、抗惊厥药、安定药、钙通道阻断剂、儿茶酚-O转甲基酶抑制剂、中枢神经系统刺激剂、皮质类固醇、多巴胺受体激动剂、多巴胺受体拮抗剂、多巴胺再摄入抑制剂、γ-氨基丁酸受体激动剂、免疫调节剂、免疫抑制剂、干扰素、左旋多巴、N-甲基-D天冬氨酸受体拮抗剂、单胺氧化酶抑制剂、毒蕈碱受体激动剂、烟碱受体激动剂、神经保护药物、降肾上腺素(去甲肾上腺素)再摄入抑制剂、其他PDE9抑制剂、其他磷酸二酯酶抑制剂、β-分泌酶抑制剂、γ-分泌酶抑制剂、血清素(5-羟色胺)1A(5-HT 1A)受体拮抗剂、血清素(5-羟色胺)6(5-HT 6)受体拮抗剂、血清素(5-HT)再摄入抑制剂和营养因子。
- 含有权利要求1-11任一项所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药的药物制剂,优选地,所述药物制剂包含一种或多种药用载体。
- 权利要求1-11任一项所述的化合物或其药学上可接受的盐、异构体、氘代化合物、代谢产物和前药或权利要求12所述的药物组合物或权利要求13所述的药物制剂在制备治疗或者预防由PDE9介导的相关疾病的药物中的用途。
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WO2021105116A1 (en) | 2019-11-28 | 2021-06-03 | Bayer Aktiengesellschaft | Substituted aminoquinolones as dgkalpha inhibitors for immune activation |
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TWI784234B (zh) | 2022-11-21 |
US20220089593A1 (en) | 2022-03-24 |
JP2022518552A (ja) | 2022-03-15 |
TW202043232A (zh) | 2020-12-01 |
EP3915992A4 (en) | 2022-11-16 |
CN111471059B (zh) | 2022-12-02 |
CN111471059A (zh) | 2020-07-31 |
EP3915992A1 (en) | 2021-12-01 |
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