WO2022253326A1 - Nlrp3炎症小体抑制剂及其应用 - Google Patents
Nlrp3炎症小体抑制剂及其应用 Download PDFInfo
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- WO2022253326A1 WO2022253326A1 PCT/CN2022/096928 CN2022096928W WO2022253326A1 WO 2022253326 A1 WO2022253326 A1 WO 2022253326A1 CN 2022096928 W CN2022096928 W CN 2022096928W WO 2022253326 A1 WO2022253326 A1 WO 2022253326A1
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- Prior art keywords
- alkyl
- membered
- group
- amino
- halogenated
- Prior art date
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- 229940127107 NLRP3 inflammasome inhibitor Drugs 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 108091008099 NLRP3 inflammasome Proteins 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 267
- -1 amino, carboxyl Chemical group 0.000 claims description 206
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 141
- 125000000623 heterocyclic group Chemical group 0.000 claims description 115
- 125000003545 alkoxy group Chemical group 0.000 claims description 96
- 125000001072 heteroaryl group Chemical group 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 90
- 150000002367 halogens Chemical group 0.000 claims description 90
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 48
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 43
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 25
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 24
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 12
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- 125000003277 amino group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 5
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 5
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 4
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- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 208000011594 Autoinflammatory disease Diseases 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 abstract description 11
- 238000011161 development Methods 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 abstract 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 39
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 39
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 38
- 239000007864 aqueous solution Substances 0.000 description 35
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 35
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- 238000005481 NMR spectroscopy Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- 238000000034 method Methods 0.000 description 26
- 239000000460 chlorine Substances 0.000 description 25
- 238000010791 quenching Methods 0.000 description 25
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 25
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 23
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 22
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
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- 230000004913 activation Effects 0.000 description 4
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Definitions
- the invention belongs to the technical field of medicine, and in particular relates to an NLRP3 inflammasome inhibitor and an application thereof.
- Nucleotide-binding oligomerization domain-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) belongs to the family of nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs), also known as It is "pyrin domain-containing protein 3".
- NLRP3 contains three modules: pyrin domain (PYD), nucleotide binding site domain (NBD) and leucine-rich repeat (LRR).
- PYD pyrin domain
- NBD nucleotide binding site domain
- LRR leucine-rich repeat
- Activation of the NLRP3 inflammasome generally requires two steps.
- the first step involves initiating a signal in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which in turn transmit the signal into the cell, mediating activation of the NF- ⁇ B signaling pathway , which in turn upregulated the transcription levels of NLRP3 inflammasome-associated components including inactive NLRP3 and pro-IL-1 ⁇ .
- PAMPs pathogen-associated molecular patterns
- DAMPs damage-associated molecular patterns
- the second step is to activate the signal.
- NLRP3 monomers oligomerize to form NLRP3 oligomers, and then recruit ASC and pro-caspase 1 to assemble into NLRP3 inflammasomes Complex. This triggers the conversion of pro-caspase 1 to caspase 1, and the production and secretion of mature IL-1 ⁇ and IL-18.
- Activation of the NLRP3 inflammasome is associated with various diseases.
- Autoinflammatory febrile syndromes such as cryopyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, pseudo- Gout (chondrocalcinosis), type 1 and type 2 diabetes mellitus and associated complications (e.g. nephropathy, retinopathy), neuroinflammation-related disorders (e.g.
- multiple sclerosis brain infection, acute injury, neurodegenerative disease, Al Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, hypertension), hidradenitis suppurativa, wound healing and scarring, and cancer (eg, colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).
- Most treatment approaches include symptomatic treatment, slowing of disease/disorder progression, and surgery as a last resort.
- the present invention studies the following compounds or their pharmaceutically acceptable salts, stereoisomers, and tautomers, and finds that the compound or its pharmaceutically acceptable salts, stereoisomers, and tautomers
- the NLRP3 inflammasome has high biological activity and has important clinical development value for the treatment of NLRP3-related diseases.
- the invention provides the following technical solutions:
- the technical scheme of the present invention includes a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
- R is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R 1 and R 2 are optionally replaced by 1-3 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- Substituents of 6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R 1 , R 2 form a 5-12-membered ring A with the carbon atoms they are connected to; the 5-12-membered ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen , carbonyl, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 Member heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents;
- R 3 is selected from -(C 1-6 alkylene) 0-2 -NR 4 R 5 , -(C 1-6 alkylene) 0-2 -NR 4 -COR 5 , -(C 1-6 alkylene Alkyl) 0-2 -CO-NR 4 -R 5 , -(C 1-6 alkylene) 0-2 -OR 5 ;
- R 4 is selected from hydrogen or C 1-6 alkyl;
- R 5 is selected from 3 -7-membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group; the R 5 is optionally replaced by 1-4 members selected from halogen, cyano group, amino group, hydroxyl group, C 1 -6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C Substi
- Y is selected from aryl group, 5-14 membered heteroaryl group, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl group, and said Y is optionally replaced by 1-3 members selected from halogen, cyano group, amino group, hydroxyl group , carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered Heteroaryl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl, C 1-6 alkane Substituents of thiol and C 1-6 alkylsulfinyl are substituted;
- R 5 C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, 3-6 membered cycloalkyl;
- Substituents on Y C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5 -7-membered heteroaryl, sulfonyl, optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, 3-6-membered cycloalkyl.
- Ring A is selected from 5-7 membered cycloalkenyl, 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-7 membered heteroaryl; Ring A is optionally replaced by 1-4 selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) Substituents of 2 are substituted.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, ring A is selected from phenyl, 5-7 membered heteroaryl; Ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, C 1-6 alkylsulfonyl, -N(C 1- 6 alkyl) substituents of 2 are substituted.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, ring A is selected from Ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, C 1-6 alkylsulfonyl, -N(C 1- 6 alkyl) substituents of 2 are substituted.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, Y is selected from phenyl, 5-7 membered heteroaryl, 3 -8-membered heterocyclic group, 3-7 membered cycloalkyl group; Y is optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkane C 1-6 alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 alkylamino group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonyl group Substituents of acyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl; the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, Y is selected from naphthyl, 8-14 membered condensed heteroaryl, 6-12 membered fused heterocyclic group, 6-12 membered condensed cycloalkyl group; Y is optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1 -6 alkyl, C 1-6 alkoxy substituent substitution.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, Y is substituted by cyano and optionally 1-2 selected from Halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl , C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl substituents; the C 1 -6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, sulfonyl are optionally selected from 1-3 halogen , cyano, amino, hydroxyl, carbonyl, C 1-6
- R 3 is selected from -NR 4 R 5 , -NH-COR 5 , -OR 5 ;
- R 4 is selected from hydrogen or C 1-3 alkyl;
- R 5 is selected from 3-7 membered cycloalkyl, 3-7 membered heterocyclic group,
- R 5 is optionally selected from 1-2 members selected from C 1-6 alkyl, hydroxyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by 3-7 membered cycloalkyl, hydroxy, halogen, C 2-6 alkenylcarbonyl, C 1-6 Alkylsulfonyl, 3-7 membered cycloalkylsulfonyl, aminosulfonyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, carboxyl, C 1-6 alkylcarbonyl substituent
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, R 3 is selected from -NH-R 5 , R 5 is -2 3-7-membered heterocyclic groups substituted by substituents selected from C 1-6 alkyl groups.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, Y is selected from phenyl, 5-7 membered heteroaryl, 3 -8-membered heterocyclic group, 3-7 membered cycloalkyl group; Y is optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkane C 1-6 alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 alkylamino group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonyl group Substituents of acyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl; the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy
- R 1 and R 2 form a 5- 8-membered ring A
- the 5-8-membered ring A is selected from 5-8-membered cycloalkyl, 5-8-membered cycloalkenyl, 5-8-membered heterocyclyl, phenyl, 5-8-membered heteroaryl
- Ring A is optionally replaced by 1-2 members selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents;
- Y is selected from phenyl, 5-7 membered heteroaryl; Y is substituted by 1-3 C selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl 1-6 alkyl, halogenated C 1-6 alkyl, aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocycle Substituent group, 3-7 membered cycloalkyl group, 5-7 membered heteroaryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group;
- R 3 is selected from -NR 4 R 5 , -NH-COR 5 , -OR 5 ;
- R 4 is selected from hydrogen or C 1-3 alkyl;
- R 5 is selected from 3-7 membered cycloalkyl, 3-7 membered hetero Cyclic group,
- R 5 is optionally substituted by 1-2 C 1-6 alkyl, hydroxyl, halogen, C 2-6 alkenes selected from C 1-6 alkyl, hydroxyl, hydroxyl or 3-7 membered cycloalkyl Carbonyl, C 1-6 alkylsulfonyl, 3-7 membered cycloalkylsulfonyl, aminosulfonyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, carboxyl, C 1-6 alkyl Carbonyl substituents are substituted.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, ring A is selected from Ring A is optionally replaced by 1-2 members selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents.
- the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer wherein, Y is selected from Y is substituted by 1-3 selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, halogenated C 1-6 alkyl , aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered Substituents of heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- the present invention also provides the compound represented by the aforementioned formula (I) or (II), its pharmaceutically acceptable salt or its stereoisomer, tautomer is shown in Table 1:
- the technical solution of the present invention also includes a pharmaceutical composition, which comprises any one of the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, and pharmaceutically acceptable carriers.
- the technical scheme of the present invention also includes the compound represented by the above-mentioned general formula (I) or general formula (II) or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the above-mentioned pharmaceutical composition in Use in the preparation of medicines for preventing and/or treating diseases related to NLRP3 inflammasomes.
- the technical scheme of the present invention also includes the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the above-mentioned pharmaceutical composition in the preparation of prevention and/or treatment of inflammasome-related diseases , an immune disease, an inflammatory disease, an autoimmune disease or a medicine for an autoinflammatory disease.
- halogen in the present invention refers to fluorine, chlorine, bromine and iodine.
- hydroxyl in the present invention refers to -OH group.
- the "cyano group” mentioned in the present invention refers to the -CN group.
- amino group refers to the -NH 2 group.
- the "carboxyl group” mentioned in the present invention refers to a -COOH group.
- nitro group refers to the -NO 2 group.
- C 1-6 alkyl in the present invention refers to a straight-chain or branched-chain alkyl group derived from a hydrocarbon part containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 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, 2-
- alkylene of "C 1-6 alkylene” in the present invention refers to a divalent group derived from a C 1-6 alkyl group by removing two hydrogen atoms.
- halogenated C 1-6 alkyl in the present invention refers to a C 1 -C 6 alkyl group substituted by one or more halogen groups as defined above.
- haloC1-6alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromo Propan-2-yl, 3-bromo-2-fluoropropyl and 1,4,4-trifluorobut-2-yl.
- C 1-6 alkoxy refers to the group that the "C 1-6 alkyl” defined above is connected to the parent molecule through an oxygen atom, that is, “C 1-6 alkyl-O- "groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentyloxy and n-hexyloxy, etc.
- halogenated C 1-6 alkoxy in the present invention refers to a C 1 -C 6 alkoxy group substituted by one or more halogen groups as defined above, examples of which include but are not limited to fluoromethoxy chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
- C 2-6 alkenyl in the present invention refers to a linear or branched alkene group derived from an alkene moiety of 2-6 carbon atoms containing at least one carbon-carbon double bond, such as vinyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadien-1-enyl, 1-penten-3-yl, 2-penten-1 -yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexene- 3-yl, 1,4-hexadien-1-yl.
- "C 2-6 alkenyl” contains a carbon-carbon double bond.
- C 2 - 6 alkynyl group in the present invention refers to a linear or branched alkyne group derived from an alkyne moiety of 2-6 carbon atoms containing at least one carbon-carbon triple bond by removing one hydrogen atom, such as acetylene base, propynyl, butynyl, pentynyl, hexynyl, etc.
- "C 2 - 6 alkynyl” contains a carbon-carbon triple bond.
- C 1-6 alkylamino refers to C 1-6 alkyl A group formed in the form of -NH-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -, NH 2 -C(O)-.
- the "5-12 membered ring" in the present invention includes carbocyclic or heterocyclic rings that may be formed chemically, such as 5-12 membered cycloalkyl, 5-7 membered cycloalkyl, 5-12 membered cycloalkenyl, 5 -7-membered cycloalkenyl, 6-12-membered condensed cycloalkyl, 5-12-membered heterocyclyl, 5-7-membered heterocyclyl, 6-12-membered condensed heterocycle, aryl, 5-12-membered heteroaryl , 8-12 membered condensed heteroaryl, 5-7 membered heteroaryl, etc.
- the "3-12 membered cycloalkyl group” in the present invention refers to a monovalent group or (as required) a divalent group (such as a 5-12 membered cycloalkyl group) derived from a 3-12 membered cycloalkane , which can be a monocyclic, bicyclic, or multicyclic cycloalkyl system.
- a certain membered cycloalkyl group (such as 5-12 membered cycloalkyl group, 5-8 membered cycloalkyl group, 5-7 membered cycloalkyl group, 3-7 membered cycloalkyl group, 3-6 membered group Membered cycloalkyl, 4-6 membered cycloalkyl) include all monocyclic rings that may be formed, and condensed rings (such as 6-12 membered fused cycloalkyl) include the cases of fusion in the form of parallel, spiro, and bridge.
- Monocyclic ring systems are generally cyclic hydrocarbon groups containing 3-12 carbon atoms, such as 3-8 or 3-6 carbon atoms.
- cycloalkyl groups include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, cyclopentane-1,3-diyl, Cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, etc.
- Fused ring cycloalkyl includes parallel cycloalkyl, bridged cycloalkyl, spirocycloalkyl.
- the cycloalkyl group can be a 6-11 membered cycloalkyl group such as a 7-10 membered cycloalkyl group, representative examples of which 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]nonyl.
- the spirocycloalkyl group can be a 7-12 membered spirocycloalkyl group such as a 7-11 membered spirocycloalkyl group, examples of which include but are not limited to: base.
- the bridged cycloalkyl group can be a 6-10 membered bridged cycloalkyl group such as a 7-10 membered bridged cycloalkyl group, examples of which include but are not limited to: base.
- the "3-7-membered cycloalkyl group” in the present invention refers to a monovalent group or (if necessary) a divalent group derived from a 3-7-membered cycloalkane.
- "3-7 membered cycloalkyl” can be 3, 4, 5, 6, 7 membered cycloalkyl, examples of 3-7 membered cycloalkyl include cyclopropyl, cyclobutanyl, cyclopentyl, cyclo Hexyl.
- cycloalkenyl group in the present invention refers to a group having at least one double bond in the above-mentioned cycloalkyl group. It may be, for example, "3-12 membered cycloalkenyl", ie may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. Unless otherwise specified, a membered cycloalkenyl group includes all possible monocyclic rings and condensed rings (including fused in the form of parallel, spiro, and bridge).
- Cycloalkenyl can be 3-12 membered cycloalkenyl, 3-8 membered cycloalkenyl, 5-8 membered cycloalkenyl, 5-7 membered cycloalkenyl, 4-6 membered cycloalkenyl, 7-11 membered spiro Cycloalkenyl, 7-11-membered cycloalkenyl, 6-11-membered bridged cycloalkenyl, etc.
- cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4- Cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl, etc., but not limited thereto.
- the "5-7 membered cycloalkenyl group” in the present invention refers to a group obtained by having at least one double bond in the 5-7 membered cycloalkyl group, such as cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, etc.
- the "3-14 membered heterocyclic group” in the present invention refers to a monovalent group or (as required) divalent group derived from a 3-14 membered heterocycloalkane, that is, a 3-14 membered at least A non-aromatic cyclic group in which one ring carbon atom is replaced by a heteroatom selected from O, S, S(O), S(O) 2 , C(O), N, preferably containing 1-3 heteroatoms atom.
- 3-14 membered heterocyclyl (such as 5-14 membered heterocyclyl, 5-12 membered heterocyclyl) includes monocyclic heterocyclyl, bicyclic heterocyclyl system or polycyclic heterocyclyl system, one or Multiple rings may be saturated or partially saturated, but do not include aromatic rings.
- a certain membered heterocyclic group (such as 3-8 membered heterocyclic group, 3-7 membered heterocyclic group, 5-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6
- the membered heterocyclic group, 4-6-membered heterocyclic group, 6-membered heterocyclic group includes all monocyclic rings, condensed rings (including fused in the form of parallel, spiro, and bridge), saturated and partially saturated situations that may be formed.
- Monocyclic heterocyclic group can be 3-8 membered heterocyclic group such as 5-7 membered heterocyclic group, 3-7 membered heterocyclic group, 4-7 membered heterocyclic group or 5-6 membered heterocyclic group, 3-8 A nitrogen-containing heterocyclic group such as a 4-7-membered nitrogen-containing heterocyclic group or a 5-6-membered nitrogen-containing heterocyclic group, a 3-8-membered saturated heterocyclic group such as a 5-6-membered saturated heterocyclic group, etc.
- Examples include, but are not limited to, aziridinyl, oxiranyl, thiiridine, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydro Pyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl , tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathia Cyclohexane, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,
- Fused heterocyclyls include heterocyclyls, spiroheterocyclyls and bridged heterocyclyls, which may be saturated, partially saturated or unsaturated, but not aromatic .
- the fused heterocyclic group can be fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic cycloalkenyl, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl A 5-6 membered monocyclic heterocyclyl ring.
- the described heterocyclic group can be a 6-12 membered heterocyclic group such as a 6-11 membered heterocyclic group or a 7-10 membered heterocyclic group, a 6-11 membered saturated heterocyclic group, a 6-11 membered
- nitrogen-containing heterocyclyl groups include, but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptanyl, 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- Dihydrobenz
- the spiroheterocyclyl can be 6-12 membered spiroheterocyclyl such as 7-12 membered spiroheterocyclyl, 7-12 membered saturated spiroheterocyclyl, 7-12 membered nitrogen-containing spiroheterocyclyl, examples including but not limited to:
- the bridged heterocyclic group can be a 6-12-membered bridged heterocyclic group such as a 6-10-membered bridged heterocyclic group (for example, a 6-10-membered nitrogen-containing bridged heterocyclic group, especially a 7-membered nitrogen-containing bridged heterocyclic group) , 7-10 member bridged heterocyclic group, examples of which include but are not limited to:
- aryl in the present invention refers to a monovalent or divalent cyclic aromatic group derived from an aromatic carbocyclic hydrocarbon containing 6-14 carbon atoms, including benzene, naphthyl, phenanthrene Base etc.
- the "5-14 membered heteroaryl” in the present invention refers to an aromatic 5-14 membered ring group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, N,
- "5-14 Member heteroaryl” can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 membered heteroaryl, preferably containing 1-3 heteroatoms, including carbon atoms, sulfur atoms are oxo , Nitrogen substitution, such as carbon atoms are replaced by C (O), sulfur atoms are replaced by S (O), S (O) 2 .
- Heteroaryl includes monoheteroaryl and condensed heteroaryl.
- certain membered heteroaryl includes all monocyclic, condensed ring, fully aromatic and partially aromatic situations that may be formed.
- Monoheteroaryl can be 5-7 membered heteroaryl such as 5-6 membered heteroaryl, examples of which include but not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl , oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl.
- a fused heteroaryl refers to a monocyclic heteroaryl ring fused to a phenyl, cycloalkenyl, heteroaryl, cycloalkyl, or heterocyclyl.
- the fused heteroaryl (such as 8-14 membered fused heteroaryl) can be 8-14 membered heteroaryl such as 9-10 membered heteroaryl, examples include but are not limited to benzimidazole Base, benzofuryl, benzothienyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5, 6-Dihydroisoquinolin-1-yl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, naphthyridyl, purinyl, quinolinyl, 5,6, 7,8-t
- the "pharmaceutically acceptable salt” in the present invention refers to the addition salts and solvates of pharmaceutically acceptable acids and bases.
- Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium and the like.
- a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
- the "stereoisomer" of the compound described in the present invention refers to the isomer produced by the atoms in the molecule due to the different arrangement in space.
- a compound has an asymmetric carbon atom, enantiomers will be produced; when a compound has a carbon-carbon double bond or a ring structure, cis-trans isomers will be produced.
- tautomer means isomers with different functional groups are in dynamic equilibrium and can quickly transform into each other, which is a special functional group isomerism.
- tautomers are produced, representative examples are: keto-enol tautomer, phenol-keto tautomer, nitroso-oxime tautomer, Imine-enamine tautomers, etc.
- the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
- the bond Indicates the point of attachment to the parent molecule.
- the present invention provides a compound represented by general formula (I) or its pharmaceutically acceptable salt, stereoisomer, tautomer:
- R is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R 1 and R 2 are optionally replaced by 1-3 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- Substituents of 6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;
- R 1 , R 2 form a 5-12-membered ring A with the carbon atoms they are connected to; the 5-12-membered ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen , carbonyl, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 Substituents of heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 alkylsulfonyl group;
- R 3 is selected from -(C 1-6 alkylene) 0-2 -NR 4 R 5 , -(C 1-6 alkylene) 0-2 NR 4 -COR 5 , -(C 1-6 alkylene Base) 0-2 -CO-NR 4 -R 5 ;
- R 4 is selected from hydrogen or C 1-6 alkyl;
- R 5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said R is optionally replaced by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;
- Y is selected from aryl group, 5-14 membered heteroaryl group, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl group, and said Y is optionally replaced by 1-3 members selected from halogen, cyano group, amino group, hydroxyl group , carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered Heteroaryl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl substituents;
- R 1 and R 2 are not hydrogen, methyl, cyano or trifluoromethyl
- R 3 is selected from -NH-R 5 , R 5 is not
- R 1 and R 2 of the present invention form a 5-12-membered ring A with the carbon atoms to which they are attached; the 5-12-membered ring A is optionally replaced by -N(C 1-6 alkyl) 2 replace.
- R 3 is selected from -(C 1-6 alkylene) 0-2 -OR 5 .
- the R 5 is optionally substituted by a substituent selected from C 2-6 alkenylcarbonyl, sulfonyl, C 1-6 alkylcarbonyl.
- the R 5 is optionally substituted with carboxy.
- the Y is optionally substituted by a substituent selected from C 1-6 alkylaminocarbonyl, sulfonyl.
- the Y is optionally substituted with a substituent selected from C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- Substituents on R 5 the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl Base, 5-7 membered heteroaryl, sulfonyl are optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, 3-6 membered cycloalkyl ;
- Substituents on Y are optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, and 3-6-membered cycloalkyl.
- R 1 and R 2 of the present invention form a 5-12-membered ring A with the carbon atoms to which they are attached; the 5-12-membered ring A is optionally replaced by -N(C 1-6 alkyl) 2 Substitution; the R is optionally substituted by a substituent selected from C 2-6 alkenylcarbonyl, sulfonyl, C 1-6 alkylcarbonyl; the Y is optionally selected from C 1-6 alkylaminocarbonyl , sulfonyl substituents; R 5 , Y substituted substituents: the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocycle group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, sulfonyl group, optionally replaced by 1-3 members selected from halogen, cyano group, amino group, hydroxyl group, carbony
- Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-12 membered heterocyclyl, aryl, 5-12 membered heteroaryl.
- Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl.
- ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, N, 5-8 membered cycloalkyl, 5-8 membered cycloalkene Base, 5-8 membered heterocyclic group.
- Ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 alkyl, -NH-C 1-6 alkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered Heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents.
- Ring A is unsubstituted.
- ring A is replaced by 1-2 members selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents;
- Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; Ring A is optionally 1-2 selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered ring Alkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, having a structure represented by general formula (II):
- Ring A is selected from 5-7 membered cycloalkenyl, 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-7 membered heteroaryl; Ring A is optionally replaced by 1-4 selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl substituent. Further, ring A is optionally substituted by -N(C 1-6 alkyl) 2 .
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein Ring A is selected from phenyl, 5-7 membered heteroaryls; Ring A Optionally 1-4 selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C Substituents of 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, C 1-6 alkylsulfonyl. Further, ring A is optionally substituted by -N(C 1-6 alkyl) 2 .
- Ring A is selected from Ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, C 1-6 alkylsulfonyl, -N(C 1- 6 alkyl) substituents of 2 are substituted.
- Ring A is selected from Ring A is optionally replaced by 1-2 members selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents.
- Ring A is X 1 is selected from H, CH 3 , F, Cl, Br, -OCH 3 , CN, -CF 3 , -NHCH 3
- X 2 is selected from H, CH 3 , F, Cl, Br, -OCH 3 , CN, -CF 3 , -NHCH 3
- ring A is not further substituted.
- Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, and said Y is optionally replaced by 1-3 members selected from halogen, Cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl base, 5-7 membered heteroaryl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl , C 1-6 alkylthio, C 1-6 alkylsulfinyl substituents.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, tautomers thereof,
- Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclic group, 3-7 membered cycloalkyl; Y is optionally selected from 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, C 1-6 alkylamino, C Substituents of 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl;
- R 1 and R 2 are not hydrogen, methyl, cyano or trifluoromethyl
- R 3 is selected from -NH-R 5 , R 5 is not
- Y is optionally substituted with substituents of C 1-6 alkylaminocarbonyl, sulfonyl.
- the membered cycloalkyl group and sulfonyl group are optionally substituted by 1-3 substituents selected from halogen, cyano group, amino group, hydroxyl group, carbonyl group and C 1-6 alkyl group.
- Y is selected from phenyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyl, and 3-7 membered cycloalkyl.
- Y is selected from phenyl, 5-7 membered heteroaryl.
- Y is selected from phenyl, 5-6 membered heteroaryl containing 1-2 N heteroatoms.
- the Y is optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkane Oxygen, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1- Substituents of 6 alkylsulfonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- the substituents on Y when Y is substituted, the substituents on Y: C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, 3 Substituents of -6-membered cycloalkyl.
- Y is substituted by 1-3 selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, halo C 1-6 alkyl, aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkane Substituents of radical, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- Y is substituted with cyano and optionally 1-2 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1 -6 alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 alkylamino group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonyl group, aminocarbonyl group , C 1-6 alkylaminocarbonyl, sulfonyl substituent substitution; the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclic group , 3-7 membered cycloalkyl, and sulfonyl are optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, and C 1-6 alkyl.
- Y is substituted by 1 cyano group and optionally substituted by 1-2 C 1-6 selected from halogen, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxy. 6 alkyl, halogenated C 1-6 alkyl, aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocyclic group, Substituents of 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- One embodiment of the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein Y is selected from Y is substituted by 1-3 selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, halogenated C 1-6 alkyl , aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered Substituents of heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, tautomers thereof,
- Y is selected from naphthyl, 8-14-membered condensed heteroaryl, 6-12-membered condensed heterocyclic group, 6-12-membered condensed cycloalkyl; Y is optionally replaced by 1-3 members selected from halogen, cyano, amino, Hydroxy, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy substituents;
- R 3 is selected from -NH-R 5 , R 5 is not
- R 3 is selected from -(C 1-6 alkylene) 0-2 -NR 4 R 5 , -(C 1-6 alkylene) 0-2 -NR 4 -COR 5 , - (C 1-6 alkylene) 0-2 -CO-NR 4 -R 5 , -(C 1-6 alkylene) 0-2 -OR 5 ;
- R 4 is selected from hydrogen or C 1-6 alkyl
- R 5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl.
- R is selected from hydrogen
- R 4 is selected from C 1-6 alkyl.
- R 4 is selected from methyl, ethyl.
- R 3 is selected from -NR 4 R 5 , -NH-COR 5 , -OR 5 ;
- R 4 is selected from hydrogen or C 1-3 alkyl;
- R 5 is selected from 3-7 membered cycloalkyl , 3-7 membered heterocyclic group.
- R 3 is selected from -NHR 5
- R 5 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group.
- R is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group containing one heteroatom selected from O, N, S.
- R is optionally replaced by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 alkenylcarbonyl, sulfonyl, C 1-6 alkylcarbonyl, carboxyl substituent Substitution; when R 5 is substituted, the substituent on R 5 : C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3- 7-membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, 3-6 The substituent of the membered
- R 5 is optionally substituted by 1-2 C 1-6 alkyl selected from C 1-6 alkyl, hydroxyl, hydroxy-substituted C 1-6 alkyl, 3-7 membered cycloalkyl substituted C 1-6 alkane radical, hydroxyl, halogen, C 2-6 alkenylcarbonyl, C 1-6 alkylsulfonyl, 3-7 membered cycloalkylsulfonyl, aminosulfonyl, 3-7 membered heterocyclyl, 3-7 membered ring Alkyl, carboxyl, C 1-6 alkylcarbonyl substituents are substituted.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein R 3 is selected from -NR 4 R 5 , -NH-COR 5 , - OR 5 ; R 4 is selected from hydrogen or C 1-3 alkyl; R 5 is selected from 3-7 membered cycloalkyl, 3-7 membered heterocyclic group, R 5 is optionally selected from 1-2 members selected from C 1- 6 alkyl, hydroxy, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by 3-7 membered cycloalkyl, hydroxy, halogen, C 2-6 alkenylcarbonyl, C 1-6 alkyl Sulfonyl, 3-7 membered cycloalkylsulfonyl, aminosulfonyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, carboxyl, C 1-6 alkylcarbonyl substituent
- R is selected from Preferably, R 5 is not further substituted.
- R is selected from Preferably, R 5 is not further substituted.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein R 3 is selected from -NH-R 5 , and R 5 is replaced by 1- A 3-7 membered heterocyclic group substituted by 2 substituents selected from C 1-6 alkyl; R is preferably a 5-6 membered heterocyclic group substituted by 1-2 substituents selected from C 1-6 alkyl Ring base.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein, ring A is selected from phenyl, 5-7 membered heteroaryl; ring A is optionally replaced by 1-4 members selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, Substituents of C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl;
- Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclic group, 3-7 membered cycloalkyl; Y is optionally selected from 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, C 1-6 alkylamino, C Substituents of 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, aminocarbonyl;
- R 3 is selected from -NH-R 5 , R 5 is a 3-7 membered heterocyclic group substituted by 1-2 substituents selected from C 1-6 alkyl; R 5 is preferably 1-2 selected from A 5-6 membered heterocyclic group substituted by a C 1-6 alkyl substituent.
- Y is optionally substituted with substituents of C 1-6 alkylaminocarbonyl, sulfonyl.
- substituents on R are optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, and C 1-6 alkyl.
- the present invention relates to the aforementioned compounds or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein R 1 and R 2 form 5-8 Member ring A, the 5-8 member ring A is selected from 5-8 member cycloalkyl, 5-8 member cycloalkenyl, 5-8 member heterocyclyl, phenyl, 5-6 member heteroaryl; ring A is optionally replaced by 1-2 members selected from cyano, halogen, C 1-6 alkyl, -NH-C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3 -7-membered cycloalkyl, 5-7-membered heteroaryl, C 1-6 alkylsulfonyl, -N(C 1-6 alkyl) 2 substituents;
- Y is selected from phenyl, 5-7 membered heteroaryl; Y is substituted by 1-3 C selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl 1-6 alkyl, halogenated C 1-6 alkyl, aminocarbonyl, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylaminocarbonyl, 3-7 membered heterocycle Substituent group, 3-7 membered cycloalkyl group, 5-7 membered heteroaryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group;
- R 3 is selected from -NR 4 R 5 , -NH-COR 5 , -OR 5 ;
- R 4 is selected from hydrogen or C 1-3 alkyl;
- R 5 is selected from 3-7 membered cycloalkyl, 3-7 membered hetero Cyclic group,
- R 5 is optionally substituted by 1-2 C 1-6 alkyl, hydroxyl, halogen, C 2-6 alkenes selected from C 1-6 alkyl, hydroxyl, hydroxyl or 3-7 membered cycloalkyl Carbonyl, C 1-6 alkylsulfonyl, 3-7 membered cycloalkylsulfonyl, aminosulfonyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, carboxyl, C 1-6 alkyl Carbonyl substituents are substituted.
- R 5 is a 6-membered heterocyclic group.
- said Y is replaced by 1-3 members selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylamino, C 1-6 alkylcarbonyl Substituents of amino, C 1-6 alkylsulfonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, sulfonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl; when When Y is substituted, substituents on Y: C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl ,
- R 1 and R 2 are not hydrogen, methyl, cyano or trifluoromethyl
- R 3 is selected from -NH-R 5 , R 5 is not
- the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers, and may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration.
- the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions , syrup, etc.
- suitable fillers, binders, disintegrants, lubricants and the like can be added.
- parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used for production.
- the pharmaceutical composition When preparing injections, no additives can be added, or appropriate additives can be added according to the properties of the medicine.
- the pharmaceutical composition For rectal administration, the pharmaceutical composition can be made into suppositories and the like.
- the pharmaceutical composition When used for pulmonary administration, can be made into inhalants or sprays and the like.
- the compounds of the invention can be prepared by a variety of methods including standard chemical methods. Unless otherwise indicated, any previously defined variable will continue to have the previously defined meaning. Exemplary general synthetic methods are set forth in the following schemes and can be readily modified to prepare other compounds of the invention. In the detailed description section that follows, methods for the synthesis of specific compounds according to the invention are described.
- the compound of formula (II) can be prepared by the coupling reaction of the compound of formula (a) with formula (III);
- X is halogen (such as iodine, bromine, chlorine); R a is selected from H, C 1-6 alkyl or R a forms a 5-7 membered heterocycle with B and O atoms; R 1 , R 2 , and Y are as mentioned above above definition.
- a compound of formula (a) and a compound of formula (III) into a suitable solvent (such as 1,4-dioxane and water), adding a suitable catalyst (such as 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride), adding a suitable base (such as sodium bicarbonate), under inert gas protection (such as nitrogen), heating and stirring at a suitable temperature (such as 90 ° C ⁇ 110 ° C) for a suitable period of time (such as 1 ⁇ 20 hours).
- a suitable solvent such as 1,4-dioxane and water
- a suitable catalyst such as 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride
- a suitable base such as sodium bicarbonate
- inert gas protection such as nitrogen
- reaction solution was added with an appropriate amount of water, extracted with a suitable extractant (such as ethyl acetate), concentrated under reduced pressure, and separated by a suitable purification method (such as silica gel column chromatography, preparative thin-layer chromatography, etc.) A compound of formula (II) is obtained.
- a suitable extractant such as ethyl acetate
- a suitable purification method such as silica gel column chromatography, preparative thin-layer chromatography, etc.
- the compound of formula (a) can be prepared by coupling reaction of compound of formula (b) with formula (IV);
- X is halogen (such as iodine, bromine, chlorine); W is OH or NH, and R 1 , R 2 , R 4 and R 5 are as defined above.
- a compound of formula (b) and a compound of formula (IV) into a suitable solvent such as 1,4-dioxane
- a suitable catalyst such as tris(dibenzylideneacetone) dipalladium
- a suitable ligand such as 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
- a suitable base such as cesium carbonate
- heat and stir at a suitable temperature (such as 90 ° C ⁇ 110 ° C)
- Appropriate time period such as 1 to 12 hours).
- the compound of formula (a) can be prepared by heating the compound of formula (IV) and the compound of formula (b);
- a suitable solvent such as N,N-dimethylacetamide
- a suitable temperature such as 120°C
- a suitable period of time such as 16-20 hours.
- pour the reaction solution into an appropriate amount of water, extract with a suitable extractant such as ethyl acetate
- concentrate under reduced pressure and pass through a suitable purification method (such as silica gel column chromatography, preparative thin-layer chromatography, etc.)
- a suitable purification method such as silica gel column chromatography, preparative thin-layer chromatography, etc.
- the compound of formula (II) can be prepared by coupling reaction of the compound of formula (i) with formula (IV);
- X, R 1 , R 2 , Y, W, R 4 and R 5 are as defined above.
- a compound of formula (i) and a compound of formula (IV) into a suitable solvent such as 1,4-dioxane
- a suitable catalyst such as tris(dibenzylideneacetone) dipalladium
- a suitable ligand such as 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
- a suitable base such as cesium carbonate
- heat and stir at a suitable temperature (such as 90 ° C ⁇ 110 ° C)
- Appropriate time period such as 1 to 12 hours).
- the compound of formula (II) can be prepared under heating conditions by the compound of formula (i) and the compound of formula (IV);
- a suitable solvent such as N,N-dimethylacetamide
- a suitable temperature such as 120° C.
- a suitable period of time such as 16-20 hours.
- pour the reaction solution into an appropriate amount of water, extract with a suitable extractant such as ethyl acetate
- a suitable purification method such as silica gel column chromatography, preparative thin-layer chromatography, etc.
- the compound of formula (i) can be prepared by coupling reaction of compound of formula (b) with formula (III);
- R 1 , R 2 , Y and R a are as defined above.
- a compound of formula (b) and a compound of formula (III) are added to a suitable solvent (such as 1,4-dioxane and water), and a suitable catalyst (such as 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride), adding a suitable base (such as sodium bicarbonate), under inert gas protection (such as nitrogen), heating and stirring at a suitable temperature (such as 90 ° C ⁇ 110 ° C) for a suitable period of time (such as 1 ⁇ 20 hours).
- a suitable solvent such as 1,4-dioxane and water
- a suitable catalyst such as 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride
- a suitable base such as sodium bicarbonate
- inert gas protection such as nitrogen
- heating and stirring at a suitable temperature (such as 90 ° C ⁇ 110 ° C) for a suitable period of time (such as 1 ⁇ 20 hours).
- reaction solution was added with an appropriate amount of water, extracted with a suitable extractant (such as ethyl acetate), concentrated under reduced pressure, and separated by a suitable purification method (such as silica gel column chromatography, preparative thin-layer chromatography, etc.) Compounds of formula (i) are obtained.
- a suitable extractant such as ethyl acetate
- a suitable purification method such as silica gel column chromatography, preparative thin-layer chromatography, etc.
- compounds of formula (b) can be prepared by halogenation of compounds of formula (c);
- R 1 and R 2 are as defined above.
- a suitable solvent such as acetonitrile
- a halogenating reagent such as phosphorus oxychloride
- heating and stirring at a suitable temperature (such as 25° C. to 90° C.) for a suitable period of time (such as 1 ⁇ 12 hours).
- a suitable temperature such as 25° C. to 90° C.
- a suitable period of time such as 1 ⁇ 12 hours.
- compounds of formula (c) can be prepared from compounds of formula (d);
- R b is C 1-6 alkyl; R 1 and R 2 are as defined above.
- the compound of formula (i) can be prepared by the following reaction formula;
- X, R 1 , R 2 , Y, and R b are as defined above.
- the compound of formula (e) is added into a suitable solvent (such as tetrahydrofuran), stirred at a suitable temperature (such as -70°C to 0°C) for a suitable period of time (such as 0.5 to 1 hour), and then stirred at a suitable temperature ( For example, at -70°C to 0°C), add a solution of the compound of formula (f) (such as tetrahydrofuran), and stir for a suitable period of time (such as 2 to 5 hours).
- a suitable solvent such as tetrahydrofuran
- compounds of formula (h) can be prepared by the following reaction formula;
- X, R 1 , R 2 and Y are as defined above.
- the compound of formula (m) is added into a suitable solvent (such as tetrahydrofuran), at a suitable temperature (such as -60°C ⁇ 0°C), an organometallic reagent (such as isopropylmagnesium chloride) is added, and stirred for a suitable period of time (such as 0.5 to 2 hours), and then at a suitable temperature (such as -70 ° C ⁇ 0 ° C), the solution is added to the solution of the compound of formula (j) (such as tetrahydrofuran), and stirred for a suitable period of time (such as 2 to 5 hours).
- a suitable solvent such as tetrahydrofuran
- a suitable temperature such as -60°C ⁇ 0°C
- an organometallic reagent such as isopropylmagnesium chloride
- THF means tetrahydrofuran
- DMF means N,N-dimethylformamide
- MeOH means methanol
- EA means ethyl acetate
- DCM means dichloromethane
- DMA refers to N,N-dimethylacetamide
- MTBE refers to methyl tert-butyl ether
- EtOH refers to ethanol
- DMAC dimethylacetamide
- PE refers to petroleum ether
- n-BuLi means n-butyllithium
- FBS means fetal bovine serum
- PBS means phosphate buffered saline
- PMA means phorbol ester
- LPS lipopolysaccharide
- Nigericin means nigericin.
- Step 4 Synthesis of (R)-tert-butyl 3-((4-(2-hydroxy-4-methylphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate
- Step 1 2-(2-Methoxy-4-methylbenzoyl)-3-methylbenzoic acid and 2-(2-methoxy-4-methylbenzoyl)-6-methyl Synthesis of Benzoic Acid
- Step 3 4-(2-methoxy-4-methylphenyl)-5-methylphthalazin-1(2H)-one and 4-(2-methoxy-4-methylphenyl) Synthesis of -8-methylphthalazin-1(2H)-one
- Step 4 1-chloro-4-(2-methoxy-4-methylphenyl)-5-methylphthalazine and 4-chloro-1-(2-methoxy-4-methylphenyl) Synthesis of )-5-methylphthalazine
- Step 5 (R)-tert-butyl 3-((4-(2-methoxy-4-methylphenyl)-5-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Esters and (R)-tert-butyl 3-((4-(2-methoxy-4-methylphenyl)-8-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Synthesis
- Step 6 (R)-5-methyl-2-(8-methyl-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol and (R)-5-methyl-2 Synthesis of -(5-methyl-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol
- Step 7 (R)-5-methyl-2-(8-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol and (R)- Synthesis of 5-methyl-2-(5-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 1 2-(2-Methoxy-4-methylbenzoyl)-5-methylbenzoic acid and 2-(2-methoxy-4-methylbenzoyl)-4-methyl Synthesis of Benzoic Acid
- Step 3 4-(2-methoxy-4-methylphenyl)-7-methylphthalazin-1(2H)-one and 4-(2-methoxy-4-methylphenyl) Synthesis of -6-Methylphthalazin-1(2H)-one
- Step 4 4-Chloro-1-(2-methoxy-4-methylphenyl)-6-methylphthalazine and 1-chloro-4-(2-methoxy-4-methylphenyl) Synthesis of )-6-methylphthalazine
- Step 5 (R)-tert-butyl 3-((4-(2-methoxy-4-methylphenyl)-7-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Esters and (R)-tert-butyl 3-((4-(2-methoxy-4-methylphenyl)-6-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Synthesis
- Step 6 (R)-5-methyl-2-(6-methyl-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol and (R)-5-methyl-2 Synthesis of -(7-methyl-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol
- Step 7 (R)-5-methyl-2-(6-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 4) and Synthesis of (R)-5-methyl-2-(7-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 3)
- Embodiment 4 the synthesis of (R)-2-(5-bromo-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol (compound 34 )
- Step 2 Synthesis of methyl 2-bromo-6-(2-methoxy-4-methylbenzoyl)benzoate
- Step 5 (R)-tert-butyl 3-((8-bromo-4-(2-methoxy-4-methylphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate synthesis
- Step 7 Synthesis of (R)-2-(5-bromo-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol
- Step 4 Synthesis of (R)-4-(2-methoxy-4,5-dimethylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine
- Step 5 Synthesis of (R)-4,5-dimethyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 1 Synthesis of diethyl thiophene-3,4-dicarboxylate
- 2,3-Dihydrothiophene[3,4-d]pyridazine-1,4-dione (1.00g, 5.95mmol, 1.0eq) was added to ACN (10mL), and POCl 3 (2.00g, 13.1mmol, 2.2eq), heated to 90°C in an oil bath, and reacted for 1 hour. Cooled to room temperature, quenched with water (20mL), extracted with EA (20mL), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 1,4-dichlorothiophene[3,4-d]pyridazine ( 780mg, yield: 64.0%).
- Step 7 Synthesis of (R)-5-methyl-2-(4-(piperidin-3-ylamino)thieno[3,4-d]pyridazin-1-yl)phenol
- Step 8 (R)-5-Methyl-2-(4-((1-methylpiperidin-3-yl)amino)thieno[3,4-d]pyridazin-1-yl)phenol synthesis
- Step 1 Synthesis of intermediate 2-(2-methoxy-4-methylbenzoyl)nicotinic acid:
- the reaction solution was poured into a mixed solution of ice water (50mL) and 2N HCl (50mL), extracted with ethyl acetate (200mL), the aqueous phase was extracted with dichloromethane (200mL), the organic phases were combined, dried, and concentrated to give the crude product ( 26g).
- Step 2 Synthesis of intermediate 2-(2-methoxy-4-methylbenzoyl)nicotinic acid methyl ester:
- Step 4 Synthesis of intermediate 5-chloro-8-(2-methoxy-4-methylphenyl)pyrido[2,3-d]pyridazine
- Step 6 Synthesis of intermediate (R)-5-methyl-2-(5-((piperidin-3-yl)amino)pyrido[2,3-d]pyridazin-8-yl)phenol
- Step 7 Compound (R)-5-methyl-2-(5-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-8-yl)phenol Synthesis
- Step 1 Synthesis of intermediate 3-(2-methoxy-4-methylbenzoyl)nicotinic acid:
- Step 2 Synthesis of intermediate 3-(2-methoxy-4-methylbenzoyl)nicotinic acid methyl ester:
- Step 4 Synthesis of intermediate 8-chloro-5-(2-methoxy-4-methylphenyl)pyrido[2,3-d]pyridazine
- Step 6 Synthesis of intermediate (R)-8-methyl-2-(5-((piperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol
- Step 7 Compound (R)-5-methyl-2-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol Synthesis
- Step 4 Synthesis of (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester
- 1,4-Dichlorophthalazine (3.67g, 18.47mmol, 1.0eq.) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.4g, 36.94mmol, 2.0eq.) were added N,N-Dimethylacetamide (15.0 mL), stirred at 120°C for 12 hours.
- Step 7 Synthesis of tert-butyl (R)-(5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenyl)carbamate
- Step 8 Synthesis of (R)-4-(2-amino-4-methylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine
- Embodiment 10 the synthesis of (R)-4-(4-methyl-2-(methylamino)phenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine ( Compound 40)
- Step 3 Synthesis of (R)-4-(4-methyl-2-(methylamino)phenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine
- Step 1 Synthesis of (R)-tert-butyl 3-((4-(2-hydroxy-4-methylphenyl)phthalazin-1-yl)(methyl)amino)piperidine-1-carboxylate
- Step 1 3-Fluoro-2-(2-methoxy-4-methylbenzoyl)benzoic acid and 2-fluoro-6-(2-methoxy-4-methylbenzoyl)benzoic acid Synthesis
- Step 2 5-fluoro-4-(2-methoxy-4-methylphenyl)phthalazin-1(2H)-one and 8-fluoro-4-(2-methoxy-4-methyl Synthesis of phenyl)phthalazin-1(2H)-one
- Step 3 1-chloro-5-fluoro-4-(2-methoxy-4-methylphenyl)phthalazine and 4-chloro-5-fluoro-1-(2-methoxy-4-methoxy Synthesis of phenyl)phthalazine
- Step 4 (R)-tert-butyl 3-((5-fluoro-4-(2-methoxy-4-methylphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate Synthesis of (R)-3-((8-fluoro-4-(2-methoxy-4-methylphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester
- Step 5 (R)-2-(8-fluoro-4-(piperidin-3-ylamino)phthalazin-1-yl)-5-methylphenol and (R)-2-(5-fluoro- Synthesis of 4-(piperidin-3-ylamino)phthalazin-1-yl)-5-methylphenol
- Step 6 (R)-2-(8-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol (compound 6) and ( Synthesis of R)-2-(5-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol (compound 9)
- Two-dimensional spectrum NOE shows that 7.33-7.31(d,1H) has a coupling signal with 7.15-7.13(d,1H) and 7.33-7.31(d,1H) has a coupling signal with 9.51(s,1H).
- Embodiment 14 the synthesis of (R)-2-(6-methoxy-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol ( Compound 16)
- Step 1 Synthesis of (R)-2-(6-methoxy-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol
- Embodiment 15 the synthesis of (R)-1-(2-hydroxyl-4-methylphenyl)-4-((1-methylpiperidin-3-yl) amino)phthalazine-6-carbonitrile (compound 20)
- Step 1 Synthesis of (R)-1-(2-hydroxy-4-methylphenyl)-4-((1-methylpiperidin-3-yl)amino)phthalazine-6-carbonitrile
- Embodiment 16 the synthesis of (R)-2-(6-cyclopropyl-4-((1-methylpiperidin-3-yl) amino) phthalazin-1-yl)-5-methylphenol ( Compound 32)
- Step 2 Synthesis of (R)-7-cyclopropyl-4-(2-methoxy-4-methylphenyl)-N-(piperidin-3-yl)phthalazin-1-amine
- Step 3 Synthesis of (R)-2-(6-cyclopropyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol
- Step 1 Synthesis of (R)-tert-butyl 3-((7-chlorothieno[2,3-d]pyridazin-4-yl)amino)piperidine-1-carboxylate
- Step 4 (R)-5-Methyl-2-(4-((1-methylpiperidin-3-yl)amino)thieno[2,3-d]pyridazin-7-yl)phenol synthesis
- Step 1 Synthesis of intermediate 4-(2-methoxy-4-methylbenzoyl)nicotinic acid:
- Step 2 Synthesis of intermediate 4-(2-methoxy-4-methylbenzoyl)nicotinic acid methyl ester:
- Methyl 4-(2-methoxy-4-methylbenzoyl)nicotinate (1.1g, 3.86mmol, 1.0eq) was dissolved in ethanol (10mL), and 85% hydrazine hydrate (341mg, 5.79mmol, 1.5eq), heated to 85°C for 10min, and LC-MS detected that the reaction was complete. After cooling to room temperature, a solid precipitated out, and the product was obtained by filtration (640 mg, yield: 62.1%).
- Step 4 Synthesis of intermediate 4-chloro-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine
- Step 6 Synthesis of intermediate (R)-5-methyl-2-(4-((piperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol
- Step 7 Compound (R)-5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol Synthesis
- Step 1 Synthesis of intermediate 3-(4-bromo-2-methoxybenzoyl)nicotinic acid:
- reaction solution was reacted at room temperature for 16 hours, and the reaction was complete by TLC.
- Step 2 Synthesis of intermediate 5-(4-bromo-2-methoxyphenyl)pyrido[2,3-d]pyridazin-8-ol:
- Step 3 Synthesis of intermediate 5-(4-bromo-2-methoxyphenyl)-8-chloropyrido[2,3-d]pyridazine
- Step 5 Intermediate (R)-3-((5-(4-bromo-2-methoxyphenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidine-1 -Synthesis of tert-butyl carboxylate
- Step 7 Synthesis of intermediate (R)-3-hydroxy-4-(8-(piperidin-3-ylamino)pyrido[2,3-d]pyridazin-5-yl)benzonitrile
- Step 8 Compound (R)-3-Hydroxy-4-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)benzidine Nitrile synthesis
- Step 2 Synthesis of methyl 5-bromo-2-(2-methoxy-4-methylbenzoyl)benzoate
- Step 5 (R)-tert-butyl 3-((7-bromo-4-(2-methoxy-4-methylphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate synthesis
- Step 7 Synthesis of (R)-2-(6-bromo-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol
- Step 4 (R)-5-Methyl-2-(7-((1-methylpiperidin-3-yl)amino)thieno[2,3-d]pyridazin-4-yl)phenol synthesis
- Step 2 Synthesis of methyl 2-(4-bromo-2-methoxybenzoyl)benzoate
- Step 5 Synthesis of (R)-tert-butyl 3-((4-(4-bromo-2-methoxyphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate
- Step 7 Synthesis of (R)-4-(4-bromo-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine
- Step 8 Synthesis of (R)-5-bromo-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 4 Synthesis of (R)-5-methoxy-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 1 Synthesis of intermediate 4-(4-bromo-2-methoxybenzoyl)nicotinic acid:
- reaction was carried out at room temperature for 1 hour, and the reaction was complete by LC-MS detection. .
- the reaction solution was poured into saturated aqueous ammonium chloride solution (200 mL), concentrated, a large amount of solids were precipitated, filtered, and the filter cake was dried to obtain a mixed product containing isomers (18.67 g, yield: 82.8%).
- Step 2 Synthesis of intermediate 1-(4-bromo-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol:
- Step 3 Synthesis of intermediate 1-(4-bromo-2-methoxyphenyl)-4-chloropyrido[3,4-d]pyridazine
- Step 5 Intermediate (R)-3-((1-(4-bromo-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1 -Synthesis of tert-butyl carboxylate
- Step 7 Synthesis of intermediate (R)-3-hydroxy-4-(4-(piperidin-3-ylamino)pyrido[3,4-d]pyridazin-1-yl)benzonitrile
- Step 8 Compound (R)-3-Hydroxy-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)benzidine Nitrile synthesis
- Step 1 Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
- Step 2 Synthesis of (R)-3-methoxy-4-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde
- Step 3 Synthesis of (R)-3-hydroxy-4-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde
- Step 4 Synthesis of (R)-5-(difluoromethyl)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 3 Synthesis of methyl 2-(4-bromo-2-methoxybenzoyl)-5-methylbenzoate
- Step 8 Synthesis of (R)-5-bromo-2-(6-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Methyl 4-cyclopropyl-2-methoxybenzoate (18 g, 87.27 mmol, 1.0 eq.) and lithium hydroxide monohydrate (7.32 g, 174.54 mmol, 2.0 eq.) were dissolved in MeOH (180 mL) and In H2O (90mL), react at 40°C for 3h, TLC monitors the reaction is complete, the reaction solution is concentrated under reduced pressure, the crude product is completely dissolved in water (100mL), the pH value is adjusted to 3 with dilute hydrochloric acid, and the water phase is DCM (200mL ⁇ 2) Extract, and wash the organic phase with 0.2mol/L sodium hydroxide aqueous solution (300mL), combine the aqueous phases, adjust the pH to 3 with dilute hydrochloric acid, extract with DCM (200mL ⁇ 2), dry the organic phase, and concentrate to obtain the product (14g, yield: 83.4%).
- Step 5 Synthesis of methyl 5-bromo-2-(4-cyclopropyl-2-methoxybenzoyl)benzoate
- Step 7 Synthesis of 6-bromo-4-chloro-1-(4-cyclopropyl-2-methoxyphenyl)phthalazine
- Step 8 Synthesis of 2-(6-bromo-4-chlorophthalazin-1-yl)-5-cyclopropylphenol
- Step 9 (R)-tert-butyl 3-((7-bromo-4-(4-cyclopropyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate synthesis
- Step 10 Synthesis of (R)-2-(6-bromo-4-(piperidin-3-ylamino)phthalazin-1-yl)-5-cyclopropylphenol
- Step 11 Synthesis of (R)-2-(6-bromo-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-cyclopropylphenol
- Step 12 Synthesis of (R)-1-(4-cyclopropyl-2-hydroxyphenyl)-4-((1-methylpiperidin-3-yl)amino)phthalazine-6-carbonitrile
- Step 1 Synthesis of (R)-5-cyclopropyl-2-(6-methyl-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol
- Step 4 Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol
- Step 5 Synthesis of methyl 2-(3-methoxy-5-methylpyridoyl)benzoate
- Step 8 (R)-tert-butyl 3-((4-(3-methoxy-5-methylpyridin-2-yl)phthalazin-1-yl)amino)piperidine-1-carboxylate synthesis
- Step 10 Synthesis of (R)-5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)pyridin-3-ol
- Step 1 Synthesis of methyl 5-fluoro-2-(2-methoxy-4-methylbenzoyl)benzoate
- Step 6 Synthesis of (R)-2-(6-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-methylphenol
- Step 3 4-(4-Hydroxy-6-methylphthalazin-1-yl)-3-methoxybenzonitrile and 4-(4-hydroxy-7-methylphthalazin-1-yl)- Synthesis of 3-methoxybenzonitrile
- Step 4 4-(4-Chloro-6-methylphthalazin-1-yl)-3-methoxybenzonitrile and 4-(4-chloro-7-methylphthalazin-1-yl)- Synthesis of 3-methoxybenzonitrile
- Step 5 (R)-tert-butyl 3-((4-(4-cyano-2-methoxyphenyl)-7-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Esters and (R)-tert-butyl 3-((4-(4-cyano-2-methoxyphenyl)-6-methylphthalazin-1-yl)amino)piperidine-1-carboxylate Synthesis
Abstract
本发明属于医药技术领域,涉及NLRP3炎症小体抑制剂及其应用。具体涉及通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体,各基团的定义如说明书中所定义。研究表明,通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体,对NLRP3炎症小体具有较高的生物活性,对于治疗NLRP3相关疾病具有重要的临床开发价值。
Description
相关申请的引用
本发明要求以下发明专利申请的优先权:
2021年06月05日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202110629439.0的发明专利申请;
2021年07月26日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202110843496.9的发明专利申请;
2021年08月13日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202110940013.7的发明专利申请;
2021年08月13日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202110940018.X的发明专利申请;
2022年01月07日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202210015181.X的发明专利申请;
2022年01月07日在中国提交的,名称为“NLRP3炎症小体抑制剂及其应用”、申请号为202210015699.3的发明专利申请。
通过引用的方式将上述专利申请的全部内容并入本文。
本发明属于医药技术领域,具体涉及NLRP3炎症小体抑制剂及其应用。
核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)属于核苷酸结合寡聚化结构域样受体(NOD-like receptors,NLRs)家族,也被称为“含热蛋白(pyrin)结构域蛋白3”。NLRP3包含热蛋白结构域(PYD)、核苷酸结合位点结构域(NBD)和富含亮氨酸的重复序列(LRR)三个模块。当接收到无菌性炎症危险信号的刺激时,NLRP3与衔接蛋白细胞凋亡相关斑点样蛋白(ASC)和胱天蛋白酶原-1(pro-caspase 1)相互作用,形成NLRP3炎症小体。NLRP3炎症小体的激活导致白介素-1β(IL-1β)和白介素-18(IL-18)的释放。
NLRP3炎症小体的激活通常需要两个步骤。第一步涉及引发信号,在该信号中,Toll 样受体识别病原相关分子模式(PAMP)或损伤相关分子模式(DAMP),进而将信号传至细胞内,介导NF-κB信号通路的激活,进而上调包括非活性NLRP3和pro-IL-1β等NLRP3炎症小体相关组分的转录水平。第二步为激活信号,P2X7受体等在接收到ATP、尼日利亚菌素等信号刺激后,NLRP3单体寡聚化形成NLRP3寡聚体,然后招募ASC和pro-caspase 1组装成NLRP3炎症小体复合物。这触发了pro-caspase 1向caspase 1的转化,以及成熟IL-1β和IL-18的产生和分泌。
NLRP3炎症小体的激活与多种疾病相关。例如:自身炎症性发热综合征如冷吡啉相关周期性综合征(CAPS)、镰状细胞疾病、***性红斑狼疮(SLE)、慢性肝病、非酒精性脂肪肝炎(NASH)、痛风、假性痛风(软骨钙质沉着病)、I型和II型糖尿病及相关并发症(例如肾病、视网膜病)、神经炎症相关障碍(例如多发性硬化症、脑感染、急性损伤、神经退行性疾病、阿尔兹海默症)、动脉粥样硬化和心血管风险(如高血压)、化脓性汗腺炎、创伤愈合和瘢痕形成以及癌症(例如大肠癌、肺癌、骨髓增生性肿瘤、白血病、骨髓发育不良症候群(MDS)、骨髓纤维化)。大多数的治疗方法包括对症治疗、减慢疾病/障碍的进展以及将手术作为最后的治疗手段。
目前在研的NLRP3炎症小体抑制剂品种较少,开发出具有较高活性、成药性更好的NLRP3炎症小体抑制剂,成为临床所需。
发明内容
本发明研究了如下的化合物或其药学上可接受的盐、立体异构体、互变异构体,研究发现,该化合物或其药学上可接受的盐、立体异构体、互变异构体对NLRP3炎症小体具有较高的生物活性,对于治疗NLRP3相关疾病具有重要的临床开发价值。
为实现上述目的,本发明提供了下述技术方案:
本发明技术方案包括一种通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体:
其中,
R
1选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
2-6烯基、C
2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;
R
2选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
2-6烯基、C
2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;
R
1、R
2分别任选被1-3个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基的取代基取代;
或
R
1、R
2与它们所连接的碳原子形成5-12元环A;所述5-12元环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代;
R
3选自-(C
1-6亚烷基)
0-2-NR
4R
5、-(C
1-6亚烷基)
0-2-NR
4-COR
5、-(C
1-6亚烷基)
0-2-CO-NR
4-R
5、-(C
1-6亚烷基)
0-2-O-R
5;R
4选自氢或C
1-6烷基;R
5选自3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;所述R
5任选被1-4个选自卤素、氰基、氨基、羟基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
2-6烯基羰基、磺酰基、C
1-6烷基羰基、羧基的取代基取代;
Y选自芳基、5-14元杂芳基、3-14元杂环基、3-12元环烷基,所述Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代;
当R
5被取代时,
R
5上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代;
当Y被取代时,
Y上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异 构体、互变异构体,具有通式(II)所示结构:
其中,环A选自5-7元环烯基、5-7元环烷基、5-7元杂环基、苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自
环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基的取代基取代;所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自萘基、8-14元稠杂芳基、6-12元稠杂环基、6-12元稠环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异 构体、互变异构体,其中,Y被氰基取代以及任选被1-2个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基的取代基取代;所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
3选自-NR
4R
5、-NH-COR
5、-O-R
5;R
4选自氢或C
1-3烷基;R
5选自3-7元环烷基、3-7元杂环基,R
5任选被1-2个选自C
1-6烷基、羟基、羟基取代的C
1-6烷基、3-7元环烷基取代的C
1-6烷基、羟基、卤素、C
2-6烯基羰基、C
1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C
1-6烷基羰基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
3选自-NH-R
5,R
5为被1-2个选自C
1-6烷基的取代基取代的3-7元杂环基。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基的取代基取代;所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代;R
3选自-NH-R
5,R
5为被1-2个选自C
1-6烷基的取代基取代的3-7元杂环基。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
1、R
2与它们所连接的碳原子形成5-8元环A,所述5-8元环A选自5-8元环烷基、5-8元环烯基、5-8元杂环基、苯基、5-8元杂芳基;环A任选被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代;
Y选自苯基、5-7元杂芳基;Y被1-3个选自卤素、氰基、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基 羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代;
R
3选自-NR
4R
5、-NH-COR
5、-O-R
5;R
4选自氢或C
1-3烷基;R
5选自3-7元环烷基、3-7元杂环基,R
5任选被1-2个选自C
1-6烷基、羟基、羟基或3-7元环烷基取代的C
1-6烷基、羟基、卤素、C
2-6烯基羰基、C
1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C
1-6烷基羰基的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自
环A任选被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在上述技术方案的基础上,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自
Y被1-3个选自卤素、氰基、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
本发明还提供如前述式(I)或(II)所示的化合物、其药学上可接受的盐或其立体异构体、互变异构体见表1:
表1
本发明的技术方案还包括一种药物组合物,其包含任一项上述的化合物或其药学上可接受的盐、立体异构体、互变异构体,和药学上可接受的载体。
本发明的技术方案还包括上述的通式(I)或通式(II)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体,或上述的药物组合物在制备预防和/或治疗NLRP3炎症小体相关的疾病的药物中的用途。
本发明的技术方案还包括上述的化合物或其药学上可接受的盐、立体异构体、互变异构体,或上述的药物组合物在制备预防和/或治疗炎性小体相关的疾病、免疫性疾病、炎症性疾病、自身免疫性疾病或自身炎症性疾病的药物中的用途。
发明详述
本发明所述的“卤素”是指氟、氯、溴和碘。
本发明所述的“羟基”是指-OH基团。
本发明所述的“氰基”是指-CN基团。
本发明所述的“氨基”是指-NH
2基团。
本发明所述的“羧基”是指-COOH基团。
本发明所述的“硝基”是指-NO
2基团。
本发明所述“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。
本发明所述的“C
1-6亚烷基”的“亚”是指C
1-6烷基基团去除两个氢原子衍生的二价基团。
本发明所述“卤代C
1-6烷基”指被如上定义的一种或多种卤素基团取代的C
1-C
6烷基基团。卤代C
1-6烷基的实例包括但不限于三氟甲基、二氟甲基、氟甲基、三氯甲基、2,2,2-三氟乙基、1,3-二溴丙-2-基、3-溴-2-氟丙基和1,4,4-三氟丁-2-基。
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。
本发明所述“卤代C
1-6烷氧基”指被如上定义的一种或多种卤素基团取代的C
1-C
6烷氧基基团,其实例包括但不限于氟甲氧基、氯甲氧基、三氟甲氧基、三氟乙氧基、氟乙氧基和氟丙氧基。
本发明所述的“C
2-6烯基”是指含有至少一个碳碳双键的2-6个碳原子的烯烃部分去除一个氢原子衍生的直链或支链的烯烃基,如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二-1-烯基、1-戊烯-3-基、2-戊烯-1-基、3-戊烯-1-基、3-戊烯-2-基、1,3-戊二烯-1-基、1,4-戊二烯-3-基、1-己烯-3-基、1,4-己二烯-1-基。优选地,“C
2-6烯基”中含有一个碳碳双键。
本发明所述的“C
2-
6炔基”是指含有至少一个碳碳三键的2-6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、丁炔基、戊炔基、己炔基等。优选地,“C
2-
6炔基”中含有一个碳碳三键。
本发明所述的“C
1-6烷基氨基”、“C
1-6烷基羰基氨基”、“C
1-6烷基磺酰基”、“氨基羰基”分别指以C
1-6烷基-NH-、C
1-6烷基-C(O)-NH-、C
1-6烷基-S(O)
2-、NH
2-C(O)-方式所形成的基团。
本发明所述的“5-12元环”包括化学上可能形成的碳环或杂环,如5-12元环烷基、5-7元环烷基、5-12元环烯基、5-7元环烯基、6-12元稠环烷基、5-12元杂环基、5-7元杂环基、6-12元稠杂环、芳基、5-12元杂芳基、8-12元稠杂芳基、5-7元杂芳基等。
本发明所述的“3-12元环烷基”是指从3-12元环烷烃衍生得到的一价基团或(根据需要的)二价基团(例如5-12元环烷基),其可以是单环、双环、或者多环环烷基***。在不特别指明的情况下,某元环烷基(例如5-12元环烷基、5-8元环烷基、5-7元环烷基、3-7元环烷基、3-6元环烷基、4-6元环烷基)包括可能形成的所有单环、稠环(如6-12元稠环烷基)包括以并、螺、桥的形式稠合的情形。
单环***通常是含3-12个碳原子如3-8个或3-6个碳原子的环烃基团。环烷基的实例包括但不限于:环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、环戊烷-1,3-二基、环己烷-1,4-二基、环庚烷-1,4-二基等。稠环环烷基包括并环烷基、桥环烷基、螺环烷基。并环烷基可以为6-11元并环烷基如7-10元并环烷基,其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]壬烷基。螺环烷基可以为7-12元螺环烷基如7-11元螺环烷基,其实例包括但 不限于:
基。桥环烷基可以是6-10元桥环烷基如7-10元桥环烷基,其实例包括但不限于:
基。
本发明所述的“3-7元环烷基”是指从3-7元环烷烃衍生得到的一价基团或(根据需要的)二价基团。“3-7元环烷基”可以是3、4、5、6、7元环烷基,3-7元环烷基的实例包括环丙烷基、环丁烷基、环戊烷基、环己烷基。
本发明所述的“环烯基”是指在上述环烷基的基团中具有至少一个双键而得的基团。其例如可以是“3-12元环烯基”,即可以具有3、4、5、6、7、8、9、10、11或12个成环碳原子。在不特别指明的情况下,某元环烯基,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。环烯基可以是3-12元环烯基、3-8元环烯基、5-8元环烯基、5-7元环烯基、4-6元环烯基、7-11元螺环烯基、7-11元并环烯基、6-11元桥环烯基等。环烯基的实例可以列举环丁烯基、环戊烯基、环戊二烯基、环己烯基、1,4-环己二烯-1-基、环庚烯基、1,4-环庚二烯-1-基、环辛烯基、1,5-环辛二烯-1-基等,但不限于此。
本发明所述的“5-7元环烯基”,是指在5-7元环烷基的基团中具有至少一个双键而得的基团,如环丁烯基、环戊烯基、环己烯基、环庚烯基等。
本发明所述的“3-14元杂环基”,是指从3-14元杂环烷烃衍生得到的一价基团或(根据需要的)二价基团,即3-14元的至少一个环碳原子被选自O、S、S(O)、S(O)
2、C(O)、N的杂原子替代的非芳香性的环状基团,其优选含有1-3个杂原子。“3-14元杂环基”(例如5-14元杂环基、5-12元杂环基)包括单环杂环基、双环杂环基***或多环杂环基***,其中一个或多个环可以是饱和或部分饱和的,但不包括芳环。在不特别指明的情况下,某元杂环基(例如3-8元杂环基、3-7元杂环基、5-8元杂环基、5-7元杂环基、5-6元杂环基、4-6元杂环基、6元杂环基)包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)、饱和和部分饱和的情形。
单环杂环基可以为3-8元杂环基如5-7元杂环基、3-7元杂环基、4-7元杂环基或5-6元杂环基,3-8元含氮杂环基如4-7元含氮杂环基或5-6元含氮杂环基,3-8元饱和杂环基如5-6元饱和杂环基等。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、四氢吡咯基、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、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。
稠杂环基(如6-12元稠杂环基)包括并杂环基、螺杂环基和桥杂环基,其可以是饱和的、部分饱和的或不饱和的,但不是芳香性的。稠杂环基可以是稠合到苯环、5-6元单环环烷基、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元并杂环基如6-11元并杂环基或7-10元并杂环基,6-11元饱和并杂环基,6-11元含氮并杂环基,其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。
本发明所述的“芳基”是指含有6-14个碳原子的从芳香性的碳环烃衍生得到一价或根据需要的二价环状芳香性基团,包括苯、萘基、菲基等。
本发明所述的“5-14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5-14元环状基团,“5-14元杂芳基”可以是5、6、7、8、9、10、11、12、13、14元杂芳基,优选含有1-3个杂原子,同时包括碳原子、硫原子被氧代、氮代的情况,例如碳原子被C(O)替代,硫原子被S(O)、S(O)
2替代。杂芳基包括单杂芳基和稠杂芳基,在不特别指明的情况下,某元杂芳基,包括可能形成的所有单环、稠环、全部芳香、部分芳香的情形。单杂芳基可以为5-7元杂芳基如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、***基和三嗪基。
在某些实施方案中,稠杂芳基是指单环杂芳环稠合到苯基、环烯基、杂芳基、环烷基或杂环基所形成的基团。在某些实施方案中,稠杂芳基(如8-14元稠杂芳基)可以为8-14元并杂芳基如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和溶剂化物。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=0~4))等。这样的可药用盐还包括诸如以下的碱的盐:钠、钾、钙、铵等。本领域技术人员知晓多种无毒的可药用加成盐。
术语“任选”或“任选地”是指随后描述的情况可能发生或可能不发生,该描述包括发生所述情况和不发生所述情况。
本发明所述的所有数值范围,均表示包括该范围的两个端点、该范围之内的所有整数以及由这些整数形成的子范围。例如“3-7元”包括3、4、5、6、7元;“0-4”包括0、1、 2、3、4。
本发明所述的化合物的“立体异构体”是指由分子中的原子因空间排列方式不同而产生的异构体。当化合物存在不对称碳原子时,会产生对映异构体;当化合物存在碳碳双键或环状结构时,会产生顺反异构体。
术语“互变异构体”是不同官能团异构体处于动态平衡,能很快地相互转变,是一种特殊的官能团异构。例如存在酮或肟时,会产生互变异构体,代表性实例如:酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。
所有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、互变异构体、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。
本发明提供一种通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体:
其中,
R
1选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
2-6烯基、C
2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;
R
2选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
2-6烯基、C
2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;
R
1、R
2分别任选被1-3个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基的取代基取代;
或
R
1、R
2与它们所连接的碳原子形成5-12元环A;所述5-12元环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C
1-6烷基、-NH-C
1-6烷基、卤代 C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基磺酰基的取代基取代;
R
3选自-(C
1-6亚烷基)
0-2-NR
4R
5、-(C
1-6亚烷基)
0-2NR
4-COR
5、-(C
1-6亚烷基)
0-2-CO-NR
4-R
5;R
4选自氢或C
1-6烷基;R
5选自3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;所述R
5任选被1-4个选自卤素、氰基、氨基、羟基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基的取代基取代;
Y选自芳基、5-14元杂芳基、3-14元杂环基、3-12元环烷基,所述Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基的取代基取代;
条件是:
当Y为羟基取代的苯基时,R
1、R
2不为氢、甲基、氰基、三氟甲基;
在一些实施方式中,本发明R
1、R
2与它们所连接的碳原子形成5-12元环A;所述5-12元环A任选被-N(C
1-6烷基)
2取代。
在一些实施方式中,R
3选自-(C
1-6亚烷基)
0-2-O-R
5。
在一些实施方式中,所述R
5任选被选自C
2-6烯基羰基、磺酰基、C
1-6烷基羰基的取代基取代。
在一些实施方式中,所述R
5任选被羧基取代。
在一些实施方式中,所述Y任选被选自C
1-6烷基氨基羰基、磺酰基的取代基取代。
在一些实施方式中,所述Y任选被选自C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
在一些实施方式中,当R
5被取代时,
R
5上的取代基:所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、 羰基、C
1-6烷基、3-6元环烷基的取代基取代;
当Y被取代时,
Y上的取代基:所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在一些实施方式中,本发明R
1、R
2与它们所连接的碳原子形成5-12元环A;所述5-12元环A任选被-N(C
1-6烷基)
2取代;所述R
5任选被选自C
2-6烯基羰基、磺酰基、C
1-6烷基羰基的取代基取代;所述Y任选被选自C
1-6烷基氨基羰基、磺酰基的取代基取代;R
5、Y被取代的取代基:所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在一些实施方式中,环A选自5-12元环烷基、5-12元环烯基、5-12元杂环基、芳基、5-12元杂芳基。
在一些实施方式中,环A选自5-8元环烷基、5-8元环烯基、5-8元杂环基、苯基、5-8元杂芳基。
在一些实施方式中,环A选自苯基、含有1-2个选自O、S、N杂原子的5-6元杂芳基、5-8元环烷基、5-8元环烯基、5-8元杂环基。
在一些实施方式中,环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在一些实施方式中,环A不被取代。
在一些实施方式中,环A被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代;
在一些实施方式中,环A选自5-8元环烷基、5-8元环烯基、5-8元杂环基、苯基、5-6元杂芳基;环A任选被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在一些实施方式中,本发明涉及前述化合物或其药学上可接受的盐、立体异构体、 互变异构体,具有通式(II)所示结构:
其中,环A选自5-7元环烯基、5-7元环烷基、5-7元杂环基、苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基磺酰基的取代基取代。进一步地,环A任选被-N(C
1-6烷基)
2取代。
在一些实施方式中,本发明涉及前述化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基磺酰基的取代基取代。进一步地,环A任选被-N(C
1-6烷基)
2取代。
在一些实施方式中,涉及前述化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自
环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在一些实施方式中,环A选自
环A任选被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代。
在一些实施方式中,环A为
X
1选自H、CH
3、F、Cl、Br、-OCH
3、CN、-CF
3、-NHCH
3、
X
2选自H、CH
3、F、Cl、Br、-OCH
3、CN、-CF
3、-NHCH
3、
优选地,环A不再进一步被取代。
在一些实施方式中,Y选自芳基、5-14元杂芳基、3-14元杂环基、3-12元环烷基,所述Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
在一些实施方式中,本发明涉及前述化合物或其药学上可接受的盐、立体异构体、互变异构体,
其中,
Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基的取代基取代;
条件是:
当Y为羟基取代的苯基时,R
1、R
2不为氢、甲基、氰基、三氟甲基;
在一些实施方式中,Y任选被C
1-6烷基氨基羰基、磺酰基的取代基取代。
在一些实施方式中,当Y被取代时,Y上的C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代。
在一些实施方式中,Y选自苯基、5-8元杂芳基、3-8元杂环基、3-7元环烷基。
在一些实施方式中,Y选自苯基、5-7元杂芳基。
在一些实施方式中,Y选自苯基、含1-2个N杂原子的5-6元杂芳基。
在一些实施方式中,所述Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
在一些实施方式中,当Y被取代时,Y上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在一些实施方式中,Y被1-3个选自卤素、氰基、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
在一些实施方式中,Y被氰基取代以及任选被1-2个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基的取代基取代;所述C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代。
在一些实施方式中,Y被1个氰基取代以及任选被1-2个选自卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
本发明的一种实施方式涉及前述的化合物或其药学上可接受的盐、立体异构体、互 变异构体,其中,Y选自
Y被1-3个选自卤素、氰基、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代。
在一些实施方式中,本发明涉及前述化合物或其药学上可接受的盐、立体异构体、互变异构体,
其中,
Y选自萘基、8-14元稠杂芳基、6-12元稠杂环基、6-12元稠环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基的取代基取代;
条件是:
在一些实施方式中,R
3选自-(C
1-6亚烷基)
0-2-NR
4R
5、-(C
1-6亚烷基)
0-2-NR
4-COR
5、-(C
1-6亚烷基)
0-2-CO-NR
4-R
5、-(C
1-6亚烷基)
0-2-O-R
5;R
4选自氢或C
1-6烷基;R
5选自3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基。
在一些实施方式中,R
4选自氢。
在一些实施方式中,R
4选自C
1-6烷基。
在一些实施方式中,R
4选自甲基、乙基。
在一些实施方式中,R
3选自-NR
4R
5、-NH-COR
5、-O-R
5;R
4选自氢或C
1-3烷基;R
5选自3-7元环烷基、3-7元杂环基。
在一些实施方式中,R
3选自-NHR
5,R
5选自4-6元环烷基、4-6元杂环基。
在一些实施方式中,R
5选自4-6元环烷基、含有1个选自O、N、S杂原子的4-6元杂环基。
在一些实施方式中,R
5任选被1-4个选自卤素、氰基、氨基、羟基、C
1-6烷基、 卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
2-6烯基羰基、磺酰基、C
1-6烷基羰基、羧基的取代基取代;当R
5被取代时,R
5上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在一些实施方式中,R
5任选被1-2个选自C
1-6烷基、羟基、羟基取代的C
1-6烷基、3-7元环烷基取代的C
1-6烷基、羟基、卤素、C
2-6烯基羰基、C
1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C
1-6烷基羰基的取代基取代。
在一些实施方式中,本发明涉及前述化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
3选自-NR
4R
5、-NH-COR
5、-O-R
5;R
4选自氢或C
1-3烷基;R
5选自3-7元环烷基、3-7元杂环基,R
5任选被1-2个选自C
1-6烷基、羟基、羟基取代的C
1-6烷基、3-7元环烷基取代的C
1-6烷基、羟基、卤素、C
2-6烯基羰基、C
1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C
1-6烷基羰基的取代基取代。
在一些实施方式中,本发明涉及前述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
3选自-NH-R
5,R
5为被1-2个选自C
1-6烷基的取代基取代的3-7元杂环基;R
5优选为被1-2个选自C
1-6烷基的取代基取代的5-6元杂环基。
在一些实施方式中,本发明涉及前述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、3-7元杂环基、3-7元环烷基的取代基取代;
Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基的取代基取代;
R
3选自-NH-R
5,R
5为被1-2个选自C
1-6烷基的取代基取代的3-7元杂环基;R
5优选为被1-2个选自C
1-6烷基的取代基取代的5-6元杂环基。
在一些实施方式中,Y任选被C
1-6烷基氨基羰基、磺酰基的取代基取代。
在一些实施方式中,当R
5被取代时,R
5上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基的取代基取代。
在一些实施方式中,本发明涉及前述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R
1、R
2与它们所连接的碳原子形成5-8元环A,所述5-8元环A选自5-8元环烷基、5-8元环烯基、5-8元杂环基、苯基、5-6元杂芳基;环A任选被1-2个选自氰基、卤素、C
1-6烷基、-NH-C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、-N(C
1-6烷基)
2的取代基取代;
Y选自苯基、5-7元杂芳基;Y被1-3个选自卤素、氰基、羟基、氨基、C
1-6烷基、C
1-6烷氧基、羟基取代的C
1-6烷基、卤代C
1-6烷基、氨基羰基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C
1-6烷基磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代;
R
3选自-NR
4R
5、-NH-COR
5、-O-R
5;R
4选自氢或C
1-3烷基;R
5选自3-7元环烷基、3-7元杂环基,R
5任选被1-2个选自C
1-6烷基、羟基、羟基或3-7元环烷基取代的C
1-6烷基、羟基、卤素、C
2-6烯基羰基、C
1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C
1-6烷基羰基的取代基取代。
在前述任一实施方式或技术方案的基础上,当Y被氯取代时,R
5为6元杂环基。
在前述任一实施方式或技术方案的基础上,所述Y被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C
1-6烷基氨基、C
1-6烷基羰基氨基、C
1-6烷基磺酰基、氨基羰基、C
1-6烷基氨基羰基、磺酰基、C
1-6烷基硫基、C
1-6烷基亚磺酰基的取代基取代;当Y被取代时,Y上的取代基:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C
1-6烷基、3-6元环烷基的取代基取代。
在前述任一实施方式或技术方案的基础上,
当Y为羟基取代的苯基时,R
1、R
2不为氢、甲基、氰基、三氟甲基;
在一些实施方式中,所述药物组合物可以包含一种或多种药用载体,可以以口服、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,所述药物组合物可制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,所述药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中的常规方法生产,配置注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。用于直肠给药时,所述药物组合物可制成栓剂等。用于经肺给药时,所述药物组合物可制成吸入剂或喷雾剂等。
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它化合物。在后面的具体实施方式部分中,描述了根据本发明的具体化合物的合成方法。
式(Ⅱ)的化合物可以通过式(a)的化合物,与式(Ⅲ)偶联反应来制备;
其中,
X为卤素(如碘,溴,氯);R
a选自H、C
1-6烷基或R
a与B、O原子形成5-7元杂环;R
1、R
2、Y如前文所述定义。
以下提供了由式(a)的化合物和式(Ⅲ)的化合物反应来制备式(Ⅱ)的化合物的方法:
例如,将式(a)的化合物和式(Ⅲ)的化合物加入合适溶剂(如1,4-二氧六环和水)中,加入合适的催化剂(如1,1'-双二苯基膦二茂铁二氯化钯),加入合适的碱(如 碳酸氢钠),惰性气体保护(如氮气)下,在合适的温度(如90℃~110℃)加热搅拌合适的时间段(如1~20小时)。反应结束后,将反应液加入适量的水,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(II)的化合物。
式(a)的化合物可以通过式(b)的化合物,与式(Ⅳ)偶联反应来制备;
其中,X为卤素(如碘,溴,氯);W为OH或NH,R
1、R
2、R
4和R
5如前文所定义。
下述提供了由式(b)的化合物和式(Ⅳ)的化合物反应来制备式(a)的化合物的方法:
例如,将式(b)的化合物和式(Ⅳ)的化合物加入合适溶剂(如1,4-二氧六环)中,加入合适的催化剂(如三(二亚苄基丙酮)二钯),加入合适的配体(如1,1'-联萘-2,2'-双二苯膦),加入合适的碱(如碳酸铯),在合适的温度(如90℃~110℃)加热搅拌合适的时间段(如1~12小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(a)的化合物。
在某些实施方案中,式(a)的化合物可以通过式(Ⅳ)的化合物与式(b)的化合物在加热条件下制备;
例如,将式(b)的化合物和式(Ⅳ)的化合物加入合适溶剂(如N,N-二甲基乙酰胺)中,在合适的温度(如120℃)加热搅拌合适的时间段(如16~20小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(a)的化合物。
在某些实施方案中,式(Ⅱ)的化合物可以通过式(i)的化合物,与式(Ⅳ)偶联反应来制备;
其中,
X、R
1、R
2、Y、W、R
4和R
5如前文所定义。
下面提供了由式(i)的化合物和式(Ⅳ)的化合物反应来制备式(Ⅱ)的化合物的方法:
例如,将式(i)的化合物和式(Ⅳ)的化合物加入合适溶剂(如1,4-二氧六环)中,加入合适的催化剂(如三(二亚苄基丙酮)二钯),加入合适的配体(如1,1'-联萘-2,2'-双二苯膦),加入合适的碱(如碳酸铯),在合适的温度(如90℃~110℃)加热搅拌合适的时间段(如1~12小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(II)的化合物。
在某些实施方案中,式(Ⅱ)的化合物可以通过式(i)的化合物和式(Ⅳ)的化合物在加热条件下制备;
例如,将式(i)的化合物和式(Ⅳ)的化合物加入合适溶剂(如N,N-二甲基乙酰胺)中,在合适的温度(如120℃)加热搅拌合适的时间段(如16~20小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(Ⅱ)的化合物。
式(i)的化合物可以通过式(b)的化合物,与式(Ⅲ)偶联反应来制备;
其中,
X、R
1、R
2、Y和R
a如前文所定义。
下述提供了由式(b)的化合物和式(Ⅲ)的化合物反应来制备式(i)的化合物的方法:
例如,将式(b)的化合物和式(Ⅲ)的化合物加入合适溶剂(如1,4-二氧六环和水)中,加入合适的催化剂(如1,1'-双二苯基膦二茂铁二氯化钯),加入合适的碱(如碳酸氢钠),惰性气体保护(如氮气)下,在合适的温度(如90℃~110℃)加热搅拌合适的时间段(如1~20小时)。反应结束后,将反应液加入适量的水,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(i)的化合物。
在某些实施方案中,式(b)的化合物可以通过式(c)的化合物通过卤化反应来制备;
R
1、R
2如前文所定义。
下面提供了由式(c)的化合物来制备式(b)的化合物的方法:
例如,将式(c)的化合物加入合适溶剂(如乙腈)中,加入卤化试剂(如三氯氧磷),在合适的温度(如25℃~90℃)加热搅拌合适的时间段(如1~12小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(b)的化合物。
在某些实施方案中,式(c)的化合物可以通过式(d)的化合物来制备;
其中,
R
b为C
1-6烷基;R
1、R
2如前文所定义。
下面提供了由式(d)的化合物来制备式(c)的化合物的方法:
例如,将式(d)的化合物(或者环A的酸酐化合物)加入合适溶剂(如乙醇)中,加入水合肼,在合适的温度(如25℃~80℃)加热搅拌合适的时间段(如0.5~5小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到 式(c)的化合物。
在某些实施方案中,式(i)的化合物可由以下反应式来制备;
其中,X、R
1、R
2、Y、R
b如前文所定义。
下述提供了式(i)的化合物具体的制备方法:
例如,将式(e)的化合物加入合适溶剂(如四氢呋喃)中,在合适的温度(如-70℃~0℃)搅拌合适的时间段(如0.5~1小时),然后在合适的温度(如-70℃~0℃)下,加入式(f)的化合物的溶液(如四氢呋喃),拌合适的时间段(如2~5小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(g)的化合物。
将式(g)的化合物加入合适溶剂(如乙醇)中,加入水合肼,在合适的温度(如25℃~80℃)加热搅拌合适的时间段(如0.5~5小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(h)的化合物。
将式(h)的化合物加入合适溶剂(如乙腈)中,加入卤化试剂(如三氯氧磷),在合适的温度(如25℃~90℃)加热搅拌合适的时间段(如1~12小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(i)的化合物。
在某些实施方案中,式(h)的化合物可由以下反应式来制备;
其中,
X、R
1、R
2和Y如前文所定义。
例如,将式(m)的化合物加入合适溶剂(如四氢呋喃)中,在合适的温度(如-60℃~0℃)下,加入有机金属试剂(如异丙基氯化镁),搅拌合适的时间段(如0.5~2小时),然后在合适的温度(如-70℃~0℃)下,将该溶液加入到式(j)的化合物的溶液(如四氢呋喃)中,拌合适的时间段(如2~5小时)。反应结束后,将反应液倒入适量的水中,调节pH值,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(n)的化合物。
将式(n)的化合物加入合适溶剂(如乙醇)中,加入水合肼,在合适的温度(如25℃~80℃)加热搅拌合适的时间段(如0.5~5小时)。反应结束后,将反应液倒入适量的水中,用合适的萃取剂(如乙酸乙酯)萃取,减压浓缩后,通过合适的纯化方法(如硅胶柱层析色谱、制备薄层色谱等)分离得到式(h)的化合物。
上述制备方法以及方法中的各个步骤的先后顺序仅仅是示例性的,本领域技术人员参照上述方法可制备本发明的化合物,并且可根据具体情况调整步骤顺序。另外,上述制备方法中的没有说明其来源的化合物通常是市售的,或者可以由本领域技术人员通过已知的方法从市售的化合物合成。
本发明的有益效果
研究发现,本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体,对NLRP3炎症小体具有良好的抑制活性,因此本发明化合物可用于预防和/或治疗与NLRP3炎症小体相关的疾病。
为使本发明的目的、技术方案、及优点更加清楚明白,以下对本发明进一步详细说明。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
在本发明中所使用的缩写和英文表述具有以下含义:
“THF”是指四氢呋喃;“DMF”是指N,N-二甲基甲酰胺;“MeOH”是指甲醇;“EA”是指乙酸乙酯;“DCM”是指二氯甲烷;“DMA”是指N,N-二甲基乙酰胺;“MTBE”是指甲基叔丁醚;“EtOH”是指乙醇;“DMAC”是指二甲基乙酰胺;“PE”是指石油醚;“n-BuLi”是指正丁基锂;
“FBS”是指胎牛血清;“PBS”是指磷酸盐缓冲盐溶液;“PMA”是指佛波酯;“LPS” 是指脂多糖;“Nigericin”是指尼日利亚菌素。
实施例1(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物1)
步骤1:(2-甲氧基-4-甲基苯基)硼酸的合成
将1-溴-2-甲氧基-4-甲基苯(8.0g,39.78mmol,1.0eq.)加入THF(60.0mL),降温至-70℃,缓慢滴加2.5M正丁基锂正己烷溶液(23.8mL,59.67mmol,1.5eq.),-70℃搅拌2小时后,缓慢滴加硼酸三异丙酯(9.72g,51.72mmol,1.3eq.),逐渐升至室温搅拌4小时,TLC监测反应完全,体系加入2mol/L的HCl水溶液(100.0mL),搅拌1小时,加入EA(200.0mL),分液,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,加入石油醚(50.0mL)打浆1小时,抽滤得产物(5.8g,收率:87.8%)。
步骤2:1-氯-4-(2-甲氧基-4-甲基苯基)酞嗪的合成
将(2-甲氧基-4-甲基苯基)硼酸(5.19g,31.26mmol,1.0eq.)加入1,4-二氧六环(60.0mL),加入1,4-二氯酞嗪(6.84g,34.39mmol,1.1eq.)、碳酸氢钠(5.25g,62.52mmol,2.0eq.)、水(15.0mL)和Pd(dppf)Cl
2(1.14g,1.56mmol,0.05eq.),氮气保护下90℃反应5小时,TLC监测反应完全,体系加入EA(200.0mL)和水(200mL),分液,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(100-200目硅胶,石油醚:乙酸乙酯=10:1-4:1)纯化得产物(4.4g,收率:49.4%)。
步骤3:2-(4-溴酞嗪-1-基)-5-甲基苯酚的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)酞嗪(4.0g,14.04mmol,1.0eq.)加入DCM(30.0mL),降温至-65℃缓慢滴加三溴化硼(7.0g,28.09mmol,2.0eq.),逐渐升至室温搅拌过夜。TLC监测反应完全,体系0℃下加入甲醇淬灭,减压浓缩后用DCM和水分液,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(2.3g,收率:52.2%)。
步骤4:(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将2-(4-溴酞嗪-1-基)-5-甲基苯酚(2.3g,7.29mmol,1.0eq.)加入DMA(10.0mL)、(R)-3-氨基哌啶-1-羧酸叔丁酯(2.19g,10.94mmol,1.5eq.),120℃搅拌过夜。TLC监测反应完全,体系加入EA(200.0mL),水洗(100.0mL×3),有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(100-200目硅胶,石油醚:乙酸乙酯=100:1-90:1)纯化得产物(1.8g,收率:56.7%)。
步骤5:(R)-5-甲基-2-(4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(750.0mg,1.72mmol,1.0eq.)加入DCM(5.0mL)和三氟乙酸(5.0mL),室温搅拌2小时。TLC监测反应完全,体系用水反萃(30.0mL×4),水相合并,用饱和碳酸钠水溶液调节pH=8-9,DCM萃取3次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得产物(550.0mg,收率:95.4%)。
步骤6:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)酞嗪-1-基)苯酚(550.0mg,1.64mmol,1.0eq.)加入甲醇(10.0mL),加入甲醛水溶液(37%)(160.1mg,1.97mmol,1.2eq.),室温搅拌1小时后加入氰基硼氢化钠(144.6mg,2.30mmol,1.4eq.),室温反应3小时。TLC监测反应完全,体系加入EA(100.0mL)和饱和碳酸氢钠水溶液,分液,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=8:1)得产物(300.0mg,收率:52.3%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.63(s,1H),8.48(s,1H),7.77-7.89(m,2H),7.52-7.54(m,1H),7.41(s,1H),7.15-7.17(m,1H),6.76-6.82(m,2H),4.65(s,1H),3.36-3.47(m,2H),3.12-3.17(m,2H),2.50-2.51(m,3H),2.33(s,3H),1.77-1.99(m,4H).
分子式:C
21H
24N
4O 分子量:348.45 LC-MS(Pos,m/z)=349.22[M+H]
+.
实施例2:(R)-5-甲基-2-(8-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物2)和(R)-5-甲基-2-(5-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物5)的合成
步骤1:2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸的合成
将1-溴-2-甲氧基-4-甲基苯(6.82g,33.91mmol,1.1eq.)溶于THF(50mL),降温至-50℃,缓慢滴加正丁基锂正己烷溶液(2.5mol/L,13.6mL,33.91mmol,1.1eq.),-50℃搅拌30min,-60℃下将上述反应液缓慢滴加至4-甲基异苯并呋喃-1,3-二酮(5g,30.83mmol,1.0eq.)的THF(50mL)溶液中,氮气保护下-60℃反应,滴毕自然升至室温,反应1h,将反应液倒 入稀盐酸溶液(100mL)中,用EA(100mL×2)萃取,有机相再用0.2mol/L的NaOH溶液(100mL)洗,水相再用盐酸调pH值至4,EA(100mL×2)萃取,有机相干燥,浓缩得2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸的混合物(7.0g,收率:79.9%)。
步骤2:2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸甲酯的合成
将2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸的混合物(7.0g,24.62mmol,1.0eq.)、碳酸钾(5.1g,36.93mmol,1.5eq.)和碘甲烷(5.24g,36.93mmol,1.5eq.)溶于DMF(100mL),室温反应1h,TLC监测反应完全,反应液倒入水中(100mL),用甲基叔丁基醚(50mL×3)萃取,有机相再用水(30mL×2)洗,干燥,浓缩得2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸甲酯的混合物(5.0g,收率:68.1%)。
步骤3:4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1(2H)-酮的合成
将2-(2-甲氧基-4-甲基苯甲酰基)-3-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-6-甲基苯甲酸甲酯的混合物(5.0g,16.76mmol,1.0eq.)和85%水合肼(1.48g,25.14mmol,1.5eq.)溶于乙醇(50mL),80℃反应9h,LC-MS检测基本反应完全,反应液减压浓缩,粗品用EtOH:MTBE=(3:1,40mL)打浆,抽滤,滤饼烘干得4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1(2H)-酮的混合物(4.0g,收率:85.1%)。
步骤4:1-氯-4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪和4-氯-1-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪的合成
将4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1(2H)-酮(4.0g,14.26mmol,1.0eq.)和三氯氧磷(4.37g,28.52mmol,2.0eq.)溶于乙腈(40mL),90℃反应13.5h,TLC监测反应完全,反应液减压浓缩,粗品用水(50mL)溶解,用碳酸钠调pH值至9,用EA(100mL×2)萃取,有机相干燥,浓缩得1-氯-4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪和4-氯-1-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪的混合物(3.6g,收率:84.5%)。
步骤5:(R)-3-((4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪和4-氯-1-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪的混合物(3.6g,12.05mmol,1.0eq.),以及(R)-3-氨基哌啶-1-羧酸叔丁酯(4.83g,24.10mmol,2.0eq.)溶于DMAC(20mL),120℃反应11h。TLC反应完全,反应液倒入水(100mL)中,有固体析出,抽滤,滤饼用EA(100mL)溶解,再用水(20mL×3)洗,有机相干燥,浓缩得(R)-3-((4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(4.0g,收率:71.8%)。
步骤6:(R)-5-甲基-2-(8-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(5-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)-5-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-8-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(4.0g, 8.64mmol,1.0eq.)溶于DCM(20mL)降温至-20℃,滴加1mol/L的三溴化硼二氯甲烷溶液(17mL,17.28mmol,2.0eq),滴毕自然升至室温,反应1h,TLC检测反应完全,反应液倒入水(20mL)中,分液,水相用NaHCO
3调pH值至9,再用DCM(30mL×2)萃取,有机相干燥,浓缩得(R)-5-甲基-2-(8-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(5-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的混合物(2.5g,收率:83.3%)。
步骤7:(R)-5-甲基-2-(8-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(5-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(8-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(5-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的混合物(1.0g,2.87mmol,1.0eq.)溶于甲醇(10mL)加入甲醛水溶液(37%)(256mg,3.16mmol,1.1eq.),室温搅拌20min,加入氰基硼氢化钠(198mg,3.16mmol,1.1eq.),室温反应20min。LC-MS监测反应完全,反应液减压浓缩,粗品中加入水(20mL)用DCM(20mL×3)萃取,有机相干燥,浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=8:1)得Rf值较小的产物(化合物2)(R)-5-甲基-2-(8-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(70mg,收率:6.7%)
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.31(s,1H),8.31(s,1H),7.74-7.72(d,1H),7.60-7.58(d,1H),7.31(s,1H),7.06-7.03(m,1H),6.73(s,2H),4.68(s,1H),2.57(s,4H),2.50(s,3H),2.31(s,3H),2.06-1.99(t,5H),1.83-1.81(m,2H).
分子式:C
21H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.26[M+H]
+.
同时得到Rf值较大产物(化合物5)(R)-5-甲基-2-(5-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(40mg,收率:3.8%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.51(s,1H),7.63-7.61(d,2H),7.34-7.32(t,1H),7.13-7.11(d,1H),6.81(s,1H),6.77-6.75(d,1H),6.17(s,1H),4.57(s,1H),2.97(s,4H),2.58(s,3H),2.50(s,3H),2.30(s,3H),1.98-1.96(d,2H),1.77(s,2H).
分子式:C
21H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.29[M+H]
+.
实施例3:(R)-5-甲基-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物4)和(R)-5-甲基-2-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物3)的合成
步骤1:2-(2-甲氧基-4-甲基苯甲酰基)-5-甲基苯甲酸和2-(2-甲氧基-4-甲基苯甲酰基)-4-甲基苯甲酸的合成
将1-溴-2-甲氧基-4-甲基苯(13.64g,67.84mmol,1.1eq.)溶于THF(50mL),降温至-50℃,缓慢滴加正丁基锂正己烷溶液(2.5mol/L,27mL,67.84mmol,1.1eq.),-50℃搅拌30min。-60℃下将上述反应液缓慢滴加至5-甲基异苯并呋喃-1,3-二酮(10g,61.68mmol,1.0eq.)的THF(100mL)溶液中,氮气保护下-60℃反应30min,滴毕自然升至室温,反应3h。反应液倒入稀盐酸溶液(200mL)中,加入EA(100mL×2)萃取,有机相再用0.2mol/L的NaOH溶液(100mL×2)洗,水相再用盐酸调pH值至4,EA(100mL×2)萃取,有机相干燥,浓缩得产物的混合物(17.51g,收率:100%)。
步骤2:2-(2-甲氧基-4-甲基苯甲酰基)-5-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-4-甲基苯甲酸甲酯的合成
将2-(2-甲氧基-4-甲基苯甲酰基)-5-甲基苯甲酸和2-(2-甲氧基-4-甲基苯甲酰基)-4-甲基苯甲酸的混合物(17.54g,61.68mmol,1.0eq.)、碳酸钾(12.83g,92.97mmol,1.5eq.)和碘甲烷(13.20g,92.97mmol,1.5eq.)溶于DMF(100mL),室温反应30min,TLC监测反应完全,反应倒入水中(200mL),用甲基叔丁基醚(150mL×3)萃取,有机相再用饱和NaCl水溶液(100mL×2)洗,有机相干燥,浓缩得2-(2-甲氧基-4-甲基苯甲酰基)-5-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-4-甲基苯甲酸甲酯的混合物(15.0g,收率:82.8%)。
步骤3:4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-6- 甲基酞嗪-1(2H)-酮的合成
将2-(2-甲氧基-4-甲基苯甲酰基)-5-甲基苯甲酸甲酯和2-(2-甲氧基-4-甲基苯甲酰基)-4-甲基苯甲酸甲酯的混合物(15g,50.28mmol,1.0eq.)和85%水合肼(4.44g,75.42mmol,1.5eq.)溶于乙醇(150mL),80℃反应6h,LC-MS检测反应完全,冷却至室温,过滤,滤饼50℃烘干得4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪-1(2H)-酮的混合物(11.0g,收率:78.0%)。
步骤4:4-氯-1-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪和1-氯-4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪的合成
将4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1(2H)-酮和4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪-1(2H)-酮的混合物(11.0g,39.24mmol,1.0eq.)和三氯氧磷(12.0g,78.48mmol,2.0eq.)溶于乙腈(100mL),90℃反应2h,TLC监测反应完全,反应液减压浓缩,加入水(50mL),用EA(100mL×2)萃取,有机相干燥,浓缩得4-氯-1-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪和1-氯-4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪的混合物(10.0g,收率:85.3%)。
步骤5:(R)-3-((4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-氯-1-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪和1-氯-4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪的混合物(2.0g,6.69mmol,1.0eq.),以及(R)-3-氨基哌啶-1-羧酸叔丁酯(2.68g,13.38mmol,2.0eq.)溶于DMAC(20mL)120℃反应19h。TLC无原料剩余,反应液倒入水(100mL) 中,有固体析出,抽滤,滤饼60℃烘干得(R)-3-((4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(2.0g,收率:64.7%)。
步骤6:(R)-5-甲基-2-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(7-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(2-甲氧基-4-甲基苯基)-6-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(2.0g,4.32mmol,1.0eq.)溶于DCM(20mL),降温至-20℃,滴加1mol/L的三溴化硼二氯甲烷溶液(21.6mL,21.60mmol,5.0eq),滴毕自然升至室温,反应2h,LC-MS检测反应完全,向瓶中加入适量的甲醇淬灭,搅拌10min,反应液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=15:1)纯化得(R)-5-甲基-2-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(7-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的混合物(1.2g,收率:80.0%)。
步骤7:(R)-5-甲基-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物4)和(R)-5-甲基-2-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物3)的合成
将(R)-5-甲基-2-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚和(R)-5-甲基-2-(7-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚混合物(1.2g,3.44mmol,1.0eq.)溶于甲醇(15mL),加入甲醛水溶液(37%)(838mg,10.32mmol,3.0eq.),室温搅拌30min,加入氰基硼氢化钠(648mg,10.32mmol,3.0eq.),室温反应30min。LC-MS监测反应完全,反应液减压浓缩,粗品中加入水(20mL),DCM(20mL×3)萃取,有机相干燥,浓缩得粗品(1.0g)。取300mg粗品经制备薄层色谱纯化(二氯:甲醇:氨水=20:1:0.5)得Rf值较大产物(化合物4)(R)-5-甲基-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(35mg,收率:9.4%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.68(s,1H),8.18(s,1H),7.61-7.58(d,1H), 7.46-7.43(d,1H),7.17-7.15(d,1H),6.91-6.89(d,1H),6.79-6.75(t,2H),4.40-4.38(t,1H),3.08-3.06(d,1H),2.72-2.69(d,1H),2.52(s,3H),2.32(s,3H),2.21(s,3H),1.99-1.92(m,3H),1.75-1.74(d,1H),1.65-1.56(m,1H),1.49-1.43(m,1H).
分子式:C
21H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.32[M+H]
+.
同时得到Rf值较小产物(化合物3)(R)-5-甲基-2-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(100mg,收率:26.8%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.62(s,1H),8.29-8.27(d,1H),7.68-7.66(d,1H),7.30(s,1H),7.16-7.14(d,1H),7.00-6.99(d,1H),6.80(s,1H),6.77-6.75(d,1H),4.43-4.42(d,1H),3.13-3.15(d,1H),2.79-2.76(d,1H),2.42(s,3H),2.33(s,3H),2.28(s,3H),2.03-1.97(m,3H),1.80-1.76(t,1H),1.64-1.61(d,1H),1.50-1.47(d,1H).
分子式:C
21H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.32[M+H]
+.
实施例4:(R)-2-(5-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物34)
步骤1:2-溴-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸的合成
将1-溴-2-甲氧基-4-甲基苯(4.87g,24.22mmol,1.1eq.)溶于THF(50mL),降温至-60℃,缓慢滴加正丁基锂正己烷溶液(2.5mol/L,9.7mL,24.22mmol,1.1eq.),-60℃搅拌30min,氮气保护下,于-60℃将上述反应液缓慢滴加至4-溴异苯并呋喃-1,3-二酮(5g,22.02mmol,1.0eq.)的THF(50mL)溶液中,滴毕自然升至室温,反应4h,LC-MS检测反应完全,反应液倒入稀盐酸溶液(100mL)中,用EA(50mL×2)萃取,有机相再用0.2mol/L的NaOH溶液(50mL×2)洗,水相再用盐酸调pH值至4,EA(100mL×2)萃取,有机相干燥,浓缩得产物(5.0g,收率:65.1%)。
步骤2:2-溴-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯的合成
将2-溴-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸(5.0g,14.32mmol,1.0eq.)、碳酸钾(2.96g,21.48mmol,1.5eq.)和碘甲烷(3.05g,21.48mmol,1.5eq.)溶于DMF(50mL),室温反应0.5h,LC-MS监测反应完全,反应液倒入水中(100mL),用甲基叔丁基醚(100mL×2)萃取,有机相再用水(50mL×2)洗,干燥,浓缩得产品(4.0g,收率:76.9%)。
步骤3:8-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮的合成
将2-溴-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯(4.0g,11.01mmol,1.0eq.)和85%水合肼(973mg,16.52mmol,1.5eq.)溶于乙醇(40mL),80℃反应15h,有大量固体析出,过滤,滤饼烘干得产品(1.4g,收率:36.8%)。
步骤4:5-溴-4-氯-1-(2-甲氧基-4-甲基苯基)酞嗪的合成
将2-溴-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯(800mg,2.32mmol,1.0eq.)和三氯氧磷(711mg,28.52mmol,2.0eq.)溶于乙腈(10mL),90℃反应1h,TLC监测反应完全,反应液减压浓缩,粗品用EA(20mL)溶解,再加入水(10mL)搅拌5min,分液,水相再用EA(20mL)萃取,有机相合并,干燥,减压浓缩得产品(600mg,收率:71.2%)。
步骤5:(R)-3-((8-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-甲酸叔丁酯的合成
将5-溴-4-氯-1-(2-甲氧基-4-甲基苯基)酞嗪(600mg,1.65mmol,1.0eq.)和(R)-3-氨基哌 啶-1-羧酸叔丁酯(660mg,3.30mmol,2.0eq.)溶于DMAC(5mL),120℃反应20h。TLC反应完全,反应液冷却至室温,倒入水(30mL)中,有固体析出,抽滤,滤饼烘干得产品(700mg,收率:80.4%)。
步骤6:(R)-2-(5-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-3-((8-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-甲酸叔丁酯(700mg,1.32mmol,1.0eq.)溶于DCM(10mL),降温至-20℃,滴加1mol/L的三溴化硼二氯甲烷溶液(6.6mL,6.60mmol,5.0eq),滴毕自然升至室温反应3h,LC-MS检测反应完全,加入适量甲醇淬灭,反应液减压浓缩,粗品用DCM(10mL)溶解,再加入水(10mL),分液,水相再用DCM(10mL×2)萃取,有机相合并,干燥,浓缩得产品(280mg,收率:51.4%)。
步骤7:(R)-2-(5-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-2-(5-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚(250mg,0.60mmol,1.0eq.)溶于甲醇(5mL),加入甲醛水溶液(37%)(146mg,1.80mmol,3.0eq.),室温搅拌30min,加入氰基硼氢化钠(113mg,1.80mmol,3.0eq.),室温反应30min。LC-MS监测无原料剩余,反应液浓缩,粗品用水(10mL)打浆,有固体析出,过滤,滤饼用EA(10mL)溶解,干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=10:1)得产品(120mg,收率:46.8%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.50(s,1H),8.15-8.13(m,1H),7.66-7.61(t,1H),7.50-7.47(m,2H),7.16-7.13(d,1H),6.80-6.76(t,2H),4.53(s,1H),2.80-2.75(t,1H),2.58(d,2H),2.33(s,7H),1.79(s,3H),1.65(s,1H).
分子式:C
21H
23Br N
4O 分子量:427.35 LC-MS(Pos,m/z)=427.25/429.25[M+H]
+.
实施例5(R)-4,5-二甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合 物35)
步骤1:2-溴-4,5-二甲基苯酚的合成
将3,4-二甲基苯酚(5.0g,40.9mmol,1.0eq)溶于DCM(50mL),冰水浴下分批加入NBS(7.28g,40.9mmol,1.0eq),反应2小时。加水洗涤反应液,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(PE:EA=50:1~20:1)得到产品(7.20g,收率:87.5%)。
步骤2:1-溴-2-甲氧基-4,5-二甲苯的合成
将2-溴-4,5-二甲基苯酚(7.20g,35.8mmol,1.0eq)溶于DMF(80mL),然后加入K
2CO
3(9.90g,71.6mmol,2.0eq)和CH
3I(7.62g,53.7mmol,1.5eq),室温搅拌3小时。加入水淬灭,用EA(50mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(PE:EA=50:1~20:1)得到产品(7.10g,收率:92.2%)。
步骤3:(2-甲氧基-4,5-二甲基苯基)硼酸的合成
将1-溴-2-甲氧基-4,5-二甲苯(5.00g,23.2mmol,1.0eq)和硼酸三异丙酯(8.73g,46.4mmol,2.0eq)溶于THF(50mL),置换氮气保护,降温至-70℃,然后滴加正丁基锂(18.6mL,46.4mmol,2.0eq),反应3小时。加入稀盐酸淬灭,pH值调至2,用EA(50mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经石油醚打浆得到产品(2.60g,收率:62.1%)。
步骤4:(R)-4-(2-甲氧基-4,5-二甲基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(2-甲氧基-4,5-二甲基苯基)硼酸(194mg,1.08mmol,1.5eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(200mg,0.723mmol,1.0eq)、Pd(dppf)Cl
2(26.5mg,0.0362mmol,0.05eq)和NaHCO
3(122mg,1.45mmol,2.0eq)依次加入到1,4-二氧六环(4mL)中,加入H
2O(2mL),置换氮气保护,油浴加热至110℃,反应1小时。冷却,加入水,用EA(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=50:1~20:1)得到产物(200mg,收率:73.5%)。
步骤5:(R)-4,5-二甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-4-(2-甲氧基-4,5-二甲基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(200mg,0.531mmol,1.0eq),溶于DCM(4mL),降温至-10℃,滴加BBr
3(266mg,1.06mmol,2.0eq),反应2小时。加入MeOH淬灭,加入饱和NaHCO
3水溶液调节pH值至8,用DCM(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=10:1)得到产物(120mg,收率:62.3%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.37(s,1H),8.41(d,J=8.1Hz,1H),7.86-7.74(m,2H),7.54(d,J=7.8Hz,1H),7.14(s,1H),7.04(s,1H),6.80(s,1H),4.49(s,1H),3.21(d,J=8.4Hz,1H),2.84(d,J=11.1Hz,1H),2.35(s,3H),2.23-2.18(m,8H),2.02-1.97(m,1H),7.84-1.80(m,1H),1.72-1.49(m,2H).
分子式:C
22H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.34[M+H]
+.
实施例6(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)噻吩并[3,4-d]哒嗪-1-基)苯酚的合 成(化合物36)
步骤1:噻吩-3,4-二甲酸二乙酯的合成
将3,4-噻吩二羧酸(5.0g,29.0mmol,1.0eq)溶于EtOH(50mL),加入H
2SO
4(5.69g,58.0mmol,2.0eq),油浴加热至80℃,反应20小时。浓缩除去EtOH,加水溶解,EA(50mL)萃取,有机相用饱和NaHCO
3水溶液(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到产品(6.20g,收率:93.5%)。
步骤2:2,3-二氢噻吩[3,4-d]哒嗪-1,4-二酮的合成
将噻吩-3,4-二甲酸二乙酯(6.20g,27.2mmol,1.0eq)溶于MeOH(30mL),然后加入水合肼(85%,8.01g,136mmol,5.0eq),油浴加热至65℃,反应4小时。降至室温,抽滤,干燥,得到产物(3.48g,收率:76.2%)。
步骤3:1,4-二氯噻吩[3,4-d]哒嗪的合成
将2,3-二氢噻吩[3,4-d]哒嗪-1,4-二酮(1.00g,5.95mmol,1.0eq),加入到ACN(10mL)中,加入POCl
3(2.00g,13.1mmol,2.2eq),油浴加热至90℃,反应1小时。冷却至室温,加水(20mL)淬灭,用EA(20mL)萃取,有机相无水硫酸钠干燥后过滤,滤液减压浓缩得到1,4-二氯噻吩[3,4-d]哒嗪(780mg,收率:64.0%)。
步骤4:4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪-1-醇的合成
将(2-甲氧基-4-甲基苯基)硼酸(631mg,3.8mmol,1.5eq)、1,4-二氯噻吩[3,4-d]哒嗪(780mg,3.80mmol,1.0eq)、Pd(dppf)Cl
2(139mg,0.190mmol,0.05eq)和NaHCO
3(1.28g,7.60mmol,2.0eq)依次加入到1,4-二氧六环(10mL)中,加入H
2O(5mL),置换氮气保护,油浴加热至110℃,反应1小时。加入水淬灭,用EA(30mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(820mg,收率:79.2%)。
步骤5:1-氯-4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪的合成
将4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪-1-醇(820mg,3.01mmol,1.0eq),加入到ACN(10mL)中,加入POCl
3(693mg,4.52mmol,1.5eq),油浴加热至90℃,反应1小时。冷却至室温,加水淬灭,用EA(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(680mg,收率:77.7%)。
步骤6:(R)-3-((4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪(600mg,2.06mmol,1.0eq)和(R)-3-氨基哌啶-1-羧酸叔丁酯(619mg,3.09mmol,1.5eq)溶于DMA(10mL),置换氮气保护,油浴加热120℃,反应20小时。加水淬灭,用EA(30mL)萃取,有机相水洗三次(30mL×3),有机相无水硫酸钠干燥后过滤,滤液减压浓缩得到(R)-3-((4-(2-甲氧基-4-甲基苯 基)噻吩并[3,4-d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(420mg,收率:44.8%)。
步骤7:(R)-5-甲基-2-(4-(哌啶-3-基氨基)噻吩并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)噻吩并[3,4-d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(420mg,0.924mmol,1.0eq)溶于DCM(8mL),降温至-10℃,滴加BBr
3(1.16mg,4.62mmol,5.0eq),反应2小时。加入MeOH淬灭,浓缩,粗品加入H
2O溶解,EA萃取,水相加入饱和NaHCO
3水溶液调节PH至8,用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产品(182mg,收率:57.9%)。
步骤8:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)噻吩并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)噻吩并[3,4-d]哒嗪-1-基)苯酚(180mg,0.529mmol,1.0eq),溶于MeOH(4mL),加入甲醛水溶液(129mg,1.59mmol,3.0eq),室温搅拌30分钟。然后加入氰基硼氢化钠(100mg,1.59mmol,3.0eq),反应1小时。加入饱和NaHCO
3水溶液淬灭,用EA(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱分离得到产品(52.0mg,收率:27.7%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):13.28(s,1H),9.01(s,1H),8.66(d,J=2.7Hz,1H),7.87(d,J=7.8Hz,2H),8.49(d,J=8.4Hz,2H),4.59(s,1H),3.11(s,2H),2.74(s,1H),2.64(s,3H),2.32(s,3H),1.99-1.74(m,5H).
分子式:C
19H
22N
4OS 分子量:354.47 LC-MS(Pos,m/z)=355.19[M+H]
+.
实施例7(R)-5-甲基-2-(5-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-8-基)苯酚的合成(化合物37)
步骤1:中间体2-(2-甲氧基-4-甲基苯甲酰基)烟酸的合成:
将1-溴-2-甲氧基-4-甲基苯(14.15g,70.38mmol,1.05eq)溶于无水THF(100mL)中,-78℃下,向其中滴加n-BuLi(33.8mL,80.48mmol,1.2eq),滴加完毕,反应30min。-78℃下,将反应液滴入2,3-吡啶二羧酸酐(10g,67.07mmol,1.0eq)的THF(100mL)溶液中,滴加完毕,常温反应16h,LC-MS检测反应完全。将反应液倒入冰水(50mL)与2N HCl(50mL)的混合溶液中,乙酸乙酯(200mL)萃取,水相使用二氯甲烷(200mL)萃取,合并有机相,干燥,浓缩得粗品(26g)。粗品经硅胶柱层析(石油醚:乙酸乙酯=2:1)得产物(1.9g,产率:10.4%)。
步骤2:中间体2-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯的合成:
将上步所得2-(2-甲氧基-4-甲基苯甲酰基)烟酸(1.9g,7mmol,1.0eq)溶于DMF(15mL)中,向其中加入碳酸钾(1.45g,10.5mmol,1.5eq)和碘甲烷(1.19g,8.4mmol,1.2eq),常温反应16h。TLC检测反应完毕。将反应液倒入水(20mL)中,EA(20mL)萃取,有机相分别用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,浓缩得粗品(1.4g)。经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1~3:1)得产物(1.23g,产率:61.5%)。
步骤3:中间体8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-5-醇的合成
将上步所得2-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯(1.23g,4.31mmol,1.0eq)溶于乙醇(10mL),向其中加入85%水合肼(324mg,4.47mmol,1.5eq),加热至85℃反应2h,TLC检测反应完毕。冷却至室温,产物析出,过滤得产物(1.02g,产率:88.6%)。
步骤4:中间体5-氯-8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪的合成
向8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-5-醇(1.02g,3.82mmol,1.0eq)中加入乙腈(10mL),向其中加入三氯氧磷(1.17g,7.64mmol,2.0eq),90℃搅拌反应6h,TLC检测反应完毕。浓缩反应液,将浓缩液倒入冰水(10mL)中,加入乙酸乙酯(10mL)萃取,有机相分别用水(10mL)、饱和食盐水(10mL)洗涤,有机相干燥,浓缩得产物(950mg,产率:87%)。
步骤5:中间体(R)-3-((8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-5-基)氨基)哌啶-1-羧酸叔丁酯的合成
将5-氯-8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪(950mg,3.325mmol,1.0eq)溶于DMA(10mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(1.33g,6.65mmol,2.0eq),120℃回流反应64h,TLC检测反应完毕,将反应液滴入水(10mL)中,乙酸乙酯(10mL)萃取,有机相用水(10mL)和饱和食盐水(10mL)洗涤,干燥,浓缩,粗品经硅胶柱层析(石油醚:乙酸乙酯=1.5:1~纯乙酸乙酯)得产品(805mg,产率:54%)。
步骤6:中间体(R)-5-甲基-2-(5-((哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-8-基)苯酚的合成
将(R)-3-((8-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-5-基)氨基)哌啶-1-羧酸叔丁酯(805mg,1.79mmol,1.0eq)溶于二氯甲烷(5mL),-20℃下,向其中滴加三溴化硼(1.35g,5.37mmol,3.0eq),常温反应1h,LC-MS检测未反应完全,补加三溴化硼(1.35g,5.37mmol,3.0eq),常温再反应1h,LCMS检测反应完毕。冰浴条件下,向反应液中缓慢滴加甲醇(1mL)和水(10mL),二氯甲烷(10mL)萃取,有机相干燥,浓缩得产物(146mg,产率:24.3%)。
步骤7:化合物(R)-5-甲基-2-(5-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-8-基)苯酚的合成
将(R)-5-甲基-2-(5-((哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-8-基)苯酚(146mg,0.435mmol,1.0eq)溶于甲醇(2mL)中,向其中加入38.5%甲醛水溶液(34mg,0.435mmol,1.0eq),搅拌5min,加入氰基硼氢化钠(30mg,0.479mmol,1.1eq)常温反应10min,TLC检测反应完毕,浓缩反应液,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产品(34mg,产率:22.3%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):11.92(brs,1H),9.20-9.22(m,1H),9.01(s,1H),8.18-8.21(d,1H),7.95-7.99(m,1H),7.84(s,1H),6.77(s,1H),6.73(s,1H),4.66(s,1H),3.55(s,3H),2.72(s,4H),2.31(s,3H),1.99-2.02(d,2H),1.79-1.83(d,2H)
分子式:C
20H
23N
5O 分子量:349.44 LC-MS:350.2[M+H]
+.
实施例8(R)-5-甲基-2-(8-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基)苯酚的合成(化合物38)
步骤1:中间体3-(2-甲氧基-4-甲基苯甲酰基)烟酸的合成:
将1-溴-2-甲氧基-4-甲基苯(14.15g,70.38mmol,1.05eq)溶于无水THF(100mL)中,-78℃下,向其中滴加n-BuLi(33.8mL,80.48mmol,1.2eq),滴加完毕,反应30min。-78℃下,将反应液滴入2,3-吡啶二羧酸酐(10g,67.07mmol,1.0eq)的THF(100mL)溶液中,滴加完毕,常温反应16h,LC-MS检测反应完全。将反应液倒入冰水(50mL)与2N HCl(50mL)的混合溶液中,乙酸乙酯(200mL)萃取,水相使用二氯甲烷(200mL)萃取,合并有机相,干燥,浓缩得粗品(26g)。经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1,二氯甲烷:甲醇=10:1)得产物(1g,产率:5.5%)。
步骤2:中间体3-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯的合成:
将上步所得3-(2-甲氧基-4-甲基苯甲酰基)烟酸(1g,3.69mmol,1.0eq)溶于DMF(15mL)中,向其中加入碳酸钾(766mg,5.54mmol,1.5eq)和碘甲烷(629mg,4.43mmol,1.2eq),常温反应16h。TLC检测反应完毕。将反应液倒入水(20mL)中,EA(20mL)萃取,有机相分别用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,浓缩得产物(456mg,产率:43.4%)。
步骤3:中间体5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-8-醇的合成
将上步所得3-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯(456mg,1.6mmol,1.0eq)溶于乙醇(10mL),向其中加入85%水合肼(142mg,2.4mmol,1.5eq),加热至85℃反应2h,TLC检测反应完毕。浓缩反应液,加入水(10mL),二氯甲烷(10mL)萃取,有机相干燥,浓缩得产物(230mg,产率:53.8%)。
步骤4:中间体8-氯-5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪的合成
向5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-8-醇(230mg,0.86mmol,1.0eq)中加入乙腈(3mL),向其中加入三氯氧磷(264mg,1.72mmol,2.0eq),85℃反应6h,TLC检测反应完毕。浓缩反应液,将浓缩液倒入冰水(10mL)中,加入二氯甲烷(10mL)萃取,有机相分别用水(10mL)、饱和食盐水(10mL)洗涤,有机相干燥,浓缩得产物(112mg,产率:45.7%)。
步骤5:中间体(R)-3-((5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯的合成
将8-氯-5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪(112mg,0.392mmol,1.0eq)溶于DMA(2mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(157mg,0.784mmol,2.0eq),120℃回流反应64h,TLC检测反应完毕,将反应液滴入水(5mL)中,乙酸乙酯(5mL)萃取,有机相用水(5mL)和饱和食盐水(5mL)洗涤,干燥,浓缩得粗品(280mg)。
步骤6:中间体(R)-8-甲基-2-(5-((哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基)苯酚的合成
将(R)-3-((5-(2-甲氧基-4-甲基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯 (280mg粗品,0.392mmol,1.0eq)溶于二氯甲烷(2mL),-20℃下,向其中滴加三溴化硼(295mg,1.176mmol,3.0eq),常温反应1h,LC-MS检测未反应完全,补加三溴化硼((295mg,1.176mmol,3.0eq),常温再反应1h,LC-MS检测反应完毕。冰浴条件下,向反应液中缓慢滴加甲醇(5mL)和水(10mL),二氯甲烷(10mL)萃取,产物在水相中。水相用饱和碳酸氢钠水溶液调节pH值至中性,二氯甲烷(10mL)萃取,有机相干燥,浓缩得产物(70mg,两步产率:53%)。
步骤7:化合物(R)-5-甲基-2-(8-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基)苯酚的合成
将(R)-8-甲基-2-(5-((哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基)苯酚(70mg,0.209mmol,1.0eq)溶于甲醇(1mL)中,向其中加入38.5%甲醛水溶液(16.3mg,0.209mmol,1.0eq),搅拌5min,加入氰基硼氢化钠(14.5mg,0.230mmol,1.1eq)常温反应10min,TLC检测反应完毕,浓缩反应液,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产品(17mg,产率:23.2%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):9.71(s,1H),9.11-9.13(m,1H),7.85-7.98(m,2H),7.54(s,1H),7.22-7.24(d,1H),6.79-6.83(m,2H),4.59(s,1H),2.92-3.04(m,2H),2.74(m,2H),2.59(s,3H),2.34(s,3H),1.78-1.92(m,4H).
分子式:C
20H
23N
5O 分子量:349.44 LC-MS:350.2[M+H]
+.
实施例9:(R)-4-(2-氨基-4-甲基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成(化合物39)
步骤1:2-溴-5-甲基苯胺的合成
将1-溴-4-甲基-2-硝基苯(20.0g,92.57mmol,1.0eq.)加入乙醇(200.0mL),加入饱和氯化铵水溶液(30.0mL)和还原铁粉(51.8g,925.7mmol,10.0eq.),80℃搅拌4小时,TLC监测反应完全,体系冷却至室温,抽滤,滤液减压浓缩,加入二氯甲烷(200.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=20:1)得产物(16.0g,收率:92.9%)。
步骤2:5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺的合成
将2-溴-5-甲基苯胺(16.0g,85.99mmol,1.0eq.)、联硼酸频那醇酯(32.7g,128.99mmol,1.5eq.)、乙酸钾(16.8g,171.98mmol.2.0eq.)和Pd(dppf)Cl
2(3.1g,4.29mmol,0.05eq.)加入1,4-二氧六环(200.0mL),氮气保护下100℃反应3小时,TLC监测反应完全,体系浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=50:1~30:1)得产物(15.0g,收率:75.0%)。
步骤3:(5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯的合成
将5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(10.0g,42.89mmol,1.0eq.)、二碳酸二叔丁酯(18.7g,85.79mmol,2.0eq.)和4-二甲氨基吡啶(7.85g,64.33mmol,1.5eq.)加入二氯甲烷(150.0mL),室温反应3小时,TLC监测反应完全,体系加入二氯甲烷(300.0mL),饱和氯化铵水溶液(200.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=100:1~80:1~60:1)得产物(8.0g,收率:57.1%)。
步骤4:(R)-3-((4-氯酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1,4-二氯酞嗪(3.67g,18.47mmol,1.0eq.)和(R)-3-氨基哌啶-1-羧酸叔丁酯(7.4g,36.94mmol,2.0eq.)加入N,N-二甲基乙酰胺(15.0mL),120℃搅拌12小时。TLC监测反应完全,体系加入乙酸乙酯(200.0mL),水(100.0mL×3)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1~2:1)得产物(1.5g,收率:22.4%)。
步骤5:(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺的合成
将(R)-3-((4-氯酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(1.5g,4.13mmol,1.0eq.)和三氟乙酸(6.0mL)加入二氯甲烷(6.0mL),室温搅拌2小时。TLC监测反应完全,体系用水(100.0mL)反萃,水相调节pH=8-9,二氯甲烷(100.0mL×3)萃取,合并有机相,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(1.0g,收率:92.1%)。
步骤6:(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(1.0g,3.80mmol,1.0eq.)、二氯甲烷(3.0mL)和甲醛水溶液(37%)(308.9mg,3.80mmol,1.0eq.)加入甲醇(10.0mL),室温搅拌1小时,加入氰基硼氢化钠(286.5mg,4.56mmol,1.2eq.),继续室温反应1小时。TLC监测反应完全,体系减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL)搅拌30分钟,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=50:1~30:1~10:1)得产物(820.0mg,收率:78.0%)。
步骤7:(R)-(5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯基)氨基甲酸叔丁酯的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(274.0mg,0.98mmol,1.0eq.)、(5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯(489.8mg,1.47mmol,1.5eq.)、碳酸氢钠(164.6mg,1.96mmol.2.0eq.)、水(3.0mL)和Pd(PPh
3)
4(113.2mg,0.098mmol,0.1eq.)加入1,4-二氧六环(8.0mL),氮气保护下110℃反应4小时,TLC监测反应完全,体系冷却至室温,过滤,滤液加乙酸乙酯(100.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(201.0mg,收率:45.8%)。
步骤8:(R)-4-(2-氨基-4-甲基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-(5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯基)氨基甲酸叔丁酯(201.0mg,0.44mmol,1.0eq.)和三氟乙酸(3.0mL)加入二氯甲烷(3.0mL),室温反应1小时,TLC监测反应完全,体系加水(50.0mL)反萃,水相调节pH=8-9,二氯甲烷(50.0mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(120.0mg,收率:76.9%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.37-8.40(d,J=9Hz,1H),7.82-7.87(m,2H),7.55-7.58(d,J=9Hz,1H),7.02-7.05(d,J=9Hz,1H),6.93-6.96(d,J=9Hz,1H),6.65(s,1H),6.50-6.53(d,J=9Hz,1H),4.89(s,2H),4.41-4.43(d,J=6Hz,1H),3.08-3.10(d,J=6Hz,1H),2.70-2.73(d,J=9Hz,1H),2.27(s,3H),2.22(s,3H),1.40-1.99(m,6H).
分子式:C
21H
25N
5 分子量:347.47 LC-MS(Pos,m/z)=348.25[M+H]
+.
实施例10:(R)-4-(4-甲基-2-(甲基氨基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成(化合物40)
步骤1:2-溴-N,5-二甲基苯胺的合成
将2-溴-5-甲基苯胺(5.0g,26.87mmol,1.0eq.)加入四氢呋喃(20.0mL),氮气保护下降温至-70℃,滴加正丁基锂正己烷溶液(2.5M)(10.7mL,26.87mmol,1.0eq.),反应1小时,升至室温滴加碘甲烷(3.8g,26.87mmol,1.0eq.),室温反应3小时,TLC监测反应完全,体系加入乙酸乙酯(200.0mL),饱和氯化铵水溶液(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=100:1)得产物(4.7g,收率:87.4%)。
步骤2:N,5-二甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺的合成
将2-溴-N,5-二甲基苯胺(1.0g,4.99mmol,1.0eq.)、联硼酸频那醇酯(1.9g,7.49mmol,1.5eq.)、乙酸钾(979.4mg,9.98mmol.2.0eq.)和Pd(PPh
3)
4(288.3mg,0.24mmol,0.05eq.)加入1,4-二氧六环(10.0mL),氮气置换5分钟,100℃反应12小时,TLC监测反应完全,反应液浓缩,经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=1:1)得产物(800.0mg,收率:64.3%)。
步骤3:(R)-4-(4-甲基-2-(甲基氨基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(160.0mg,0.57mmol,1.0eq.)、N,5-二甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(211.3mg,0.85mmol,1.5eq.)、碳酸氢钠(95.7mg,1.14mmol.2.0eq.)、水(2.0mL)和Pd(PPh
3)
4(32.9mg,0.02mmol,0.05eq.)加入1,4-二氧六环(6.0mL),氮气保护下110℃反应12小时,TLC监测反应完全,体系冷却至室温,过滤,滤液加乙酸乙酯(100.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=8:1)得产物(70.0mg,收率:33.9%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.42-8.45(d,J=9Hz,1H),7.75-7.88(m,2H),7.49-7.51(d,J=6Hz,1H),7.24(s,1H),6.93-6.96(d,J=9Hz,1H),6.53-6.56(m,2H),5.02-5.03(d,J=3Hz,1H),4.56(s,1H),2.95-2.98(d,J=9Hz,1H),2.62-2.63(d,J=3Hz,3H),2.46(s,3H),2.34(s,3H),1.60-2.28(m,6H).
分子式:C
22H
27N
5 分子量:361.49 LC-MS(Pos,m/z)=362.26[M+H]
+.
实施例11:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物41)
步骤1:(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)(甲基)氨基)哌啶-1-羧酸叔丁酯的合成
将2-(4-溴酞嗪-1-基)-5-甲基苯酚(300.0mg,0.95mmol,1.0eq.)和(R)-3-(甲氨基)哌啶-1-羧酸叔丁酯(407.9mg,1.90mmol,2.0eq.)加入N,N-二甲基乙酰胺(10.0mL),120℃搅拌12小时,TLC监测反应完全,体系冷却至室温,加入乙酸乙酯(100.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=20:1~6:1)得产物(160.0mg,收率:37.5%)。
步骤2:(R)-5-甲基-2-(4-(甲基(哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)(甲基)氨基)哌啶-1-羧酸叔丁酯(160.0mg,0.35mmol,1.0eq.)和三氟乙酸(5.0mL)加入二氯甲烷(5.0mL),室温搅拌2小时,TLC监测反应完全,体系加入水(80.0mL)反萃,水相调节pH=8~9,二氯甲烷(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得产物(98.0mg,收率:80.3%)。
步骤3:(R)-5-甲基-2-(4-(甲基(1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(甲基(哌啶-3-基)氨基)酞嗪-1-基)苯酚(98.0mg,0.28mmol,1.0eq.)和甲醛水溶液(37%)(22.8mg,0.28mmol,1.0eq.)加入甲醇(5.0mL),室温搅拌1小时,加入氰基硼氢化钠(19.3mg,0.30mmol,1.1eq.),继续室温反应2小时,TLC监测反应完全,体系加入饱和碳酸氢钠水溶液(50.0mL)搅拌30分钟,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(30.0mg,收率:29.5%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.63(s,1H),8.36-8.48(m,1H),8.11-8.19(m,1H),7.89-7.94(m,1H),7.79-7.85(m,1H),7.54-7.57(d,J=9Hz,1H),7.03(s,1H),6.85-6.88(d,J=9Hz,1H),4.26(s,1H),3.46-3.49(m,1H),3.19-3.28(m,4H),2.66(s,3H),2.08(m,1H),2.45(s,3H),1.96-2.06(m,5H).
分子式:C
22H
26N
4O 分子量:362.48 LC-MS(Pos,m/z)=363.33[M+H]
+.
实施例12:(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯腈的合成(化合物42)
步骤1:3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯腈的合成
将4-溴-3-甲氧基苯腈(5.0g,23.50mmol,1.0eq.)、联硼酸频那醇酯(11.97g,47.15mmol,2.0eq.)、乙酸钾(6.94g,70.73mmol.3.0eq.)和Pd(PPh
3)
4(1.36g,1.17mmol,0.05eq.)加入1,4-二氧六环(100.0mL),氮气保护下100℃反应12小时,TLC监测反应完全,体系直接浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=20:1)得产物(5.1g,收率:85.0%)。
步骤2:(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯腈的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(154.0mg,0.55mmol,1.0eq.)、3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯腈(288.3mg,1.11mmol,2.0eq.)、碳酸氢钠(140.1mg,1.66mmol.3.0eq.)、水(1.0mL)和Pd(PPh
3)
4(32.1mg,0.027mmol,0.05eq.)加入1,4-二氧六环(3.0mL),氮气保护下110℃反应3小时,TLC监测反应完全,体系冷却至室温,过滤,滤液加乙酸乙酯(100.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=50:1~10:1)得产物(165.0mg,收率:79.7%)。
步骤3:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯腈(165.0mg,0.44mmol,1.0eq.)加入二氯甲烷(4.0mL),氮气保护下降温至-20℃,滴加三溴化硼(330.6mg,1.32mmol,3.0eq.),逐渐升至室温反应2小时,TLC监测反应完全,体系缓慢滴加甲醇(5.0mL)淬灭,减压浓缩,慢慢加入饱和碳酸氢钠水溶液(50.0mL)搅拌30分钟,调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=5:1)得产物(60.0mg,收率:37.9%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):10.55(s,1H),8.49(s,1H),7.79-7.92(m,2H),7.37-7.50(m,5H),4.64(s,1H),3.12-3.16(m,2H),2.63-2.68(m,4H),1.75-2.01(m,5H).
分子式:C
21H
21N
5O 分子量:359.43 LC-MS(Pos,m/z)=360.22[M+H]
+.
实施例13:(R)-2-(8-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(化合物6)和(R)-2-(5-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(化合物9)的合成
步骤1:3-氟-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸和2-氟-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸的合成
将1-溴-2-甲氧基-4-甲基苯(6.66g,30.10mmol,1.1eq.)溶于THF(50mL),降温至-50℃,缓慢滴加正丁基锂正己烷溶液(2.5mol/L,13.2mL,30.10mmol,1.1eq.),搅拌30min,-60℃下将上述反应液缓慢滴加至4-氟异苯并呋喃-1,3-二酮(5g,30.10mmol,1.0eq.)的THF(50mL)溶液中,氮气保护下-60℃反应,滴毕自然升至室温,反应0.5h,将反应液倒入稀盐酸溶液(100mL)中,用EA(100mL×2)萃取,有机相干燥,浓缩得3-氟-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸和2-氟-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸的混合物(8.67g,收率:100%)。
步骤2:5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮和8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮的合成
将3-氟-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸和2-氟-6-(2-甲氧基-4-甲基苯甲酰基)苯甲酸的混合物(8.67g,30.10mmol,1.0eq.)和85%水合肼(2.66g,45.15mmol,1.5eq.)溶于乙醇(100mL),80℃反应3h,LC-MS检测有目标产物生成,反应液减压浓缩,粗品经柱层析(PE:EA=3:1)纯化得5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮和8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮的混合物(1.2g,收率:14.0%)。
步骤3:1-氯-5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪和4-氯-5-氟-1-(2-甲氧基-4-甲基苯基)酞嗪的合成
将5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮和8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮(1.2g,4.22mmol,1.0eq.)和三氯氧磷(1.29g,8.44mmol,2.0eq.)溶于乙腈(20mL),90℃反应26h,TLC监测反应完全,反应液减压浓缩,粗品用EA(20mL)溶解,加入水(20mL),用碳酸钠调pH值至9,分液,水相再用EA(20mL×2)萃取,合并有机相,干燥,浓缩,粗品经硅胶柱层析(PE:EA=6:1)纯化得1-氯-5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪和4-氯-5-氟-1-(2-甲氧基-4-甲基苯基)酞嗪的混合物(0.5g,收率:39.4%)。
步骤4:(R)-3-((5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪和4-氯-5-氟-1-(2-甲氧基-4-甲基苯基)酞嗪的混合物(0.5g,1.65mmol,1.0eq.),以及(R)-3-氨基哌啶-1-羧酸叔丁酯(396mg,1.98mmol,1.2eq.),Pd
2(dba)
3(146mg,0.16mmol,0.1eq.),BINAP(205mg,0.33mmol,0.2eq.)和碳酸铯(1.08g,3.30mmol,2.0eq.)溶于1,4-二氧六环(10mL),氮气保护下80℃反应22h。LC-MS反应完全,反应液减压浓缩,粗品经硅胶柱层析(MeOH:DCM=1:60)纯化得(R)-3-((5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(400mg,收率:52.0%)。
步骤5:(R)-2-(8-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚和(R)-2-(5-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-3-((5-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和 (R)-3-((8-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(0.4g,0.85mmol,1.0eq.)溶于DCM(20mL),降温至-20℃,滴加1mol/L的三溴化硼二氯甲烷溶液(2.6mL,2.55mmol,3.0eq),滴毕自然升至室温反应1h,LC-MS检测反应完全,向瓶中加入适量的甲醇淬灭,反应液减压浓缩,粗品用DCM(10mL)溶清,加入水(20mL),用DCM(10mL×2)萃取,水相用NaHCO
3调pH值至9,再用(MeOH:DCM=1:10)(15mL×2)萃取,有机相干燥,浓缩得(R)-2-(8-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚和(R)-2-(5-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的混合物(80mg,收率:26.7%)。
步骤6:(R)-2-(8-氟-4–((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(化合物6)和(R)-2-(5-氟-4–((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(化合物9)的合成
将(R)-2-(8-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚和(R)-2-(5-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的混合物(80mg,0.22mmol,1.0eq.)溶于甲醇(2mL),加入甲醛水溶液(37%)(18mg,0.22mmol,1.0eq.),室温搅拌5min,加入氰基硼氢化钠(16mg,0.22mmol,1.0eq.),室温反应5min。LC-MS监测有目标产物生成,反应液减压浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=7:1)得Rf值较小的产物(化合物6)(R)-2-(8-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(10mg,收率:12.5%)
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.26(s,1H),8.24-8.22(d,1H),7.90-7.85(m,1H),7.58-7.54(m,1H),7.27(s,1H),7.15-7.13(d,1H),6.70-6.69(d,1H),4.52(s,1H),2.97(s,1H),2.51(s,3H),2.50(s,2H),2.30(s,3H),2.02-2.00(d,3H),1.86(s,1H),1.71-1.69(d,1H).
分子式:C
21H
23FN
4O 分子量:366.44 LC-MS(Pos,m/z)=367.20[M+H]
+.
同时得到Rf值较大产物(化合物9)(R)-2-(5-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(15mg,收率:18.8%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.51(s,1H),7.82-7.76(m,1H),7.70-7.65(m,1H),7.33-7.31(d,1H),7.15-7.13(d,1H),6.81(s,1H),6.78-6.76(d,1H),6.69-6.65(m,1H),4.56(s,1H),2.95(s,1H),2.52(s,1H),2.50(s,3H),2.42-2.40(d,2H),2.33(s,3H),1.80(s,3H),1.66(s,1H).
二维谱NOE显示7.33-7.31(d,1H),与7.15-7.13(d,1H)有耦合信号7.33-7.31(d,1H)与9.51(s,1H)有耦合信号。
分子式:C
21H
23FN
4O 分子量:366.44 LC-MS(Pos,m/z)=367.22[M+H]
+.
实施例14:(R)-2-(6-甲氧基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物16)
步骤1:(R)-2-(6-甲氧基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(100mg,0.23mmol,1.0eq.)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(21mg,0.05mmol,0.2eq.)、碳酸铯(150mg,0.46mmol,2.0eq.)和氯化烯丙基钯二聚物(18mg,0.05mmol,0.2eq.)加入MeOH(1mL)和二甲苯(2mL)混合溶液中,氮气保护下80℃反应1h。LC-MS监测反应完全,反应液减压浓缩,粗品经制备薄层色谱纯化(MeOH:DCM=1:7)得产品(15mg,产率:17.2%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):7.74(s,1H),7.50-7.47(d,1H),7.40-7.37(d,1H),7.17-7.15(d,1H),6.80-6.75(d,2H),4.48(s,1H),3.96(s,3H),3.42(s,3H),2.88(s,1H),2.38(s,3H),2.33(s,4H),2.19-2.02(d,2H),1.70-1.54(d,2H).
分子式:C
22H
26N
4O
2 分子量:378.48 LC-MS(Pos,m/z):379.17[M+H]
+.
实施例15:(R)-1-(2-羟基-4-甲基苯基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-6-腈的合成(化合物20)
步骤1:(R)-1-(2-羟基-4-甲基苯基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-6-腈的合成
将(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(120mg,0.28mmol,1.0eq.)、氰化锌(33mg,0.28mmol,1.0eq.)和四(三苯基膦)钯(65mg,0.026mmol,0.2eq.)溶于DMAC(2mL),氮气保护下120℃反应16h。LC-MS监测反应完全,冷却至室温,反应液倒入水(10mL)中,用EA(10mL×3)萃取,有机相合并,用水(15mL×3)洗,减压浓缩,粗品经制备薄层色谱纯化(MeOH:DCM=1:8)得产品(50mg,产率:48.1%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.61(s,1H),9.08(s,1H),8.13-8.11(d,1H),7.61-7.58(d,1H),7.50-7.52(d,1H),7.19-7.17(d,1H),6.83-6.78(t,2H),4.53(s,1H),3.41(s,4H),2.96-2.92(d,1H),2.45(s,2H),2.34(s,3H),2.02-1.88(d,2H),1.73-1.59(m,2H).
分子式:C
22H
23N
5O 分子量:373.46 LC-MS(Pos,m/z):374.17[M+H]
+.
实施例16:(R)-2-(6-环丙基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物32)
步骤1:(R)-3-((7-环丙基-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将(R)-3-((7-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-甲酸叔丁酯(0.5g,0.94mmol,1.0eq.)、环丙基硼酸(242mg,2.82mmol,3.0eq.)、三环己基磷(131mg,0.47mmol,0.5eq.)、醋酸钯(43mg,0.19mmol,0.2eq.)和磷酸钾(399mg,1.88mmol,2.0eq.)加入甲苯(10mL)和水(2mL)混合液中,氮气保护下100℃反应2h,TLC检测反应完全,反应液倒入水(10mL)中,用EA(10mL×3)萃取,有机相干燥,浓缩得产物(400mg,产率:87.1%)。
步骤2:(R)-7-环丙基-4-(2-甲氧基-4-甲基苯基)-N-(哌啶-3-基)酞嗪-1-胺的合成
将(R)-3-((7-环丙基-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(400mg,0.81mmol,1.0eq.)溶于DCM(10mL),室温滴加1mol/L的三溴化硼二氯甲烷溶液(2.4mL,2.43mmol,3.0eq),室温反应20min,LC-MS检测反应完全,向体系中加入适量的甲醇淬灭,反应液减压浓缩,粗品用水(10mL)溶解,水相用DCM(10mL×2)萃取,保留水相,用NaHCO
3调pH值至9,再用DCM(10mL×4)萃取,有机相合并,干燥,浓缩得产物(150mg,产率:47.7%)。
步骤3:(R)-2-(6-环丙基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-7-环丙基-4-(2-甲氧基-4-甲基苯基)-N-(哌啶-3-基)酞嗪-1-胺(150mg,0.40mmol,1.0eq.)溶于甲醇(3mL),加入甲醛水溶液(37%)(32mg,0.40mmol,1.0eq.),室温搅拌5min,加入氰基硼氢化钠(25mg,0.40mmol,1.0eq.),室温反应5min。LC-MS监测反应完全,反应液减压浓缩,向体系中加入用水(5mL)和DCM(10mL),分液,水相再用DCM(10mL×2)萃取,有机相合并,干燥,浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=7:1)得产物(45mg,产率:29.0%)
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.03(s,1H),7.54-7.51(d,1H),7.43-7.41(d,1H),7.16-7.14(d,1H),6.80-6.75(t,2H),4.54(s,1H),3.43(s,5H),2.99(s,1H),2.51(s,4H),2.33(s,3H),2.16-2.10(m,1H),2.02-1.88(t,2H),1.74-1.62(m,2H),1.13-1.10(t,2H),0.92-0.91(d,2H).
分子式:C
24H
28N
4O 分子量:388.52 LC-MS(Pos,m/z):389.23[M+H]
+.
实施例17(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯酚的合成(化合物48)
步骤1:(R)-3-((7-氯噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4,7-二氯噻吩并[2,3-d]哒嗪(1.0g,4.88mmol,1.0eq)和(R)-3-氨基哌啶-1-羧酸叔丁酯(1.17g,5.86mmol,1.2eq)溶于DMA(10mL),氮气保护下,加热至120℃反应20小时。加水(50mL)淬灭,用EA(50mL)萃取,有机相水洗(30mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)分离得到产物(1.40g,收率:77.8%)。
步骤2:(R)-3-((7-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将(2-甲氧基-4-甲基苯基)硼酸(0.630g,3.80mmol,1.0eq)、(R)-3-((7-氯噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.40g,3.80mmol,1.0eq),Pd(dppf)Cl
2(0.139g,0.190mmol,0.05eq)和NaHCO
3(0.638g,7.60mmol,2.0eq)依次加入到1,4-二氧六环(20mL)中,加入H
2O(10mL),氮气保护下,加热至110℃反应6小时。加入水(60mL),用EA(50mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(920mg,收率:53.3%)。
步骤3:(R)-5-甲基-2-(4-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-7-基)苯酚的合成
将(R)-3-((7-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(900mg,1.98mmol,1.0eq)溶于DCM(18mL),降温至-10℃,滴加BBr
3(1.98g,7.92mmol,4.0eq),反应4小时。加入MeOH(5mL)淬灭,加入饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)纯化得到产物(490mg,收率:72.7%)。
步骤4:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-7-基)苯酚(490mg,1.44mmol,1.0eq)溶于MeOH(4mL),加入37%的甲醛水溶液(351mg,4.32mmol,3.0eq),室温搅拌30分钟,然后加入NaBH
3CN(271mg,4.32mmol,3.0eq),反应1小时。加入饱和NaHCO
3水溶液淬灭,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩, 粗品经制备薄层色谱分离(DCM:MeOH=15:1)得到产物(120mg,收率:23.5%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):12.26(s,1H),8.25(d,J=5.2Hz,1H),8.07(d,J=5.2Hz,1H),7.78(d,J=8.4Hz,1H),7.32(d,J=6.8Hz,1H),6.84(d,J=6.4Hz,2H),4.40(s,1H),3.16(d,J=9.6Hz,1H),2.81(d,J=10.3Hz,1H),2.32(s,6H),2.09-1.99(m,3H),1.82-1.79(m,1H),1.69-1.60(m,1H),1.50-1.45(m,1H).
分子式:C
19H
22N
4OS 分子量:354.47 LC-MS(Pos,m/z)=355.13[M+H]
+.
实施例18(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成(化合物50):
步骤1:中间体4-(2-甲氧基-4-甲基苯甲酰基)烟酸的合成:
将1-溴-2-甲氧基-4-甲基苯(14.16g,70.41mmol,1.05eq)溶于无水THF(100mL)中,-78℃下,向其中滴加n-BuLi(32.2mL,80.47mmol,1.2eq),滴加完毕,反应30min。-78℃下,将反应液滴入3,4-吡啶二羧酸酐(10g,67.06mmol,1.0eq)的THF(100mL)溶液中,滴加完毕,常温反应1h,TLC检测反应完全。将反应液倒入冰水(50mL)与2mol/L盐酸(50mL)的混合溶液中,二氯甲烷(200mL×3)萃取,有机相合并,干燥,浓缩得粗品(20g)。取5g粗品粗品经硅胶柱层析(石油醚:乙酸乙酯=1:3(含0.5%AcOH),二氯甲烷:甲醇=10:1(含0.5%AcOH))得产物(2.5g,产率:55.6%)。
步骤2:中间体4-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯的合成:
将4-(2-甲氧基-4-甲基苯甲酰基)烟酸(2.5g,9.22mmol,1.0eq)溶于DMF(30mL)中,向其中加入碳酸钾(1.91g,13.83mmol,1.5eq)和碘甲烷(1.31g,9.22mmol,1.0eq),常温反应2h。TLC检测反应完毕。将反应液倒入水(20mL)中,EA(50mL×3)萃取,有机相合并,无水硫酸钠干燥,浓缩得产物(1.1g,产率:41.8%)。
步骤3:中间体1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-4-醇的合成
将4-(2-甲氧基-4-甲基苯甲酰基)烟酸甲酯(1.1g,3.86mmol,1.0eq)溶于乙醇(10mL)中,向其中加入85%水合肼(341mg,5.79mmol,1.5eq),加热至85℃反应10min,LC-MS检测反应完毕。冷却至室温,固体析出,过滤得产物(640mg,产率:62.1%)。
步骤4:中间体4-氯-1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪的合成
向1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-4-醇(640mg,2.39mmol,1.0eq)中加入乙腈(8mL),加入三氯氧磷(733mg,4.78mmol,2.0eq),90℃反应16h,TLC检测反应完毕。浓缩反应液,残余物倒入冰水(10mL)中,加入二氯甲烷(20mL)萃取,有机相干燥,浓缩,粗品经硅胶柱层析(石油醚:乙酸乙酯=3:1)得产物(536mg,产率:78.4%)。
步骤5:中间体(R)-3-((1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-氯-1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪(536mg,1.876mmol,1.0eq)溶于DMA(5mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(752mg,3.752mmol,2.0eq),120℃回流反应16h,TLC检测反应完毕,将反应液滴入水(5mL)中,乙酸乙酯(10mL)萃取, DCM(10mL×3)萃取,有机相合并,干燥,浓缩得产物(647mg,产率:76.7%)。
步骤6:中间体(R)-5-甲基-2-(4-((哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-3-((1-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(647mg,1.44mmol,1.0eq)溶于DCM(5mL),-20℃下,向其中滴加三溴化硼(1.08g,4.32mmol,3.0eq),常温反应1h,LC-MS检测仍有原料剩余,补加三溴化硼(1.08g,4.32mmol,3.0eq),常温反应1h,LC-MS检测反应完毕。冰浴条件下,向反应液中缓慢滴加甲醇(3mL)和水(10mL),DCM(10mL)反萃,水相用饱和碳酸氢钠水溶液调节pH值至中性,DCM(10mL)反萃,水相浓缩,用DCM/MeOH混合溶剂溶解,无水硫酸镁干燥,浓缩,粗品直接投入下一步。
步骤7:化合物(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-((哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚(1.44mmol,1.0eq)溶于甲醇(5mL)中,向其中加入38.5%乙醛水溶液(112mg,1.44mmol,1.0eq),常温搅拌5min,加入氰基硼氢化钠(100mg,1.584mmol,1.1eq),常温反应5min,TLC检测反应完毕。反应液浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产品(12mg,两步产率:2.3%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):9.86(brs,1H),9.67(s,1H),8.86-8.88(d,1H),7.84(s,1H),7.33-7.35(d,1H),7.19-7.21(d,1H),6.79-6.84(m,2H),4.66(s,1H),3.13(s,3H),2.64-2.74(m,4H),2.34(s,3H),1.77-2.02(m,4H).
分子式:C
20H
23N
5O 分子量:349.44 LC-MS=350.23[M+H]
+
实施例19化合物(R)-3-羟基-4-(8-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基) 苯甲腈的合成(化合物59):
步骤1:中间体3-(4-溴-2-甲氧基苯甲酰基)烟酸的合成:
将4-溴-1-碘-2-甲氧基苯(10g,31.96mmol,1.0eq)溶于无水THF(100mL)中,-20℃下,向其中滴加i-PrMgCl·LiCl的THF溶液(1.3mol/L,26mL,33.6mmol,1.05eq),滴加完毕,反应30min。-20℃下,将上述反应液滴入2,3-吡啶二羧酸酐(4.77g,31.96mmol,1.0eq)的THF(100mL)溶液中,滴加完毕,常温反应16h,TLC检测反应完全。将反应液倒入饱和氯化铵水溶液(200mL)中,浓缩,二氯甲烷萃取(200mL×5),有机相合并,无水硫酸镁干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1,v/v,加5‰醋酸)得产物(3.9g,产率:36.3%)。
步骤2:中间体5-(4-溴-2-甲氧基苯基)吡啶并[2,3-d]哒嗪-8-醇的合成:
将3-(4-溴-2-甲氧基苯甲酰基)烟酸(3.9g,11.6mmol,1.0eq)加入EtOH(40mL)中,向其中加入85%水合肼(1.37g,23.2mmol,2.0eq),加热至90℃反应8h,TLC检测反应完毕。浓缩反应液,过滤,滤饼用乙醇洗涤得产物(2.02g,产率:52.4%)。
步骤3:中间体5-(4-溴-2-甲氧基苯基)-8-氯吡啶并[2,3-d]哒嗪的合成
将5-(4-溴-2-甲氧基苯基)吡啶并[2,3-d]哒嗪-8-醇(2.02g,6.08mmol,1.0eq)加入到乙腈(20mL)中,向其中加入三氯氧磷(1.86g,12.16mmol,2.0eq),100℃反应16h,TLC检测反应完毕。浓缩反应液,将浓缩液倒入冰水(10mL)中,碳酸氢钠调节pH值至碱性,二氯甲烷萃取(30mL×3),有机相合并,干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v)得产物(2.0g,产率:93.8%)。
步骤4:中间体5-溴-2-(8-氯吡啶并[2,3-d]哒嗪-5-基)苯酚的合成
将5-(4-溴-2-甲氧基苯基)-8-氯吡啶并[2,3-d]哒嗪(2g,5.7mmol,1.0eq)溶于二氯甲烷(20mL)中,-20℃下,向其中缓慢滴加三溴化硼的正庚烷溶液(1mol/L,8.6mL,8.6mmol,1.5eq),滴加完毕,常温反应10min,TLC检测反应完全。冰浴条件下,向反应液中缓慢滴加饱和碳酸氢钠水溶液(10mL),DCM(20mL×3)萃取,有机相合并,干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=2:1,v/v)得产物(900mg,产率:47.3%)。
步骤5:中间体(R)-3-((5-(4-溴-2-甲氧基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯的合成
将5-溴-2-(8-氯吡啶并[2,3-d]哒嗪-5-基)苯酚(900mg,2.7mmol,1.0eq)溶于DMAc(10mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(1.08g,5.4mmol,2.0eq),120℃回流反应1h,TLC检测反应完毕。将反应液滴入水(5mL)中,乙酸乙酯(10mL×2)萃取,有机相合并,干燥,浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=200:1)得产物(1.05g,产率:78.3%)。(1900326-179)
步骤6:中间体(R)-3-((5-(4-氰基-2-羟基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯的合成
将(R)-3-((5-(4-溴-2-甲氧基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯(500mg,1mmol,1.0eq)溶于DMAc(5mL)中,氮气保护下向其中加入氰化锌(94mg,0.8mmol,0.8eq)和四(三苯基膦)钯(112mg,0.1mmol,0.1eq),120℃反应45min,LC-MS检测反应完毕。将反应液倒入水中,EA(10mL×2)萃取,有机相合并,干燥,浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=200:1~100:1,v/v)得产物(480mg粗品)。
步骤7:中间体(R)-3-羟基-4-(8-(哌啶-3-基氨基)吡啶并[2,3-d]哒嗪-5-基)苯甲腈的合成
将(R)-3-((5-(4-氰基-2-羟基苯基)吡啶并[2,3-d]哒嗪-8-基)氨基)哌啶-1-羧酸叔丁酯(1mmol,1.0eq)溶于二氯甲烷(2mL),将其滴入4mol/L的氯化氢/1,4-二氧六环溶液(4mL)中,滴加完毕,大量固体析出,常温反应5min,TLC检测反应完毕。向反应液中加入水(5mL),碳酸氢钠调节pH值至碱性,浓缩水相得粗品。用二氯甲烷/甲醇(20:1,20mL)溶解粗品,过滤,滤液干燥,浓缩得产物(279mg,两步产率:80.6%)。
步骤8:化合物(R)-3-羟基-4-(8-((1-甲基哌啶-3-基)氨基)吡啶并[2,3-d]哒嗪-5-基)苯甲腈的合成
将(R)-3-羟基-4-(8-(哌啶-3-基氨基)吡啶并[2,3-d]哒嗪-5-基)苯甲腈(279mg,0.832mmol,1.0eq)溶于甲醇(3mL)中,向其中加入37%甲醛水溶液(68mg,0.832mmol,1.0eq),常温搅拌5min,加入氰基硼氢化钠(58mg,0.915mmol,1.1eq),常温反应5min,TLC检测反应完毕。浓缩反应液,加入饱和食盐水(1mL),碳酸氢钠调节pH值至碱性,用混合溶剂萃取(二氯甲烷:甲醇:氨水=20:1:0.5,20mL×3),有机相合并,干燥,浓缩,粗品经硅 胶柱层析纯化(二氯甲烷:甲醇=50:1~20:1,v/v),冻干得产物(112mg,产率:37.3%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):11.93(brs,1H),9.14(s,1H),8.92-8.90(d,1H),8.20-8.18(d,1H),7.93(s,1H),7.61-7.60(d,1H),7.38-7.31(m,2H),4.43(s,1H),3.11-3.09(d,1H),2.75-2.73(d,1H),2.24(s,3H),1.99-1.76(m,4H),1.63-1.45(m,2H).
分子式:C
20H
20N
6O 精确分子量:360.17 LC-MS(m/z)=361.11[M+H]
+
实施例20化合物(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物60)
步骤1:2-甲氧基-4-甲基苯甲酰氯的合成
将2-甲氧基-4-甲基苯甲酸(5.0g,30.08mmol,1.0eq.)和DMF(0.1mL)溶于DCM(100mL),加入草酰氯(2.30g,18.05mmol,0.6eq.),室温反应15h,反应液减压浓缩得产物(5.55g,产率:100%)。
步骤2:5-溴-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯的合成
将5-溴-2-碘苯甲酸甲酯(10.3g,30.06mmol,1.0eq.)溶于THF(50mL),降温至-30℃,缓慢滴加异丙基氯化镁氯化锂四氢呋喃溶液(1.3mol/L,25.4mL,33.07mmol,1.1eq.),搅拌30min,-60℃下将上述反应液缓慢滴加至2-甲氧基-4-甲基苯甲酰氯(5.55g,30.06mmol,1.0eq.)的THF(50mL)溶液中,-70℃反应,滴毕自然升至室温反应2.5h,将反应液倒入水(100mL)中,用EA(100mL×2)萃取,有机相干燥,浓缩,粗品经硅胶柱层析纯化(PE:EA=20:1)得产物(3.5g,产率:32.1%)。
步骤3:7-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-醇的合成
将5-溴-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯(3.5g,9.63mmol,1.0eq.)和85%水合肼(0.85g,14.44mmol,1.5eq.)溶于乙醇(35mL),80℃反应1.5h,TLC监测反应完全,冷却至室温,有大量固体析出,抽滤得产物(1.8g,产率:54.2%)。
步骤4:6-溴-4-氯-1-(2-甲氧基-4-甲基苯基)酞嗪的合成
将7-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-醇(1.8g,5.21mmol,1.0eq.)和三氯氧磷(1.6g,10.42mmol,2.0eq.)溶于乙腈(20mL),90℃反应2h,LC-MS监测反应完全,反应液减压浓缩,粗品用EA(30mL)溶解,加入水(10mL),用饱和碳酸氢钠水溶液调pH值至9,分液,水相再用EA(20mL)萃取,有机相合并,干燥,浓缩得产物(1.6g,产率:84.6%)。
步骤5:(R)-3-((7-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-甲酸叔丁酯的合成
将6-溴-4-氯-1-(2-甲氧基-4-甲基苯基)酞嗪(1.6g,4.40mmol,1.0eq.)和(R)-3-氨基哌啶-1-羧酸叔丁酯(1.76g,8.80mmol,2.0eq.)溶于DMAC(16mL),120℃反应26h。LC-MS检测反应完全,反应液倒入水(50mL)中,有固体析出,抽滤,滤饼用EA(50mL)溶解,干燥,有机相减压浓缩得产物(1.2g,产率:51.7%)。
步骤6:(R)-2-(6-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-3-((7-溴-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-甲酸叔丁酯(1.0g,1.89mmol,1.0eq.)溶于DCM(10mL),降温至-20℃,滴加1mol/L的三溴化硼二氯甲烷溶液(5.7mL,5.67mmol,3.0eq),滴毕自然升至室温,反应1h,LC-MS检测反应完全,向瓶中加入适量的甲醇淬灭,反应液减压浓缩,粗品用水(20mL)溶解,用EA(20mL×2)萃取,保留水相,用NaHCO
3调pH值至9,再用DCM(20mL×2)萃取,有机相合并,干燥,浓缩得产物(400mg,产率:51.2%)。
步骤7:(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-2-(6-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚(400mg,0.96mmol,1.0eq.)溶于甲醇(4mL),加入甲醛水溶液(37%)(78mg,0.96mmol,1.0eq.),室温搅拌5min,加入氰基硼氢化钠(60mg,0.96mmol,1.0eq.),室温反应5min。LC-MS监测有目标产物生成,反应液减压浓缩,粗品用水(10mL)打浆,抽滤,滤饼经硅胶柱层析纯化(DCM:MeOH=30:1)得产物(200mg,产率:48.8%)
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.60(s,1H),8.75(s,1H),7.97-7.94(d,1H),7.45-7.42(d,1H),7.35(s,1H),7.17-7.15(d,1H),6.82-6.77(t,2H),4.53(s,1H),3.03(s,2H),2.51(s,4H),2.33(s,4H),2.02-1.92(d,2H),1.74-1.62(m,2H).
分子式:C
21H
23BrN
4O 分子量:427.35 LC-MS(Pos,m/z):427.05/429.08[M+H]
+.
实施例21化合物(R)-5-甲基-2-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯酚的合成(化合物70)
步骤1:7-氯-4-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪的合成
将(2-甲氧基-4-甲基苯基)硼酸(0.809g,4.88mmol,1.0eq)、4,7-二氯噻吩并[2,3-d]哒嗪(1.00g,4.88mmol,1.0eq)、Pd(dppf)Cl
2(0.179g,0.244mmol,0.05eq)和NaHCO
3(0.820g,9.76mmol,2.0eq)依次加入到1,4-二氧六环(20mL)中,加入H
2O(10mL),氮气保护下,加热至110℃反应2小时。加入水(60mL),用EA(50mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(PE:EA=5:1~1:1)分离得到产品(820mg,收率:57.9%)。
步骤2:(R)-3-((4-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
将7-氯-4-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪(820mg,2.92mmol,1.0eq)和(R)-3-氨基哌啶-1-羧酸叔丁酯(877mg,4.38mmol,1.5eq)溶于DMA(10mL),氮气保护下,加热至120℃反应16小时。加水(50mL)淬灭,用EA(50mL)萃取,有机相水洗(20mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)分离得到产物(610mg,收率:47.6%)。
步骤3:(R)-5-甲基-2-(7-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-4-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)噻吩并[2,3-d]哒嗪-7-基)氨基)哌啶-1-羧酸叔丁酯(610mg,1.34mmol,1.0eq)溶于DCM(12mL),降温至-10℃,滴加BBr
3(1.34g,5.36mmol,4.0eq),反应4小时。加入MeOH(5mL)淬灭,用饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产品(380mg,收率:83.2%)。
步骤4:(R)-5-甲基-2-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯酚的合成
将(R)-5-甲基-2-(7-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-4-基)苯酚(380mg,1.12mmol,1.0eq)溶于MeOH(4mL),加入37%的甲醛水溶液(273mg,3.36mmol,3.0eq),室温搅拌30分钟。然后加入NaBH
3CN(211mg,3.36mmol,3.0eq),反应1小时。加入饱和NaHCO
3水溶液淬灭,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱分离(DCM:MeOH=15:1)得到产物(70mg,收率:17.7%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.43(s,1H),8.12(d,J=5.2Hz,1H),7.56(d,J=5.6Hz,1H),7.52(d,J=8.0Hz,1H),7.07(d,J=7.6Hz,1H),6.82(s,1H),6.79(d,J=8.0Hz,1H),4.40-4.38(m,1H),3.09(d,J=8.8Hz,1H),2.75(d,J=10.4Hz,1H),2.32(s,3H),2.26(s,3H),1.99-1.96(m,3H),1.77-1.74(m,1H),1.66-1.57(m,1H),1.50-1.41(m,1H).
分子式:C
19H
22N
4OS 分子量:354.47 LC-MS(Pos,m/z)=355.13[M+H]
+.
实施例22化合物(R)-5-溴-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物73)
步骤1:2-(4-溴-2-甲氧基苯甲酰基)苯甲酸的合成
将4-溴-1-碘-2-甲氧基苯(5.0g,15.97mmol,1.0eq.)加入四氢呋喃(50.0mL),氮气保护下降温至-20℃,滴加异丙基氯化镁-氯化锂的四氢呋喃溶液(1.3mol/L,14.7mL,19.17mmol,1.2eq.),-20℃反应0.5小时后,将此反应液滴加到冷却至-20℃的邻苯二甲酸酐(2.6g,17.56mmol,1.1eq.)的四氢呋喃(20.0mL)溶液中,升至室温反应2小时,TLC监测反应完全,加入乙酸乙酯(200.0mL),用饱和氯化铵水溶液(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(5.0g,产率:93.4%)。
步骤2:2-(4-溴-2-甲氧基苯甲酰基)苯甲酸甲酯的合成
将2-(4-溴-2-甲氧基苯甲酰基)苯甲酸(5.0g,14.91mmol,1.0eq.)、碳酸钾(3.0g,22.36mmol,1.5eq.)和碘甲烷(2.7g,19.39mmol,1.3eq.)加入N,N-二甲基甲酰胺(30.0mL),室温反应4小时,TLC监测反应完全,加入乙酸乙酯(200.0mL),水洗(100.0mL×3),有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=30:1~10:1)得产物(3.68g,产率:70.7%)。
步骤3:4-(4-溴-2-甲氧基苯基)酞嗪-1-醇的合成
将2-(4-溴-2-甲氧基苯甲酰基)苯甲酸甲酯(2.0g,5.72mmol,1.0eq.)加入乙醇(20.0mL)和水合肼(85%)(505.9mg,8.59mmol,1.5eq.),室温反应1小时,LC-MS监测反应完全,过滤,滤饼用乙醇(50.0mL)洗涤,干燥得产物(1.25g,产率:66.1%)。
步骤4:1-(4-溴-2-甲氧基苯基)-4-氯酞嗪的合成
将4-(4-溴-2-甲氧基苯基)酞嗪-1-醇(1.25g,3.77mmol,1.0eq.)和三氯氧磷(3.47g,22.64mmol,6.0eq.)加入乙腈(20.0mL),回流反应1小时,TLC监测反应完全,倒入冰水(200.0mL)中,乙酸乙酯萃取(100.0mL),有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(1.1g,产率:83.9%)。
步骤5:(R)-3-((4-(4-溴-2-甲氧基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-(4-溴-2-甲氧基苯基)-4-氯酞嗪(1.1g,3.14mmol,1.0eq.)和(R)-3-氨基哌啶-1-羧酸叔丁酯(1.26g,6.29mmol,2.0eq.)加入N,N-二甲基乙酰胺(20.0mL),120℃搅拌12小时,TLC监测反应完全,冷却至室温,加入乙酸乙酯(100.0mL),水洗(100.0mL),有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=4:1~1:1)得产物(920.0mg,产率:57.1%)。
步骤6:(R)-4-(4-溴-2-甲氧基苯基)-N-(哌啶-3-基)酞嗪-1-胺的合成
将(R)-3-((4-(4-溴-2-甲氧基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(920.0mg,1.79mmol,1.0eq.)加入二氯甲烷(6.0mL)和三氟乙酸(6.0mL),室温搅拌1小时,TLC监测反应完全,饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(720mg,产率:97.3%)。
步骤7:(R)-4-(4-溴-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-(4-溴-2-甲氧基苯基)-N-(哌啶-3-基)酞嗪-1-胺(720.0mg,1.74mmol,1.0eq.)和甲醛水溶液(37%)(169.6mg,2.09mmol,1.2eq.)加入甲醇(8.0mL),室温搅拌0.5小时,加入氰基硼氢化钠(153.0mg,2.43mmol,1.4eq.),室温继续反应1小时,TLC监测反应完全,加入饱和碳酸氢钠水溶液(50.0mL)搅拌30分钟,调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=40:1~10:1)得产物(520.0mg,产率:69.9%)。
步骤8:(R)-5-溴-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-4-(4-溴-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(260.0mg,0.60mmol,1.0eq.)加入二氯甲烷(5.0mL),氮气保护下降温至-20℃,滴加三溴化硼(300.6mg,1.20mmol,2.0eq.),逐渐升至室温反应2小时,TLC监测反应完全,冰浴下缓慢滴加甲醇(5.0mL)淬灭,减压浓缩,加入饱和碳酸氢钠水溶液(50.0mL)搅拌30分钟,调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(90.0mg,产率:36.2%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):10.15(s,1H),8.40-8.37(d,J=9Hz,1H),7.87-7.75(m,2H),7.48-7.45(d,J=9Hz,1H),7.26-7.23(d,J=9Hz,1H),7.17-7.07(m,3H),4.41(s,1H),3.09-3.07(d,J=6Hz,1H),2.73-2.69(d,J=12Hz,1H),2.22(s,3H),1.99-1.89(m,3H),1.78-1.43(m,3H).
分子式:C
20H
21BrN
4O 精确分子量:412.09 LC-MS(m/z)=413.01/415.03[M+H]
+.
实施例23化合物(R)-5-甲氧基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物74)
步骤1:1-溴-2-(乙氧基甲基)-4-甲氧基苯的合成
将2-溴-5-甲氧基苯酚(1.8g,8.86mmol,1.0eq.)加入干燥四氢呋喃(20.0mL),氮气保护下降温至0℃,缓慢加氢化钠(60%)(531.6mg,13.29mmol,1.5eq.),反应0.5小时,加入氯甲氧基乙烷(1.17g,12.40mmol,1.4eq.),升至室温反应12小时,TLC监测反应完全,体系加水(20.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1)得到产物(2.1g,产率:91.3%)。
步骤2:2-(2-(乙氧基甲氧基)-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷的合成
将1-溴-2-(乙氧基甲基)-4-甲氧基苯(2.1g,8.04mmol,1.0eq.)、联硼酸频那醇酯(3.06g,12.06mmol,1.5eq.)、乙酸钾(1.57g,16.08mmol.2.0eq.)和Pd(dppf)Cl
2(294.0mg,0.40mmol,0.05eq.)加入1,4-二氧六环(20.0mL),氮气置换5分钟,100℃反应2小时,TLC监测反应完全,经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1)得产物(2.1g,产率:87.5%)。
步骤3:(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(505.0mg,1.82mmol,1.0eq.)、2-(2-(乙氧基 甲氧基)-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(843.4mg,2.73mmol,1.5eq.)、碳酸氢钠(305.7mg,3.64mmol,2.0eq.)、水(5.0mL)和四(三苯基膦)钯(105.1mg,0.09mmol,0.05eq.)加入1,4-二氧六环(10.0mL),氮气保护下,110℃反应4小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=40:1~10:1)得到产物(470.0mg,产率:61.1%)。
步骤4:(R)-5-甲氧基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(470.0mg,1.11mmol,1.0eq.)加入二氯甲烷(5.0mL),滴加三氟乙酸(3.0mL),室温反应2小时,TLC监测反应完全,冰浴下用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(50.0mg,产率:12.3%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.90(s,1H),8.47(s,1H),7.77-7.88(m,2H),7.55-7.58(m,1H),7.36(s,1H),7.20-7.23(d,J=6Hz,1H),6.54-6.59(m,2H),4.61(s,1H),3.79(s,3H),3.36(m,1H),3.05(m,2H),2.58(s,3H),1.74-2.04(m,5H).
分子式:C
21H
24N
4O
2 分子量:364.45 LC-MS(Pos,m/z):365.15[M+H]
+.
实施例24化合物(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯甲腈的合成(化合物79):
步骤1:中间体4-(4-溴-2-甲氧基苯甲酰基)烟酸的合成:
将4-溴-1-碘-2-甲氧基苯(21g,67.06mmol,1.0eq)溶于无水THF(200mL)中,-20℃下,向其中滴加i-PrMgCl·LiCl的THF溶液(1.3mol/L,55mL,70.41mmol,1.05eq),滴加完毕,反应30min。-20℃下,将上述反应液滴入3,4-吡啶二羧酸酐(10g,67.06mmol,1.0eq)的THF(100mL)溶液中,滴加完毕,常温反应1h,LC-MS检测反应完全。将反应液倒入饱和氯化铵水溶液(200mL)中,浓缩,大量固体析出,过滤,滤饼干燥得含异构体的混合产物(18.67g,产率:82.8%)。
步骤2:中间体1-(4-溴-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-醇的合成:
将上步所得混合物(5g,14.87mmol,1.0eq)加入EtOH(30mL)中,向其中加入85%水合肼(1.76g,29.74mmol,2.0eq),加热至90℃反应2h,TLC检测反应完毕。浓缩反应液,粗品经硅胶柱层析(二氯甲烷:甲醇=1200:1~300:1,v/v)纯化得产物(3.6g,产率:72.8%)。
步骤3:中间体1-(4-溴-2-甲氧基苯基)-4-氯吡啶并[3,4-d]哒嗪的合成
将1-(4-溴-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-醇(3g,9.03mmol,1.0eq)加入到乙腈(50mL)中,向其中加入三氯氧磷(2.77g,18.06mmol,2.0eq),100℃反应16h,TLC检测反应完毕。浓缩反应液,将浓缩液倒入冰水(10mL)中,碳酸氢钠调节pH值至碱性,二氯甲烷萃取(30mL×3),有机相合并,干燥,浓缩,粗品经硅胶柱层析(石油醚:乙酸乙酯=10:1~5:1,v/v)纯化得产物(2.1g,产率:66%)。
步骤4:中间体5-溴-2-(4-氯吡啶并[3,4-d]哒嗪-1-基)苯酚的合成
将1-(4-溴-2-甲氧基苯基)-4-氯吡啶并[3,4-d]哒嗪(2.1g,5.99mmol,1.0eq)溶于二氯甲烷(20mL)中,-20℃下,向其中缓慢滴加三溴化硼的正庚烷溶液(1mol/L,9mL,8.96mmol,1.5eq),滴加完毕,常温反应10min,TLC检测反应完全。冰浴条件下,向反应液中缓慢滴加饱和碳酸氢钠溶液(10mL),二氯甲烷萃取(20mL×3),有机相合并,干燥,浓缩,粗品经硅胶柱层析(石油醚:乙酸乙酯=2:1,v/v)得产物(1.52g,产率:76%)。
步骤5:中间体(R)-3-((1-(4-溴-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将5-溴-2-(4-氯吡啶并[3,4-d]哒嗪-1-基)苯酚(520mg,1.55mmol,1.0eq)溶于DMAc(5mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(621mg,3.1mmol,2.0eq),120℃回流反应1h,TLC检测反应完毕,将反应液滴入水(5mL)中,乙酸乙酯萃取(10mL×2),有机相合并,干燥,浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇=200:1~50:1)纯化得产物(500mg,产率:64.5%)。
步骤6:中间体(R)-3-((1-(4-氰基-2-羟基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将(R)-3-((1-(4-溴-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(500mg,1mmol,1.0eq)溶于DMAc(5mL)中,氮气保护下向其中加入氰化锌(94mg,0.8mmol,0.8eq)和四(三苯基膦)钯(112mg,0.1mmol,0.1eq),120℃反应45min,LC-MS检测反应完毕。将反应液倒入水中,EA萃取(10mL×2),有机相合并,干燥,浓缩,粗品经硅胶 柱层析(二氯甲烷:甲醇=200:1,v/v)纯化得产物(350mg,产率:78.5%)。
步骤7:中间体(R)-3-羟基-4-(4-(哌啶-3-基氨基)吡啶并[3,4-d]哒嗪-1-基)苯甲腈的合成
将(R)-3-((1-(4-氰基-2-羟基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(350mg,0.784mmol,1.0eq)溶于EA(1mL),将其滴入4mol/L的氯化氢/1,4-二氧六环溶液(4mL)中,滴加完毕,大量固体析出,常温反应5min,TLC检测反应完毕。向反应液中加入水(2mL),碳酸氢钠调节pH值至碱性,浓缩水相得粗品。用二氯甲烷/甲醇(20:1,20mL)溶解粗品,过滤,滤液干燥,浓缩,粗品直接投入下一步。
步骤8:化合物(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯甲腈的合成
将(R)-3-羟基-4-(4-(哌啶-3-基氨基)吡啶并[3,4-d]哒嗪-1-基)苯甲腈(0.783mmol,1.0eq)溶于甲醇(2mL)中,向其中加入37%甲醛水溶液(63mg,0.783mmol,1.0eq),常温搅拌5min,加入氰基硼氢化钠(55mg,0.862mmol,1.1eq),常温反应5min,TLC检测反应完毕。浓缩反应液,加入饱和食盐水(1mL),碳酸氢钠调节pH值至碱性,用混合溶剂萃取(二氯甲烷:甲醇:氨水=20:1:0.5,20mL×2),有机相合并,干燥,浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇=50:1~10:1,v/v)纯化,经冻干得产品(91mg,两步产率:32.2%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):10.62(brs,1H),9.84(s,1H),8.87-8.86(d,1H),7.83(s,1H),7.54-7.52(d,1H),7.45-7.43(m,1H),7.38-7.37(d,1H),7.28-7.26(d,1H),4.55(s,1H),2.40(s,2H),2.24(m,2H),2.02(s,3H),1.85(m,2H),1.67(m,2H).
分子式:C
20H
20N
6O 精确分子量:360.17 LC-MS(m/z)=361.10[M+H]
+
实施例25化合物(R)-5-(二氟甲基)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物87)
步骤1:3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲醛的合成
将4-溴-3-甲氧基苯甲醛(5.0g,23.25mmol,1.0eq.)、联硼酸频那醇酯(8.8g,34.87mmol,1.5eq.)、乙酸钾(4.5g,46.50mmol.2.0eq.)和Pd(dppf)Cl
2(850.6mg,1.16mmol,0.05eq.)加入1,4-二氧六环(30.0mL),氮气保护下,100℃反应4小时,TLC监测反应完全,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=5:1)得产物(5.5g,产率:91.6%)。
步骤2:(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲醛的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(443.7mg,1.60mmol,1.0eq.)、3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲醛(630.3mg,2.40mmol,1.5eq.)、碳酸氢钠(268.8mg,3.20mmol,2.0eq.)和四三苯基膦钯(92.4mg,0.08mmol,0.05eq.)加入1,4-二氧六环(10.0mL)和水(5.0mL),氮气保护下,110℃反应4小时,TLC监测反应完全,加入乙酸乙酯(200.0mL),用饱和氯化钠水溶液(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=40:1~10:1)得产物(410.0mg,产率:68.1%)。
步骤3:(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲醛的合成
将(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲醛(410.0mg,1.08mmol,1.0eq.)加入二氯甲烷(10.0mL),冰浴下滴加三溴化硼(818.5mg,3.26mmol,3.0eq.),升至室温搅拌4小时。TLC监测反应完全,冰浴下滴加甲醇(5.0mL)淬灭,减压浓缩,加入二氯甲烷(100.0mL),用水(50.0mL)反萃,水相用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(260.0mg,产率:66.4%)。
步骤4:(R)-5-(二氟甲基)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲醛(260.0mg,0.71mmol,1.0eq.)和二乙胺基三氟化硫(1.15g,7.1mmol,10.0eq.)加入二氯甲烷(10.0mL),室温搅拌12小时。TLC监测反应完全,慢慢滴到冰水中,用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(70.0mg,产率:25.6%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):10.10(s,1H),8.41-8.38(d,J=9Hz,1H),7.87-7.75(m,2H),7.46-7.41(m,2H),7.26(s,0.29H),7.17-7.09(m,3H),7.07(s,0.47H),6.88(s,0.25H),4.44-4.41(m,1H),3.10-3.08(d,J=6Hz,1H),2.74-2.70(d,J=12Hz,1H),2.22(s,3H),2.00-1.90(m,3H),1.78-1.44(m,3H).
分子式:C
21H
22F
2N
4O 精确分子量:384.18 LC-MS(m/z)=385.12[M+H]
+.
实施例26化合物(R)-5-溴-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物88)
步骤1:2-碘-5-甲基苯甲酸甲酯的合成
将2-碘-5-甲基苯甲酸(20.0g,76.32mmol,1.0eq.)、碘甲烷(16.25g,114.48mmol,1.5eq.)和碳酸钾(15.82g,114.48mmol,1.5eq.)溶于DMF(200mL),室温反应0.5h,LC-MS监测反应完全,将反应液倒入水(200mL)中,用MTBE(200mL×2)萃取,有机相干燥,浓缩得产物(20g,收率:94.9%)。
步骤2:4-溴-2-甲氧基苯甲酰氯的合成
将4-溴-2-甲氧基苯甲酸(40.0g,173.12mmol,1.0eq.)和DMF(0.5mL)溶于DCM(400mL),滴加草酰氯(13.18g,103.87mmol,0.6eq.),反应1h,TLC监测反应完全,反应液减压浓缩得产物(40g,收率:92.6%)。
步骤3:2-(4-溴-2-甲氧基苯甲酰基)-5-甲基苯甲酸甲酯的合成
将2-碘-5-甲基苯甲酸甲酯(20g,72.44mmol,1.0eq.)溶于THF(200mL),降温至-20℃,加入异丙基氯化镁氯化锂的四氢呋喃溶液(1.3mol/L,61.3mL,79.68mmol,1.1eq.),搅拌1h,向体系中滴加4-溴-2-甲氧基苯甲酰氯(18.07g,72.44mmol,1.0eq.)的THF溶液(200mL),反应20min,LC-MS监测反应完全,将反应液倒入水中(200mL),用MTBE(200mL×2)萃取,有机相干燥,浓缩得产物(20g,收率:76.0%)。
步骤4:4-(4-溴-2-甲氧基苯基)-7-甲基酞嗪-1-醇的合成
将2-(4-溴-2-甲氧基苯甲酰基)-5-甲基苯甲酸甲酯(20.0g,55.06mmol,1.0eq.)和85%水合肼(4.13g,82.59mmol,1.5eq.)溶于乙醇(100mL),80℃反应1h,LC-MS监测反应完全,反应液冷却至室温,过滤,滤饼抽干得产物(11g,收率:57.8%)。
步骤5:1-(4-溴-2-甲氧基苯基)-4-氯-6-甲基酞嗪的合成
将4-(4-溴-2-甲氧基苯基)-7-甲基酞嗪-1-醇(11.0g,31.86mmol,1.0eq.)和三氯氧膦(9.77g,63.72mmol,2.0eq.)溶于乙腈(110mL),90℃反应1h,LC-MS监测反应完全,反应液减压浓缩,粗品用DCM(300mL)完全溶解,加入水(300mL),用NaHCO
3调pH值至9,分液,水相用DCM(100mL)萃取,有机相合并,干燥,浓缩得产物(10g,收率:86.3%)。
步骤6:(R)-3-((4-(4-溴-2-甲氧基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-(4-溴-2-甲氧基苯基)-4-氯-6-甲基酞嗪(10g,27.50mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(8.26g,41.25mmol,1.5eq.)和DIPEA(10.66g,82.50mmol,3.0eq.)溶于DMAC(100mL),120℃反应12h。TLC检测反应完全,反应液倒入水(200mL)中,用EA萃取(200mL×2),有机相合并,用水(200mL×2)洗,干燥,浓缩,粗品经硅胶柱层析纯化(PE:EA=2:1)得产物(11g,收率:75.8%)。
步骤7:(R)-5-溴-2-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(4-溴-2-甲氧基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(11g,20.85mmol,1.0eq.)溶于DCM(220mL),滴加三溴化硼(15.7g,62.55mmol,3.0eq),反应1h,LC-MS检测反应完全,向体系加入适量的甲醇,反应液减压浓缩,粗品用水(50mL)完全溶解,分液,水相用NaHCO
3调pH值至9,用二氯甲烷和甲醇的混合溶剂萃取(10:1,100mL×3),有机相干燥,浓缩得产物(6.0g,收率:69.6%)。
步骤8:(R)-5-溴-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-5-溴-2-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯酚(6.0g,14.51mmol,1.0eq.)溶于甲醇(60mL),加入甲醛水溶液(37%)(1.18g,14.51mmol,1.0eq.),室温搅拌5min,加入氰基硼氢化钠(911mg,14.51mmol,1.0eq.),室温反应5min。TLC监测反应完全,反应液减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=10:1)得产物(4.5g,收率:72.5%)
1HNMR(300MHz,DMSO-d
6)δ(ppm):10.20-10.16(d,1H),8.20(s,1H),7.63-7.60(d,1H),7.40-7.37(d,1H),7.25-7.23(d,1H),7.17-7.12(m,2H),7.00-6.97(d,1H),4.41(s,1H),3.11-3.08(d,1H),2.75-2.71(d,1H),2.53(s,3H),2.24(s,3H),2.00-1.96(d,3H),1.80-1.75(d,1H),1.68-1.60(m,1H),1.52-1.45(m,1H).
分子式:C
21H
23BrN
4O 分子量:426.11 LC-MS(m/z)=427.01/429.01[M+H]
+.
实施例27化合物(R)-1-(4-环丙基-2-羟基苯基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-6-腈的合成(化合物89)
步骤1:4-溴-2-甲氧基苯甲酸甲酯的合成
将4-溴-2-甲氧基苯甲酸(25.0g,108.20mmol,1.0eq.)、碘甲烷(23.04g,162.30mmol,1.5eq.)和碳酸钾(22.40g,162.30mmol,1.5eq.)溶于DMF(250mL),室温反应1h,TLC监测反应完全,将反应液倒入水(500mL)中,用MTBE(500mL×2)萃取,有机相再用水(500mL×2)洗,干燥,浓缩得产物(26.5g,产率:100%)。
步骤2:4-环丙基-2-甲氧基苯甲酸甲酯的合成
将4-溴-2-甲氧基苯甲酸甲酯(26.5g,108.20mmol,1.0eq.)、环丙基硼酸(18.59g,216.40mmol,2.0eq.)、三环己基磷(15.20g,54.10mmol,0.5eq.)、醋酸钯(2.43g,10.82mmol,0.1eq.)和磷酸钾(45.94g,216.40mmol,2.0eq.)溶于甲苯(520mL)和水(100mL)中,氮气保护下100℃反应23h,TLC检测反应完全,反应液减压浓缩,水相用EA(200mL×3)萃取,有机相干燥,减压浓缩,粗品经硅胶柱层析纯化(PE:EA=20:1)得产物(18g,产率:80.7%)。
步骤3:4-环丙基-2-甲氧基苯甲酸的合成
将4-环丙基-2-甲氧基苯甲酸甲酯(18g,87.27mmol,1.0eq.)和一水合氢氧化锂(7.32g,174.54mmol,2.0eq.)溶于MeOH(180mL)和H
2O(90mL)中,40℃反应3h,TLC监测反应完全,反应液减压浓缩,粗品用水(100mL)完全溶解,用稀盐酸调pH值至3,水相用 DCM(200mL×2)萃取,有机相再用0.2mol/L氢氧化钠溶液水溶液(300mL)洗,水相合并,再用稀盐酸调pH值至3,用DCM(200mL×2)萃取,有机相干燥,浓缩得产物(14g,产率:83.4%)。
步骤4:4-环丙基-2-甲氧基苯甲酰氯的合成
将4-环丙基-2-甲氧基苯甲酸(14g,72.83mmol,1.0eq.)和DMF(0.15mL)溶于DCM(280mL),滴加草酰氯(5.55g,43.70mmol,0.6eq.),反应1h,反应液减压浓缩得产物(15.34g,产率:100%)。
步骤5:5-溴-2-(4-环丙基-2-甲氧基苯甲酰基)苯甲酸甲酯的合成
将5-溴-2-碘苯甲酸甲酯(20g,58.66mmol,1.0eq.)溶于THF(200mL),降温至-30℃,加入异丙基氯化镁氯化锂的四氢呋喃溶液(1.3mol/L,49.6mL,64.53mmol,1.1eq.),搅拌0.5h,向体系中滴加4-环丙基-2-甲氧基苯甲酰氯(13.6g,64.53mmol,1.1eq.)的THF(100mL)溶液,反应20min,TLC监测反应完全,反应液倒入水中(200mL),用EA(200mL×2)萃取,有机相干燥,浓缩得产物(22.83g,产率:100%)。
步骤6:7-溴-4-(4-环丙基-2-甲氧基苯基)酞嗪-1-醇的合成
将5-溴-2-(4-环丙基-2-甲氧基苯甲酰基)苯甲酸甲酯(22.83g,58.66mmol,1.0eq.)和85%水合肼(4.99g,117.32mmol,2.0eq.)溶于乙醇(150mL),80℃反应0.5h,TLC监测反应完全,反应液冷却至室温,过滤,滤饼干燥得产物(9g,产率:41.5%)。
步骤7:6-溴-4-氯-1-(4-环丙基-2-甲氧基苯基)酞嗪的合成
将7-溴-4-(4-环丙基-2-甲氧基苯基)酞嗪-1-醇(9.0g,24.24mmol,1.0eq.)和三氯氧磷(7.43g,48.48mmol,2.0eq.)溶于乙腈(90mL),90℃反应3h,TLC监测反应完全,反应液减压浓缩,粗品用EA(300mL)溶解,用NaHCO
3水溶液调pH值至9,分液,水相用EA(50mL)萃取,合并有机相,干燥,浓缩,粗品再用(PE:EA=20:1,100mL)打浆,抽滤,滤饼干燥得产物(8.0g,产率:84.7%)。
步骤8:2-(6-溴-4-氯酞嗪-1-基)-5-环丙基苯酚的合成
将6-溴-4-氯-1-(4-环丙基-2-甲氧基苯基)酞嗪(8.0g,20.53mmol,1.0eq.)溶于DCM(160mL),滴加1mol/L的三溴化硼二氯甲烷溶液(30.8mL,30.80mmol,1.5eq),反应1h,TLC检测反应完全,反应液倒入饱和NaHCO
3中(200mL)搅拌10min,分液,水相用DCM(100mL)萃取,有机相合并,干燥,浓缩得产物(6.0g,产率:77.8%)。
步骤9:(R)-3-((7-溴-4-(4-环丙基-2-羟基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将2-(6-溴-4-氯酞嗪-1-基)-5-环丙基苯酚(6.0g,15.97mmol,1.0eq.)和(R)-3-氨基哌啶-1-羧酸叔丁酯(6.40g,91.94mmol,2.0eq.)溶于甲苯(500mL),100℃反应18h。TLC检测反应完全,反应液减压浓缩,粗品经硅胶柱层析纯化(PE:EA=2:1)得产物(2.3g,产率: 26.7%)。
步骤10:(R)-2-(6-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-环丙基苯酚的合成
将(R)-3-((7-溴-4-(4-环丙基-2-羟基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(2.0g,3.71mmol,1.0eq.)溶于EA(20mL),滴加氯化氢的1,4-二氧六环溶液(4mol/L,20mL),室温反应2h。LC-MS监测反应完全,反应液减压浓缩,粗品用水(20mL)完全溶解,水相用EA(20mL)萃取,再用NaHCO
3将水相调pH值至9,用DCM(20mL×3)萃取,有机相干燥,浓缩得产物(1.3g,产率:79.7%)。
步骤11:(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-环丙基苯酚的合成
将(R)-2-(6-溴-4-(哌啶-3-基氨基)酞嗪-1-基)-5-环丙基苯酚(1.3g,2.95mmol,1.0eq.)溶于甲醇(13mL),加入甲醛水溶液(37%)(240mg,2.95mmol,1.0eq.),室温搅拌10min,加入氰基硼氢化钠(186mg,2.95mmol,1.0eq.),室温反应10min。TLC监测反应完全,反应液减压浓缩,粗品用水(20mL)分散,用DCM(20mL×2)萃取,有机相干燥,浓缩,粗品再经硅胶柱层析纯化(DCM:MeOH=50:1)得产物(1.0g,产率:74.6%)。
步骤12:(R)-1-(4-环丙基-2-羟基苯基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-6-腈的合成
将(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-环丙基苯酚(500mg,1.10mmol, 1.0eq.)、氰化锌(130mg,1.10mmol,1.0eq.)和四(三苯基膦)钯(127mg,0.11mmol,0.1eq.)加入DMAC(10mL),氮气条件下120℃反应3h。LC-MS监测反应完全,反应液倒入水(20mL)中,水相用EA(20mL×2)萃取,有机相合并,再用水(20mL×3)洗,干燥,浓缩,粗品经制备薄层色谱纯化(MeOH:DCM=1:10)得产品(150mg,产率:34.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.6(s,1H),9.08(s,1H),8.13-8.11(m,1H),7.61-7.59(d,1H),7.53(s,1H),7.18-7.16(d,1H),6.71-6.68(t,2H),4.54(s,1H),2.96(s,1H),2.47(s,4H),2.01-1.90(m,3H),1.72-1.59(t,3H),1.23(s,1H),1.01-0.98(m,2H),0.71-0.69(m,2H).
分子式:C
24H
25N
5O 精确分子量:399.21 LC-MS(m/z)=400.15[M+H]
+.
实施例28化合物(R)-5-环丙基-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物90)
步骤1:(R)-5-环丙基-2-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-2-(6-溴-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-环丙基苯酚(500mg,1.10mmol,1.0eq.)、50%三甲基环三硼氧烷(1.10g,4.40mmol,4.0eq.)、碳酸铯(717mg,2.20mmol,2.0eq.)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.11mmol,0.1eq.)溶于H
2O(2mL)和1,4-二氧六环(10mL),氮气保护下100℃反应18h。LC-MS监测反应完全,反应液倒入水(20mL),用EA(20mL×2)萃取,有机相干燥,浓缩,粗品经制备薄层色谱纯化(MeOH:DCM=1:10)得产品(110mg,产率:25.7%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.72(s,1H),8.27(s,1H),7.65-7.62(m,1H),7.48-7.46(d,1H),7.27(s,1H),7.17-7.15(d,1H),6.70-6.66(m,2H),4.62(s,1H),3.48(s,1H),3.14(s,1H),2.65(s,3H),2.54(s,3H),1.99-1.91(m,3H),1.83-1.77(m,3H),1.01-0.97(m, 2H),0.72-0.69(m,2H).
分子式:C
24H
28N
4O
1 精确分子量:388.23 LC-MS(m/z)=389.16[M+H]
+.
实施例29化合物(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(三氟甲基)苯酚的合成(化合物93)
步骤1:1-溴-2-(乙氧基甲氧基)-4-(三氟甲基)苯的合成
将2-溴-5-三氟甲基苯酚(5.00g,20.7mmol,1.0eq)溶于THF(50mL)中,降温至0℃,分批加入NaH(60%,2.94g,31.1mmol,1.5eq),搅拌20分钟,再加入氯甲基***(1.24g,31.1mmol,1.5eq)。反应4小时后,加入饱和NH
4Cl水溶液淬灭,用EA(50mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,得到产物(6.08g,产率:98.0%)。
步骤2:(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)硼酸的合成
将1-溴-2-(乙氧基甲氧基)-4-(三氟甲基)苯(3.00g,10.0mmol,1.0eq)和硼酸三异丙酯(2.82g,15.0mmol,1.5eq)溶于THF(30mL),氮气保护下,降温至-60℃,然后滴加正丁基锂(1.6mol/L的THF溶液,9.4mL,15.0mmol,1.5eq),反应3小时。加入饱和NH
4Cl水溶液淬灭,EA(50mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经石油醚打浆得到产物(2.20g,产率:83.1%)。
步骤3:(R)-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)硼酸(229mg,0.867mmol,1.2eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(200mg,0.723mmol,1.0eq)、Pd(dppf)Cl
2(26.5mg,0.0362mmol,0.05eq)和NaHCO
3(122mg,1.45mmol,2.0eq)依次加入到1,4-二氧六环(4mL)中,加入H
2O(2mL),氮气保护下,加热至110℃反应3小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)纯化得到产物(245mg,产率:73.6%)。
步骤4:(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(三氟甲基)苯酚的合成
将(R)-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(245mg,0.532mmol,1.0eq)溶于DCM(4mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,1.3mL,5.32mmol,10.0eq),室温搅拌1小时。然后加入水(20mL)淬灭,DCM洗涤(20mL×2),水相用饱和NaHCO
3水溶液调节pH值至8,再用DCM(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产物(166mg,产率:77.5%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.51(s,1H),8.55(s,1H),7.91-7.88(m,1H),7.83-7.80(m,1H),7.59(s,1H),7.51(d,J=7.8Hz,1H),7.46(d,J=8.0Hz,1H),7.35(s,1H),7.31(d,J=7.9Hz,1H),4.73(s,1H),3.56(s,2H),3.22(s,2H),2.73(s,3H),1.99(s,2H),1.83(d,J=9.2Hz,2H).
分子式:C
21H
21F
3N
4O 精确分子量:402.17 LC-MS(m/z)=403.11[M+H]
+.
实施例30化合物(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-3-醇的合成(化合物108)
步骤1:5-甲基-3-羟基吡啶的合成
将3-溴-5-甲基吡啶(20.0g,0.116mol,1.0eq)和硼酸三异丙酯(26.1g,0.139mol,1.2eq)溶于THF(200mL),氮气保护下,降温至-60℃,然后滴加正丁基锂(2.5mol/L的THF溶液,55.6mL,0.139mol,1.2eq),继续反应2小时。加入稀盐酸淬灭,pH值调至3,分液,水相用EA(100mL×3)萃取,有机相合并,无水硫酸钠干燥,过滤,滤液减压浓缩。得到的粗品再溶于MeOH(100mL),加入间氯过氧苯甲酸(16.0g,0.0928mol,0.8eq),室温搅拌1小时后加入饱和硫代硫酸钠水溶液淬灭,然后用DCM(100mL×3)萃取,有机用无水硫酸钠干燥,浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)纯化得到产品(10.8g,产率:85.1%)。
步骤2:2-碘-5-甲基-3-羟基吡啶的合成
将5-甲基-3-羟基吡啶(10.0g,0.0916mol,1.0eq)和KOH(10.3g,0.183mol,2.0eq)加入到水(500mL)中,然后加入碘单质(23.2g,0.0916mol,1.0eq),室温反应16小时。用饱和NH
4Cl水溶液调节pH值至7,用EA(100mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)纯化得到产物(11.0g,产率:51.1%)。
步骤3:2-碘-3-甲氧基-5-甲基吡啶的合成
将2-碘-5-甲基-3-羟基吡啶(5.0g,21.3mmol,1.0eq)溶于DMF(50mL),加入碘甲烷(4.53g,31.9mmol,1.5eq)和K
2CO
3(5.89g,42.6mmol,2.0eq),室温反应2小时。加入水 (250mL)淬灭,用EA(100mL)萃取,有机相水洗(50mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)纯化得到产物(4.20g,产率:79.3%)。
步骤4:2-(3-甲氧基-5-甲基吡啶酰)苯甲酸的合成
将2-碘-3-甲氧基-5-甲基吡啶(4.00g,16.1mmol,1.0eq)溶于THF(40mL),氮气保护下,降温至-60℃,滴加正丁基锂(2.5mol/L的THF溶液,6.44mL,16.1mmol,1.0eq),搅拌30分钟。将邻苯二甲酸酐(2.38g,16.1mmol,1.0eq)溶于THF(40mL),降温至-60℃,然后滴加到上述反应液中,滴加完毕后反应1小时。用稀盐酸调节pH值至6,用EA萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产物(3.20g粗品)。
步骤5:2-(3-甲氧基-5-甲基吡啶酰)苯甲酸甲酯的合成
将2-(3-甲氧基-5-甲基吡啶酰)苯甲酸(3.2g,11.8mmol,1.0eq)溶于DMF(50mL),加入K
2CO
3(3.26g,23.6mmol,2.0eq)和碘甲烷(2.51g,17.7mmol,1.5eq),室温反应1小时。加入水(200mL)淬灭,用EA(100mL)萃取,有机相水洗(50mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)纯化得到产物(1.30g,两步产率:28.4%)。
步骤6:4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪-1-醇的合成
将2-(3-甲氧基-5-甲基吡啶酰)苯甲酸甲酯(1.20g,4.21mmol,1.0eq)溶于EtOH(12 mL),然后加入水合肼(85%,496mg,8.42mmol,2.0eq),加热至80℃反应1小时。降至室温,浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)纯化得到产物(920mg,产率:81.8%)。
步骤7:1-氯-4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪的合成
将4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪-1-醇(900mg,3.37mmol,1.0eq)加入到ACN(20mL)中,加入POCl
3(5.17g,33.7mmol,10.0eq),加热至90℃反应4小时。冷却至室温,加水淬灭,用饱和NaHCO
3水溶液调节pH值至8,再用EA(50mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)纯化得到产物(610mg,产率:63.4%)。
步骤8:(R)-3-((4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪(600mg,2.10mmol,1.0eq)、(R)-3-氨基哌啶-1-羧酸叔丁酯(631mg,3.15mmol,1.5eq)、Pd
2(dba)
3(385mg,0.420mmol,0.2eq)、BINAP(523mg,0.840mmol,0.4eq)和Cs
2CO
3(1.37g,4.20mmol,2.0eq)依次加入到1,4-二氧六环(20mL)中,氮气保护下,加热至90℃反应6小时。冷却至室温,加水(50mL)淬灭,用EA(30mL×2)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(DCM:MeOH=100:1~20:1)纯化得到产物(485mg,产率:51.4%)。
步骤9:(R)-5-甲基-2-(4-(哌啶-3-基氨基)酞嗪-1-基)吡啶-3-醇的合成
将(R)-3-((4-(3-甲氧基-5-甲基吡啶-2-基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(485mg,1.08mmol,1.0eq)溶于DCM(15mL),降温至-40℃,滴加BBr
3(2.71g,10.8mmol,10.0eq),自然升至室温,反应20小时。浓缩,加入MeOH淬灭,加入饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~10:1)纯化得到产物(160mg,产率:44.2%)。
步骤10:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-3-醇的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)酞嗪-1-基)吡啶-3-醇(160mg,0.477mmol,1.0eq)溶于MeOH(4mL),加入甲醛水溶液(37%,116mg,1.43mmol,3.0eq),室温搅拌30分钟。然后加入NaBH
3CN(90.0mg,1.43mmol,3.0eq),反应1小时。加入饱和NaHCO
3水溶液淬灭,用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(DCM:MeOH=10:1)纯化得到产物(70mg,产率:42.0%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):14.29(s,1H),9.63-9.61(m,1H),8.62(s,1H),8.11(d,J=1.4Hz,1H),7.99-7.94(m,2H),7.82(s,1H),7.25(d,J=1.1Hz,1H),4.64(s,1H),3.39(d,J=10.0Hz,2H),3.05(d,J=9.0Hz,1H),2.57(s,4H),2.34(s,3H),2.01-1.92(m,2H),1.79-1.74(m,2H).
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z)=350.14[M+H]
+.
实施例31:(R)-2-(6-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物8)
步骤1:5-氟-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯的合成
将5-氟-2-碘苯甲酸甲酯(5.0g,17.85mmol,1.0eq.)溶于THF(50mL),降温至-30℃,缓慢滴加异丙基氯化镁氯化锂的四氢呋喃溶液(1.3mol/L,16.5mL,21.42mmol,1.2eq.),搅拌30min,-60℃下将上述反应液缓慢滴加至2-甲氧基-4-甲基苯甲酰氯(3.30g,17.85mmol,1.0eq.)的THF(30mL)溶液中,滴毕,自然升至室温,反应1h,LC-MS监测有产物生成,将反应液倒入水(100mL)中,用EA(50mL×2)萃取,有机相干燥,浓缩得产物(5.4g,产率:100%)。
步骤2:7-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-醇的合成
将5-氟-2-(2-甲氧基-4-甲基苯甲酰基)苯甲酸甲酯(5.4g,17.85mmol,1.0eq.)和85%水合肼(1.05g,17.85mmol,1.0eq.)溶于乙醇(50mL),室温反应12h,LC-MS监测有产物生成,反应液过滤得产物(1.0g,产率:19.7%)。
步骤3:4-氯-6-氟-1-(2-甲氧基-4-甲基苯基)酞嗪的合成
将7-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-醇(1.0g,3.51mmol,1.0eq.)和三氯氧磷(1.07g,7.02mmol,2.0eq.)溶于乙腈(10mL),90℃反应0.5h,LC-MS监测反应完全,反应液减压浓缩,粗品用EA(20mL)溶解,用饱和碳酸氢钠水溶液调pH值至9,分液,水相再用EA(20mL)萃取,有机相合并,干燥,浓缩得产物(0.9g,产率:84.9%)。
步骤4:(R)-3-((7-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-氯-6-氟-1-(2-甲氧基-4-甲基苯基)酞嗪(0.9g,2.97mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(894mg,4.46mmol,1.5eq.)、Pd
2(dba)
3(274mg,0.30mmol,0.1eq.)、BINAP(367mg,0.59mmol,0.2eq.)和碳酸铯(1.94g,5.94mmol,2.0eq.)加入1,4-二氧六环(20mL),氮气保护下90℃反应21h。LC-MS检测反应完全,反应液减压浓缩,粗品经硅胶柱层析(MeOH:DCM=1:80)纯化得产品(0.8g,产率:57.9%)。
步骤5:(R)-2-(6-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-3-((7-氟-4-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(0.8g,1.71mmol,1.0eq.)溶于DCM(10mL),滴加1mol/L的三溴化硼的二氯甲烷溶液(5.2mL,5.13mmol,3.0eq),反应4h,LC-MS检测反应完全,向瓶中加入适量的甲醇淬灭,加入水(5mL),分液,水相用饱和碳酸氢钠水溶液调pH值至9,水相用DCM(15mL×3)萃取,有机相干燥,浓缩得产物(300mg,产率:49.8%)。
步骤6:(R)-2-(6-氟-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-2-(6-氟-4-(哌啶-3-基氨基)酞嗪-1-基)-5-甲基苯酚(300mg,0.85mmol,1.0eq.)溶于甲醇(5mL),加入甲醛水溶液(37%)(69mg,0.85mmol,1.0eq.),室温搅拌10min,加入氰基硼氢化钠(53mg,0.85mmol,1.0eq.),室温反应10min。LC-MS监测反应完全,反应液减压浓缩,粗品经硅胶柱层析纯化(DCM:MeOH=20:1)得产物(160mg,产率:51.4%)
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.59(s,1H),8.28-8.25(m,1H),7.69-7.64(m,1H),7.61-7.57(m,1H),7.18-7.16(d,1H),7.03-7.01(d,1H),6.81(s,1H),6.79-6.77(d,1H),4.41-4.39(d,1H),3.14-3.12(d,1H),2.78-2.75(d,1H),2.33(s,3H),2.26(s,1H),2.02-1.99(d,3H),1.79-1.76(d,1H),1.64-1.58(t,1H),1.49-1.41(m,1H).
分子式:C
21H
23FN
4O 精确分子量:366.19 LC-MS(Pos,m/z)=367.14[M+H]
+.
实施例32:(R)-3-羟基-4-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物55)和(R)-3-羟基-4-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物54)的合成
步骤1:6-甲基-2,3-二氢-酞嗪-1,4-二酮合成
将5-甲基异苯并呋喃-1,3-二酮(5g,30.83mmol,1.0eq.)和85%水合肼(2.73g,46.25mmol,1.5eq.)加入1,4-二氧六环(100mL)溶液中,80℃反应1h,LC-MS监测反应液完全,反应液抽滤,滤饼干燥得产物(5.43g,产率:100%)。
步骤2:1,4-二氯-6-甲基酞嗪的合成
将6-甲基-2,3-二氢-酞嗪-1,4-二酮(5.43g,30.83mmol,1.0eq.)和三氯氧磷(18.91g,123.32mmol,4.0eq.)溶于乙腈(100mL),90℃反应18h,反应液减压浓缩,粗品加入水(50mL)和EA(50mL),分液,水相用EA(50mL×2)萃取,有机相合并,干燥,浓缩,粗品经硅胶柱层析(PE:EA=10:1)纯化得产物(2.4g,产率:36.4%)。
步骤3:4-(4-羟基-6-甲基酞嗪-1-基)-3-甲氧基苯甲腈和4-(4-羟基-7-甲基酞嗪-1-基)-3-甲氧基苯甲腈的合成
将1,4-二氯-6-甲基酞嗪(1.0g,4.69mmol,1.0eq.)、3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(1.46g,5.63mmol,1.2eq.)、PdCl
2(dppf)(344mg,0.47mmol,0.1eq.)和碳酸氢钠(788mg,9.38mmol,2.0eq.)溶于1,4-二氧六环(20mL)和H
2O(4mL)中,氮气保护下100℃反应3h,LC-MS检测反应完全,反应液减压浓缩,粗品经硅胶柱层析(PE:EA=3:1)纯化得产物(0.4g,产率:29.4%)。
步骤4:4-(4-氯-6-甲基酞嗪-1-基)-3-甲氧基苯甲腈和4-(4-氯-7-甲基酞嗪-1-基)-3-甲氧基苯甲腈的合成
将4-(4-羟基-6-甲基酞嗪-1-基)-3-甲氧基苯甲腈和4-(4-羟基-7-甲基酞嗪-1-基)-3-甲氧基苯甲腈的混合物(0.4g,1.37mmol,1.0eq.)与三氯氧磷(0.42g,2.74mmol,1.0eq.)溶于乙腈(100mL),90℃反应1.5h,TLC监测反应完全,反应液减压浓缩,粗品用EA(10mL) 溶解,加入饱和碳酸氢钠溶液调pH值至9,分液,有机相干燥,浓缩得产物(0.4g,产率:94.3%)。
步骤5:(R)-3-((4-(4-氰基-2-甲氧基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(4-氰基-2-甲氧基苯基)-6-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-(4-氯-6-甲基酞嗪-1-基)-3-甲氧基苯甲腈和4-(4-氯-7-甲基酞嗪-1-基)-3-甲氧基苯甲腈的混合物(380mg,1.23mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(368mg,1.84mmol,1.5eq.)、Pd
2(dba)
3(110mg,0.12mmol,0.1eq.)、BINAP(174mg,0.25mmol,0.2eq.)和碳酸铯(802mg,2.46mmol,2.0eq.)加入1,4-二氧六环(10mL),氮气保护下90℃反应17h。LC-MS检测反应完全,反应液减压浓缩,粗品经硅胶柱层析(MeOH:DCM=1:50)纯化得产品(0.3g,产率:78.9%)。
步骤6:(R)-3-羟基-4-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯甲腈和(R)-3-羟基-4-(7-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-((4-(4-氰基-2-甲氧基苯基)-7-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((4-(4-氰基-2-甲氧基苯基)-6-甲基酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的混合物(300mg,0.63mmol,1.0eq.)溶于DCM(5mL),室温滴加1mol/L的三溴化硼的二氯甲烷溶液(1.9mL,1.89mmol,3.0eq),室温反应3h,LC-MS检测反应完全,向体系加入适量的甲醇淬灭,加入水(10mL),分液,水相用碳酸氢钠调pH值至9,水相再用DCM(15mL×3)萃取,有机相干燥,浓缩得产品(150mg,产率:66.3%)。
步骤7:(R)-3-羟基-4-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物55)和(R)-3-羟基-4-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物54)的合成
将(R)-3-羟基-4-(6-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯甲腈和(R)-3-羟基-4-(7-甲基-4-(哌啶-3-基氨基)酞嗪-1-基)苯甲腈混合物(150m g,0.42mmol,1.0eq.)与甲醛水溶液(37%)(34mg,0.42mmol,1.0eq.)溶于甲醇(3mL),室温搅拌5min,加入氰基硼氢化钠(26mg,0.42mmol,1.0eq.),室温反应5min。LC-MS监测反应完全,反应液减压浓缩,粗品用DCM(10mL)溶解,加入水(10mL),分液,有机相干燥,浓缩,粗品经制备薄层色谱纯化(二氯:甲醇:氨水=10:1:0.5)得Rf值较大产物(R)-3-羟基-4-(6-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(23mg,产率:14.7%)(化合物55)
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.48(s,1H),8.21(s,1H),7.62-7.60(d,1H),7.49-7.47(d,1H),7.41-7.39(t,1H),7.34-7.32(d,2H),7.04-7.02(d,1H),4.42-4.40(t,1H),3.08-3.06(d,1H),2.72-2.69(d,1H),2.53(s,3H),2.21(s,3H),1.99-1.90(m,3H),1.78-1.74(m,1H),1.62-1.59(d,1H),1.49-1.43(m,1H).
二维谱NOE显示7.49-7.47(d,1H)与7.34-7.32(d,1H)有耦合信号,8.21(s,1H)与7.04-7.02(d,1H)有耦合信号
分子式:C
22H
26N
4O 精确分子量:373.19 LC-MS(Pos,m/z)=374.14[M+H]
+.
同时得到Rf值较小产物(R)-3-羟基-4-(7-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(20mg,产率:12.8%)(化合物54)
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.43(s,1H),8.31-8.29(d,1H),7.70-7.68(d,1H),7.48-7.46(d,1H),7.42-7.39(m,1H),7.32(s,1H),7.19(s,1H),7.08-7.06(d,1H),4.41-4.39(t,1H),3.08-3.06(d,1H),2.72-2.69(d,1H),2.42(s,3H),2.21(s,3H),1.98-1.89(m,3H),1.76-1.73(t,1H),1.62-1.59(d,1H),1.49-1.43(m,1H).
二维谱NOE显示10.43(s,1H)与7.19(s,1H)有耦合信号,8.31-8.29(d,1H)与7.08-7.06(d,1H)有耦合信号,8.31-8.29(d,1H)与7.70-7.68(d,1H)有耦合信号。
分子式:C
22H
26N
4O 精确分子量:373.19 LC-MS(Pos,m/z)=374.13[M+H]
+.
实施例33:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6-(三氟甲基)酞嗪-1-基)苯酚的合成(化合物24)
步骤1:2-溴-5-(三氟甲基)苯甲酸甲酯的合成
将2-溴-5-(三氟甲基)苯甲酸(10.0g,37.17mmol,1.0eq.)、碘甲烷(7.91g,55.76mmol,1.5eq.)和碳酸钾(7.69g,55.76mmol,1.5eq.)溶于DMF(50mL),室温反应1h,TLC监测无原料剩余,将反应液倒入水(50mL)中,用MTBE(50mL×2)萃取,有机相干燥,浓缩得产物(10.52g,产率:100%)。
步骤2:2-(2-甲氧基-4-甲基苯甲酰基)-5-(三氟甲基)苯甲酸甲酯的合成
将2-溴-5-(三氟甲基)苯甲酸甲酯(8.0g,28.26mmol,1.0eq.)溶于THF(50mL),降温至 -30℃,缓慢滴加异丙基氯化镁氯化锂的四氢呋喃溶液(1.3mol/L,26mL,33.91mmol,1.2eq.),搅拌2h,降温至-60℃,向体系中滴加2-甲氧基-4-甲基苯甲酰氯(5.21g,28.26mmol,1.0eq.)的THF(50mL)溶液中,反应1h,LC-MS监测有产物生成,将反应液倒入饱和碳酸钾水溶液中(200mL),用EA(100mL×2)萃取,有机相干燥,浓缩得产物(5.0g,产率:50.2%)。
步骤3:4-(2-甲氧基-4-甲基苯基)-7-(三氟甲基)酞嗪-1-醇的合成
将2-(2-甲氧基-4-甲基苯甲酰基)-5-(三氟甲基)苯甲酸甲酯(5.0g,14.19mmol,1.0eq.)和85%水合肼(1.25g,21.28mmol,1.5eq.)溶于乙醇(50mL),80℃反应17h,LC-MS监测反应完全,反应液减压浓缩粗品经硅胶柱层析(MEOH:DCM=1:100)纯化得产物(1.1g,产率:23.2%)。
步骤4:4-氯-1-(2-甲氧基-4-甲基苯基)-6-(三氟甲基)酞嗪的合成
将4-(2-甲氧基-4-甲基苯基)-7-(三氟甲基)酞嗪-1-醇(1.0g,2.99mmol,1.0eq.)和三氯氧磷(917mg,5.98mmol,2.0eq.)溶于乙腈(20mL),90℃反应1h,TLC监测反应完全,反应液减压浓缩,粗品经硅胶柱层析(PE:EA=10:1)纯化得产物(0.5g,产率:47.6%)。
步骤5:(R)-3-((4-(2-甲氧基-4-甲基苯基)-7-(三氟甲基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-氯-1-(2-甲氧基-4-甲基苯基)-6-(三氟甲基)酞嗪(0.5g,1.41mmol,1.0eq.)、(R)-3- 氨基哌啶-1-羧酸叔丁酯(424mg,2.12mmol,1.5eq.)、Pd
2(dba)
3(128mg,0.14mmol,0.1eq.)、BINAP(174mg,0.28mmol,0.2eq.)和碳酸铯(919mg,2.82mmol,2.0eq.)加入1,4-二氧六环(10mL),氮气保护下90℃反应21h。LC-MS检测反应完全,反应液减压浓缩,粗品经硅胶柱层析(PE:EA=2:1)纯化得产品(0.3g,产率:41.2%)。
步骤6:(R)-5-甲基-2-(4-(哌啶-3-基氨基)-6-(三氟甲基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)-7-(三氟甲基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(0.3g,0.58mmol,1.0eq.)溶于DCM(5mL),滴加1mol/L的三溴化硼的二氯甲烷溶液(1.7mL,1.74mmol,3.0eq),反应1h,LC-MS检测反应完全,向体系加入适量的甲醇淬灭,加入水(5mL),分液,水相用碳酸氢钠调pH值至9,用DCM(10mL×3)萃取,有机相干燥,浓缩得产物(100mg,产率:42.9%)。
步骤7:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6-(三氟甲基)酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)-6-(三氟甲基)酞嗪-1-基)苯酚(100mg,0.24mmol,1.0eq.)溶于甲醇(2mL),加入甲醛水溶液(37%)(19mg,0.24mmol,1.0eq.),室温搅拌5min,加入氰基硼氢化钠(15mg,0.24mmol,1.0eq.),室温反应5min。LC-MS监测反应完全,反应液减压浓缩,粗品经制备薄层色谱纯化(DCM:MeOH=8:1)得产物(20mg,产率:20%)
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.56(s,1H),8.90(s,1H),8.09-8.06(d,1H),7.68-7.66(d,1H),7.50-7.47(d,1H),7.20-7.18(d,1H),6.82-6.78(d,1H),4.46-4.44(d,1H),3.17-3.13(d,1H),2.34(s,3H),2.26(s,1H),2.02-1.98(d,3H),1.82-1.77(d,1H),1.65-1.62(d,1H),1.51-1.45(m,1H).
分子式:C
22H
23F
3N
4O 精确分子量:416.18 LC-MS(Pos,m/z)=417.13[M+H]
+.
实施例34:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氧基)酞嗪-1-基)苯酚的合成(化合物130)
步骤1:(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)氧基)哌啶-1-羧酸叔丁酯的合成
将(R)-3-羟基哌啶-1-羧酸叔丁酯(287.3mg,1.42mmol,1.5eq.)加入到无水N,N-二甲基甲酰胺(3.0mL)中,冰浴下加入氢化钠(60%)(56.8mg,1.42mmol,1.5eq.),氮气保护下反应0.5小时,滴加2-(4-溴酞嗪-1-基)-5-甲基苯酚(300.0mg,0.95mmol,1.0eq.)的N,N-二甲基甲酰胺溶液(5.0mL),室温反应12小时,TLC监测反应完全,体系用水(50.0mL)淬灭,乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得粗产物(360.0mg,直接用于下一步)。
步骤2:(R)-5-甲基-2-(4-(哌啶-3-基氧基)酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)氧基)哌啶-1-羧酸叔丁酯(360.0mg粗品,0.82mmol,1.0eq.)加入到二氯甲烷(5.0mL)中,滴加三氟乙酸(5.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(硅胶规格:100-200目,二氯甲烷:甲醇=10:1)得产物(51.0mg,产率:18.5%)。
步骤3:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氧基)酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氧基)酞嗪-1-基)苯酚(51.0mg,0.15mmol,1.0eq.)、甲醛水溶液(37%)(14.8mg,0.18mmol,1.2eq.)加入到甲醇(5.0mL)中,室温搅拌0.5小时后加入氰基硼氢化钠(13.2mg,0.21mmol,1.4eq.),室温反应2小时。TLC监测反应完全,减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL)搅拌0.5小时,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(30.0mg,产率:57.2%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.58(s,1H),8.22-8.20(d,J=6Hz,1H),7.98-7.87(m,2H),7.61-7.58(m,1H),7.20-7.18(m,1H),6.84-6.79(m,2H),5.49(s,1H),3.36-3.34(m,1H),3.04-3.01(m,1H),2.55-2.49(m,2H),2.35(s,3H),2.26(s,3H),1.87-1.66(m,4H).
分子式:C
21H
23N
3O
2 精确分子量:349.18 LC-MS(m/z)=350.17[M+H]
+.
实施例35:(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物72)
步骤1:(R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(350.0mg,1.26mmol,1.0eq.)、(4-环丙基-2-甲氧基苯基)硼酸(364.2mg,1.89mmol,1.5eq.)、碳酸氢钠(317.5mg,3.78mmol.3.0eq.)和Pd(PPh
3)
4(72.8mg,0.06mmol,0.05eq.)加入到1,4-二氧六环(12.0mL)和水(6.0mL)的混合溶液中,氮气保护下,110℃反应12小时,TLC监测反应完全。水(50.0mL)洗,乙酸乙 酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=40:1-10:1)得产物(387.0mg,产率:79.1%)。
步骤2:(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(387.0mg,0.99mmol,1.0eq.)加入到二氯甲烷(5.0mL)中,冰浴下滴加三溴化硼(748.6mg,2.98mmol,3.0eq.),升至室温反应2小时,TLC监测反应完全,体系冰浴下用甲醇(10.0mL)小心淬灭,减压浓缩,加入二氯甲烷(100.0mL),用水(50.0mL)反萃,水相用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(160.0mg,产率:43.2%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.66(s,1H),8.47-8.45(d,J=6Hz,1H),7.88-7.76(m,2H),7.55-7.53(m,1H),7.32(s,1H),7.17-7.15(m,1H),6.70-6.66(m,2H),4.59(s,1H),3.06-3.03(m,2H),2.55(s,3H),2.01-1.70(m,6H),1.02-0.96(m,2H),0.88-0.84(m,1H),0.72-0.67(m,2H).
分子式:C
23H
26N
4O 精确分子量:374.21 LC-MS(m/z)=375.16[M+H]
+.
实施例36化合物(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成(化合物95)
步骤1:中间体4-环丙基-2-甲氧基苯甲酰氯的合成
将4-环丙基-2-甲氧基苯甲酸(5g,26.01mmol,1.0eq)溶于二氯甲烷(50mL)中,向其中 滴加N,N-二甲基甲酰胺(0.05mL),缓慢滴加草酰氯(9.9g,78.03mmol,3.0eq),滴加完毕,室温反应20min,TLC检测反应完全。反应液浓缩,直接投入下一步。
步骤2:中间体2-氯-4-(4-环丙基-2-甲氧基苯甲酰基)烟酸甲酯的合成
将4-环丙基-2-甲氧基苯甲酰氯(7.74g,26.01mmol,1.0eq)溶于四氢呋喃(80mL)中,氮气置换,-40℃下,向其中缓慢滴加1.3mol/L异丙基氯化镁氯化锂的四氢呋喃溶液(22mL,28.61mmol,1.1eq),滴加完毕,-40℃搅拌20min。向其中加入氰化亚铜(2.33g,26.01mmol,1.0eq),-40℃再反应30min。向其中滴加4-环丙基-2-甲氧基苯甲酰氯(26.01mmol,1.0eq)的四氢呋喃溶液(50mL),滴加完毕,5℃反应1h,TLC检测反应完毕。向反应液中加入饱和食盐水(100mL)与饱和碳酸氢钠水溶液(50mL),乙酸乙酯(50mL×3),有机相合并,无水硫酸钠干燥,浓缩,得产物(7.37g,两步产率:82%)。
步骤3:中间体4-(4-环丙基-2-甲氧基苯甲酰基)烟酸甲酯的合成
将2-氯-4-(4-环丙基-2-甲氧基苯甲酰基)烟酸甲酯(7.37g,21.32mmol,1.0eq)溶于甲醇(100mL)中,向其中加入三乙胺(6.47g,63.96mmol,2.0eq)和5%钯碳(3.6g),氢气置换,室温25℃反应1h。TLC检测反应完毕。反应液经硅藻土过滤,滤液浓缩,经硅胶柱层析(乙酸乙酯:石油醚=1:5)纯化得产物(4.06g,产率:61.1%)。
步骤4:中间体1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4(3H)-酮的合成
将4-(4-环丙基-2-甲氧基苯甲酰基)烟酸甲酯(4.06g,13.01mmol,1.0eq)加入到乙醇 (50mL)中,向其中加入85%水合肼(1.53g,26.02mmol,2.0eq),加热至90℃反应2h,TLC检测反应完毕。过滤反应液,滤饼用乙醇(5mL)淋洗,干燥得产物(2.44g,产率:64%)。(2100054-002)。
步骤5:中间体4-氯-1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪的合成
将1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4(3H)-酮(2.44g,8.32mmol,1.0eq)加入到乙腈(30mL)中,向其中加入三氯氧磷(2.55g,16.64mmol,2.0eq),100℃反应16h,TLC检测反应完毕。反应液浓缩,二氯甲烷(20mL)溶解,将其滴入饱和碳酸氢钠水溶液(100mL)中,萃取,水相用二氯甲烷萃取(50mL×3),有机相合并,饱和食盐水(50mL)洗涤,无水硫酸镁干燥,浓缩,粗品经硅胶柱层析(乙酸乙酯:石油醚=1:10~1:5)纯化得产物(1.94g,产率:74.9%)。
步骤6:中间体2-(4-氯吡啶并[3,4-d]哒嗪-1-基)-5-环丙基苯酚的合成
将4-氯-1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪(1.94g,6.22mmol,1.0eq)溶于二氯甲烷(20mL)中,0℃下,向其中缓慢滴加三溴化硼(4.67g,18.66mmol,3.0eq),滴加完毕,室温25℃反应30min,TLC检测反应完全。将反应液缓慢滴入饱和碳酸氢钠水溶液(50mL)中,二氯甲烷萃取(20mL×3),有机相合并,无水硫酸镁干燥,浓缩,得产物(1.2g)。
步骤7:中间体(R)-3-((1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将2-(4-氯吡啶并[3,4-d]哒嗪-1-基)-5-环丙基-苯酚(1.2g,4.03mmol,1.0eq)溶于N,N-二甲基乙酰胺(12mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(1.61g,8.06mmol,2.0eq),120℃反应16h,TLC检测反应完毕。将反应液倒入水(20mL)中,乙酸乙酯(20mL)萃取,有机相无水硫酸钠干燥,浓缩。粗品经硅胶柱层析(乙酸乙酯:石油醚=1:3~1:1)得产物(1.19g,两步产率:41.4%)。
步骤8:中间体(R)-5-环丙基-2-(4-(哌啶-3-基氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-3-((1-(4-环丙基-2-甲氧基苯基)吡啶并[3,4-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.19g,2.58mmol,1.0eq)溶于二氯甲烷(3mL),将其滴入4moL/L的氯化氢的1,4-二氧六环溶液(15mL)中,滴加完毕,常温反应5min,TLC检测反应完毕。向反应液中加入水(15mL),碳酸氢钠调节pH值至弱碱性,甲醇/二氯甲烷混合溶剂萃取(1:5,30mL×3)。有机相合并,无水硫酸镁干燥,浓缩,直接投入下一步。
步骤9:化合物(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚的合成
将(R)-5-环丙基-2-(4-(哌啶-3-基氨基)吡啶并[3,4-d]哒嗪-1-基)苯酚(2.58mmol,1.0eq)溶于甲醇(10mL)中,向其中加入37%的甲醛水溶液(210mg,2.58mmol,1.0eq),常温搅拌5min,加入氰基硼氢化钠(179mg,2.84mmol,1.1eq),常温反应5min,TLC检测反应完毕。反应液浓缩,加入饱和食盐水(2mL),用7mol/L氨的甲醇溶液/二氯甲烷萃取(1:7,10mL×3),有机相合并,干燥,浓缩,粗品经制备薄层色谱纯化得产物(265mg,两步产率:27%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):9.79(s,1H),9.65(s,1H),8.85-8.84(d,1H),7.63-7.61(d,1H),7.34-7.32(d,1H),7.20-7.18(d,1H),6.71-6.68(m,2H),4.51(s,1H),3.22(s,1H),2.85-2.83(d,1H),2.30(s,3H),2.12-2.01(m,2H),1.97-1.90(m,1H),1.81-1.52(m,4H), 1.02-0.97(m,2H),0.72-0.68(m,2H)。
分子式:C
22H
25N
5O 精确分子量:375.21 LC-MS(m/z):376.12[M+H]
+
实施例37:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈的合成(化合物111)
步骤1:(R)-4-氯-N-(1-环丙基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(505.0mg,1.92mmol,1.0eq.)、(1-甲氧基环丙氧基)三甲基硅烷(1.34g,7.68mmol,4.0eq.)、乙酸(1.0mL.)、氟化铯(291.9mg,1.92mmol,1.5eq.)和氰基硼氢化钠(603.8mg,9.61mmol,5.0eq.)加入甲醇(15.0mL),60℃反应12小时,TLC监测反应完全,体系加入饱和碳酸氢钠水溶液(50.0mL),二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=80:1-50:1)得产物(350.0mg,产率:60.1%)。
步骤2:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈的合成
将(R)-4-氯-N-(1-环丙基哌啶-3-基)酞嗪-1-胺(350.0mg,1.15mmol,1.0eq.)、3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(700.8mg,2.31mmol,2.0eq.)、碳酸氢钠(291.0mg,3.46mmol.3.0eq.)和Pd(dppf)Cl
2(42.2mg,0.05mmol,0.05eq.)加入1,4-二氧六环(10.0mL)和水(5.0mL)中,氮气保护下,110℃反应5小时,TLC监测反应完全,体系冷却至室温,加水(50.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸 钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=80:1~60:1)得产物(300.0mg,产率:58.5%)。
步骤3:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈的合成
将(R)-4-(4-((1-环丙基哌啶-3-基)氨基)酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(290.0mg,0.65mmol,1.0eq.)加入乙醇(5.0mL)和氯化氢-乙醇溶液(2.0mol/L,10.0mL),室温反应1小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=80:1~40:1)得产物(190.0mg,产率:75.3%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.40-8.38(d,J=8Hz,1H),7.86(t,J=8Hz,1H),7.78(t,J=8Hz,1H),7.51-7.49(d,J=8Hz,1H),7.43(s,1H),7.41-7.33(m,2H),7.16-7.14(d,J=8Hz,1H),4.36-4.34(m,1H),3.29-3.27(m,1H),2.92-2.89(m,1H),2.22-2.17(m,2H),2.01-1.99(m,1H),1.74-1.66(m,2H),1.57-1.44(m,2H),0.46-0.34(m,4H).
分子式:C
23H
23N
5O 精确分子量:385.19 LC-MS(Pos,m/z)=386.11[M+H]
+.
实施例38:(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(甲硫基)苯酚的合成(化合物114)
步骤1:2-溴-5-碘苯酚的合成
将1-溴-4-碘-2-甲氧基苯(6.0g,19.17mmol,1.0eq.)加入二氯甲烷(20.0mL),慢慢滴加三溴化硼(14.4g,57.50mmol,3.0eq.),室温反应5小时,TLC监测反应完全,冰浴下用甲醇淬灭,减压浓缩,加水(50mL),二氯甲烷(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(5.3g,产率:92.4%)。
步骤2:1-溴-2-(乙基甲氧基)-4-碘苯的合成
将2-溴-5-碘苯酚(5.3g,17.73mmol,1.0eq.)加入无水四氢呋喃(20.0mL),冰浴下加入氢化钠(质量分数60%,1.0g,26.59mmol,1.5eq.),反应0.5小时后加入氯甲基***(2.5g,26.59mmol,1.5eq.),升至室温反应12小时,TLC监测反应完全,体系加入饱和氯化铵水溶液(100.0mL),乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,石油醚:乙酸乙酯=100:1)得产物(6.15g,产率:97.3%)。
步骤3:(4-溴-3-(乙氧基甲氧基)苯基)(甲基)硫烷的合成
将1-溴-2-(乙基甲氧基)-4-碘苯(6.15g,17.22mmol,1.0eq.)加入无水四氢呋喃(20.0mL),降温至-30℃,滴加异丙基氯化镁氯化锂的四氢呋喃溶液(1.3mol/L,15.9mL,20.67mmol,1.2eq.),反应0.5小时后加入1,2-二甲基二硫烷(1.78g,18.95mmol,1.1eq.),升至室温搅拌2小时。TLC监测反应完全,体系加入饱和氯化铵水溶液(100.0mL),乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(4.5g,产率:94.3%)。
步骤4:2-(2-(乙氧基甲氧基)-4-(甲硫基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷的合成
将(4-溴-3-(乙氧基甲氧基)苯基)(甲基)硫烷(4.5g,16.23mmol,1.0eq.)、4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(6.18g,24.35mmol,1.5eq.)、醋酸钾(3.18g,32.46mmol,2.0q.)和Pd(dppf)Cl
2(593.9mg,0.81mmol,0.05eq.)加入1,4-二氧六环(25.0mL)中,氮气保护下,110℃搅拌6小时,TLC监测反应完全,加水(200.0mL),乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,石油醚:乙酸乙酯=10:1)得产物(4.8g,产率:91.2%)。
步骤5:(R)-4-(2-(乙氧基甲氧基)-4-(甲硫基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合 成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(1.0g,3.61mmol,1.0eq.)、2-(2-(乙氧基甲氧基)-4-(甲硫基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.75g,5.41mmol,1.5eq.)、碳酸氢钠(607.0mg,7.22mmol,2.0eq.)和Pd(dppf)Cl
2(132.1mg,0.18mmol,0.05eq.)加入到1,4-二氧六环(15.0mL)和水(7.0mL)的混合溶液中,氮气保护下,110℃搅拌6小时,TLC监测反应完全,加(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=40:1-10:1)得产物(1.2g,产率:75.9%)。
步骤6:(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(甲硫基)苯酚的合成
将(R)-4-(2-(乙氧基甲氧基)-4-(甲硫基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(100.0mg,0.22mmol,1.0eq.)和氯化氢-1,4-二氧六环溶液(4.0mol/L,3.0mL)加入二氯甲烷(1.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(60.0mg,产率:69.7%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.92(s,1H),8.38-8.36(d,J=8Hz,1H),7.84(t,J=8Hz,1H),7.77(t,J=8Hz,1H),7.54-7.52(d,J=8Hz,1H),7.25-7.23(d,J=8Hz,1H),7.04-7.02(d,J=8Hz,1H),6.86-6.83(m,2H),4.40(s,1H),3.08-3.06(d,J=8Hz,1H),2.72-2.69(d,J=12Hz,1H),2.51(s,3H),2.21(s,3H),1.99-1.88(m,3H),1.77-1.41(m,3H).
分子式:C
21H
24N
4OS 精确分子量:380.17 LC-MS(Pos,m/z)=381.03[M+H]
+.
实施例39:(R)-3-羟基-4-(4-((四氢-2H-吡喃-3-基)氨基)酞嗪-1-基)苯甲腈的合成(化合物112)
步骤1:(R)-4-氯-N-(四氢-2H-吡喃-3-基)酞嗪-1-胺的合成
将1,4-二氯酞嗪(157.0mg,0.78mmol,1.0eq.)、(R)-四氢-2H-吡喃-3-胺盐酸盐(162.8mg,1.18mmol,1.5eq.)和二异丙基乙胺(203.6mg,1.57mmol,2.0eq.)加入N,N-二甲基乙酰胺(3.0mL),120℃搅拌12小时,TLC监测反应完全,体系冷却至室温,加入水(100.0mL),EA(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(67.0mg,产率:32.2%)。
步骤2:(R)-3-(乙氧基甲氧基)-4-(4-((四氢-2H-吡喃-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-4-氯-N-(四氢-2H-吡喃-3-基)酞嗪-1-胺(67.0mg,0.25mmol,1.0eq.)、3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(154.0mg,0.50mmol,2.0eq.)、碳酸氢钠(64.0mg,0.76mmol.3.0eq.)和Pd(dppf)Cl
2(9.29mg,0.01mmol,0.05eq.)加入1,4-二氧六环(4.0mL)和水(2.0mL)中,氮气保护下,110℃反应5小时,TLC监测反应完全,体系冷却至室温,加水(50.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(60.0mg,产率:58.4%)。
步骤3:(R)-3-羟基-4-(4-((四氢-2H-吡喃-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((四氢-2H-吡喃-3-基)氨基)酞嗪-1-基)苯甲腈(60.0mg,0.14mmol,1.0eq.)和氯化氢-乙醇溶液(2.0mol/L,4.0mL)加入乙醇(2.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(30.0mg,产率:58.5%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.43-8.40(d,J=12Hz,1H),7.87(t,J=8Hz,1H),7.79(t,J=8Hz,1H),7.51-7.49(d,J=8Hz,1H),7.43(s,1H),7.41(s,1H),7.33(s,1H),7.23-7.21(d,J=8Hz,1H),4.44-4.39(m,1H),4.09-4.06(m,1H),3.85-3.82(d,J=12Hz,1H),3.28-3.16(m,2H),2.11(s,1H),1.79-1.65(m,3H).
分子式:C
20H
18N
4O
2 精确分子量:346.14 LC-MS(Pos,m/z)=347.02[M+H]
+.
实施例40:4-(4-(((3R,5R)-5-氟-1-甲基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈的合成(化合物123)
步骤1:(3R,5R)-3-((4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)氨基)-5-氟哌啶-1-羧酸叔丁酯的合成
将4-(4-氯酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(292.0mg,0.85mmol,1.0eq.)、(3R,5R)-3-氨基-5-氟哌啶-1-羧酸叔丁酯(206.3mg,0.94mmol,1.1eq.)、碳酸铯(559.7mg,1.71mmol,2.0eq.)、Pd
2(dba)
3(78.6mg,0.08mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(106.9mg,0.17mmol,0.2eq.)加入1,4-二氧六环(15.0mL),氮气保护下,90℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过 滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=100:1-60:1)得产物(220.0mg,产率:49.1%)。
步骤2:4-(4-(((3R,5R)-5-氟哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈的合成
将(3R,5R)-3-((4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)氨基)-5-氟哌啶-1-羧酸叔丁酯(220.0mg,0.42mmol,1.0eq.)和氯化氢-1,4-二氧六环溶液(4.0mol/L,5.0mL)加入二氯甲烷(3.0mL),室温搅拌1小时。TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(150.0mg,产率:98.0%)。
步骤3:4-(4-(((3R,5R)-5-氟-1-甲基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈的合成
将4-(4-(((3R,5R)-5-氟哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈(150.0mg,0.41mmol,1.0eq.)和甲醛水溶液(质量分数37%,50.2mg,0.61mmol,1.5eq.)加入甲醇(6.0mL),室温搅拌0.5小时,加入氰基硼氢化钠(38.8mg,0.61mmol,1.5eq.),继续室温反应2小时,TLC监测反应完全,加入饱和碳酸氢钠水溶液(50.0mL),二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(80.0mg,产率:51.6%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.40-8.38(d,J=8Hz,1H),7.90-7.86(m,1H),7.81-7.78(m,1H),7.51-7.49(d,J=8Hz,1H),7.44-7.41(m,2H),7.33(s,1H),7.25-7.23(d,J=8Hz,1H),5.07-4.96(m,1H),4.75-4.74(m,1H),3.11-3.09(d,J=8Hz,1H),2.97-2.92(m,1H),2.24(s,3H),2.21(s,1H),2.14-2.11(m,1H),2.02-1.73(m,2H).
分子式:C
21H
20FN
5O 精确分子量:377.17 LC-MS(Pos,m/z)=378.11[M+H]
+.
实施例41(R)-5-氯-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物101)
步骤1:(R)-4-(4-氯-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将4-氯-2-甲氧基苯硼酸(2.02g,10.8mmol,1.0eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(3.00g,10.8mmol,1.0eq)、Pd(dppf)Cl
2(790mg,1.08mmol,0.1eq)和NaHCO
3(1.81g,21.6mmol,2.0eq),依次加入到1,4-二氧六环(30mL)和水(15mL)中,氮气保护下加热至110℃,反应2小时。冷却至室温,加入水(60mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(3.50g,产率:84.3%)。
步骤2:(R)-5-氯-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成
将(R)-4-(4-氯-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(3.50g,9.14mmol,1.0eq)溶于DCM(30mL),降温至0℃,滴加BBr
3(4.58g,18.3mmol,2.0eq),反应6小时。加入MeOH淬灭,加入饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(1.44g,产率:42.7%)。
1HNMR(400MHz,CDCl
3)δ(ppm):8.26-8.24(s,1H),8.01(d,J=8.0Hz,1H),7.91-7.82(m,2H),7.55(d,J=8.4Hz,1H),7.19(d,J=2.4Hz,1H),7.00-6.98(m,1H),6.29(s,1H),4.71-4.69(m,1H),2.82(s,2H),2.52(d,J=9.6Hz,1H),2.35(s,3H),2.18-2.10(m,2H), 1.89-1.80(m,1H),1.68-1.64(m,2H).
分子式:C
20H
21ClN
4O 精确分子量:368.14 LC-MS(Pos,m/z)=369.08[M+H]
+.
实施例42(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-3-醇的合成(化合物110)
步骤1:3-溴-5-(乙氧基甲氧基)吡啶的合成
将3-溴-5-羟基吡啶(10.0g,57.5mmol,1.0eq)溶于THF(150mL)中,降温至0℃,分批加入质量分数为60%的NaH(3.45g,86.2mmol,1.5eq),搅拌20分钟,再加入氯甲基***(8.15g,86.2mmol,1.5eq)。反应1小时后,加入饱和NH
4Cl水溶液淬灭,分液,水相用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)分离得到产物(10.8g,产率:81.0%)。
步骤2:3-环丙基-5-(乙氧基甲氧基)吡啶的合成
将3-溴-5-(乙氧基甲氧基)吡啶(10.0g,43.1mmol,1.0eq)、环丙基硼酸(4.44g,51.7mmol,1.2eq)、Pd(dppf)Cl
2(3.15g,4.31mmol,0.1eq)和NaHCO
3(7.24g,86.2mmol,2.0eq)依次加入到1,4-二氧六环(100mL)和水(20mL)中,氮气保护下加热至110℃,反应6小时。冷却至室温,加入水(50mL)淬灭,用EA(50mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~50:1)分离得到产物(6.20g,产率:74.5%)。
步骤3:3-羟基-5-环丙基吡啶的合成
将3-环丙基-5-(乙氧基甲氧基)吡啶(6.00g,31.0mmol,1.0eq)溶于DCM(50mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,15.5mL,62.0mmol,2.0eq),室温搅拌6小时。饱和NaHCO
3水溶液调节pH值至8,再用DCM:MeOH=10:1混合溶剂(50mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(3.30g,产率:78.6%)。
步骤4:5-环丙基-2-碘-3-羟基吡啶的合成
将3-羟基-5-环丙基吡啶(3.20g,23.7mmol,1.0eq)加入到H
2O(50mL)中,加入K
2CO
3(6.55g,47.4mmol,2.0eq),搅拌溶解,再加入I
2(6.01g,23.7mmol,1.0eq),室温反应20小时。稀盐酸调节pH值至7,再用EA(50mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(4.70g,产率:76.0%)。
步骤5:5-环丙基-3-(乙氧基甲氧基)-2-碘吡啶的合成
将5-环丙基-2-碘-3-羟基吡啶(4.00g,15.3mmol,1.0eq)溶于THF(80mL),降温至0℃,分批加入质量分数为60%的NaH(0.920g,23.0mmol,1.5eq),搅拌30分钟,再加入氯甲基***(2.17g,23.0mmol,1.5eq),反应4小时。加入饱和NH
4Cl水溶液淬灭,用EA(50mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(PE:EA=20:1~5:1)分离得到产物(4.20g,产率:85.9%)。
步骤6:5-环丙基-3-(乙氧基甲氧基)-2-(三丁基锡基)吡啶的合成
将5-环丙基-3-(乙氧基甲氧基)-2-碘吡啶(2.00g,6.27mmol,1.0eq)溶于THF(40mL),氮气保护下,降温至-60℃,滴加正丁基锂(1.6mol/L的四氢呋喃溶液,4.7mL,7.52mmol,1.2eq),搅拌1小时,再加入三丁基氯化锡(2.45g,7.52mmol,1.2eq),反应1小时。加入饱和氟化钾水溶液淬灭,用EA(30mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(PE:EA=10:1)分离得到产物(2.40g,产率:79.4%)。
步骤7:(R)-4-(5-环丙基-3-(乙氧基甲氧基)吡啶-2-基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成
将5-环丙基-3-(乙氧基甲氧基)-2-(三丁基锡基)吡啶(1.05g,2.17mmol,1.5eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(400mg,1.45mmol,1.0eq)、四三苯基膦钯(167mg,0.145mmol,0.1eq)、碘化亚铜(27.5mg,0.145mmol,0.1eq)和氟化铯(440mg,2.90mmol,2.0eq)依次加入到DMF(15mL)中,氮气保护下加热至80℃,反应2小时。冷却至室温,加入饱和氟化钾水溶液淬灭,用EA(30mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=20:1~10:1)分离得到产物(530mg,产率:84.6%)。
步骤8:(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-3-醇的合成
将(R)-4-(5-环丙基-3-(乙氧基甲氧基)吡啶-2-基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺(530mg,1.22mmol,1.0eq)溶于DCM(8mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L, 1.53mL,6.10mmol,5.0eq),室温搅拌1小时。用饱和Na
2CO
3水溶液调节pH值至9,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(DCM:MeOH=50:1)分离得到产物(432mg,产率:94.1%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):14.55(s,1H),9.73-9.71(m,1H),8.60(s,1H),8.11(d,J=2.0Hz,1H),7.97-7.94(m,2H),7.75(s,1H),7.01(d,J=2.0Hz,1H),4.59(s,1H),3.31(d,J=8.8Hz,1H),2.96(d,J=11.2Hz,1H),2.48(s,4H),2.00-1.97(m,2H),1.87(s,1H),1.75-1.69(m,2H),1.06-1.03(m,2H),0.84-0.82(m,1H).
分子式:C
22H
25N
5O 精确分子量:375.21 LC-MS(Pos,m/z)=376.11[M+H]
+.
实施例43(R)-3-羟基-4-(4-((1-(四氢-2H-吡喃-4-基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成(化合物124)
步骤1:(R)-4-氯-N-(1-(四氢-2H-吡喃-4-基)哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(300mg,1.14mmol,1.0eq)和四氢-4H-吡喃-4-酮(171mg,1.71mmol,1.5eq)溶于MeOH(5mL),室温搅拌1小时。加入NaBH
3CN(107mg,3.36mmol,1.5eq),反应25小时。加入饱和NaHCO
3水溶液淬灭,用DCM(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)分离得到产物(312mg,产率:78.8%)。
步骤2:(R)-3-(乙氧基甲氧基)-4-(4-((1-(四氢-2H-吡喃-4-基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲腈(324mg,1.07mmol,1.2eq)、(R)-4-氯-N-(1-(四氢-2H-吡喃-4-基)哌啶-3-基)酞嗪-1-胺(310mg,0.894mmol,1.0eq)、Pd(dppf)Cl
2(65.4mg,0.0894mmol,0.1eq)和NaHCO
3(150mg,1.79mmol,2.0eq),依次加入到1,4-二氧六环(6mL)和水(3mL)中,氮气保护下加热至110℃,反应2小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)分离得到产物(290mg,产率:67.7%)。
步骤3:(R)-3-羟基-4-(4-((1-(四氢-2H-吡喃-4-基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-(四氢-2H-吡喃-4-基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(290mg,0.595mmol,1.0eq)溶于DCM(3mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.75mL,2.98mmol,5.0eq),室温搅拌2小时。饱和Na
2CO
3水溶液调节pH值至9,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经PE:EA=10:1混合溶剂打浆,得到产物(165mg,产率:64.6%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.61(s,1H),8.39(s,1H),7.86(s,1H),7.79(s,1H),7.49(d,J=6.8Hz,1H),7.41(s,2H),7.31(s,1H),7.15(s,1H),4.39(s,1H),3.88(d,J=9.2Hz,2H),3.30-3.24(m,4H),2.84(d,J=8.0Hz,1H),2.17(d,J=6.8Hz,2H),2.01(s,1H),1.75(s,1H),1.66(s,2H),1.52-1.49(m,4H).
分子式:C
25H
27N
5O
2 精确分子量:429.22 LC-MS(Pos,m/z)=430.17[M+H]
+.
实施例44(R)-3-羟基-4-(4-((1-异丙基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成(化合物125)
步骤1:(R)-4-氯-N-(1-异丙基哌啶-3-基)酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(300mg,1.14mmol,1.0eq)溶于MeOH(5mL),加入丙酮(99.3mg,1.71mmol,1.5eq),室温搅拌2小时。加入NaBH
3CN(107mg,3.36mmol,1.5eq),反应25小时。加入饱和NaHCO
3水溶液淬灭,用DCM(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)分离得到产物(280mg,产率:80.4%)。
步骤2:(R)-3-(乙氧基甲氧基)-4-(4-((1-异丙基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲腈(334mg,1.10mmol,1.2eq)、(R)-4-氯-N-(1-异丙基哌啶-3-基)酞嗪-1-胺(280mg,0.919mmol,1.0eq)、Pd(dppf)Cl
2(67.2mg,0.0917mmol,0.1eq)和NaHCO
3(155mg,1.84mmol,2.0eq),依次加 入到1,4-二氧六环(6mL)和水(3mL)中,氮气保护下加热至110℃,反应2小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(295mg,产率:65.5%)。
步骤3:(R)-3-羟基-4-(4-((1-异丙基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-异丙基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(295mg,0.662mmol,1.0eq)溶于DCM(3mL),滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.83mL,3.31mmol,5.0eq),室温搅拌2小时。饱和Na
2CO
3水溶液调节pH值至9,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱分离(DCM:MeOH=10:1)得到产物(152mg,产率:59.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.51(s,1H),8.39(d,J=8.4Hz,1H),7.88-7.84(m,1H),7.80-7.77(m,1H),7.50(d,J=7.6Hz,1H),7.42(d,J=7.6Hz,2H),7.32(d,J=1.2Hz,1H),7.15(d,J=8.0Hz,1H),4.41-4.39(m,1H),3.11(d,J=8.0Hz,1H),2.76(s,2H),2.17-2.15(m,2H),2.01-2.99(m,1H),1.77-1.74(m,1H),1.57-1.46(m,2H),1.01-0.98(m,6H).
分子式:C
23H
25N
5O 精确分子量:387.21 LC-MS(Pos,m/z)=388.14[M+H]
+.
实施例45(R)-6-甲基-3-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-2-醇的合成(化合物106)
步骤1:(2-甲氧基-6-甲基吡啶-3-基)硼酸的合成
将3-溴-2-甲氧基-6-甲基吡啶(6.00g,29.7mmol,1.0eq)和硼酸三异丙酯(11.3g,59.4mmol,2.0eq)溶于THF(60mL),置换氮气保护,降温至-70℃,然后滴加正丁基锂(23.8mL,59.4mmol,2.0eq),反应2小时。加入稀盐酸淬灭,pH值调至3,室温搅拌30分钟,用混合溶剂DCM:MeOH=10:1(50mL×5)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经石油醚打浆得到(2-甲氧基-6-甲基吡啶-3-基)硼酸(4.20g,收率:84.7%)。
步骤2:1-氯-4-(2-甲氧基-6-甲基吡啶-3-基)酞嗪的合成
将(2-甲氧基-6-甲基吡啶-3-基)硼酸(3.0g,18.0mmol,1.0eq)、1,4-二氯酞嗪(4.30g,21.6mmol,1.2eq)、Pd(dppf)Cl
2(659mg,0.900mmol,0.05eq)和NaHCO
3(3.02g,36.0mmol,2.0eq)依次加入到1,4-二氧六环(30mL)中,加入H
2O(15mL),置换氮气保护,油浴加热至110℃反应2小时。冷却,加入水,用EA(40mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(PE:EA=10:1)纯化得到产物(2.20g,收率:42.9%)。
步骤3:(R)-3-((4-(2-甲氧基-6-甲基吡啶-3-基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(2-甲氧基-6-甲基吡啶-3-基)酞嗪(2.00g,7.00mmol,1.0eq)、(R)-3-氨基哌啶-1-羧酸叔丁酯(1.54g,7.70mmol,1.1eq)、Pd
2(dba)
3(641mg,0.700mmol,0.1eq)、BINAP(871mg,1.40mmol,0.2eq)和Cs
2CO
3(4.56g,14.0mmol,2.0eq)依次加入到甲苯(40mL)中,置换氮气保护,油浴加热至90℃反应20小时。冷却,加入水,用EA萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=100~40:1) 纯化得到产品(1.50g,收率:47.7%)。
步骤4:(R)-6-甲基-3-(4-(哌啶-3-基氨基)酞嗪-1-基)吡啶-2-醇的合成
将(R)-3-((4-(2-甲氧基-6-甲基吡啶-3-基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(1.00g,2.22mmol,1.0eq)溶于DCM(20mL),降温至-10℃,滴加BBr
3(2.78g,11.1mmol,5.0eq),反应4小时。加入MeOH淬灭,浓缩,粗品加入H
2O溶解,EA萃取,水相加入饱和NaHCO
3水溶液调节pH值至8,用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产品(480mg,收率:64.3%)
步骤5:(R)-6-甲基-3-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-2-醇的合成
将(R)-6-甲基-3-(4-(哌啶-3-基氨基)酞嗪-1-基)吡啶-2-醇(400mg,1.19mmol,1.0eq),溶于MeOH(10mL),加入甲醛水溶液(37%,143mg,3.57mmol,3.0eq),室温搅拌30分钟。然后加入NaBH
3CN(224mg,3.57mmol,3.0eq),反应2小时。加水淬灭,用EA(30mL×3)萃取,水相减压浓缩,粗品经反相制备柱层析分离(乙腈:0.1%氨水=4:1)得到产物(180mg,收率:43.2%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):11.95(s,1H),8.50(s,1H),7.89-7.77(m,2H),7.60-7.52(m,3H),6.19(d,J=6.9Hz,1H),4.74(s,1H),3.63-3.59(m,2H),3.17(s,1H),2.78(s,4H),2.30(s,3H),2.08(s,1H),1.84(s,3H).
分子式:C
20H
23N
5O 分子量:349.44 LC-MS(Pos,m/z)=350.28[M+H]
+.
实施例46:3-羟基-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)苯甲腈的合成(化合物116)
步骤1:4-(4-氯酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈的合成
将1,4-二氯酞嗪(1.0g,5.02mmol,1.0eq.)、3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(1.82g,6.02mmol,1.2eq.)、碳酸氢钠(844.1mg,10.04mmol,2.0eq.)、Pd(dppf)Cl
2(183.8mg,0.25mmol,0.05eq.)加入到1,4-二氧六环(15.0mL)和水(7.0mL)的混合溶液中,氮气保护下,95℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=20:1-2:1)得产物(680.4mg,产率:40.0%)。
步骤2:3-(乙氧基甲氧基)-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)苯甲腈的合成
将4-(4-氯酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(200.0mg,0.58mmol,1.0eq.)、(顺式)-3-氨基-1-甲基环丁烷-1-醇盐酸盐(161.9mg,1.17mmol,2.0eq.)和N,N-二异丙基乙胺(303.9mg,2.35mmol,4.0q.)加入到N,N-二甲基乙酰胺(6.0mL)中,110℃反应5小时,TLC监测反应完全,加水(50.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得粗产物(315.0mg,直接用于下一步)。
步骤3:3-羟基-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)苯甲腈(315.0mg粗品,0.58mmol,1.0eq.)加入到二氯甲烷(2.0mL)中,滴加氯化氢-1,4-二氧六环溶液(4.0mol/L,3.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(20.0mg,产率:9.8%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.44-8.42(d,J=8Hz,1H),7.86(t,J=8Hz,1H),7.78(t,J=8Hz,1H),7.67-7.65(d,J=8Hz,1H),7.50-7.48(d,J=8Hz,1H),7.42-7.40(d,J=8Hz,2H),7.33-7.32(d,J=4Hz,1H),5.02(s,1H),4.27-4.22(m,1H),2.50-2.46(m,2H),2.20-2.15(m,2H),1.34(s,3H).
分子式:C
20H
18N
4O
2 精确分子量:346.14 LC-MS(m/z)=347.10[M+H]
+.
实施例47:(R)-3-甲基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成(化合物118)
步骤1:3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈的合成
将4-溴-3-甲基苯甲腈(1.0g,5.10mmol,1.0eq.)、4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.94g,7.65mmol,1.5eq.)、乙酸钾(1.0g,10.20mmol,2.0q.)和Pd(dppf)Cl
2(186.5mg,0.25mmol,0.05eq.)加入到1,4-二氧六环(20.0mL)中,氮气保护下,100℃反应4小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯 =10:1)得产物(1.0g,产率:80.7%)。
步骤2:(R)-3-甲基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)酞嗪-1-胺(100.0mg,0.36mmol,1.0eq.)、3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(131.7mg,0.54mmol,1.5eq.)、碳酸氢钠(60.6mg,0.72mmol,2.0eq.)和Pd(dppf)Cl
2(13.2mg,0.01mmol,0.05eq.)加入到1,4-二氧六环(10.0mL)和水(5.0mL)的混合溶液中,氮气保护下,110℃反应3小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(40.0mg,产率:31.0%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.47-8.45(d,J=8Hz,1H),7.91-7.87(m,2H),7.83-7.78(m,2H),7.51-7.49(d,J=8Hz,1H),7.26-7.25(d,J=4Hz,1H),7.21-7.19(d,J=8Hz,1H),4.44-4.42(m,1H),3.09-3.07(d,J=8Hz,1H),2.72-2.70(d,J=8Hz,1H),2.21(s,3H),2.06(s,3H),2.01-1.89(m,3H),1.77-1.40(m,3H).
分子式:C
22H
23N
5 精确分子量:357.20 LC-MS(m/z)=358.12[M+H]
+.
实施例48:2-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)-5-(三氟甲基)苯酚的合成(化合物129)
步骤1:(顺式)-3-((4-氯酞嗪-1-基)氨基)-1-甲基环丁烷-1-醇的合成
将1,4-二氯酞嗪(1.92g,9.68mmol,1.0eq.)、(顺式)-3-氨基-1-甲基环丁烷-1-醇盐酸盐 (1.6g,11.62mmol,1.2eq.)和N,N-二异丙基乙胺(1.87g,14.53mmol,1.5q.)加入到N,N-二甲基乙酰胺(20.0mL)中,120℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=100:1-40:1)得产物(900.0mg,产率:36.0%)。
步骤2:(顺式)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)酞嗪-1-基)氨基)-1-甲基环丁-1-醇的合成
将(顺式)-3-((4-氯酞嗪-1-基)氨基)-1-甲基环丁烷-1-醇(250.0mg,0.94mmol,1.0eq.)、(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)硼酸(350.3mg,1.32mmol,1.4eq.)、碳酸氢钠(159.1mg,1.89mmol,2.0eq.)和Pd(dppf)Cl
2(34.6mg,0.04mmol,0.05eq.)加入到1,4-二氧六环(10.0mL)和水(5.0mL)的混合溶液中,氮气保护下,110℃反应2小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=80:1-30:1)得产物(320.0mg,产率:75.0%)。
步骤3:2-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)酞嗪-1-基)-5-(三氟甲基)苯酚的合成
将(顺式)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)酞嗪-1-基)氨基)-1-甲基环丁-1-醇(310.0mg,0.69mmol,1.0eq.)加入到二氯甲烷(2.0mL)中,滴加氯化氢-1,4-二氧六环溶液(4.0mol/L,4.0mL),室温反应1小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=40:1-30:1)得产物(180.0mg,产率:66.9%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.37(s,1H),8.44-8.42(d,J=8Hz,1H),7.86(t,J=8Hz,1H),7.77(t,J=8Hz,1H),7.64-7.62(d,J=8Hz,1H),7.52-7.50(d,J=8Hz,1H), 7.45-7.43(d,J=8Hz,1H),7.31-7.28(m,2H),5.02(s,1H),4.27-4.22(m,1H),2.48-2.47(m,2H),2.20-2.15(m,2H),1.34(s,3H).
分子式:C
20H
18F
3N
3O
2 精确分子量:389.14 LC-MS(m/z)=390.06[M+H]
+.
实施例49:(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)-1-甲基哌啶-2-羧酸的合成(化合物132)
步骤1:1-(叔丁基)2-乙基(2S,5R)-5-((4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)氨基)哌啶-1,2-二羧酸酯的合成
将4-(4-氯酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(310.0mg,0.91mmol,1.0eq.)、1-(叔丁基)2-乙基(2S,5R)-5-氨基哌啶-1,2-二羧酸酯(298.1mg,1.09mmol,1.2eq.)、碳酸铯(594.2mg,1.82mmol,2.0q.)、Pd
2(dba)
3(83.5mg,0.09mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(113.5mg,0.18mmol,0.2eq.)加入到1,4-二氧六环(15.0mL)中,氮气保护下,90℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=100:1-60:1)得产物(262.5mg,产率:50%)。
步骤2:(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)哌啶-2-羧酸乙酯的合成
将1-(叔丁基)2-乙基(2S,5R)-5-((4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)氨基)哌啶-1,2-二羧酸酯(260.0mg,0.45mmol,1.0eq.)加入到二氯甲烷(2.0mL)中,滴加氯化氢 -1,4-二氧六环溶液(4.0mol/L,4.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(159.4mg,产率:90%)。
步骤3:(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)-1-甲基哌啶-2-甲酸乙酯的合成
将(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)哌啶-2-羧酸乙酯(169.0mg,0.40mmol,1.0eq.)、甲醛水溶液(37%)(46.0mg,0.56mmol,1.4eq.)和醋酸(0.5mL)加入到甲醇(10.0mL)中,室温搅拌0.5小时后加入氰基硼氢化钠(38.0mg,0.60mmol,1.5eq.),室温反应2小时。TLC监测反应完全,体系减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL)搅拌0.5小时,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(139.4mg,产率:80.0%)。
步骤4:(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)-1-甲基哌啶-2-羧酸的合成
将(2S,5R)-5-((4-(4-氰基-2-羟基苯基)酞嗪-1-基)氨基)-1-甲基哌啶-2-甲酸乙酯(139.4mg,0.32mmol,1.0eq.)、氢氧化锂(135.5mg,3.23mmol,10.0eq.)加入到甲醇(10.0mL)和水(4.0mL)的混合溶液中,室温搅拌72小时。TLC监测反应完全,体系减压浓缩,经反相柱层析纯化(乙腈:0.1%氨水=4:6)得产物的铵盐(84.0mg,收率:64.4%)。
1HNMR(400MHz,CD
3OD)δ(ppm):8.39-8.37(d,J=8Hz,1H),8.01-7.97(m,1H),7.90(t,J=8Hz,1H),7.67-7.65(d,J=8Hz,1H),7.56-7.54(d,J=8Hz,1H),7.41-7.39(m,1H),7.32(s,1H),4.74-4.68(m,1H),3.99-3.96(m,1H),3.54-3.51(m,1H),3.02-2.93(m,4H),2.52-2.33(m,2H),2.06-1.91(m,2H).
分子式:C
22H
21N
5O
3 精确分子量:403.16 LC-MS(m/z)=404.13[M+H]
+.
实施例50(R)-3-羟基-4-(4-((1-(2-甲基丙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成 (化合物126)
步骤1:(R)-2-(3-((4-氯酞嗪-1-基)氨基)哌啶-1-基)-2-甲基-2-丙醇的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(300mg,1.14mmol,1.0eq)、1-氯-2-甲基-2-丙醇(248mg,2.28mmol,2.0eq)和K
2CO
3(315mg,2.28mmol,2.0eq)加入到DMF(5mL)中,加热至90℃反应24小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL)萃取,有机相水洗(20mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(240mg,产率:62.8%)。
步骤2:(R)-3-(乙氧基甲氧基)-4-(4-((1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(261mg,0.860mmol,1.2eq)、(R)-2-(3-((4-氯酞嗪-1-基)氨基)哌啶-1-基)-2-甲基-2-丙醇(240mg,0.717mmol,1.0eq)、Pd(dppf)Cl
2(52.5mg,0.0717mmol,0.1eq)和NaHCO
3(120mg,1.43mmol,2.0eq)依次加入到1,4-二氧六环(6mL)中,加入H
2O(3mL),氮气保护下,加热至110℃,反应2小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL×2)萃取,有机相 无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=50:1~20:1)分离得到产物(285mg,产率:83.6%)。
步骤3:(R)-3-羟基-4-(4-((1-(2-甲基丙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(285mg,0.599mmol,1.0eq)溶于DCM(3mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.75mL,3.00mmol,5.0eq),室温搅拌1小时。饱和Na
2CO
3水溶液调节pH值至9,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(146mg,产率:58.4%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.53(s,1H),8.40(d,J=8.0Hz,1H),7.89-7.85(m,1H),7.81-7.77(m,1H),7.50(d,J=8.0Hz,1H),7.43-7.40(m,2H),7.37(d,J=0.8Hz,1H),7.18(s,1H),4.51(s,1H),4.13(s,1H),3.20(s,1H),2.90(s,1H),2.28(s,3H),1.96(s,1H),1.75-1.51(m,3H),1.14(s,6H).
分子式:C
24H
27N
5O
2 精确分子量:417.22 LC-MS(Pos,m/z)=418.13[M+H]
+.
实施例51(R)-3-羟基-4-(4-((1-(2-羟乙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成(化合物127)
步骤1:(R)-2-(3-((4-氯酞嗪-1-基)氨基)哌啶-1-基)-1-乙醇的合成
将(R)-4-氯-N-(哌啶-3-基)酞嗪-1-胺(300mg,1.14mmol,1.0eq)、2-溴乙醇(712mg,5.70mmol,5.0eq)和三乙胺(577mg,5.70mmol,5.0eq)加入到DCM(10mL)中,室温反应25小时。加入水(20mL)淬灭,用DCM(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=50:1~15:1)分离得到产物(212mg,产率:60.5%)。
步骤2:(R)-3-(乙氧基甲氧基)-4-(4-((1-(2-羟乙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(249mg,0.822mmol,1.2eq)、(R)-2-(3-((4-氯酞嗪-1-基)氨基)哌啶-1-基)-1-乙醇(210mg,0.685mmol,1.0eq)、Pd(dppf)Cl
2(50.1mg,0.0685mmol,0.1eq)和NaHCO
3(115mg,1.37mmol,2.0eq)依次加入到1,4-二氧六环(6mL)中,加入H
2O(3mL),氮气保护下,加热至110℃,反应2小时。冷却至室温,加入水(30mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(180mg,产率:58.8%)。
步骤3:(R)-3-羟基-4-(4-((1-(2-羟乙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-(2-羟乙基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(180mg,0.402mmol,1.0eq)溶于DCM(3mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.50mL,2.01mmol,5.0eq),室温搅拌1小时。饱和Na
2CO
3水溶液调节pH值至9,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经反相柱层析分离(乙腈:0.1%氨水溶液=2:5)得到产物(72.0mg,产率:46.0%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.50(s,1H),8.40(d,J=8.0Hz,1H),7.88-7.84(m,1H),7.80-7.77(m,1H),7.50(d,J=8.0Hz,1H),7.43-7.42(m,2H),7.33(s,1H),7.15(d,J=7.6Hz,1H),4.43(s,2H),3.54-3.51(m,2H),3.17-3.14(m,1H),2.81(d,J=8.0Hz,1H),2.47-2.44(m,2H),2.11-2.03(m,2H),1.98(d,J=8.0Hz,1H),1.75(d,J=12.0Hz,1H),1.61-1.52(m,2H).
分子式:C
22H
23N
5O
2 精确分子量:389.19 LC-MS(Pos,m/z)=390.12[M+H]
+.
实施例52(S)-N-(4-(4-氰基-2-羟基苯基)酞嗪-1-基)-1-甲基哌啶-2-甲酰胺的合成(化合物131)
步骤1:(S)-N-(4-氯酞嗪-1-基)-1-甲基哌啶-2-甲酰胺的合成
将(S)-1-甲基哌啶-2-羧酸(180mg,1.26mmol,1.0eq)溶于DCM(5mL),加入N-甲基吗啉(191mg,1.89mmol,1.5eq)和氯甲酸异丙酯(232mg,1.89mmol,1.5eq),室温搅拌2小时,然后加入4-氯酞嗪-1-胺(226mg,1.26mmol,1.0eq),室温搅拌20小时。加入H
2O(20mL),用DCM(20mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(160mg,产率:41.8%)。
步骤2:(S)-N-(4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)-1-甲基哌啶-2-甲酰胺的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(191mg,0.630mmol,1.2eq)、(S)-N-(4-氯酞嗪-1-基)-1-甲基哌啶-2-甲酰胺(160mg,0.525mmol,1.0eq)、Pd(dppf)Cl
2(38.4mg,0.0525mmol,0.1eq)和NaHCO
3(88.2mg,1.05mmol,2.0eq)依次加入到1,4-二氧六环(6mL)中,加入H
2O(3mL),氮气保护下,加热至110℃,反应2小时。冷却至室温,加入水(20mL)淬灭,用EA(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(DCM:MeOH=100:1~20:1)分离得到产物(80.0mg,产率:34.2%)。
步骤3:(S)-N-(4-(4-氰基-2-羟基苯基)酞嗪-1-基)-1-甲基哌啶-2-甲酰胺的合成
将(S)-N-(4-(4-氰基-2-(乙氧基甲氧基)苯基)酞嗪-1-基)-1-甲基哌啶-2-甲酰胺(80.0mg,0.182mmol,1.0eq)溶于DCM(2mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.23mL,0.90mmol,5.0eq),室温搅拌1小时。加入H
2O(5mL),DCM(5mL)洗涤,水相用饱和Na
2CO
3水溶液调节pH值至9,用DCM:MeOH=10:1混合溶剂(10mL×5)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,经制备薄层色谱分离(DCM:MeOH=10:1)得到产物(38.2mg,产率:54.9%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.39(s,1H),8.07-7.98(m,2H),7.76(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.42-7.40(m,1H),7.33(d,J=1.2Hz,1H),3.25-3.22(m,2H),2.63(s,3H),2.53(s,1H),2.28(d,J=11.2Hz,1H),1.96-1.89(m,2H),1.87-1.77(m,2H),1.60-1.53(m,1H).
分子式:C
22H
21N
5O
2 精确分子量:387.17 LC-MS(Pos,m/z)=388.13[M+H]
+.
实施例53(R)-3-羟基-4-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈(化 合物77)和(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈(化合物78)的合成
步骤1:4-(7-氯噻吩并[2,3-d]哒嗪-4-基)-3-甲氧基苯甲腈和4-(4-氯噻吩并[2,3-d]哒嗪-7-基)-3-甲氧基苯甲腈的合成
将3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(1.26g,4.86mmol,1.0eq)、4,7-二氯噻吩并[2,3-d]哒嗪(997mg,4.86mmol,1.0eq)、Pd(dppf)Cl
2(178mg,0.243mmol,0.05eq)和NaHCO
3(817g,9.72mmol,2.0eq)依次加入到1,4-二氧六环(16mL)中,加入H
2O(8mL),氮气保护下,加热至110℃反应2小时。加入水(30mL),用EA(40mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(PE:EA=5:1~1:1)分离得到产品(500mg,产率:34.1%)。
步骤2:(R)-3-((4-(4-氰基-2-甲氧基苯基)噻吩并[2,3-d]哒嗪-7-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((7-(4-氰基-2-甲氧基苯基)噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-(7-氯噻吩并[2,3-d]哒嗪-4-基)-3-甲氧基苯甲腈和4-(4-氯噻吩并[2,3-d]哒嗪-7-基)-3-甲氧基苯甲腈的混合物(500g,1.16mmol,1.0eq)和(R)-3-氨基哌啶-1-羧酸叔丁酯(499mg,2.49mmol,1.5eq)、Pd
2(dba)
3(152mg,0.166mmol,0.1eq)、BINAP(207mg,0.332mmol,0.2eq)和Cs
2CO
3(1.05g,3.22mmol,2.0eq)依次加入到1,4-二氧六环(20mL)中,氮气保护下,加热至90℃,反应20小时。冷却至室温,加水(40mL)淬灭,用EA(30mL×2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩,经硅胶柱层析纯化(DCM:MeOH=100:1~20:1)分离得到产物(610mg,产率:79.1%)。
步骤3:(R)-3-羟基-4-(7-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈和(R)-3-羟基-4-(4-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈的合成
将(R)-3-((4-(4-氰基-2-甲氧基苯基)噻吩并[2,3-d]哒嗪-7-基)氨基)哌啶-1-羧酸叔丁酯和(R)-3-((7-(4-氰基-2-甲氧基苯基)噻吩并[2,3-d]哒嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的混合物(600mg,1.29mmol,1.0eq)溶于DCM(15mL),降温至-10℃,滴加BBr
3(1.29g,5.16mmol,4.0eq),反应5小时。加入MeOH(5mL)淬灭,用饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产品(280mg,产率:61.8%)。
步骤4:(R)-3-羟基-4-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈和(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈的合成
将(R)-3-羟基-4-(7-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈和(R)-3-羟基-4-(4-(哌啶-3-基氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈的混合物(200mg,0.596mmol,1.0eq)溶于MeOH(4mL),加入37%的甲醛水溶液(139mg,1.71mmol,3.0eq),室温搅拌30分钟。然后加入NaBH
3CN(107mg,1.71mmol,3.0eq),反应1小时。加入饱和NaHCO
3水溶液淬灭,用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱分离(DCM:MeOH=10:1)得到(R)-3-羟基-4-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈(22.0mg,产率:10.6%)和(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈(23.0mg,产率:11.1%)。
(R)-3-羟基-4-(7-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-4-基)苯甲腈:
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.11(d,J=5.2Hz,1H),7.71(d,J=8.4Hz,1H),7.41-7.38(m,3H),7.19(d,J=7.6Hz,1H),4.41-4.39(m,1H),3.05(d,J=7.6Hz,1H),2.70(d,J=10.8Hz,1H),2.21(s,3H),1.97-1.92(m,3H),1.75-1.71(m,1H),1.64-1.55(m,1H),1.49-1.35(m,1H).
分子式:C
19H
19N
5OS 精确分子量:365.13 LC-MS(m/z):366.08[M+H]
+
(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)噻吩并[2,3-d]哒嗪-7-基)苯甲腈:
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.25(d,J=5.2Hz,1H),8.12(d,J=4.8Hz,1H),7.92(d,J=8.4Hz,1H),7.60(s,1H),7.45(d,J=6.8Hz,2H),4.48(s,1H),3.20(d,J=8.8Hz,1H),2.86(d,J=10.4Hz,1H),2.37(s,3H),2.23(s,2H),2.01-1.98(m,3H),1.82(s,1H),1.72-1.63(m,1H),1.54(s,1H).
分子式:C
19H
19N
5OS 精确分子量:365.13 LC-MS(m/z):366.14[M+H]
+
实施例54化合物(R)-5-甲基-2-(1-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-4-基)苯酚的合成(化合物49)
步骤1:中间体4-(2-甲氧基-4-甲基苯甲酰基)烟酸的合成:
将1-溴-2-甲氧基-4-甲基苯(20.96g,104.22mmol,1.05eq)溶于无水四氢呋喃(150mL)中,-78℃下,向其中滴加正丁基锂(48mL,119.11mmol,1.2eq),滴加完毕,-78℃下,将反应液滴入3,4-吡啶二羧酸酐(14.8g,99.26mmol,1.0eq)的四氢呋喃(150mL)溶液中,滴加完毕,常温反应1h,TLC检测反应完全。将反应液倒入冰水(200mL)与2mol/L盐酸(200mL)的混合溶液中,减压浓缩,用二氯甲烷(200mL×3)萃取,有机相合并,干燥,浓缩得粗品(13.7g),直接投入下一步。
步骤2:中间体4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-1-醇的合成
将上步所得混合物溶于乙醇(120mL)中,向其中加入85%的水合肼(3.97g,67.4mmol,1.5eq),加热至80℃反应2h,LC-MS检测反应完毕。冷却至室温,固体析出,过滤,滤液浓缩,经硅胶柱层析纯化(二氯甲烷:甲醇=1200:1~200:1)得产物(2.35g,两步产率:8.8%)。
步骤3:中间体1-氯-4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪的合成
向4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-1-醇(2g,7.48mmol,1.0eq)中加入乙腈(20mL)和三氯氧磷(2.29g,14.96mmol,2.0eq),100℃反应16h,TLC检测仍有原料剩余。补加三氯氧磷(2.29g,14.96mmol,2.0eq),100℃反应1h,TLC检测反应基本完全。反应液浓缩,将浓缩液倒入冰水(10mL)中,加入二氯甲烷(20mL),碳酸氢钠调节pH值至弱碱性,二氯甲烷(20mL×3)萃取。有机相合并,干燥,浓缩,经硅胶柱层析纯化(石油醚:乙酸乙酯=6:1)得产物(955mg,产率:44.6%)。
步骤4:中间体(R)-3-((4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪(955mg,3.34mmol,1.0eq)溶于DMAc(10mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(1.34g,6.68mmol,2.0eq),120℃反应20h,TLC检测反应完毕。将反应液倒入水(20mL)中,乙酸乙酯(2 0mL×2)萃取,有机相合并,干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1~1:1)得产物(980mg,产率:65.3%)。
步骤5:中间体(R)-5-甲基-2-(1-((哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-4-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)吡啶并[3,4-d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(980mg,2.18mmol,1.0eq)溶于二氯甲烷(10mL),0℃下,向其中滴加三溴化硼(1.64g,6.54mmol,3.0eq),常温反应2h,TLC检测仍有原料剩余,补加三溴化硼(1.64g,6.54mmol,3.0eq),常温反应2h,TLC检测反应基本完全。冰浴条件下,向反应液中依次缓慢滴加甲醇(5mL)和水(10mL),二氯甲烷(20mL)反萃,水相用饱和碳酸氢钠水溶液调节pH值至碱性,二氯甲烷(10mL)萃取,水相浓缩,二氯甲烷/甲醇混合溶液溶解,无水硫酸镁干燥,浓缩,粗品直接投入下一步。
步骤6:化合物(R)-5-甲基-2-(1-((1-甲基哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-4-基)苯酚 的合成
将(R)-5-甲基-2-(1-((哌啶-3-基)氨基)吡啶并[3,4-d]哒嗪-4-基)苯酚(474mg,1.41mmol,1.0eq)溶于甲醇(5mL)中,向其中加入37%的甲醛水溶液(112mg,1.41mmol,1.0eq)和氰基硼氢化钠(97mg,1.55mmol,1.1eq),常温反应5min,TLC检测反应完毕。反应液浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产物(110mg,两步产率:22.3%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):9.71(brs,1H),8.94-8.92(d,1H),8.87(s,1H),8.30-8.27(d,1H),7.42-7.40(d,1H),7.27-7.25(d,1H),6.83-6.80(d,2H),4.47(s,1H),3.27-3.18(m,2H),2.90-2.88(m,1H),2.39-2.20(m,7H),2.04-1.83(m,2H),1.73-1.52(m,2H)。
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z):350.10[M+H]
+
实施例55化合物(R)-2-(6-氯-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物12)
步骤1:中间体4-(2-甲氧基-4-甲基苯甲酰基)烟酸的合成:
将5-氯-2-碘苯甲酸甲酯(10.3g,34.67mmol,1.0eq)溶于无水四氢呋喃(100mL)中,-28℃下,向其中滴加1.3mol/L异丙基氯化镁氯化锂的四氢呋喃溶液(32mL,41.6mmol,1.2eq),滴加完毕,在该温度下反应30min。-78℃下,将反应液滴入2-甲氧基-4-甲基苯甲酰氯(9.6g,52mmol,1.5eq)的四氢呋喃(100mL)溶液中,滴加完毕,常温反应1h,TLC检测反应 完全。反应液浓缩,倒入冰水(100mL),加入碳酸钾,二氯甲烷(200mL×3)萃取,有机相合并,干燥,浓缩得产物(10.3g,产率:93.2%)。
步骤2:中间体7-氯-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮的合成
将4-(2-甲氧基-4-甲基苯甲酰基)烟酸(10.3g,32.3mmol,1.0eq)溶于乙醇(100mL)中,向其中加入85%的水合肼(2.86g,48.45mmol,1.5eq),加热至90℃反应3h,TLC检测反应完毕。冷却至室温,固体析出,过滤,滤饼为产物(1.5g,产率:15.4%)。
步骤3:中间体4,6-二氯-1-(2-甲氧基-4-甲基苯基)酞嗪的合成
向7-氯-4-(2-甲氧基-4-甲基苯基)酞嗪-1(2H)-酮(1.5g,4.99mmol,1.0eq)中加入乙腈(10mL)和三氯氧磷(1.53g,9.98mmol,2.0eq),90℃反应3h,TLC检测反应完全。反应液浓缩,将浓缩液倒入冰水(10mL)中,碳酸氢钠调节pH值至弱碱性,二氯甲烷(10mL×3)萃取。有机相合并,干燥,浓缩得产物(1.31g,产率:82.3%)。
步骤4:中间体(R)-3-((7-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4,6-二氯-1-(2-甲氧基-4-甲基苯基)酞嗪(1.31g,4.1mmol,1.0eq)溶于DMAc(10mL)中,向其中加入(R)-1-叔丁氧羰基-3-氨基哌啶(1.64g,8.2mmol,2.0eq),120℃反应24h,TLC检测反应完毕。将反应液倒入水(20mL)中,乙酸乙酯(20mL×2)萃取,有机相合并, 干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1~1:1)得产物(870mg,产率:40.9%)。
步骤5:中间体(R)-2-(6-氯-4-((哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-3-((7-(2-甲氧基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(300mg,0.621mmol,1.0eq)溶于二氯甲烷(5mL),0℃下,向其中滴加三溴化硼(467mg,1.863mmol,3.0eq),常温反应30min,TLC检测反应完全。冰浴条件下,向反应液中缓慢滴加甲醇(5mL)和水(5mL),二氯甲烷反萃(20mL×1,10mL×3),水相用碳酸氢钠调节pH值至碱性,二氯甲烷:甲醇=10:1萃取(10mL×3),有机相合并,无水硫酸镁干燥,浓缩得产物(78mg,产率:34%)。
步骤6:化合物(R)-2-(6-氯-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成
将(R)-2-(6-氯-4-((哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(78mg,0.211mmol,1.0eq)溶于甲醇(1mL)中,向其中加入37%的甲醛水溶液(17mg,0.211mmol,1.0eq)和氰基硼氢化钠(15mg,0.232mmol,1.1eq),常温反应5min,TLC检测反应完毕。反应液浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产物(27mg,产率:33.3%)。
1H-NMR(300MHz,DMSO-d
6)δ(ppm):9.61(brs,1H),8.62(s,1H),7.85-7.82(dd,1H),7.53-7.50(d,2H),7.14-7.17(d,1H),6.82-6.76(m,2H),4.65(s,1H),3.60-3.56(m,3H),2.73(s,4H),2.32(s,3H),2.03-2.01(m,2H),1.83-1.80(m,2H)
分子式:C
21H
23ClN
4O 精确分子量:382.16 LC-MS(m/z):383.09/385.03[M+H]
+
实施例56(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物1a)
步骤1:2-(2-甲氧基-4-甲基苯甲酰基)环己-1-烯-1-羧酸的合成
将1-溴-2-甲氧基-4-甲基苯(10.0g,49.73mmol,1.0eq.)加入四氢呋喃(30.0mL),氮气保护下降温至-65℃,缓慢滴加2.5mol/L正丁基锂正己烷溶液(19.9mL,49.73mmol,1.0eq.),反应1小时,将此反应液缓慢滴加到-65℃的4,5,6,7-四氢异苯并呋喃-1,3-二酮(7.56g,49.73mmol,1.0eq.)四氢呋喃(30.0mL)溶液中,升至室温反应12小时,TLC监测反应完全,体系加2mol/L HCl水溶液搅拌0.5小时,乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品用石油醚(100.0mL)打浆2小时,抽滤,滤饼干燥得产物(5.88g,收率:43.1%)。
步骤2:2-(2-甲氧基-4-甲基苯甲酰基)环己-1-烯-1-羧酸甲酯的合成
将2-(2-甲氧基-4-甲基苯甲酰基)环己-1-烯-1-羧酸(5.88g,21.43mmol,1.0eq.)加入N,N-二甲基甲酰胺(20.0mL),加入碳酸钾(3.85g,27.85mmol,1.3eq.)和碘甲烷(3.65g,25.71mmol,1.2eq.),室温反应2小时,TLC监测反应完全,加入乙酸乙酯(200.0mL),水洗(100.0mL×4),有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(5.24g,收率:84.7%)。
步骤3:4-(2-甲氧基-4-甲基苯基)-5,6,7,8-四氢酞嗪-1-醇的合成
将2-(2-甲氧基-4-甲基苯甲酰基)环己-1-烯-1-羧酸甲酯(5.24g,18.17mmol,1.0eq.)加入乙醇(80.0mL),加入水合肼(9.0g,181.7mmol,10.0eq.),80℃反应12小时,TLC监测反应完全,体系减压浓缩,粗品经硅胶柱层析分离(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1~2:1)得到产物(820.0mg,收率:16.7%)。
步骤4:1-氯-4-(2-甲氧基-4-甲基苯基)-5,6,7,8-四氢酞嗪的合成
将4-(2-甲氧基-4-甲基苯基)-5,6,7,8-四氢酞嗪-1-醇(820.0mg,3.03mmol,1.0eq.)加入乙腈(10.0mL),加入三氯氧磷(2.78g,18.19mmol,6.0eq.),88℃搅拌6小时。TLC监测反应完全,冷却至室温,饱和碳酸氢钠水溶液淬灭,加入乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=2:1)得产物(600.0mg,收率:68.5%)。
步骤5:2-(4-氯-5,6,7,8-四氢酞嗪-1-基)-5-甲基苯酚的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)-5,6,7,8-四氢酞嗪(600.0mg,4.13mmol,1.0eq.)加入二氯甲烷(10.0mL),降温至-65℃,缓慢滴加三溴化硼(1.56g,6.23mmol,3.0eq.),升至室温搅拌3小时。TLC监测反应完全,体系用甲醇淬灭,减压浓缩,饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(400.0mg,收率:70.4%)。
步骤6:(R)-3-((4-(2-羟基-4-甲基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将2-(4-氯-5,6,7,8-四氢酞嗪-1-基)-5-甲基苯酚(370.0mg,1.34mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(539.4mg,2.68mmol,2.0eq.)、叔丁醇钠(386.3mg,4.02mmol,3.0eq.)、Pd
2(dba)
3(368.1mg,0.40mmol,0.3eq.)和1,1'-联萘-2,2'-双二苯膦(375.1mg,0.60mmol,0.45eq.)加入1,4-二氧六环(15.0mL),氮气置换3分钟,90℃反应12小时,TLC监测反应完全,体系冷却至室温,过滤,滤液减压浓缩得粗品产物(600.0mg,直接用于下一步)。
步骤7:(R)-5-甲基-2-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-3-((4-(2-羟基-4-甲基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯粗品(600.0mg,1.34mmol,1.0eq.)加入二氯甲烷(6.0mL)和三氟乙酸(6mL.)的混合液,室温反应1小时,TLC监测反应完全,加水(50.0mL)反萃,水相调节pH=8-9,二氯甲烷(50.0mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(130.0mg,两步收率:28.6%)。
步骤8:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚(130.0mg,0.38mmol,1.0eq.)加入甲醇(3.0mL),加入甲醛水溶液(37%)(34.2mg,0.42mmol,1.1eq.),室温搅拌1小时,加入氰基硼氢化钠(31.0mg,0.49mmol,1.3eq.),室温反应2小时。TLC监测反应完全,体系减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL),搅拌0.5小时,二氯甲烷 (100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=8:1)得产物(30.0mg,收率:22.4%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.63(s,1H),6.98-7.00(m,1H),6.67-6.72(m,2H),5.71(s,1H),4.37(s,1H),2.89-3.20(m,3H),2.37-2.45(m,6H),2.27(s,3H),1.59-1.85(m,7H),1.24(s,3H).
分子式:C
21H
28N
4O 分子量:352.48 LC-MS(Pos,m/z)=353.26[M+H]
+.
实施例57化合物(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-基)苯酚的合成(化合物3a)
步骤1:2-(2-甲氧基-4-甲基苯甲酰基)环戊-1-烯-1-羧酸的合成
将1-溴-2-甲氧基-4-甲基苯(7.27g,36.2mmol,1.0eq.)加入干燥四氢呋喃(30.0mL),氮气保护下降温至-65℃,缓慢滴加2.5mol/L正丁基锂正己烷溶液(14.5mL,36.2mmol,1.0eq.),反应1小时,将此反应液缓慢滴加到-65℃的5,6-二氢-1H-环戊二烯并[c]呋喃-1,3(4H)-二酮(5.0g,36.2mmol,1.0eq.)的四氢呋喃(20.0mL)溶液中,升至室温反应12小时,TLC监测反应完全,体系加2mol/L的HCl水溶液搅拌0.5小时,乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得粗产物(7.0g),直接用于下一步。
步骤2:2-(2-甲氧基-4-甲基苯甲酰基)环戊-1-烯-1-羧酸甲酯的合成
将2-(2-甲氧基-4-甲基苯甲酰基)环戊-1-烯-1-羧酸(7.0g,26.9mmol,1.0eq.)、碳酸钾(5.57g,40.35mmol,1.5eq.)和碘甲烷(4.97g,35.0mmol,1.3eq.)加入N,N-二甲基甲酰胺(20.0mL),室温反应12小时,TLC监测反应完全,体系加入乙酸乙酯(200.0mL),水洗(100.0mL×4),有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅 胶规格:100-200目,石油醚:乙酸乙酯=20:1~2:1)得产物(5.0g,两步收率:68.4%)。
步骤3:4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-醇的合成
将2-(2-甲氧基-4-甲基苯甲酰基)环戊-1-烯-1-羧酸甲酯(4.75g,17.31mmol,1.0eq.)加入乙醇(50.0mL),加入水合肼(5.2g,103.89mmol,6.0eq.),先室温反应12小时,再80℃反应8小时,TLC监测反应完全,体系减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=20:1~10:1)得到产物(3.2g,收率:72.2%)。
步骤4:1-氯-4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪的合成
将4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-醇(3.2g,12.48mmol,1.0eq.)和三氯氧磷(11.4g,74.88mmol,6.0eq.)加入乙腈(20.0mL),80℃搅拌2小时。TLC监测反应完全,冷却至室温,饱和碳酸氢钠水溶液小心淬灭,体系加入乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(2.8g,收率:81.8%)。
步骤5:叔丁基(R)-3-((4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-基)氨基)哌啶-1-羧酸酯的合成
将1-氯-4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪(2.2g,8.0mmol,1.0eq.)加入1,4-二氧六环(20.0mL)中,依次加入(R)-3-氨基哌啶-1-羧酸叔丁酯(3.2g,16.0mmol,2.0eq.)、碳酸铯(7.8g,24.0mmol,3.0eq.)、Pd
2(dba)
3(732.5mg,0.80mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(996.2mg,1.6mmol,0.2eq.),氮气保护下90℃反应12小时,TLC监测反应完全,体系冷却至室温,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1~1:1)得到产物(2.8g,收率:80%)。
步骤6:(R)-4-(2-甲氧基-4-甲基苯基)-N-(哌啶-3-基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-胺的合成
将叔丁基(R)-3-((4-(2-甲氧基-4-甲基苯基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-基)氨基)哌啶-1-羧酸酯(2.8g,6.38mmol,1.0eq.)和三氟乙酸(10.0mL)加入二氯甲烷(10.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸钠水溶液调节pH=8-9,二氯甲烷(100.0mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(2.0g,收率:93.0%)。
步骤7:(R)-4-(2-甲氧基-4-甲基苯基)-N-(1-甲基哌啶-3-基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-胺的合成
将(R)-4-(2-甲氧基-4-甲基苯基)-N-(哌啶-3-基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-胺(500.0mg,1.47mmol,1.0eq.)和甲醛水溶液(37%)(143.8mg,1.77mmol,1.2eq.)加入甲醇(5.0mL),室温搅拌1小时后加入氰基硼氢化钠(129.3mg,2.05mmol,1.4eq.),室温反应1小时。TLC监测反应完全,体系减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL),搅拌0.5小时,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=50:1~10:1)得产物(370.0mg,收率:71.4%)。
步骤8:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-基)苯酚的合成
将(R)-4-(2-甲氧基-4-甲基苯基)-N-(1-甲基哌啶-3-基)-6,7-二氢-5H-环戊二烯并[d]哒嗪 -1-胺(370.0mg,1.04mmol,1.0eq.)加入二氯甲烷(50.0mL),降温至-50℃,缓慢滴加三溴化硼(788.9mg,3.14mmol,3.0eq.),升至室温搅拌12小时。TLC监测反应完全,体系用甲醇淬灭,减压浓缩,饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=8:1)得产物(165.0mg,收率:46.8%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):7.48-7.51(d,J=9Hz,1H),6.91(s,1H),6.70-6.73(m,1H),4.70(s,1H),3.26-3.31(m,2H),2.86-2.98(m,4H),2.71-2.74(m,1H),2.48(s,3H),2.40-2.42(m,1H),2.35(s,3H),2.17-2.26(m,2H),1.69-2.06(m,4H).
分子式:C
20H
26N
4O 分子量:338.46 LC-MS(Pos,m/z)=339.17[M+H]
+.
实施例58化合物(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物5a)
步骤1:1-氯-4-(4-环丙基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪的合成
将1,4-二氯-5,6,7,8-四氢酞嗪(613.3mg,3.02mmol,1.0eq.)、(4-环丙基-2-甲氧基苯基)硼酸(580.0mg,3.02mmol,1.0eq.)、碳酸氢钠(507.5mg,6.04mmol.2.0eq.)和Pd(pph
3)
4(348.9mg,0.30mmol,0.1eq.)加入1,4-二氧六环(10.0mL)和水(5.0mL)中,氮气保护下,110℃反应2小时,TLC监测反应完全,体系冷却至室温,加乙酸乙酯(100.0mL),水洗(50.0mL),有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,石油醚:乙酸乙酯=10:1~4:1)得产物(500.0mg,产率:52.6%)。
步骤2:(R)-3-((4-(4-环丙基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(4-环丙基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪(500.0mg,1.58mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(636.1mg,3.17mmol,2.0eq.)、碳酸铯(1.54g,4.74mmol.3.0eq.)、Pd
2(dba)
3(144.6mg,0.15mmol,0.1eq.)和BINAP(196.7mg,0.31mmol,0.2eq.)加入1,4-二氧六环(15.0mL),氮气保护下,90℃反应12小时,TLC监测反应完全,冷却,加入乙酸乙酯(200.0mL),水(100.0mL)洗,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=100:1~80:1)得产物(680.0mg,产率:89.9%)。
步骤3:(R)-4-(4-环丙基-2-甲氧基苯基)-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-3-((4-(4-环丙基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(680.0mg,1.42mmol,1.0eq.)和三氟乙酸(5.0mL)加入二氯甲烷(10.0mL),室温搅拌2小时。TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(530.0mg,产率:98.6%)。
步骤4:(R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-4-(4-环丙基-2-甲氧基苯基)-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(530.0mg,1.40mmol,1.0eq.)和甲醛水溶液(37%)(136.3mg,1.68mmol,1.2eq.)加入甲醇(10.0mL),室温搅拌0.5小时,加入氰基硼氢化钠(123.1mg,1.96mmol,1.4eq.),室温继续反应2小时。 TLC监测反应完全,减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL)搅拌30分钟,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=50:1~10:1)得产物(412.1mg,产率:75.0%)。
步骤5:(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(400.0mg,1.01mmol,1.0eq.)加入二氯甲烷(4.0mL),冰浴下滴加三溴化硼(765.8mg,3.03mmol,3.0eq.),升至室温搅拌4小时。TLC监测反应完全,冰浴下用甲醇(5.0mL)淬灭,减压浓缩,加入二氯甲烷(100.0mL),用水(50.0mL)反萃,水相用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(170.0mg,产率:44.4%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.66(s,1H),7.08-6.98(m,1H),6.87-6.56(m,2H),5.53-5.50(m,1H),4.26(s,1H),2.95-2.93(m,1H),2.65-2.62(m,1H),2.35-2.33(m,4H),2.23(s,3H),2.04-2.01(m,2H),1.87-1.69(m,6H),1.58-1.47(m,4H),0.96-0.93(m,2H),0.86-0.83(m,1H),0.66-0.63(m,1H).
分子式:C
23H
30N
4O 精确分子量:378.24 LC-MS(m/z)=379.17[M+H]
+.
实施例59化合物(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯酚的合成(化合物6a)
步骤1:(R)-3-((4-氯-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1,4-二氯-5,6,7,8-四氢-5,8-乙烷酞嗪(4.50g,19.6mmol,1.0eq)、(R)-3-氨基哌啶-1-羧酸叔丁酯(4.32g,21.6mmol,1.1eq)、Pd
2(dba)
3(1.79g,1.96mmol,0.1eq)、BINAP(2.44g,3.92mmol,0.2eq)和Cs
2CO
3(12.8g,39.2mmol,2.0eq)依次加入到1,4-二氧六环(100mL)中,氮气保护下,加热至90℃反应20小时。冷却至室温,加水淬灭,用EA(100mL×2)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(PE:EA=10:1~1:1)纯化得到产物(5.90g,产率:76.4%)。
步骤2:(R)-4-氯-N-(哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺的合成
将(R)-3-((4-氯-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(5.90g,15.0mmol,1.0eq)溶于DCM(50mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,37.5mL,150mmol,10.0eq),室温搅拌4小时。然后加入水(80mL),分液,除去有机相,水相用饱和NaHCO
3水溶液调节pH值至8,用DCM(50mL×5)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产物(3.60g,产率:81.9%)。
步骤3:(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(3.60g,12.3mmol,1.0eq)溶于MeOH(40mL),加入甲醛水溶液(37%,1.20g,14.8mmol,1.2eq),室温搅拌30分钟。然后加入NaBH
3CN(930mg,14.8mmol,1.2eq),室温反应1小时。浓缩除去MeOH,然后加入DCM溶解,用饱和NaHCO
3水溶液洗涤,水相再用DCM(50mL×2)萃取,有机相 合并,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)纯化得到产物(3.20g,产率:84.8%)。
步骤4:(R)-4-(2-甲氧基-4-甲基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺的合成
将(2-甲氧基-4-甲基苯基)硼酸(200mg,1.20mmol,1.0eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(370mg,1.20mmol,1.0eq)、Pd(dppf)Cl
2(43.9mg,0.060mmol,0.05eq)和NaHCO
3(202mg,2.40mmol,2.0eq)依次加入到1,4-二氧六环(6mL)中,加入H
2O(3mL),氮气保护下,加热至110℃反应2小时。冷却至室温,加入水(30mL)淬灭,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)纯化得到产物(320mg,产率:67.7%)。
步骤5:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯酚的合成
将(R)-4-(2-甲氧基-4-甲基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(320mg,0.815mmol,1.0eq)溶于DCM(10mL),降温至-10℃,滴加BBr
3(1.02g,4.07mmol,5.0eq),自然升至室温,反应16小时。加入MeOH(10mL)淬灭,用饱和NaHCO
3水溶液调节pH值至8,用DCM(30mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)纯化得到产物(160mg,产率:51.9%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.90(s,1H),7.10(d,J=7.6Hz,1H),6.76(s,1H),6.71(d,J=7.7Hz,1H),6.41(s,1H),4.43(s,1H),3.45(s,1H),3.06(s,1H),2.83(s,1H),2.59(s,4H),2.28(s,3H),1.92(d,J=3.3Hz,2H),1.74-1.66(m,7H),1.74-1.24(s,5H).
分子式:C
23H
30N
4O 分子量:378.24 LC-MS(m/z)=379.19[M+H]
+.
实施例60化合物(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯腈的合成(化合物7a)
步骤1:(R)-3-(乙氧基甲氧基)-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯腈的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲腈(300mg,0.990mmol,1.0eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(304mg,0.990mmol,1.0eq)、Pd(dppf)Cl
2(36.2mg,0.0495mmol,0.05eq)和NaHCO
3(166mg,1.98mmol,2.0eq)依次加入到1,4-二氧六环(6mL)和H
2O(3mL)中,氮气保护下,加热至110℃反应2小时。冷却至室温,加入水(30mL)淬灭,用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)纯化得到产物(265mg,产率:59.8%)。
步骤2:(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯腈(265mg,0.592mmol,1.0eq)溶于DCM(4mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,0.74mL,2.96mmol,5.0eq),室温搅拌1小时。加入水(20mL)淬灭,DCM洗 涤(20mL×2),水相用饱和NaHCO
3水溶液调节pH值至8,用DCM(20mL×2)萃取,有机相无水硫酸钠干燥后过滤,滤液减压浓缩,经EA打浆得到产物(172mg,产率:74.6%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):7.40(d,J=7.5Hz,1H),7.29(s,1H),7.21(s,1H),6.14(s,1H),4.20(s,1H),3.57(s,1H),2.99(s,1H),2.72(s,1H),2.65(s,1H),2.18(s,3H),1.88-1.57(m,9H),1.35-1.18(m,5H).
分子式:C
23H
27N
5O 精确分子量:389.22 LC-MS(m/z)=390.14[M+H]
+.
实施例61化合物(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚的合成(化合物8a)
步骤1:1-氯-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪的合成
将(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)硼酸(1.00g,3.79mmol,1.0eq)、1,4-二氯-5,6,7,8-四氢酞嗪(769mg,3.79mmol,1.0eq)、Pd(dppf)Cl
2(139mg,0.190mmol,0.05eq)和NaHCO
3(637mg,7.58mmol,2.0eq)依次加入到1,4-二氧六环(10mL)中,加入H
2O(5mL),氮气保护下,加热至110℃反应3小时。冷却至室温,加入水(40mL)淬灭,用EA(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(PE:EA=20:1~5:1)纯化得到产物(890mg,产率:60.7%)。
步骤2:(R)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1-氯-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪(890mg,2.30mmol,1.0eq)、(R)-3-氨基哌啶-1-羧酸叔丁酯(691mg,2.45mmol,1.5eq)、Pd
2(dba)
3(211mg,0.230mmol,0.1eq)、BINAP(286mg,0.460mmol,0.2eq)和Cs
2CO
3(1.50g,4.60mmol,2.0eq)依次加入到1,4-二氧六环(20mL)中,氮气保护下,加热至90℃反应4小时。冷却至室温,加水(50mL)淬灭,用EA(40mL×2)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(DCM:MeOH=100:1~50:1)纯化得到产物(1.10g,产率:86.8%)。
步骤3:(R)-2-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚的合成
将(R)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(1.10g,2.00mmol,1.0eq)溶于DCM(10mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,5.0mL,20.0mmol,10.0eq),室温搅拌1小时。然后加入水(30mL),DCM洗涤(30mL×2),水相用饱和NaHCO
3水溶液调节pH值至8,再用DCM(30mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得到产物(620mg,产率:79.1%)。
步骤4:(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚的合成
将(R)-2-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚(620mg,1.58mmol,1.0eq)溶于MeOH(10mL),加入甲醛水溶液(37%,154mg,1.90mmol,1.2eq),室温搅拌20分钟。然后加入NaBH
3CN(119mg,1.90mmol,1.2eq),室温反应1小时。浓缩, 然后加入DCM溶解,用饱和NaHCO
3水溶液洗涤,水相再用DCM(20mL×2)萃取,有机相合并,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~20:1)纯化得到产物(410mg,产率:63.9%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.43(s,1H),7.34(d,J=7.5Hz,1H),7.21(d,J=7.5Hz,2H),5.63(d,J=7.8Hz,1H),4.30-4.24(m,1H),2.93(d,J=8.4Hz,1H),2.61(s,1H),2.38-2.35(m,2H),2.32-2.30(m,2H),2.21(s,3H),1.99(d,J=8.8Hz,2H),1.83(d,J=8.8Hz,1H),1.76-1.69(m,3H),1.61-1.54(m,3H),1.48-1.43(m,1H).
分子式:C
21H
25F
3N
4O 精确分子量:406.20 LC-MS(m/z)=407.12[M+H]
+.
实施例62化合物(R)-3-羟基-4-(4-((1-(甲基磺酰基)哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成(化合物13a)
步骤1:(R)-3-(乙氧基甲氧基)-4-(4-((1-(甲基磺酰基)哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(317.0mg,0.77mmol,1.0eq.)、三乙胺(116.8mg,1.15mmol,1.5eq.)和甲磺酸酐(176.1mg,1.01mmol.1.3eq.)加入二氯甲烷(10.0mL),室温反应12小时,TLC监测反应完全,加入饱和氯化铵水溶液(50.0mL),二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(343.0mg,产率:91.9%)。
步骤2:(R)-3-羟基-4-(4-((1-(甲基磺酰基)哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-(甲基磺酰基)哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(343.0mg,0.70mmol,1.0eq.)和氯化氢的1,4-二氧六环溶液(4.0mol/L,3.0mL)加入二氯甲烷(3.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(207.0mg,产率:69.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.50(s,1H),7.33(s,2H),7.24(s,1H),5.84-5.82(d,J=4Hz,1H),4.26-4.24(m,1H),3.88-3.84(m,1H),3.52-3.47(m,1H),2.88(s,3H),2.75-2.70(m,1H),2.58-2.53(m,1H),2.40-2.37(m,2H),2.31-2.28(m,2H),1.97-1.95(m,1H),1.88-1.86(m,1H),1.77-1.75(m,2H),1.61-1.60(m,4H).
分子式:C
21H
25N
5O
3S 精确分子量:427.17 LC-MS(m/z)=428.1[M+H]
+.
实施例63:(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成(化合物2a)
步骤1:4-(4-氯-5,6,7,8-四氢酞嗪-1-基)-3-甲氧基苯甲腈的合成
将1,4-二氯-5,6,7,8-四氢酞嗪(3.0g,14.77mmol,1.0eq.)、3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(3.0g,11.81mmol,0.8eq.)、碳酸氢钠(2.48g,29.54mmol,2.0eq.)、Pd(PPh
3)
4(853.3mg,0.73mmol,0.05eq.)加入到1,4-二氧六环(20.0mL)和水(10.0mL)的混合溶液中,氮气保护下,110℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经 硅胶柱层析纯化(石油醚:乙酸乙酯=15:1-3:1)得产物(2.2g,产率:49.7%)。
步骤2:(R)-3-((4-(4-氰基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将4-(4-氯-5,6,7,8-四氢酞嗪-1-基)-3-甲氧基苯甲腈(1.5g,5.00mmol,1.0eq.)、(R)-3-氨基哌啶-1-羧酸叔丁酯(2.0g,10.00mmol,2.0eq.)、碳酸铯(4.88g,15.00mmol,3.0q.)、Pd
2(dba)
3(457.8mg,0.50mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(622.67mg,1.00mmol,0.2eq.)加入到1,4-二氧六环(30.0mL)中,氮气保护下,90℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=100:1-80:1)得产物(1.1g,产率:47.6%)。
步骤3:(R)-3-甲氧基-4-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(R)-3-((4-(4-氰基-2-甲氧基苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(1.0g,2.15mmol,1.0eq.)加入到二氯甲烷(10.0mL)中,滴加三氟乙酸(5.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(750.0mg,产率:96.0%)。
步骤4:(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(R)-3-甲氧基-4-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(750.0mg,2.06 mmol,1.0eq.)、甲醛水溶液(37%)(167.4mg,2.06mmol,1.0eq.)加入到甲醇(10.0mL)中,室温搅拌0.5小时后加入氰基硼氢化钠(168.2mg,2.67mmol,1.3eq.),室温反应2小时。TLC监测反应完全,体系减压浓缩,加入饱和碳酸氢钠水溶液(100.0mL)搅拌0.5小时,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=40:1-30:1)得产物(600.0mg,产率:77.2%)。
步骤5:(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(R)-3-甲氧基-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(247.0mg,0.65mmol,1.0eq.)加入到二氯甲烷(10.0mL)中,冰浴下滴加三溴化硼(491.7mg,1.96mmol,3.0eq.),升至室温反应4小时,TLC监测反应完全,体系冰浴下用甲醇(10.0mL)淬灭,减压浓缩,加入二氯甲烷(50.0mL),用水(50.0mL)反萃,水相用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(130.0mg,产率:55.0%)。
1HNMR(300MHz,DMSO-d
6)δ(ppm):10.59(s,1H),7.33-7.30(m,3H),5.94(s,1H),4.46(s,1H),2.99(s,1H),2.55-2.51(s,3H),2.42-2.29(m,6H),1.88-1.69(m,5H),1.61-1.60(m,4H).
分子式:C
21H
25N
5O 精确分子量:363.21 LC-MS(m/z)=364.14[M+H]
+.
实施例64:3-羟基-4-(4-(((1R,2R)-2-羟基环己基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成(化合物34a)
步骤1:3-(乙氧基甲氧基)-4-(4-(((1R,2R)-2-羟基环己基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将4-(4-氯-5,6,7,8-四氢酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(400.0mg,1.16mmol,1.0eq.)、(1R,2R)-2-氨基环己-1-醇(267.9mg,2.32mmol,2.0eq.)、碳酸铯(1.22g,3.48mmol,3.0q.)、Pd
2(dba)
3(106.2mg,0.11mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(144.4mg,0.22mmol,0.2eq.)加入到1,4-二氧六环(20.0mL)中,氮气保护下,90℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二氯甲烷:甲醇=80:1-50:1)得产物(251.0mg,产率:51.2%)。
步骤2:3-羟基-4-(4-(((1R,2R)-2-羟基环己基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4-(((1R,2R)-2-羟基环己基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(251.0mg,0.59mmol,1.0eq.)加入到乙醇(3.0mL)中,滴加氯化氢-乙醇溶液(2.0mol/L,8.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化(二氯甲烷:甲醇=10:1)得产物(77.0mg,产率:35.5%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.55(s,1H),7.33-7.32(m,2H),7.25-7.24(m,1H),5.62-5.60(d,J=8Hz,1H),4.81(s,1H),3.93-3.87(m,1H),3.52-3.47(m,1H),2.42-2.29(m,5H),2.11-2.08(m,1H),1.99-1.92(m,1H),1.77-1.59(m,8H).
分子式:C
21H
24N
4O
2 精确分子量:364.19 LC-MS(m/z)=365.12[M+H]
+.
实施例65化合物(R)-5-氟-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物24a):
步骤1:中间体2,3,5,6,7,8-六氢酞嗪-1,4-二酮的合成:
将4,5,6,7-四氢异苯并呋喃-1,3-二酮(50g,329mmol,1.0eq)溶于乙醇(500mL)中,加入水合肼(20.64g,413mmol,1.25eq),室温下搅拌过夜,TLC检测反应完全。反应液抽滤,滤饼烘干得产物(47g,产率:86.0%)。
步骤2:中间体1,4-二氯-5,6,7,8-四氢酞嗪的合成:
将上步所得2,3,5,6,7,8-六氢酞嗪-1,4-二酮(25g,150mmol,1.0eq)溶于乙腈(250mL)中,加入三氯氧磷(138g,904mmol,6.0eq),80℃下搅拌4h,TLC检测反应完全。反应液缓慢倒入冰水中,有大量固体析出,搅拌1h后,抽滤,滤饼烘干得产物(24g,产率:78.8%)。
步骤3:中间体(R)-3-((4-氯-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将上步所得1,4-二氯-5,6,7,8-四氢酞嗪(15g,73.9mmol,1.0eq)溶于甲苯(300mL)中,依次加入(R)-3-氨基哌啶-1-羧酸叔丁酯(29.6g,147.8mmol,2.0eq)、BINAP(9.2g,14.78mmol,0.2eq)、碳酸铯(72.3g,221.7mmol,3.0eq)和Pd
2(dba)
3(6.8g,7.39mmol,0.1eq),氮气保护,90℃下搅拌过夜。TLC检测反应完全,反应液硅藻土抽滤,滤液浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=50:1-30:1)得产物(13g,产率:43.9%)。
步骤4:中间体(R)-4-氯-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将上步所得(R)-3-((4-氯-5,6,7,8-四氢酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(13g,35.5mmol,1.0eq)溶于二氯甲烷(100mL)中,加入4mol/L的HCl/1,4-二氧六环溶液(45mL,5.0eq),室温下搅拌30min,TLC检测反应完全。反应液倒入水中,分液,水相用碳酸氢钠固体调节pH值至8,浓缩,粗品用DCM溶解,抽滤,浓缩得产物(8g,产率:84.4%)。
步骤5:中间体(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将上步所得(R)-4-氯-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(8g,30mmol,1.0eq)溶于甲醇(100mL)中,加入37%甲醛水溶液(2.43g,30mmol,1.0eq),室温下搅拌30min,加入NaBH
3CN(2.45g,39mmol,1.3eq),室温下搅拌1h,TLC检测反应完全。反应液浓缩,用DCM(100mL)溶解,饱和碳酸氢钠水溶液(100mL×2)洗涤,有机相干燥,抽滤,滤液浓缩,经硅胶柱层析纯化(二氯甲烷:甲醇=50:1-30:1)得产物(5g,产率:59.3%)。
步骤6:化合物(R)-5-氟-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将上步所得(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(500mg,1.78mmol,1.0eq)溶于1,4-二氧六环(4mL)和水(2mL)中,依次加入(4-氟-2-羟基苯基)硼酸(333mg,2.14mmol,1.2eq)、碳酸氢钠(300mg,3.56mmol,2.0eq)和Pd(dppf)Cl
2(130mg,0.178mmol,0.1eq),氮气保护下,110℃搅拌过夜。TLC检测反应完全,反应液浓缩,二氯甲烷(5mL×3)萃取,有机相干燥,抽滤,滤液浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇 =20:1-10:1)纯化得粗产物(600mg),取粗产物(200mg)经制备薄层色谱纯化得(150mg,产率:71.0%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):10.26(s,1H),7.13(t,J=7.96Hz,1H),6.74-6.69(m,2H),5.69(s,1H),4.34(s,1H),3.35(s,1H),3.08(s,1H),2.79(s,1H),2.38-2.31(m,8H),1.87-1.52(m,8H)。
分子式:C
20H
25FN
4O 精确分子量:356.20 LC-MS(m/z):357.12[M+H]
+
实施例66化合物(R)-2-氟-3-甲基-6-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物29a):
步骤1:中间体6-溴-2-氟-3-甲基苯酚的合成:
将4-溴-2-氟-1-甲基苯(2g,10.58mmol,1.0eq)溶于干燥的四氢呋喃(15mL)中,降温至-70℃,滴加2mol/L的LDA的正己烷溶液(6mL,12mmol,1.13eq),搅拌2h后,滴加硼酸三异丙酯(2.07g,11mmol,1.05eq),搅拌20min后,再滴加2mol/L的LDA的正己烷溶液(2mL,4mmol,0.38eq),搅拌20min后,滴加硼酸三异丙酯(0.6g,3.2mmol,0.3eq),搅拌1h,升温至0℃,将醋酸(2mL)的水(15mL)溶液倒入反应液中,向体系中滴加入30%的过氧化氢水溶液(5mL),室温下反应过夜,TLC检测反应完全。分液,水相调节pH值至6,乙酸乙酯(15mL)萃取,有机相合并,依次用饱和亚硫酸钠水溶液(15mL)和1mol/L盐酸水溶液(15mL)洗涤,用1mol/L氢氧化钠水溶液(15mL×2)萃取,水相调节pH值至6,二氯甲烷(15mL×2)萃取,有机相合并,干燥,浓缩得产物(2.1g,产率:96.8%)。
步骤2:中间体1-溴-2-(乙氧基甲氧基)-3-氟-4-甲基苯的合成:
将上步所得6-溴-2-氟-3-甲基苯酚(1g,4.88mmol,1.0eq)溶于干燥四氢呋喃(6mL)中,冰水浴下分批次加入质量分数为60%的NaH(293mg,7.32mmol,1.5eq),搅拌30min后,加入氯甲基***(599mg,634mmol,1.3eq),室温下搅拌过夜,TLC检测反应完全。反应液加水淬灭,浓缩,加水(5mL)和乙酸乙酯(10mL),分液,有机相干燥,浓缩得产物(1.1g,产率:85.7%)。
步骤3:中间体(2-(乙氧基甲氧基)-3-氟-4-甲基苯基)硼酸的合成
将上步所得1-溴-2-(乙氧基甲氧基)-3-氟-4-甲基苯(526mg,2mmol,1.0eq)溶于干燥四氢呋喃(6mL)中,降温至-70℃,滴加1.6mol/L正丁基锂的正己烷溶液(1.9mL,3mmol,1.5eq),搅拌2h后,滴加硼酸三异丙酯(489mg,2.6mmol,1.3eq),室温下搅拌三小时。TLC检测反应完全,反应液加水淬灭,浓缩,用2mol/L盐酸水溶液调节pH值至6,加水(5mL)和乙酸乙酯(10mL),分液,有机相干燥,浓缩得产物(450mg,产率:98.7%)。
步骤4:中间体(R)-4-(2-(乙氧基甲氧基)-3-氟-4-甲基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(250mg,0.89mmol,1.0eq)溶于1,4-二氧六环(2mL)和水(1mL)中,依次加入(2-(乙氧基甲氧基)-3-氟-4-甲基苯基)硼酸(406mg,1.78mmol,2eq)、碳酸氢钠(150mg,1.78mmol,2.0eq)和Pd(dppf)Cl
2(65mg,0.089mmol,0.1eq),氮气保护下,110℃搅拌过夜。TLC检测反应完全。反应液浓缩,加水(5mL),二氯甲烷(5mL×3)萃取,有机相干燥,抽滤,滤液浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇=20:1-10:1)纯化得产物(300mg,产率:78.7%)。
步骤5:化合物(R)-2-氟-3-甲基-6-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基) 苯酚的合成
将上步所得(R)-4-(2-(乙氧基甲氧基)-3-氟-4-甲基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(300mg,0.7mmol,1.0eq)溶于二氯甲烷(3mL)中,加入4mol/L的HCl/1,4-二氧六环溶液(0.88mL,5.0eq),室温下搅拌3h,TLC检测反应完全。反应液倒入水中,用碳酸氢钠固体调节pH值至8,分液,二氯甲烷(5mL×2)萃取,干燥,抽滤,浓缩,粗品经制备薄层色谱纯化得产物(200mg,产率:77.1%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):9.84(s,1H),6.85(d,J=7.84Hz,1H),6.75(t,J=7.4Hz,1H),5.72(s,1H),4.33(s,1H),3.35(s,1H),3.06(s,1H),2.77(s,1H),2.38-2.33(m,7H),2.26(s,3H),1.87-1.52(m,9H)。
分子式:C
21H
27FN
4O 精确分子量:370.22 LC-MS(m/z):371.20[M+H]
+
实施例67:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-羟基苯甲腈的合成(化合物21a)
步骤1:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈的合成
将(R)-3-(乙氧基甲氧基)-4-(4-(哌啶-3-基氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(370.0mg,0.90mmol,1.0eq.)、(1-甲氧基环丙氧基)三甲基硅烷(627.5mg,3.60mmol,4.0eq.)、 乙酸(1.0mL.)、氟化铯(205.0mg,1.35mmol,1.5eq.)和氰基硼氢化钠(282.7mg,4.50mmol,5.0eq.)加入甲醇(15.0mL),60℃反应12小时,TLC监测反应完全,加入饱和碳酸氢钠水溶液(50.0mL),二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=40:1-30:1)得产物(310.0mg,产率:77.1%)。
步骤2:(R)-4-(4-((1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-羟基苯甲腈的合成
将(R)-4-(4-((1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-(乙氧基甲氧基)苯甲腈(280.0mg,0.62mmol,1.0eq.)加入乙醇(3.0mL)和氯化氢-乙醇溶液(2.0mol/L)(5.0mL),室温反应4小时,TLC监测反应完全,用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(130.0mg,产率:53.4%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.50(s,1H),7.33(s,2H),7.24(s,1H),5.61-5.59(d,J=8Hz,1H),4.19-4.17(m,1H),3.10-3.08(d,J=8Hz,1H),2.80-2.78(d,J=8Hz,1H),2.39-2.16(m,5H),1.84-1.45(m,9H),0.87-0.84(m,1H),0.41-0.37(m,2H),0.34-0.30(m,2H).
分子式:C
23H
27N
5O 精确分子量:389.22 LC-MS(Pos,m/z)=390.15[M+H]
+.
实施例68:(R)-5-甲氧基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物23a)
步骤1:(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-4-氯-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(504.0mg,1.88mmol,1.0eq.)、2-(2-(乙氧基甲氧基)-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.74g,5.66mmol,3.0eq.)、碳酸氢钠(631.7mg,7.52mmol.4.0eq.)和Pd(dppf)Cl
2(137.5mg,0.18mmol,0.1eq.)加入1,4-二氧六环(15.0mL)和水(7.0mL)中,氮气保护下,110℃反应2小时,TLC监测反应完全,体系冷却至室温,加水(50.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=40:1~10:1)得产物(503.0mg,产率:64.8%)。
步骤2:(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(342.0mg,0.82mmol,1.0eq.)加入甲醇(12.0mL),加入甲醛水溶液(质量分数37%,80.7mg,0.99mmol,1.2eq.),室温反应0.5小时,加入氰基硼氢化钠(67.7mg,1.07mmol,1.3eq.),继续反应1小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=40:1~20:1)得产物(270.0mg,产率:76.3%)。
步骤3:(R)-5-甲氧基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-4-(2-(乙氧基甲氧基)-4-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(270.0mg,0.63mmol,1.0eq.)和氯化氢-乙醇溶液(2.0mol/L,10.0mL)加入乙醇(10.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(130.0mg,产率:56.0%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.94(s,1H),7.05-7.03(d,J=8Hz,1H),6.46-6.44(m,2H),5.59-5.58(d,J=4Hz,1H),4.28(s,1H),3.74(s,3H),3.00(s,1H),2.70(s,1H),2.37-2.34(m,4H),2.28(s,3H),2.09(s,1H),1.85-1.82(m,1H),1.75-1.73(m,3H),1.59-1.47(m,5H).
分子式:C
21H
28N
4O
2 精确分子量:368.22 LC-MS(Pos,m/z)=369.18[M+H]
+.
实施例69:(R)-5-(二氟甲基)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物15a)
步骤1:(R)-3-(乙氧基甲氧基)-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞-1-基)苯甲醛的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(500.0mg,1.78mmol,1.0eq.)、3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲醛(817.7mg,2.67mmol,1.5eq.)、碳酸氢钠(299.0mg,3.56mmol,2.0eq.)和Pd(dppf)Cl
2(65.1mg,0.08mmol,0.05eq.)加入1,4-二氧六环(10.0mL)和水(5.0mL),氮气保护下,110℃反应4小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(200.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(100-200目硅胶,二氯甲烷:甲醇=40:1~10:1) 得产物(430.0mg,产率:56.9%)。
步骤2:(R)-4-(4-(二氟甲基)-2-(乙氧基甲氧基)苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-3-(乙氧基甲氧基)-4-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞-1-基)苯甲醛(430.0mg,1.01mmol,1.0eq.)加入二氯甲烷(10.0mL),冰浴下滴加二乙胺基三氟化硫(244.8mg,1.51mmol,1.5eq.),升至室温搅拌12小时。TLC监测反应完全,在冰浴下用饱和碳酸钠水溶液调节pH=8-9,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(220.0mg,产率:48.7%)。
步骤3:(R)-5-(二氟甲基)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-4-(4-(二氟甲基)-2-(乙氧基甲氧基)苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(180.0mg,0.40mmol,1.0eq.)和氯化氢-1,4-二氧六环溶液(4.0mol/L,3.0mL)加入二氯甲烷(1.0mL),室温搅拌2小时。TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱纯化得产物(30.0mg,产率:19.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.16(s,1H),7.25-7.23(d,J=8Hz,1H),7.14(s,0.20H),7.06-7.03(m,2H),7.00(s,0.43H),6.86(s,0.24H),5.54-5.52(d,J=8Hz,1H),4.28-4.22(m,1H),2.90-2.88(d,J=8Hz,1H),2.59-2.57(d,J=8Hz,1H),2.38-2.31(m,4H),2.18(s,3H),1.99-1.91(m,2H),1.84-1.40(m,8H).
分子式:C
21H
26F
2N
4O 精确分子量:388.21 LC-MS(Pos,m/z)=389.14[M+H]
+
实施例70 3-羟基-4-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,8-二氢-5,8-乙烷酞嗪-1-基)苯甲腈的合成(化合物9a)
步骤1:双环[2.2.2]辛-2,5-二烯-2,3-二羧酸二甲酯的合成
将丁炔二酸二甲酯(10.0g,70.4mmol,1.0eq)和1,3-环己二烯(6.77g,84.5mmol,1.2eq)溶于THF(50mL)中,氮气保护下加热至65℃,反应20小时。冷却至室温,减压浓缩,粗品经硅胶柱层析(PE:EA=50:1)分离得到产品(12.5g,产率:79.9%)。
步骤2:5,8-二氢-5,8-乙烷酞嗪-1,4-二醇的合成
将双环[2.2.2]辛-2,5-二烯-2,3-二羧酸二甲酯(12.0g,54.0mmol,1.0eq)溶于EtOH(50mL),然后加入水合肼(85%,32.0g,540mmol,10.0eq),室温反应30小时,浓缩得到产物(10.0g,产率:97.4%)。
步骤3:1,4-二氯-5,8-二氢-5,8-乙烷酞嗪的合成
将5,8-二氢-5,8-乙烷酞嗪-1,4-二醇(10.0g,52.6mmol,1.0eq)加入到ACN(50mL)中,加入POCl
3(50mL),油浴加热至100℃,反应5小时。冷却至室温,浓缩,加水(50mL)洗涤,抽滤,得到产物(2.60g,产率:21.8%)。
步骤4:(3R)-3-((4-氯-5,8-二氢-5,8-乙烷酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1,4-二氯-5,8-二氢-5,8-乙烷酞嗪(2.60g,11.4mmol,1.0eq)、(R)-3-氨基哌啶-1-羧酸叔丁酯(2.52g,12.6mmol,1.1eq)、Pd
2(dba)
3(1.05g,1.14mmol,0.1eq)、BINAP(1.42g,2.28mmol,0.2eq)和Cs
2CO
3(7.46g,22.4mmol,2.0eq)依次加入到甲苯(50mL)中,氮气保护下加热至90℃,反应2小时。冷却至室温,加水淬灭,用EA(30mL×2)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(DCM:MeOH=100:1~50:1)分离得到产物(2.70g,产率:60.3%)。
步骤5:(3R)-3-((4-(4-氰基-2-(乙氧基甲氧基)苯基)-5,8-二氢-5,8-乙烷酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲腈(349mg,1.15mmol,1.5eq)、(R)-4-氯-N-(1-(四氢-2H-吡喃-4-基)哌啶-3-基)酞嗪-1-胺(300mg,0.767mmol,1.0eq)、Pd(dppf)Cl
2(28.1mg,0.0384mmol,0.05eq)和NaHCO
3(128mg,1.53mmol,2.0eq),依次加入到1,4-二氧六环(6mL)和水(3mL)中,氮气保护下加热至110℃,反应2小时。冷却至室温,加入水淬灭,用EA(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1)分离得到产物(280mg,产率:68.6%)。
步骤6:3-羟基-4-(4-(((R)-哌啶-3-基)氨基)-5,8-二氢-5,8-乙烷酞嗪-1-基)苯甲腈的合成
将(3R)-3-((4-(4-氰基-2-(乙氧基甲氧基)苯基)-5,8-二氢-5,8-乙烷酞嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(270mg,0.508mmol,1.0eq)溶于DCM(3mL),然后滴加氯化氢的1,4-二氧六环溶液(4mol/L,1.27mL,5.08mmol,10.0eq),室温搅拌2小时。加水(20mL)淬灭,DCM(15mL×2)洗涤,水相用饱和NaHCO
3水溶液调节pH值至8,再用DCM(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,得到产物(168mg,产率:88.6%)。
步骤7:3-羟基-4-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,8-二氢-5,8-乙烷酞嗪-1-基)苯甲腈的合成
将3-羟基-4-(4-(((R)-哌啶-3-基)氨基)-5,8-二氢-5,8-乙烷酞嗪-1-基)苯甲腈(168mg,0.434mmol,1.0eq)溶于MeOH(4mL),加入甲醛水溶液(37%,42.3mg,0.521mmol,1.2eq),室温搅拌20分钟。然后加入NaBH
3CN(32.7mg,0.521mmol,1.2eq),反应1小时。浓缩,加入DCM溶解,饱和NaHCO
3水溶液调节pH值至8,用DCM(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(DCM:MeOH=10:1)分离得到产物(36.8mg,产率:21.1%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.75(s,1H),7.44(d,J=8.0Hz,1H),7.39-7.36(m,1H),7.33(s,1H),6.49-6.41(m,3H),4.48(s,1H),4.29(s,1H),3.76(d,J=5.6Hz,1H),3.15(s,2H),2.83(s,1H),2.34(s,3H),2.08(s,1H),1.92(s,1H),1.78(s,1H),1.64-1.61(m,1H),1.47-1.39(m,4H),1.34-1.31(m,1H).
分子式:C
23H
25N
5O 精确分子量:387.21 LC-MS(Pos,m/z)=388.13[M+H]
+.
实施例71(R)-5-环丙-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯酚的合成(化合物10a)
步骤1:(R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺的合成
将2-(4-环丙基-2-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(313mg,1.14mmol,1.1eq)、(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(320mg,1.04mmol,1.0eq)、Pd(dppf)Cl
2(76.1mg,0.104mmol,0.1eq)和NaHCO
3(175mg,2.08mmol,2.0eq),依次加入到1,4-二氧六环(6mL)和H
2O(3mL)中,氮气保护下加热至110℃,反应2小时。冷却至室温,加入水淬灭,用EA(20mL×3)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析(DCM:MeOH=50:1~10:1)分离得到产物(360mg,产率:82.5%)。
步骤2:(R)-5-环丙基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-基)苯酚的合成
将((R)-4-(4-环丙基-2-甲氧基苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-乙烷酞嗪-1-胺(340mg,0.812mmol,1.0eq)溶于DCM(10mL),降温至-10℃,滴加BBr
3(611mg,2.44mmol,3.0eq),反应2小时。加入MeOH淬灭,加入饱和NaHCO
3水溶液调节pH值至8,用DCM(20mL×2)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备薄层色谱(DCM:MeOH=8:1)分离得到产物(38.0mg,产率:11.6%)。
1HNMR(400MHz,CDCl
3)δ(ppm):11.75(s,1H),7.19(d,J=8.0Hz,1H),6.79(d,J=1.6Hz,1H),6.69-6.67(m,1H),5.24(s,1H),4.48(s,1H),3.59(s,1H),5.10(s,1H),2.66(s,1H),2.50(s,1H),2.29(s,3H),2.14(m,1H),1.93-1.82(m,6H),1.76-1.70(m,2H),1.46-1.39(m,4H),1.02-1.97(m,2H),0.91-0.88(m,1H),0.79-0.85(m,2H).
分子式:C
25H
32N
4O 精确分子量:404.26 LC-MS(Pos,m/z)=405.17[M+H]
+.
实施例72:2-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟 甲基)苯酚的合成(化合物32a)
步骤1:1-氯-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪的合成
将1,4-二氯-5,6,7,8-四氢酞嗪(518.0mg,2.55mmol,1.0eq.)、(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)硼酸(740.7mg,2.80mmol,1.1eq.)、碳酸氢钠(428.0mg,5.10mmol,2.0eq.)和Pd(dppf)Cl
2(93.2mg,0.12mmol,0.05eq.)加入到1,4-二氧六环(10.0mL)和水(4.0mL)的混合溶液中,氮气保护下,110℃反应3小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=20:1~8:1)得产物(450.0mg,产率:45.6%)。
步骤2:(顺式)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)-1-甲基环丁-1-醇的合成
将1-氯-4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪(400.0mg,1.03mmol,1.0eq.)、(顺式)-3-氨基-1-甲基环丁烷-1-醇盐酸盐(213.4mg,1.55mmol,1.5eq.)、碳酸铯(673.7mg,2.06mmol,2.0q.)、Pd
2(dba)
3(94.6mg,0.10mmol,0.1eq.)和1,1'-联萘-2,2'-双二苯膦(128.7mg,0.20mmol,0.2eq.)加入到1,4-二氧六环(15.0mL)中,氮气保护下,90℃反应12小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(硅胶规格:100-200目,二 氯甲烷:甲醇=80:1-50:1)得产物(380.0mg,产率:81.5%)。
步骤3:2-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚的合成
将(顺式)-3-((4-(2-(乙氧基甲氧基)-4-(三氟甲基)苯基)-5,6,7,8-四氢酞嗪-1-基)氨基)-1-甲基环丁-1-醇(380.0mg,0.84mmol,1.0eq.)加入到二氯甲烷(2.0mL)中,滴加氯化氢-1,4-二氧六环溶液(4.0mol/L,6.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(222.0mg,产率:67.2%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.14(s,1H),8.28(s,1H),7.48-7.46(d,J=8Hz,1H),7.42(s,1H),7.30-7.28(d,J=8Hz,1H),5.16(s,1H),4.05-4.00(m,1H),3.57(s,1H),2.61-2.59(m,2H),2.42-2.41(m,2H),2.30-2.25(m,2H),1.79-1.65(m,4H),1.30(s,3H).
分子式:C
20H
22F
3N
3O
2 精确分子量:393.17 LC-MS(m/z)=394.11[M+H]
+.
实施例73:3-羟基-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成(化合物33a)
步骤1:3-(乙氧基甲氧基)-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将(顺式)-3-((4-氯-5,6,7,8-四氢酞嗪-1-基)氨基)-1-甲基环丁-1-醇(180.0mg,0.67mmol,1.0eq.)、3-(乙氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈(305.5mg, 1.00mmol,1.5eq.)、碳酸氢钠(112.9mg,1.34mmol,2.0eq.)和Pd(dppf)Cl
2(24.5mg,0.03mmol,0.05eq.)加入到1,4-二氧六环(10.0mL)和水(5.0mL)的混合溶液中,氮气保护下,110℃反应4小时,TLC监测反应完全,加水(100.0mL),乙酸乙酯(100.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(二氯甲烷:甲醇=80:1~30:1)得产物(130.0mg,产率:47.3%)。
步骤2:3-羟基-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈的合成
将3-(乙氧基甲氧基)-4-(4-(((顺式)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯甲腈(130.0mg,0.31mmol,1.0eq.)加入到二氯甲烷(2.0mL)中,滴加氯化氢-1,4-二氧六环溶液(4.0mol/L,4.0mL),室温反应2小时,TLC监测反应完全,体系用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷(50.0mL)萃取,有机相无水硫酸钠干燥,过滤,滤液减压浓缩得产物(100.0mg,产率:90.0%)。
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.53(s,1H),7.32(s,2H),7.24(s,1H),6.17-6.16(t,J=4Hz,1H),4.93(s,1H),4.11-4.06(m,1H),2.39-2.29(m,6H),2.09-2.05(m,2H),1.75-1.59(m,4H),1.29(s,3H).
分子式:C
20H
22N
4O
2 精确分子量:350.17 LC-MS(m/z)=351.08[M+H]
+.
实施例74化合物(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)苯酚的合成(化合物26a)
步骤1:中间体2-(((三氟甲基)磺酰基)氧基)环庚-1-烯-1-羧酸甲酯的合成
将NaH(6.64g,166mmol,1.2eq)悬浮于二氯甲烷(600mL)中,0℃下滴加2-氧代环庚烷-1-羧酸甲酯(23.5g,138mmol,1.0eq)的二氯甲烷溶液(50mL),0℃下搅拌30min,滴加三氟甲磺酸酐(47g,166mmol,1.2eq)的二氯甲烷溶液(100mL),25℃反应30min,补加二氯甲烷(450mL),25℃反应16h。向反应液中滴加水淬灭反应,分液,有机相浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=30:1)得粗产品(35g,产率:83%)。
步骤2:中间体5,6,7,8-四氢-1H-环庚烷并[c]呋喃-1,3(4H)-二酮的合成
将甲酸钠(4.1g,59.60mmol,3.0eq)、DIEA(5.12g,39.74mmol,2.0eq)和醋酸酐(4g,39.74mmol,2.0eq)于DMF(20mL)中,搅拌30min,加入DMF(40mL)、2-(((三氟甲基)磺酰基)氧基)环庚-1-烯-1-羧酸甲酯(6g,19.87mmol,1.0eq)、醋酸钯(220mg,0.99mmol,0.05eq)和氯化锂(2.5g,59.60mmol,3.0eq),25℃反应12h。TLC监测原料反应完全。将反应液倒入乙酸乙酯和2mol/L盐酸的溶液中,搅拌5min后分液,有机相干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得粗产品(3g,产率:91%)。
步骤3:中间体2,3,6,7,8,9-六氢-1H-环庚烷并[d]哒嗪-1,4(5H)-二酮的合成
将5,6,7,8-四氢-1H-环庚烷并[c]呋喃-1,3(4H)-二酮(3g,18.07mmol,1.0eq)于醋酸(18mL)和水(20mL)中,加入醋酸钠(2.2g,27.1mmol,1.5eq)和水合肼(1.35g,27.1mmol,1.5eq),110℃反应18h。减压除去溶剂,粗品用MTBE打浆,抽滤,滤饼用乙酸乙酯洗涤得粗产品(3.5g)。
步骤4:中间体1,4-二氯-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪的合成
将2,3,6,7,8,9-六氢-1H-环庚烷并[d]哒嗪-1,4(5H)-二酮(3.5g,19.4mmol,1.0eq)和DIPEA(2.5g,19.4mmol,1.0eq)加入三氯氧磷(20mL)中,110℃反应40min。减压除去溶剂,粗产物用二氯甲烷稀释,饱和碳酸氢钠水溶液调节pH值至碱性,分液,有机相干燥,浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得产品(800mg,两步产率:20%)。
步骤5:中间体(R)-3-((4-氯-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将1,4-二氯-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪(800mg,3.69mmol,1.0eq)于二氧六环(15mL)中,加入Pd
2(dba)
3(337mg,0.37mmol,0.1eq)、BINAP(458mg,0.74mmol,0.2eq)、碳酸铯(3.6g,11.06mmol,3.0eq)和(R)-3-氨基哌啶-1-羧酸叔丁酯(737mg,3.69mmol,1.0eq),氮气保护下,110℃反应3小时,TLC检测原料少量剩余。将反应液经硅藻土抽滤,滤液浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1~1:1)得产品(1g,产率:71%)。
步骤6:中间体(R)-3-((4-(2-甲氧基-4-甲基苯基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯的合成
将(R)-3-((4-氯-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(600mg,1.58mmol,1.0eq)加入二氧六环(10mL)和水(2mL)中,加入Pd(PPh
3)
4(182mg,0.16mmol,0.1eq)、碳酸钾(653mg,4.74mmol,2.5eq)和(2-甲氧基-4-甲基苯基)硼酸(288mg,1.74mmol,1.1eq),氮气保护下,90℃反应5h,TLC监测原料反应完全。将反应液经硅藻土抽滤,滤液浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1~1:1)得产品(660mg, 产率:90%)。
步骤7:中间体(R)-5-甲基-2-(4-(哌啶-3-基氨基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)苯酚的合成
将(R)-3-((4-(2-甲氧基-4-甲基苯基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)氨基)哌啶-1-羧酸叔丁酯(660mg,1.43mmol,1.0eq)溶于二氯甲烷(12mL)中,加入三溴化硼(1.8g,7.08mmol,5.0eq),25℃反应1小时,TLC监测原料反应完全。0℃下向反应液中加入水淬灭,分液,水相用饱和碳酸氢钠水溶液调节pH值至碱性,二氯甲烷萃取,有机相干燥,浓缩得产品(380mg,产率:76%)。
步骤8:(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)苯酚的合成
将(R)-5-甲基-2-(4-(哌啶-3-基氨基)-6,7,8,9-四氢-5H-环庚烷并[d]哒嗪-1-基)苯酚(380mg,1.08mmol,1.0eq)于甲醇(8mL)中,加入37%的甲醛水溶液(87mg,1.08mmol,1.0eq)和氰基硼氢化钠(75mg,1.19mmol,1.1eq),25℃反应20min,TLC监测原料反应完全。将反应液浓缩,加入二氯甲烷和饱和碳酸氢钠,分液,有机相干燥,浓缩,经制备薄层色谱纯化(二氯甲烷:甲醇=7:1)得产品(212mg,产率:54%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):9.49(s,1H),7.99-7.97(d,J=7.6Hz,1H),6.73(s,1H),6.68-6.66(d,J=7.6Hz,1H),6.29(s,1H),4.50(s,1H),3.68-3.51(m,1H),3.45-3.43(m,1H),3.26(m,1H),2.74(m,6H),2.48(s,1H),2.27(s,3H),2.08-1.89(m,2H),1.77-1.76(m,4H),1.52-1.46(m,5H).
分子式:C
22H
30N
4O 精确分子量:366.24 LC-MS(m/z):367.17[M+H]
+.
实施例75(R)-2,3-二氟-6-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成(化合物31a)
步骤1:中间体1-溴-2-(乙氧基甲氧基)-3,4-二氟苯的合成
将6-溴-2,3-二氟苯酚(1g,4.78mmol,1.0eq)溶于无水四氢呋喃(6mL)中,冰水浴下分批次加入质量分数为60%的NaH(287mg,7.17mmol,1.5eq),搅拌30min后,加入氯甲基***(587mg,6.21mmol,1.3eq),室温下搅拌2h,TLC检测反应完全。反应液加水淬灭,浓缩,加水(5mL)和乙酸乙酯(10mL),分液,有机相依次用水(15mL×2)和饱和食盐水(15mL×2)洗涤,干燥,浓缩得产物(1.1g,产率:86.2%)。
步骤2:中间体(2-(乙氧基甲氧基)-3,4-二氟苯基)硼酸的合成
将1-溴-2-(乙氧基甲氧基)-3,4-二氟苯(1.06g,4mmol,1.0eq)溶于无水四氢呋喃(12mL)中,降温至-70℃,滴加1.6mol/L正丁基锂的正己烷溶液(3.8mL,6mmol,1.5eq),搅拌2h后,滴加硼酸三异丙酯(978mg,5.2mmol,1.3eq),室温下搅拌三小时。TLC检测反应完全,反应液加水淬灭,浓缩,用2mol/L盐酸水溶液调节pH值至6,加水(5mL)和乙酸乙酯(10mL),分液,有机相干燥,浓缩得产物(750mg,产率:80.8%)。
步骤3:中间体(R)-4-(2-(乙氧基甲氧基)-3,4-二氟苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺的合成
将(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(250mg,0.89mmol,1.0eq)溶于1,4-二氧六环(2mL)和水(1mL)中,依次加入(2-(乙氧基甲氧基)-3,4-二氟苯基)硼酸(413mg,1.78mmol,2.0eq)、碳酸氢钠(150mg,1.78mmol,2.0eq)和Pd(dppf)Cl
2(65mg,0.089mmol,0.1eq),氮气保护下,110℃搅拌过夜。TLC检测仍有少量原料剩余。反应液浓缩,加水(5mL),二氯甲烷(5mL×3)萃取,有机相干燥,抽滤,滤液浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇=20:1-10:1)纯化得产物(80mg,产率:20.8%)。
步骤4:化合物(R)-2,3-二氟-6-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚的合成
将(R)-4-(2-(乙氧基甲氧基)-3,4-二氟苯基)-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(80mg,0.19mmol,1.0eq)溶于二氯甲烷(1mL)中,加入4mol/L的氯化氢的1,4-二氧六环溶液(0.23mL,5.0eq),室温下搅拌3h,TLC检测反应完全。反应液倒入水中,用碳酸氢钠调节pH值至8,分液,二氯甲烷(5mL×2)萃取,干燥,抽滤,浓缩,粗品经制备薄层色谱纯化得产物(37mg,产率:53.4%)。
1H-NMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),7.00-6.89(m,2H),5.82(s,1H),4.38(s,1H),3.15(s,1H),2.87(s,1H),2.77(s,1H),2.40-2.31(m,6H),1.85-1.60(m,10H)。
分子式:C
20H
24F
2N
4O 精确分子量:374.19 LC-MS(m/z):375.26[M+H]
+
实施例76(R)-6-甲基-3-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-2-醇(化合物106)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):11.95(s,1H),8.50(s,1H),7.89-7.77(m,2H),7.60-7.52(m,3H),6.19(d,J=6.9Hz,1H),4.74(s,1H),3.63-3.59(m,2H),3.17(s,1H),2.78(s,4H),2.30(s,3H),2.08(s,1H),1.84(s,3H).
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z):350.28[M+H]
+
实施例77(R)-4,5-二甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物35)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.37(s,1H),8.41(d,J=8.1Hz,1H),7.86-7.74(m,2H),7.54(d,J=7.8Hz,1H),7.14(s,1H),7.04(s,1H),6.80(s,1H),4.49(s,1H),3.21(d,J=8.4Hz,1H),2.84(d,J=11.1Hz,1H),2.35(s,3H),2.23-2.18(m,8H),2.02-1.97(m,1H),7.84-1.80(m,1H),1.72-1.49(m,2H).
分子式:C
22H
26N
4O 精确分子量:362.21 LC-MS(m/z):363.34[M+H]
+
实施例78(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)呋喃并[3,4-d]哒嗪-1-基)苯酚(化合物44)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):15.0(s,1H),9.20(d,J=1.2Hz,1H),8.96(s,2H),8.03(s,1H),7.82(d,J=8.4Hz,1H),6.77(d,J=5.7Hz,1H),4.47(s,1H),3.34(d,J=8.4Hz,3H),3.01(d,J=11.7Hz,1H),2.54(s,3H),2.31(s,3H),1.95-1.89(m,2H),1.75-1.59(m,2H).
分子式:C
19H
22N
4O
2 精确分子量:338.17 LC-MS(m/z):339.15[M+H]
+
实施例79(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)噻吩并[3,4-d]哒嗪-1-基)苯甲腈(化合物58)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.00(s,1H),8.58(d,J=2.7Hz,1H),8.05(d,J=8.1Hz,2H),7.42-7.38(m,2H),4.62(s,1H),3.18(s,2H),2.79-2.73(m,1H),2.68(s,3H),2.04-1.99(m,3H),1.81-1.77(m,2H).
分子式:C
19H
19N
5OS 精确分子量:365.13 LC-MS(m/z):366.14[M+H]
+
实施例80(R)-2-甲基-5-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-4-醇(化合物107)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.30(d,J=7.5Hz,1H),7.94(s,1H),7.90-7.83(m,2H),7.73(d,J=7.8Hz,1H),6.51(s,1H),4.63(s,1H),3.78(s,3H),3.43(d,J=9.6Hz,1H),3.09(s,2H),2.90(s,3H),2.47(s,3H),2.15(s,2H),1.91(s,2H).
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z):350.12[M+H]
+
实施例81 5-(1-羟乙基)-2-(4-(((R)-1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物92)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.75(s,1H),8.53(s,1H),7.91-7.83(m,2H),7.55(d,J=8.0Hz,1H),7.46-7.35(m,3H),7.23(d,J=7.6Hz,2H),7.05(s,1H),6.94-6.91(m,1H),5.26(d,J=3.2Hz,1H),4.75-4.73(m,2H),3.72(s,1H),2.94(s,2H),2.81(s,3H),2.20-1.78(m,4H),1.38(d,J=6.4Hz,3H).
分子式:C
22H
26N
4O
2 精确分子量:378.21 LC-MS(m/z):379.16[M+H]
+
实施例82(R)-5-(2-羟基丙-2-基)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物94)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.61(s,1H),8.44(d,J=6.8Hz,1H),7.88-7.78(m,2H),7.53(d,J=8.0Hz,1H),7.28(s,1H),7.21(d,J=8.0Hz,1H),7.15(d,J=1.2Hz,1H),7.03-7.01(m,1H),5.07(s,1H),4.57(s,1H),3.02(s,2H),2.01-1.89(m,3H),1.74-1.63(m,3H),1.47(s,6H).
分子式:C
23H
28N
4O
2 精确分子量:392.22 LC-MS(m/z):393.13[M+H]
+
实施例83(R)-5-羟基-6-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)烟腈(化合物109)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):15.41(s,1H),9.46(d,J=6.0Hz,1H),8.57(s,1H),8.49(d,J=6.4Hz,1H),7.96(s,2H),7.83(s,1H),7.71(d,J=6.8Hz,1H),4.42(s,1H),3.05(d,J=8.0Hz,1H),2.72(d,J=10.0Hz,1H),2.22(s,3H),1.99-1.92(m,3H),1.77-1.74(m,1H),1.63-1.48(m,2H).
分子式:C
20H
20N
6O 精确分子量:360.17 LC-MS(m/z):361.09[M+H]
+
实施例84(R)-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)吡啶-3-醇(化合物115)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.22(s,1H),8.58(s,1H),8.40(s,1H),8.21(d, J=4.8Hz,1H),7.92-7.88(m,1H),7.85-7.81(m,1H),7.67(s,1H),7.47(d,J=8.0Hz,1H),7.47(d,J=4.8Hz,1H),4.75(s,1H),3.56(s,2H),3.23(s,1H),2.74(s,4H),2.01(s,2H),1.83(s,2H).
分子式:C
19H
21N
5O 精确分子量:335.17 LC-MS(m/z):336.12[M+H]
+
实施例85(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(恶唑-2-基)苯酚(化合物119)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.18(d,J=5.2Hz,1H),10.24(s,1H),8.59(s,1H),7.88-7.86(m,1H),7.82-7.78(m,2H),7.62(s,2H),7.46(d,J=7.6Hz,1H),7.04-7.01(m,1H),6.53(d,J=7.2Hz,1H),4.75(s,1H),3.51(s,2H),3.17(s,1H),2.69(s,4H),2.00(s,2H),1.82(s,2H).
分子式:C
23H
23N
5O
2 精确分子量:401.19 LC-MS(m/z):402.13[M+H]
+
实施例86(R)-3-羟基-4-(4-((1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物128)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.48(s,1H),8.39(d,J=8.0Hz,1H),7.88-7.84(m,1H),7.81-7.77(m,1H),7.50(d,J=7.6Hz,1H),7.43-7.41(m,1H),7.33(d,J=1.2Hz,1H),7.19(d,J=7.6Hz,1H),4.56-4.52(m,2H),4.49-4.44(m,3H),3.48-3.45(m,1H),3.04-3.01(m,1H),2.67(d,J=10.8Hz,1H),2.05(d,J=8.8Hz,1H),1.88-1.77(m,3H),1.67-1.61(m,1H),1.55-1.49(m,1H).
分子式:C
23H
23N
5O
2 精确分子量:401.19 LC-MS(m/z):402.14[M+H]
+
实施例87(R)-5-甲基-2-(5-((1-甲基哌啶-3-基)氨基)-吡啶并[2,3-d]哒嗪-8-基)苯酚(化合物37)的合成参照前述实施例
1H-NMR(300MHz,DMSO-d
6)δ(ppm):11.92(brs,1H),9.20-9.22(m,1H),9.01(s,1H),8.18-8.21(d,1H),7.95-7.99(m,1H),7.84(s,1H),6.77(s,1H),6.73(s,1H),4.66(s,1H),3.55(s,3H),2.72(s,4H),2.31(s,3H),1.99-2.02(d,2H),1.79-1.83(d,2H).
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z):350.22[M+H]
+
实施例88(R)-5-甲基-2-(8-甲基-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚(化合物2)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.31(s,1H),8.31(s,1H),7.74-7.72(d,1H),7.60-7.58(d,1H),7.31(s,1H),7.06-7.03(m,1H),6.73(s,2H),4.68(s,1H),2.57(s,4H),2.50(s,3H),2.31(s,3H),2.06-1.99(t,5H),1.83-1.81(m,2H).
二维谱NOE显示7.60-7.58(d,1H)与7.74-7.72(d,1H)有耦合信号,7.31(s,1H)与8.31(s,1H)有耦合信号。
分子式:C
21H
26N
4O 精确分子量:362.21 LC-MS(m/z):363.26[M+H]
+
实施例89(R)-5-甲基-2-(7-((1-甲基哌啶-3-基)氨基)-1H-咪唑并[4,5-d]哒嗪-4-基)苯酚(化合物134)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.03(s,1H),8.60(s,1H),7.45-7.43(d,1H),6.79-6.77(d,2H),4.44(s,1H),3.33(s,3H),2.95(s,1H),2.66(s,2H),2.55(s,3H),2.31(s,3H),1.97-1.92(d,2H),1.75-1.59(m,2H).
分子式:C
18H
22N
6O 精确分子量:338.19 LC-MS(m/z):339.27[M+H]
+
实施例90(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-6-(甲磺酰基)酞嗪-1-基)苯酚(化合物82)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.66(s,1H),9.11(s,1H),8.29-8.26(d,1H),7.72-7.70(d,1H),7.20-7.17(d,1H),6.85-6.79(t,2H),4.73(s,1H),3.38(s,5H),2.80(s,3H),2.55(s,2H),2.34(s,3H),2.08-2.02(t,2H),1.88-1.84(d,2H).
分子式:C
22H
26N
4O
3S 精确分子量:426.17 LC-MS(m/z):427.13[M+H]
+
实施例91(R)-2-(6-(呋喃-2-基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚的合成(化合物83)的合成参照前述实施例
1HNMR(300MHz,CDCl
3)δ(ppm):8.43(s,1H),8.28-8.25(d,1H),8.08-8.05(d,1H),7.62-7.59(d,1H),7.51-7.48(d,1H),7.09-7.02(d,2H),6.85-6.83(d,1H),6.60(s,2H),4.79(s,1H),2.95-2.93(d,2H),2.68(s,1H),2.44-2.42(d,6H),2.14(s,1H),2.00(s,2H),1.73(s,2H).
分子式:C
25H
26N
4O
2 精确分子量:414.21 LC-MS(m/z):415.21[M+H]
+
实施例92(R)-2-(6-(二甲基氨基)-4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-甲基苯酚(化合物84)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):7.51-7.48(d,1H),7.37-7.34(d,2H),7.23-7.21(d,1H),6.85(s,1H),6.80-6.78(d,1H),4.57(s,1H),3.50-3.42(d,2H),2.44-3.42(m,2H),3.41-3.40(d,1H),3.16(s,6H),3.06(s,1H),2.57(s,3H),2.34(s,3H),2.02-1.99(t,2H),1.78-1.74(d,2H).
分子式:C
23H
29N
5O 精确分子量:391.24 LC-MS(m/z):392.19[M+H]
+
实施例93 3,5-二氟-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚(化合物28a)的合成参照前述实施例
1H-NMR(400MHz,DMSO-d
6)δ(ppm):10.48(s,1H),6.73(t,J=9.04Hz,1H),6.61(d,J=10.4Hz,1H),5.77(s,1H),4.33(s,1H),3.07(s,1H),2.77(s,1H),2.37-2.35(m,7H),1.84-1.51(m,10H).
分子式:C
20H
24F
2N
4O 精确分子量:374.19 LC-MS(m/z):375.16[M+H]
+
实施例94(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚(化合物25a)的合成参照前述实施例
1H-NMR(400MHz,DMSO-d
6)δ(ppm):9.69(s,1H),7.24-7.20(m,1H),7.12-7.09(m,1H),6.92(d,J=8.0Hz,1H),6.80(t,J=7.4Hz,1H),5.77(s,1H),4.41(s,1H),3.21(s,1H),3.04-2.92(m,2H),2.48-2.33(m,8H),1.87-1.58(m,8H).
分子式:C
20H
26N
4O 精确分子量:338.21 LC-MS(m/z):339.12[M+H]
+
实施例95(R)-4-氟-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚(化合物27a)的合成参照前述实施例
1H-NMR(400MHz,DMSO-d
6)δ(ppm):9.60(s,1H),6.86(d,J=9.84Hz,1H),6.77(d,J=6.76Hz,1H),5.87(s,1H),4.42(s,1H),3.31-3.20(m,2H),3.16(s,1H),2.99(s,1H),2.40-2.35(m,5H),2.20(s,3H),1.88-1.59(m,10H).
分子式:C
21H
27FN
4O 精确分子量:370.22 LC-MS(m/z):371.21[M+H]
+
实施例96(R)-4,5-二氟-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)苯酚(化合物30a)的合成参照前述实施例
1H-NMR(400MHz,DMSO-d
6)δ(ppm):10.61(s,1H),6.99-6.94(m,1H),6.91-6.87(m,1H),5.85(s,1H),4.39(s,1H),3.13(s,1H),2.85(s,1H),2.41-2.28(m,7H),1.85-1.62(m,10H).
分子式:C
20H
24F
2N
4O 精确分子量:374.19 LC-MS(m/z):375.22[M+H]
+
实施例97(R)-4-(2-氨基-4-甲基苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成(化合物39)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.40-8.37(d,J=9Hz,1H),7.87-7.82(m,2H),7.58-7.55(d,J=9Hz,1H),7.05-7.02(d,J=9Hz,1H),6.96-6.93(d,J=9Hz,1H),6.65(s,1H),6.53-6.50(d,J=9Hz,1H),4.89(s,2H),4.43-4.41(d,J=6Hz,1H),3.10-3.08(d,J=6Hz,1H), 2.73-2.70(d,J=9Hz,1H),2.27(s,3H),2.22(s,3H),1.99-1.40(m,6H).
分子式:C
21H
25N
5 精确分子量:347.47 LC-MS(m/z):348.25[M+H]
+
实施例98(R)-4-(4-甲基-2-(甲基氨基)苯基)-N-(1-甲基哌啶-3-基)酞嗪-1-胺的合成(化合物40)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.45-8.42(d,J=9Hz,1H),7.88-7.75(m,2H),7.51-7.49(d,J=6Hz,1H),7.24(s,1H),6.96-6.93(d,J=9Hz,1H),6.56-6.53(m,2H),5.03-5.02(d,J=3Hz,1H),4.56(s,1H),2.98-2.95(d,J=9Hz,1H),2.63-2.62(d,J=3Hz,3H),2.46(s,3H),2.34(s,3H),2.28-1.60(m,6H).
分子式:C
22H
27N
5 精确分子量:361.49 LC-MS(m/z):362.26[M+H]
+
实施例99(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯酚的合成(化合物41)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.63(s,1H),8.48(s,1H),7.89-7.77(m,2H),7.54-7.52(m,1H),7.41(s,1H),7.17-7.15(m,1H),6.82-6.76(m,2H),4.65(s,1H),3.47-3.36(m,2H),3.17-3.12(m,2H),2.51-2.50(m,3H),2.33(s,3H),1.99-1.77(m,4H).
分子式:C
22H
26N
4O 精确分子量:362.48 LC-MS(m/z):363.33[M+H]
+
实施例100(R)-N-(5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯基)乙酰胺(化合物43)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.19(s,1H),8.41-8.38(m,1H),7.86-7.64(m,3H),7.39-7.36(m,1H),7.29-7.26(m,1H),7.12-7.10(m,2H),4.45-4.43(m,1H),3.14-3.11(m,1H),2.79-2.77(m,1H),2.39(s,3H),2.25(s,3H),2.01-1.91(m,3H),1.80-1.54(m,6H).
分子式:C
23H
27N
5O 精确分子量:389.22 LC-MS(m/z):390.30[M+H]
+
实施例101(R)-5-甲基-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲酰胺(化合物76)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):8.51(s,1H),7.86-7.68(m,3H),7.53(s,1H),7.46-7.06(m,4H),4.63(s,1H),3.02(s,1H),2.56(s,3H),2.37(s,3H),2.04-1.34(m,7H).
分子式:C
22H
25N
5O 精确分子量:375.21 LC-MS(m/z):376.22[M+H]
+
实施例102(R)-1-(3-((4-(2-羟基-4-甲基苯基)酞嗪-1-基)氨基)哌啶-1-基)丙-2-烯-1-酮(化合物85)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.61(s,1H),8.40-8.38(m,1H),7.88-7.76(m,2H),7.54-7.52(m,1H),7.19-7.17(m,2H),6.81-6.76(m,2H),6.14-6.05(m,1H),5.70-5.59(m,1H),4.70-4.00(m,3H),3.35-2.71(m,2H),2.33(s,3H),2.15-1.24(m,5H).
分子式:C
23H
24N
4O
2 精确分子量:388.19 LC-MS(m/z):389.12[M+H]
+
实施例103(R)-3-羟基-N-甲基-4-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲酰胺(化合物86)的合成参照前述实施例
1HNMR(300MHz,DMSO-d
6)δ(ppm):9.99(s,1H),8.51-8.47(m,2H),7.90-7.78(m,2H),7.66(s,1H),7.49-7.34(m,4H),4.76(s,1H),3.56(s,1H),3.24-3.09(m,2H),2.89-2.75(m,6H),2.13-1.80(m,5H).
分子式:C
22H
25N
5O
2 精确分子量:391.20 LC-MS(m/z):392.14[M+H]
+
实施例104(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-吗啉代苯酚(化合物91)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):9.96(s,1H),8.47(s,1H),7.89-7.79(m,2H),7.67-7.65(d,J=8Hz,1H),7.37(s,1H),7.21-7.19(d,J=8Hz,1H),6.59-6.53(m,2H),4.63(s,1H),3.49(s,3H),3.16-3.14(m,5H),2.65(s,3H),2.03-1.77(m,4H).
分子式:C
25H
29N
5O
2 精确分子量:419.23 LC-MS(m/z):420.19[M+H]
+
实施例105(R)-4-(4-((1-(环丙基甲基)哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-羟基苯甲腈(化合物11a)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.53(s,1H),7.35-7.24(m,3H),5.69-5.68(m,1H),4.29(s,1H),3.09(s,1H),2.83(s,1H),2.37-2.09(m,9H),1.86-1.70(m,4H),1.61-1.46(m,4H),0.87-0.84(m,2H),0.47-0.44(m,2H).
分子式:C
24H
29N
5O 精确分子量:403.24 LC-MS(m/z):404.15[M+H]
+
实施例106(R)-4-(4-((1-乙酰哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-3-羟基苯甲腈(化合物12a)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.50(s,1H),7.33(s,2H),7.24(s,1H),5.89-5.77(m,1H),4.49-4.10(m,3H),3.04-2.90(m,1H),2.67-2.59(m,1H),2.41-2.28(m,4H),2.02-2.01(m,4H),1.76-1.60(m,7H).
分子式:C
22H
25N
5O
2 精确分子量:391.20 LC-MS(m/z):392.11[M+H]
+
实施例107(R)-2-(4-((1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(甲基磺酰基)苯酚(化合物75)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.06(s,1H),7.80-7.71(m,3H),7.59-7.57(m,1H),7.30-7.28(m,1H),6.94-6.81(m,2H),4.70(s,1H),3.68-6.65(m,1H),3.17(s,3H),2.68(s,3H),2.42-2.39(m,2H),2.16-2.12(m,2H),1.60-1.53(m,2H).
分子式:C
21H
24N
4O
3S 精确分子量:412.16 LC-MS(m/z):413.09[M+H]
+
实施例108(R)-4-(4-((1-(环丙基磺酰基)哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈(化合物103)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.42-8.40(d,J=8Hz,1H),7.89(t,J=8Hz,1H),7.81(t,J=8Hz,1H),7.52-7.50(d,J=8Hz,1H),7.44-7.42(d,J=8Hz,2H),7.34-7.33(m,2H),4.42(s,1H),4.03-4.00(m,1H),3.63-3.60(m,1H),2.91-2.86(m,1H),2.78-2.73(m,1H),2.68-2.62(m,1H),2.08-1.92(m,2H),1.69-1.68(m,2H)1.01-0.92(m,4H).
分子式:C
23H
23N
5O
3S 精确分子量:449.15 LC-MS(m/z):450.07[M+H]
+
实施例109(R)-3-羟基-4-(4-((1-(甲基磺酰基)哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物102)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.46(s,1H),8.43-8.41(d,J=8Hz,1H),7.89(t,J=8Hz,1H),7.82-7.81(m,1H),7.52-7.50(d,J=8Hz,1H),7.43-7.42(d,J=4Hz,1H),7.33-7.32(m,2H),4.43(s,1H),4.01-3.98(m,1H),3.56-3.53(m,1H),2.90(s,3H),2.80-2.75(m,1H),2.65-2.60(m,1H),2.06-1.93(m,2H),1.71-1.69(m,2H).
分子式:C
21H
21N
5O
3S 精确分子量:423.14 LC-MS(m/z):424.06[M+H]
+
实施例110(R)-N-(4-(4-氰基-2-羟基苯基)酞嗪-1-基)-1-甲基哌啶-3-甲酰胺(化合物113)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.17(s,1H),10.76(s,1H),8.03-7.97(m,3H),7.64-7.57(m,2H),7.49-7.44(m,2H),3.55(s,1H),3.22(s,2H),3.11-3.09(m,1H),2.89(s,1H),2.75(s,3H),2.24(s,1H),2.01-1.65(m,4H).
分子式:C
22H
21N
5O
2 精确分子量:387.17 LC-MS(m/z):388.09[M+H]
+
实施例111 3-羟基-4-(4-(((顺式)-3-羟基环丁基)氨基)酞嗪-1-基)苯甲腈(化合物117)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.07(s,1H),10.15(s,1H),9.00-8.98(d,J=8Hz,1H),8.16-8.06(m,2H),7.61-7.55(m,2H),7.50-7.47(m,2H),5.37(s,1H),4.09-3.90(m,2H), 2.90-2.88(m,2H),2.27-2.20(m,2H).
分子式:C
19H
16N
4O
2 精确分子量:332.13 LC-MS(m/z):333.02[M+H]
+
实施例112 2-(4-(((R)-1-甲基哌啶-3-基)氨基)酞嗪-1-基)-5-(甲基亚磺酰基)苯酚(化合物120)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):11.06(s,1H),10.33(s,1H),7.81-7.73(m,3H),7.54-7.52(d,J=8Hz,1H),7.25-7.23(d,J=8Hz,1H),6.87-6.83(m,2H),4.70(s,1H),3.69-3.66(m,1H),3.46-3.40(m,1H),3.14(s,3H),2.43-2.33(m,1H),2.13-1.97(m,1H),1.61-1.55(m,2H).
分子式:C
21H
24N
4O
2S 精确分子量:396.16 LC-MS(m/z):397.08[M+H]
+
实施例113(R)-4-(4-((5,5-二氟-1-甲基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈(化合物121)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.34-8.32(d,J=8Hz,1H),7.92-7.88(m,1H),7.83-7.79(m,1H),7.50-7.39(m,3H),7.34-7.30(m,2H),4.71-4.61(m,1H),3.18-3.03(m,2H),2.49(s,1H),2.51(s,1H),2.40-2.29(m,4H),2.10-2.05(m,2H).
分子式:C
21H
19F
2N
5O
2 精确分子量:395.16 LC-MS(m/z):396.07[M+H]
+
实施例114 4-(4-(((3R,5S)-5-氟-1-甲基哌啶-3-基)氨基)酞嗪-1-基)-3-羟基苯甲腈(化合物122)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):10.47(s,1H),8.36-8.34(d,J=8Hz,1H),7.89(t,J=8Hz,1H),7.80(t,J=8Hz,1H),7.50-7.49(m,1H),7.43-7.41(m,2H),7.33-7.28(m,2H), 4.86-4.48(m,2H),3.09-3.07(m,2H),2.44-2.43(m,1H),2.29(s,3H),2.06-1.90(m,2H),1.77-1.66(m,2H).
分子式:C
21H
20F N
5O 精确分子量:377.17 LC-MS(m/z):378.08[M+H]
+
实施例115 3-羟基-4-(4-(((3R,5S)-5-羟基-1-甲基哌啶-3-基)氨基)酞嗪-1-基)苯甲腈(化合物133)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):8.39-8.37(d,J=8Hz,1H),7.87(t,J=8Hz,1H),7.79(t,J=8Hz,1H),7.50-7.48(d,J=8Hz,1H),7.43-7.41(m,2H),7.34-7.28(m,2H),4.95(s,1H),4.47-4.46(m,1H),3.72-3.67(m,1H),3.17-3.09(m,1H),2.90-2.89(m,1H),2.20-2.27(m,4H),1.91-1.80(m,2H),1.47-1.34(m,2H).
分子式:C
21H
21N
5O
2 精确分子量:375.17 LC-MS(m/z):376.10[M+H]
+
实施例116(R)-3-羟基-4-(4-((1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊二烯并[d]哒嗪-1-基)苯甲腈(化合物4a)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):13.47(s,1H),7.71-7.69(d,J=8.1Hz,1H),7.35-7.32(m,2H),6.62(s,1H),4.37(s,1H),3.30(s,1H),3.19-3.17(m,1H),3.11-3.07(m,2H),2.90(s,1H),2.82-2.79(m,2H),2.43(s,3H),2.25(br,1H),2.11-2.03(m,2H),1.91(m,1H),1.81(s,1H),1.68-1.64(m,1H),1.50(s,1H).
分子式:C
20H
23N
5O 精确分子量:349.19 LC-MS(m/z):350.09[M+H]
+.
实施例117 3-羟基-4-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基酞嗪-1-基)苯甲腈(化合物16a)的合成参照前述实施例
1HNMR(400MHz,DMSO-d
6)δ(ppm):12.91(s,1H),7.70-7.68(d,J=8.4Hz,1H),7.38-7.36(m,2H),6.96(s,1H),4.44(s,1H),4.11(s,1H),3.78(s,1H),3.60(s,1H),3.17-3.10(m,3H),2.62(s,4H),2.02-1.91(m,4H),1.74(s,1H),1.64-1.60(m,1H),1.52-1.50(m,1H),1.23-1.20(m,1H),1.10-1.00(m,1H).
分子式:C
22H
25N
5O 精确分子量:375.21 LC-MS(m/z):376.22[M+H]
+.
实验例1:本发明化合物的细胞NLRP3炎症小体抑制活性测试
测试物:本发明化合物,按照实施例方法制备
THP-1为永生化人源巨噬细胞系
测试仪器:酶标仪(PE制)
试验方法:
1.THP-1细胞,1640完全培养基(500ml 1640+56ml FBS+560ul 1000×的P/S+2ul巯基乙醇)培养,3-20代之内使用。
2.包被培养板:96孔细胞培养板中,加100ul多聚赖氨酸溶液,37摄氏度30min,弃掉溶液,PBS洗两遍,备用。
3.THP-1的诱导分化:THP-1细胞用适量的含10ng/ml PMA的完全培养基重悬,使细胞悬液密度为5×10^
5个细胞/ml,加入96孔板中,每孔100ul细胞悬液,37摄氏度二氧化碳细胞培养箱中过夜培养16个小时。
4.THP-1的刺激:
a.加入含LPS的无血清THP-1培养基,终浓度500ng/ml,37摄氏度二氧化碳细胞培养箱培养3h;
b.待测化合物用DMSO配置梯度浓度的母液,加入细胞中,混匀,最终1:1000倍稀释,37摄氏度二氧化碳细胞培养箱培养1h。
c.每个孔中加入Nigericin,终浓度10μg/ml,37摄氏度二氧化碳细胞培养箱培养30min。
d.转移孔内培养基到新的培养板,然后3000rpm,5min离心,再转移上清至新的96孔板。
e.收集的细胞培养基上清样品用商品化的Elisa检测试剂盒,按照说明书的规定检测人源的IL-1β含量。
测试结果如下表2所示:
表2本发明化合物对THP-1细胞NLRP3的抑制活性
测试物 | IC50(nM) |
化合物1 | 1.8 |
化合物3 | 24 |
化合物4 | 9 |
化合物5 | 14 |
化合物6 | 11 |
化合物8 | 3 |
化合物9 | 3 |
化合物12 | 4 |
化合物16 | 7 |
化合物20 | 12 |
化合物24 | 14 |
化合物32 | 15 |
化合物34 | 8 |
化合物36 | 11 |
化合物38 | 12 |
化合物42 | 13 |
化合物48 | 2 |
化合物49 | 9 |
化合物50 | 1 |
化合物54 | 13 |
化合物55 | 4 |
化合物60 | 13 |
化合物70 | 1 |
化合物72 | 1 |
化合物73 | 1 |
化合物74 | 6 |
化合物77 | 2 |
化合物78 | 2 |
化合物79 | 13 |
化合物87 | 2 |
化合物88 | 1 |
化合物89 | 7 |
化合物90 | 7 |
化合物93 | 6 |
化合物95 | 1 |
化合物101 | 5 |
化合物108 | 15 |
化合物111 | 4 |
化合物112 | 16 |
化合物116 | 21 |
化合物118 | 23 |
化合物123 | 6 |
化合物124 | 5 |
化合物125 | 3 |
化合物126 | 5 |
化合物127 | 4 |
化合物129 | 4 |
化合物1a | 7 |
化合物2a | 3 |
化合物3a | 4 |
化合物5a | 5 |
化合物6a | 1 |
化合物8a | 4 |
化合物15a | 2 |
化合物21a | 14 |
化合物23a | 6 |
化合物24a | 1 |
化合物26a | 4 |
化合物29a | 1 |
化合物31a | 6 |
化合物32a | 7 |
由表2实验结果可见,本发明的化合物对NLRP3炎症小体具有良好的抑制活性,因此本发明化合物可用于预防和/或治疗与NLRP3炎症小体相关的疾病。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明保护的范围之内。
Claims (17)
- 通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体:其中,R 1选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;R 2选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6炔基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;R 1、R 2分别任选被1-3个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基的取代基取代;或R 1、R 2与它们所连接的碳原子形成5-12元环A;所述5-12元环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、羰基、C 1-6烷基、-NH-C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C 1-6烷基磺酰基、-N(C 1-6烷基) 2的取代基取代;R 3选自-(C 1-6亚烷基) 0-2-NR 4R 5、-(C 1-6亚烷基) 0-2-NR 4-COR 5、-(C 1-6亚烷基) 0-2-CO-NR 4-R 5、-(C 1-6亚烷基) 0-2-O-R 5;R 4选自氢或C 1-6烷基;R 5选自3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基;所述R 5任选被1-4个选自卤素、氰基、氨基、羟基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C 2-6烯基羰基、磺酰基、C 1-6烷基羰基、羧基的取代基取代;Y选自芳基、5-14元杂芳基、3-14元杂环基、3-12元环烷基,所述Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、C 1-6烷基氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基、氨基羰基、C 1-6烷基氨基羰基、磺酰基、C 1-6烷基硫基、C 1-6烷基亚磺酰基的取代基取代;当R 5被取代时,R 5上的取代基:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环 烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、3-6元环烷基的取代基取代;当Y被取代时,Y上的取代基:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、芳基、5-7元杂芳基、磺酰基,任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、3-6元环烷基的取代基取代。
- 根据权利要求2所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,环A选自苯基、5-7元杂芳基;环A任选被1-4个选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、-NH-C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、3-7元杂环基、3-7元环烷基、C 1-6烷基磺酰基、-N(C 1-6烷基) 2的取代基取代。
- 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7 元杂环基、3-7元环烷基、C 1-6烷基氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基、氨基羰基、C 1-6烷基氨基羰基、磺酰基的取代基取代;所述C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基的取代基取代。
- 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自萘基、8-14元稠杂芳基、6-12元稠杂环基、6-12元稠环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基的取代基取代。
- 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y被氰基取代以及任选被1-2个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、C 1-6烷基氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基、氨基羰基、C 1-6烷基氨基羰基、磺酰基的取代基取代;所述C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基的取代基取代。
- 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R 3选自-NR 4R 5、-NH-COR 5、-O-R 5;R 4选自氢或C 1-3烷基;R 5选自3-7元环烷基、3-7元杂环基,R 5任选被1-2个选自C 1-6烷基、羟基、羟基取代的C 1-6烷基、3-7元环烷基取代的C 1-6烷基、羟基、卤素、C 2-6烯基羰基、C 1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C 1-6烷基羰基的取代基取代。
- 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R 3选自-NH-R 5,R 5为被1-2个选自C 1-6烷基的取代基取代的3-7元杂环基。
- 根据权利要求3或4所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,Y选自苯基、5-7元杂芳基、3-8元杂环基、3-7元环烷基;Y任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7 元杂环基、3-7元环烷基、C 1-6烷基氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基、氨基羰基、C 1-6烷基氨基羰基、磺酰基的取代基取代;所述C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元杂环基、3-7元环烷基、磺酰基任选被1-3个选自卤素、氰基、氨基、羟基、羰基、C 1-6烷基的取代基取代;R 3选自-NH-R 5,R 5为被1-2个选自C 1-6烷基的取代基取代的3-7元杂环基。
- 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,其中,R 1、R 2与它们所连接的碳原子形成5-8元环A,所述5-8元环A选自5-8元环烷基、5-8元环烯基、5-8元杂环基、苯基、5-8元杂芳基;环A任选被1-2个选自氰基、卤素、C 1-6烷基、-NH-C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、3-7元环烷基、5-7元杂芳基、C 1-6烷基磺酰基、-N(C 1-6烷基) 2的取代基取代;Y选自苯基、5-7元杂芳基;Y被1-3个选自卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6烷氧基、羟基取代的C 1-6烷基、卤代C 1-6烷基、氨基羰基、C 1-6烷基氨基、C 1-6烷基羰基氨基、C 1-6烷基氨基羰基、3-7元杂环基、3-7元环烷基、5-7元杂芳基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 1-6烷基亚磺酰基的取代基取代;R 3选自-NR 4R 5、-NH-COR 5、-O-R 5;R 4选自氢或C 1-3烷基;R 5选自3-7元环烷基、3-7元杂环基,R 5任选被1-2个选自C 1-6烷基、羟基、羟基或3-7元环烷基取代的C 1-6烷基、羟基、卤素、C 2-6烯基羰基、C 1-6烷基磺酰基、3-7元环烷基磺酰基、氨基磺酰基、3-7元杂环基、3-7元环烷基、羧基、C 1-6烷基羰基的取代基取代。
- 一种药物组合物,其包含权利要求1~14任一项所述的化合物或其药学上可 接受的盐、立体异构体、互变异构体,和药学上可接受的载体。
- 如权利要求1~14任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,或权利要求15所述的药物组合物在制备预防和/或治疗NLRP3炎症小体相关的疾病的药物中的用途。
- 如权利要求1~14任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体,或权利要求15所述的药物组合物在制备预防和/或治疗炎性小体相关的疾病、免疫性疾病、炎症性疾病、自身免疫性疾病或自身炎症性疾病的药物中的用途。
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