WO2025247243A1 - 一种含氮杂环化合物及其应用 - Google Patents

一种含氮杂环化合物及其应用

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Publication number
WO2025247243A1
WO2025247243A1 PCT/CN2025/097596 CN2025097596W WO2025247243A1 WO 2025247243 A1 WO2025247243 A1 WO 2025247243A1 CN 2025097596 W CN2025097596 W CN 2025097596W WO 2025247243 A1 WO2025247243 A1 WO 2025247243A1
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compound
group
atom
fluoropyridin
methyl
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French (fr)
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王平
徐石林
余蕾
孙姚良
安琪
郑泽柠
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Tongji University
Shanghai Institute of Materia Medica of CAS
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Tongji University
Shanghai Institute of Materia Medica of CAS
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to the field of chemical and pharmaceutical technology, to a nitrogen-containing heterocyclic compound and its application, and particularly to a nitrogen-containing heterocyclic compound, its application in inhibiting glutamine cyclase, a pharmaceutical composition comprising the nitrogen-containing heterocyclic compound, and its application.
  • Cancer is a leading cause of death worldwide, and combating cancer is a serious challenge to human health.
  • chemotherapy, radiotherapy, surgery, and immunotherapy have been common medical treatments for cancer.
  • Cancer immunotherapy is a treatment method that enhances the body's natural immune defenses to fight tumors.
  • the rapid development of this method has brought new hope to the treatment of cancer.
  • Existing cancer immunotherapy drugs are mainly antibody drugs targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4/B7.
  • these drugs suffer from problems in clinical practice, including immune-related toxicity, poor pharmacokinetic properties, weak penetration into tumor cells, and a narrow range of applicable populations. Meanwhile, tumor cells can achieve immune escape by inducing immunosuppression and reducing their own immunogenicity.
  • immunosuppressive signaling molecules that interact with immune cells, such as the interaction between PD-L1 and PD1, or CD47 and SIRP ⁇ , they express "don't eat me” signals, directly inhibiting the immune response and promoting tumor cell evasion of immune surveillance.
  • Glutaminyl cyclase (EC2.3.2.5) is an enzyme that catalyzes the intramolecular cyclization of N-terminal glutamine residues in peptides and proteins to generate pyroglutamic acid (pGlu*). It has important biological functions such as altering the N-terminal chemical structure of proteins, regulating activity, and enhancing stability.
  • Pyroglutamylation is a post-translational modification in which glutamine or glutamate amino acids are converted into pyroglutamic acid moieties.
  • glutamine acyl cyclase/protein sQC, QPCT
  • QPCT glutamine acyl cyclase gene
  • gQC, QPCTL, isoQC glutamine acyl cyclase-like protein
  • QPCT catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*), releasing ammonia.
  • the gene encoding QPCT is located on chromosome 2p22.3.
  • Human QPCT consists of 361 amino acids and has an N-terminal secretion signal.
  • QPCT was first isolated by Messer in 1963 from the latex of the tropical plant Carica papaya (Messer, M. 1963, Nature 4874, 1299). Twenty-four years later, the corresponding enzymatic activity was found in the animal pituitary gland (Busby, W.H.J. et al. 1987, J Biol Chem 262, 8532-8536; Fischer, W.H.
  • the enzyme QPCT is a target for drug development for the treatment of Alzheimer's disease (J Med. Chem. 2017, 60, 2573-2590; Alzheimers Res Ther 2018, 10, 107).
  • Glutamine acyl-peptide cyclotransferase-like protein also catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamate (pGlu*), releasing ammonia.
  • QPCTL is located in the Golgi complex and is encoded by chromosome 19q13.32. Mammalian QPCTLs were identified in 2008, including human and mouse QPCTL (J. Mol. Biol. 2008, 379, 966-80). Compared to QPCT, QPCTL exhibits 2 to 15-fold lower catalytic activity for several synthetic substrates.
  • QPCT is expressed at higher levels in neuronal tissues, while QPCTL expression shows no significant difference between different tissues and organs (FEBS J. 2009, 276, 6522-36).
  • the highest enzymatic QPCT/QPCTL activity was observed in the ventral brain, followed by the cortex and hippocampus.
  • QPCT knockout significantly reduced QPCT activity in the mouse brain, particularly in the hypothalamus and plasma, although activity was still detectable in peripheral organs such as the liver and spleen, which may be a result of QPCTL expression (Int. J.Dev. Neurosci. 2014, 36, 64-73).
  • the QPCTL protein contains 382 amino acid residues, including an active catalytic domain (Ser53-Leu382), a transmembrane domain (Leu35-Trp52), and an extracellular domain (Met1-Arg34) (J Biol Chem. 286, 14199-14208).
  • CD47 Cluster of Differentiation 47
  • integrin-associated protein belongs to the immunoglobulin superfamily and is expressed on the surface of various cells, including normal cells (such as erythrocytes) and various tumor cells.
  • CD47 binds to the signal regulatory protein SIRP ⁇ , thereby mediating a series of cascade reactions such as apoptosis, proliferation, and immune responses.
  • SIRP ⁇ is mainly expressed in monocytes, most macrophages in tissue subsets, and granulocytes. Its expression on macrophages is relatively stable and is not affected by factors such as inflammation.
  • SIRP ⁇ binds to the N-terminal domain of CD47
  • tyrosine residues on the immunoreceptor tyrosine-based inhibitory motif (ITIM) of SIRP ⁇ are phosphorylated, and phosphatases SHP-1/SHP-2 are recruited and activated, which in turn triggers the dephosphorylation of downstream pathway molecules, releasing a "don't eat me” signal and inhibiting the phagocytic activity of macrophages.
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • CD47 expression is closely related to the survival rate of cancer patients; patients with high CD47 expression often have poor survival rates and prognoses.
  • CD47-targeting antibody drugs have entered clinical trials. In solid tumors and hematological malignancies, CD47 antibodies can effectively inhibit tumor growth; however, these drugs can cause serious adverse reactions. This is because CD47 is also expressed in normal human erythrocytes.
  • CD47 antibodies can bind not only to CD47 on the surface of tumor cells but also to CD47 on the surface of erythrocytes, causing severe erythrocyte toxicity and other side effects. Furthermore, due to the broad expression range of CD47, antibody drugs exhibit antigen silencing effects, requiring high doses or frequent administration to achieve effective treatment. Therefore, there is an urgent clinical need to find new CD47 inhibition strategies to provide effective means for tumor immunotherapy.
  • QPCTLs can specifically regulate the CD47/SIRP ⁇ signaling axis in various cell types, and this regulation depends on QPCTL enzyme activity (Nat. Med. 2019, 25, 612-619; Cell Res. 2019, 29, 502-505). Furthermore, knocking out QPCTLs in cells or using QPCTL chemical inhibitors effectively inhibits the N-terminal pyroglutamate level of CD47 and the binding of CD47/SIRP ⁇ , but has no significant effect on the expression of CD47 on the cell surface. QPCTLs regulate the binding of CD47 and SIRP ⁇ by catalyzing the formation of pyroglutamate from glutamine at position 19 of CD47.
  • QPCTL is a potential target for tumor immunotherapy mediated by the CD47/SIRP ⁇ pathway.
  • QPCT and QPCTL can also pyroglutamate other proteins.
  • ⁇ -amyloid protein which is known to be involved in Alzheimer's disease, is pyroglutamate-modified by QPCT (Pharmacological Research, 2019 147, 104342), while C-C motif chemokine ligand 2 (CCL2) protein is pyroglutamate-modified by QPCTL (EMBO Mol Med, 2011, 3, 510-512).
  • CX3CL1 can also be pyroglutamate-modified by QPCT and QPCTL (Bioscience Reports, 2017 37, BSR20170712).
  • This invention provides a novel QPCT or QPCTL inhibitor for cancer treatment, specifically a nitrogen-containing heterocyclic compound, its use in inhibiting glutamine cyclase, a pharmaceutical composition comprising the nitrogen-containing heterocyclic compound, and its use.
  • the present invention provides the following technical solution:
  • This invention provides a nitrogen-containing heterocyclic compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof:
  • n is any integer from 0 to 3;
  • X is a carbon atom or a nitrogen atom
  • R1 is a 5-10 heteroaryl group optionally substituted by one or more R7s ;
  • R4 is a 5-10 heteroaryl group optionally substituted with one or more C1-20 alkyl groups
  • R5 is a hydrogen atom, a halogen atom, a hydroxyl group, a C1-20 alkyl group, or a C1-20 alkoxy group; optionally, when R5 is a C1-20 alkyl group, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-10 membered ring structure.
  • Each R 7 is independently a halogen atom, a C 1-20 alkyl atom optionally substituted with a C 3-10 cycloalkyl atom, a C 1-20 alkoxy atom optionally substituted with a C 3-10 cycloalkyl atom, or a C 3-10 cycloalkyloxy atom optionally substituted with a C 1-20 alkyl atom;
  • Each R 8 is independently a hydrogen atom or a C1-20 alkyl group
  • n 0 or 1;
  • X is a carbon atom or a nitrogen atom
  • R1 is a 5-10 nitrogen-containing heteroaryl group optionally substituted by one or more R7 ;
  • R4 is a 5-10 nitrogen-containing heteroaryl group optionally substituted with one or more C1-10 alkyl groups
  • R5 is a hydrogen atom, a halogen atom, a hydroxyl group, a C1-10 alkyl group, or a C1-10 alkoxy group; optionally, when R5 is a C1-10 alkyl group, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-6 membered ring structure.
  • Each R 7 is independently a halogen atom, a C1-10 alkyl group, a C1-10 alkyl group optionally substituted with a C3-6 cycloalkyl group, a C1-10 alkoxy group optionally substituted with a C3-6 cycloalkyl group, or a C3-6 cycloalkyloxy group optionally substituted with a C1-10 alkyl group.
  • Each R 8 is independently a hydrogen atom or a C1-10 alkyl group
  • n 0 or 1
  • m and n are not both 0 at the same time
  • X is a carbon atom or a nitrogen atom
  • R1 is a pyridinyl group optionally substituted with one or more R7 groups;
  • R4 is any of the following groups optionally substituted with one or more C1-10 alkyl groups: in, Indicates the combination of keys;
  • R5 is a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-10 alkyl group; optionally, when R5 is a C1-10 alkyl group, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-6 membered ring structure.
  • Each R 7 is independently substituted with a methyl, methoxy, or cyclopropyl methoxy or halogen atom;
  • Each R 8 is independently a hydrogen atom or a C1-10 alkyl group
  • the compound is as shown in formula (II):
  • the compound is as shown in formula (III):
  • p is any integer from 0 to 3, preferably 1 or 2.
  • the compound is as shown in formula (IV):
  • the compound is as shown in formula (V):
  • the compound is as shown in formula (VI) or (VII):
  • R4 is a group optionally substituted with one or two C1-10 alkyl groups, such as the following groups: in, Indicates the combination of keys;
  • R5 is a hydrogen atom or a halogen atom.
  • the compound is as shown in formula (VIII):
  • Z represents a hydrogen atom or a nitrogen atom
  • R10 is a benzyl group substituted with a hydrogen atom, a C1-10 alkyl group, or a C1-10 alkoxy group; optionally, R5 and R10 are linked to form a 5-10 membered ring structure.
  • R 11 is a hydrogen atom, a C1-10 alkyl group, or an amino group.
  • R10 is a C1-10 alkyl group. More preferably, R10 is a C1-2 alkyl group.
  • the C1-2 alkyl group includes methyl, ethyl, and -CD3 .
  • R11 is a hydrogen atom, a C1-5 alkyl group, or an amino group.
  • R4 is Z, R10 , and R11 have the definitions described in equation (VIII).
  • R1 is one of the following groups:
  • Each R 12 is an independent halogen atom
  • R 13 is a methoxy or halogen atom substituted with methyl, methoxy, or cyclopropyl groups
  • Each R 14 is independently a C1-10 alkyl group.
  • the specific structural formula of the nitrogen-containing heterocyclic compound of the present invention is as follows:
  • the present invention also provides a pharmaceutical composition in which the above-mentioned nitrogen-containing heterocyclic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug is used as the active ingredient.
  • the pharmaceutical composition contains at least one pharmaceutically acceptable carrier. Those skilled in the art can select the pharmaceutical composition according to actual needs to ensure that the active ingredient therein exerts its full effect.
  • This invention also provides a drug combination formulation comprising the above-described nitrogen-containing heterocyclic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug, or the above-described pharmaceutical composition, and an antibody.
  • the antibody is a PD-1/PD-L1 antibody or a CD47 antibody.
  • the present invention also provides the application of the above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope-labeled substances or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations, in the inhibition of glutamine cyclase.
  • the above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope-labeled substances or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations can act as glutamine cyclase inhibitors, capable of inhibiting glutamine cyclotransferase-like (QPCTL) enzymes and/or glutamine acyltransferase (QPCT), that is, capable of inhibiting, reducing or blocking the activity of QPCTL or QPCT.
  • glutamine cyclase inhibitors capable of inhibiting glutamine cyclotransferase-like (QPCTL) enzymes and/or glutamine acyltransferase (QPCT)
  • the present invention also provides the use of the above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope labels or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations in the preparation of medicaments for the prevention and/or treatment of tumors, immune diseases, neurological diseases, obesity or aging.
  • the tumor is selected from at least one of colorectal cancer, lung cancer, gastric cancer, melanoma, myeloma, breast cancer, adenocarcinoma, bladder cancer, and hematologic malignancy.
  • the immune disease is selected from at least one of eczema, alopecia areata, psoriasis, vitiligo, rheumatoid arthritis, lupus syndrome, acne, and hidradenitis suppurativa.
  • the neurological disease is selected from at least one of Alzheimer's disease, Huntington's disease, neurodegeneration of Down syndrome, depression, anxiety disorder, psychosis, and multiple sclerosis.
  • the QPCTL/QPCT activity mentioned above refers to the cyclization of the N-terminal glutamine residue into pyroglutamic acid (pGlu*) or the intramolecular cyclization of the N-terminal L-high glutamine or L- ⁇ -high glutamine into cyclopyroglutamine derivatives when ammonia is released.
  • pGlu* pyroglutamic acid
  • pGlu* intramolecular cyclization of the N-terminal L-high glutamine or L- ⁇ -high glutamine into cyclopyroglutamine derivatives when ammonia is released.
  • EC includes QPCT and QPCTL as glutamate cyclase (EC) activities, which are further defined as EC activities.
  • QPCT inhibitors and glutamine acyl cyclase inhibitors are well known to those skilled in the art, specifically enzyme inhibitors that inhibit the catalytic activity of glutamine acyl cyclase (QPCT) or the activity of its glutamine cyclase (EC).
  • QPCTL inhibitors and glutamine cyclotransferase-like protein inhibitors are well known to those skilled in the art, specifically enzyme inhibitors that inhibit the catalytic activity of glutamine cyclotransferase-like protein (QPCTL) or its glutamine cyclase (EC) activity.
  • Glutamine cyclase inhibitors include QPCT inhibitors and/or QPCTL inhibitors, which inhibit QPCT/QPCTL and have the same or similar pharmacological effects.
  • the IC50 of QPCTL inhibition is 10 ⁇ M or less, preferably 1 ⁇ M or less, even more preferably 0.1 ⁇ M or less, or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less. Therefore, although the active substance is described herein as a QPCTL inhibitor for convenience, it should be understood that such nomenclature is not intended to limit the subject matter of the invention to a specific mechanism of action.
  • This invention provides a novel nitrogen-containing heterocyclic compound that exhibits excellent inhibitory effects on glutamine cyclases (especially QPCTL and QPCT enzymes), and has promising applications in the treatment of tumors, immune diseases, neurological diseases, obesity, or aging.
  • Step a Compound MC1 (111 mg, 0.36 mmol, 1.5 eq), compound MC2 (39 mg, 0.24 mmol, 1.0 eq), and Na2CO3 (51 mg , 0.48 mmol, 2.0 eq) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and H2O (0.2 mL). Pd(dppf) Cl2 (18 mg, 0.024 mmol, 0.1 eq) was added under argon protection. The system was heated to 90 °C and reacted for 16 hours.
  • Step b Intermediate MC3 (1.47 g, 1.0 eq) was dissolved in MeOH (20 mL). Pd/C (10%, 200 mg) was added under argon protection. The system was purged three times with hydrogen at room temperature, and the reaction was carried out overnight at 45 °C. After the reaction was complete, the mixture was filtered, and the organic phase was concentrated to obtain compound MC4 (1.2 g).
  • Step c After removing the Boc protecting group from intermediate MC4, the crude 5-(piperidin-4-yl)thiazole product (0.20 g, 1.21 mmol, 1.0 eq) was dissolved in DMSO (4 mL). Then, 3-bromo-2-fluorobenzonitrile (MC5) (0.29 g, 1.45 mmol, 1.2 eq) and anhydrous potassium carbonate (0.25 g, 1.82 mmol, 1.5 eq) were added sequentially, and the mixture was heated and stirred at 100 °C for 16 hours. After the reaction was completed by TLC monitoring, dichloromethane and water were added for extraction, followed by extraction again with saturated brine and dichloromethane. The organic phase was collected and purified using a SepaBean machine T200 to finally obtain 0.15 g of intermediate MC6.
  • MC5 3-bromo-2-fluorobenzonitrile
  • anhydrous potassium carbonate (0.25 g, 1.82 mmol, 1.5 eq
  • step d intermediate MC6 (35 mg, 0.10 mmol, 1.0 eq), sodium carbonate (21 mg, 0.2 mmol, 2.0 eq), and 4-fluoro-3-pyridineboronic acid (34 mg, 0.15 mmol, 1.5 eq) were dissolved in a mixed solvent of 2 mL dioxane and 0.2 mL water. Under nitrogen protection, Pd(dppf) Cl2 (7 mg, 0.01 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product.
  • step a compound MC7 (1.05 g, 5.00 mmol, 1.0 eq), trimethylsilyl azido (636 mg, 5.5 mmol, 1.1 eq), and CuI (48 mg, 0.25 mmol, 0.05 equiv) were dissolved in DMF (9 mL) and MeOH (1 mL) under argon protection. The reaction was heated to 100 °C and stirred for 8 h. After the reaction was completed, EA (50 mL) was added for dilution, followed by washing with water (50 mL) and brine (50 mL), drying with anhydrous sodium sulfate, and then concentrating under reduced pressure.
  • Step b Under argon protection at 0°C, intermediate MC8 (30 mg, 0.12 mmol, 1.0 eq) and potassium carbonate (33 mg, 0.24 mmol, 2.0 eq) were dissolved in DMF (2 mL). Iodomethane (25 mg, 0.18 mmol, 1.5 eq) was slowly added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, EA (50 mL) was added for dilution, followed by washing with H2O (50 mL) and saline solution (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step a Under argon protection at 0°C, compound MC12 (500 mg, 7.24 mmol, 1.0 eq) was dissolved in DMF (5 mL), and then NaH (320 mg, 60% mmol, 8.0 mmol, 1.1 eq) was slowly added. The reaction was slowly heated to room temperature and stirred for 2 hours. Then, compound MC11 (2.4 g, 8.69 mmol, 1.2 eq) was added to the system, and the system was heated to 60°C and stirred overnight. After the reaction was completed, EA (50 mL) was added for dilution, followed by washing with H2O (50 mL) and brine (50 mL).
  • step a compound MC32 (251 mg, 1.2 mmol, 1.2 eq), CuSO4 ⁇ 5H2O (3 mg, 0.01 mmol, 0.01 eq), (+)-sodium ascorbate (10 mg, 0.05 mmol, 0.05 eq), and urea (2 mg, 0.02 mmol, 0.02 eq) were dissolved in MeOH/ H2O (2 mL/2 mL). Benzyl azide (133 mg, 1.0 mmol, 1.0 eq) was then added to the system, and the reaction was continued at room temperature for 16 hours.
  • Step b Intermediate MC33 (40 mg, 0.12 mmol, 1.0 eq) was dissolved in MeCN (2 mL), and then methyl iodide (103 mg, 0.72 mmol, 6.0 eq) was added. The reaction system was heated to 60 °C and reacted overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC34 (50 mg, crude).
  • step c intermediates MC34 (50 mg, 1.0 mmol, 1.0 eq) and t-BuOK (29 mg, 2.5 mmol, 2.5 eq) were dissolved in MeCN (10 mL) under argon protection at 0 °C, and the mixture was slowly heated to room temperature and reacted overnight. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC35 (20 mg, 74.9% yield).
  • Step a Dissolve compound MC37 (814 mg, 11.0 mmol, 1.0 eq) in acetonitrile (5 mL), then add DMFDMA (1.35 g, 11.0 mmol, 1.0 eq) to the system, heat to 50 °C and stir for 1 hour. Then add compound MC38 (1.0 g, 5.5 mmol, 0.5 eq) and HOAc (1 mL) to the system, heat to 100 °C and stir for 18 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate MC39 (1.5 g, 52.0% yield).
  • Steps b and c Using intermediate MC39, the reaction proceeds as described in step c of Example 1 to generate intermediate MC40. Then, as described in step d of Example 1, compound 11 is synthesized.
  • step a compound MC60 (536 mg, 2.0 mmol, 1.0 eq) and Lawesson's reagent (409 mg, 2.1 mmol, 1.05 eq) were dissolved in toluene (20 mL), and the reaction system was heated to reflux and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC61 (290 mg, 51.1% yield).
  • step b intermediate MC61 (284 mg, 1.0 mmol, 1.0 eq) and compound MC62 (72 mg, 1.2 mmol, 1.2 eq) were dissolved in DCM (5 mL), and then AgOBz (460 mg, 2.0 mmol, 2.0 eq) and HOAc (0.17 mL) were added. The reaction system was heated to reflux and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC63 (170 mg, 58.0% yield).
  • Step a Dissolve MC71 (1.32 g, 16.0 mmol, 1.0 eq) in THF (30 mL). Under argon protection, cool the system to 78 °C, slowly add n-BuLi (10 mL, 1.6 M, 1.0 eq), and continue stirring for 1 hour. Then add triethylchlorosilane (2.4 g, 16.0 mmol, 1.0 eq), slowly heat to room temperature, then cool again to -78 °C, slowly add n-BuLi (10 mL, 1.6 M, 1.0 eq), and continue stirring for 1 hour. Then heat the system to -15 °C and cool again to -78 °C.
  • intermediate MC74 is obtained as in step c of the synthetic route in Example 1.
  • Step a Intermediate MC73 (300 mg, 1.07 mmol, 1.0 eq) was dissolved in DMF (10 mL). NaH (85 mg, 60%, 2.14 mmol, 2.0 eq) was added to the system under argon protection at 0 °C. The system was heated to room temperature and stirred for 2 hours. Then, iodomethane (303 mg, 2.14 mmol, 2.0 eq) was added, and the system was heated to reflux and stirred overnight.
  • intermediate MC75 is obtained as in step c of the synthetic route in Example 1.
  • Step a Intermediate MC74 (10 mg, 0.027 mmol, 1.0 eq) was dissolved in DCM (2 ml). DAST (18 mg, 0.11 mmol, 4.0 eq) was added to the above system at 0 °C and stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. The intermediate MC80 was obtained by silica gel column chromatography as a white oily liquid (7 mg, 71.6% yield).
  • Step a Compound MC81 (500 mg, 2.325 mmol, 1.0 eq), butyryl chloride (250 mg, 2.325 mmol, 1.0 eq), and DIPEA (460 ⁇ L, 1.2 eq) were dissolved in DCM (10 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was cooled to room temperature, and water and EA were added for extraction. The organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a yellow oily compound MC82 (410 mg, 62.4% yield).
  • Step b After removing the Cbz protecting group from intermediate MC83, the crude product (0.20 g, 1.21 mmol, 1.0 eq) was dissolved in DMSO (4 mL). Then, intermediate 3 (0.41 g, 1.45 mmol, 1.2 eq) and anhydrous potassium carbonate (0.25 g, 1.82 mmol, 1.5 eq) were added sequentially, and the mixture was heated and stirred at 100 °C for 16 hours. After the reaction was completed by TLC monitoring, dichloromethane and water were added for extraction, followed by extraction again with saturated brine and dichloromethane. The organic phase was collected and purified using a SepaBean machine T200, finally yielding 0.15 g of intermediate 5.
  • Step c Intermediate MC84 (43 mg, 0.10 mmol, 1.0 eq), sodium carbonate (21 mg, 0.2 mmol, 2.0 eq), and 4-fluoro-3-pyridineboronic acid (34 mg, 0.15 mmol, 1.5 eq) were dissolved in a mixed solvent of 2 mL dioxane and 0.2 mL water. Under nitrogen protection, Pd(dppf) Cl2 (7 mg, 0.01 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product.
  • Step a 1-Bromo-2-fluorobenzene MC85 (1.75 g, 10.0 mmol, 10.0 eq) was dissolved in tetrahydrofuran (30 mL) under argon protection. After cooling the system to -78 °C, LDA (6 mL, 2 M, 1.2 eq) was added dropwise over 1 h while maintaining the temperature at -78 °C. Then, DMSO (1.1 mL, 13.0 mmol, 1.3 eq) was added to the system, and the mixture was stirred at -78 °C for 2 h.
  • LDA 6 mL, 2 M, 1.2 eq
  • Step b MC86 (1.40 g, 6.4 mmol, 1.0 equiv) was dissolved in DCM (30 mL) under argon protection. After the reaction system was cooled to 0 °C, m-CPBA (2.2 g, 30.0 mmol, 2.2 eq) was slowly added. The system was slowly warmed to room temperature to continue the reaction. After the reaction was completed, DCM (70 mL) was added to dilute the system, and then the mixture was washed with saturated NaHCO3 aq (500 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • DCM 70 mL
  • brine 50 mL
  • Step c Using intermediate MC87 and compound MC83, MC88 (105 mg, 21.7% yield) was obtained via the synthetic route step c in Example 1.
  • Step a After removing the Cbz protecting group from compound MC83, 4-(4-methyl-4H-[1,2,4]triazol-3-yl)-piperidine (1.0 g, 6.02 mmol, 1.0 eq) was dissolved in DMSO (15 mL). Potassium carbonate (2.5 g, 18.06 mmol, 3.0 eq) and 1-bromo-2-fluoro-3-nitrobenzene (MC89) (2.6 g, 12.04 mmol, 2 eq) were added to the system. The mixture was heated to 60 °C and reacted with stirring for 4 hours. After cooling to room temperature, the mixture was filtered, and the solution was concentrated under pressure.
  • Step b Intermediate 1-(2-bromo-6-nitrobenzene)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (0.65 g, 1.78 mmol, 1.0 eq), Na2CO3 ( 0.38 g, 3.56 mmol, 2.0 eq), and pinacol ester of 2-fluoropyridine 5-borate (0.6 g, 2.67 mmol, 1.5 eq) were dissolved in a mixed solvent of 1,4-dioxane (9 mL) and H2O (1 mL). After purging the reaction system with nitrogen, Pd(dppf) Cl2 (0.13 g, 0.18 mmol, 0.1 eq) was added.
  • Step a Compound 33 (0.6 g, 1.57 mmol, 1.0 eq) and reduced iron powder (0.88 g, 15.7 mmol, 10.0 eq) were dissolved in a mixed solvent of EtOH (9 mL) and H2O (1 mL), and then NH4Cl (0.83 g, 15.7 mmol, 10.0 eq) was added. The reaction system was heated to 70 °C and stirred for 3 h. After the reaction was completed, DCM (20 mL) was added to dilute the system, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product MC91 (500 mg).
  • Step b At room temperature, MC91 (25 mg, 0.071 mmol, 1.0 eq) was dissolved in Ac2O (0.1 mL) and HCOOH (0.3 mL) solution, and the system was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and compound 33 was purified by prep-HPLC to obtain a white solid (14 mg, 51.7% yield).
  • the synthetic route of compound 36 is shown in the figure above.
  • the crude MC91 obtained above (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM (2.0 mL), and methanesulfonyl chloride (16 mg, 0.14 mmol, 1.5 eq) and TEA (18 mg, 0.18 mmol, 1.5 eq) were added at 0 °C.
  • the reaction was heated to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure.
  • the product was separated and purified by prep-HPLC to obtain compound 36 as a yellow solid product (20 mg, yield 54%).
  • Step a compound 90 (365 mg, 1.0 mmol, 1.0 eq) and reduced iron powder (560 mg, 10.0 mmol, 10.0 eq) were dissolved in a mixed solvent of EtOH (20 mL) and H2O ( 2 mL), and then NH4Cl (560 g, 10.0 mmol, 10.0 eq) was added.
  • EtOH 20 mL
  • H2O 2 mL
  • NH4Cl 560 g, 10.0 mmol, 10.0 eq
  • the reaction system was heated to 50 °C and stirred for 3 h. After the reaction was completed, DCM (200 mL) was added to dilute the system, and the mixture was filtered and concentrated under reduced pressure to obtain crude product (500 mg).
  • step b intermediates N-(3-bromo-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (0.735 g, 1.78 mmol, 1.0 eq), Na2CO3 ( 0.38 g, 3.56 mmol, 2.0 eq) and 3-(cyclopropylmethoxy)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridine (0.6 g, 2.67 mmol, 1.5 eq) were dissolved in a mixed solvent of 1,4-dioxane (9 mL) and H2O (1 mL).
  • step a MC53 (500 mg, 3.01 mmol, 1 eq), MC104 (1.07 g, 4.52 mmol, 1.5 eq), and potassium carbonate (541 mg, 3.91 mmol) were dissolved in DMSO (5 mL), and the reaction was carried out at 50 °C for 2 h. The reaction was quenched with water and then extracted with EA and water. The organic phase was distilled under reduced pressure, and the concentrate was purified by silica gel column chromatography using DCM:MeOH (40:1-10:1) to give a pale yellow oily liquid compound MC105 (580 mg, 53% yield).
  • step b MC105 (142 mg, 0.39 mmol, 1 eq), Fe (219 mg, 3.9 mmol, 10 eq), and NH4Cl (211 mg, 3.9 mmol, 10 eq) were dissolved in ethanol (5 mL) and water (1 mL). The temperature was raised to 70 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was filtered while hot, concentrated under reduced pressure, and the concentrate was dissolved in DCM and filtered to remove salt. The filtrate was concentrated under reduced pressure to obtain a grayish-white solid, crude MC106.
  • step c MC106 (131 mg, 0.39 mmol, 1 eq), methanesulfonyl chloride (89 mg, 0.78 mmol, 2 eq) and pyridine (62 mg, 0.78 mmol, 2 eq) were dissolved in DCM (5 mL), the temperature was raised to 50 °C, and the reaction was stirred for 12 h. The solution was quenched with water, extracted with EA and water, concentrated under reduced pressure, and purified by silica gel column chromatography with DCM:MeOH (40:1-10:1) to give a brown oily liquid compound MC107 (138 mg, 88%).
  • step d MC108 (162 mg, 0.39 mmol, 1 eq), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (132 mg, 0.59 mmol, 1.5 eq), and sodium carbonate (100 mg, 0.78 mmol, 2 eq) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Pd(dppf) Cl2 was added under argon protection. The temperature was raised to 85 °C, and the reaction was stirred for 12 h. The reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by prep-HPLC to obtain a yellow solid compound 94.
  • Step a Compound MC89 (1.18 g, 5.0 mmol, 1.0 eq), compound MC1 (1.43 g, 10.0 mmol, 2.0 eq), and K3PO4 (2.12 g, 10.0 mmol, 2.0 eq) were dissolved in a mixed solvent of DMSO (10 mL) . The system was heated to 80 °C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and EA, and the organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a yellow oily compound MC2 (1.6 g, 93.3% yield).
  • step b compound MC2 (1.6 g, 4.66 mmol, 1.0 eq) and reduced iron powder (2.8 g, 10.0 mmol, 50.0 eq) were dissolved in a mixed solvent of EtOH (20 mL) and H2O (2 mL), and then NH4Cl (2.8 g, 10.0 mmol, 50.0 eq) was added.
  • EtOH 20 mL
  • H2O 2 mL
  • NH4Cl 2.8 g, 10.0 mmol, 50.0 eq
  • Step c Dissolve crude product MC3 (2.0 g, crude) in DCM (20.0 mL), and add methanesulfonyl chloride (773 mg, 6.75 mmol, 1.5 eq) and pyridine (712 mg, 9 mmol, 2.0 eq) at 0 °C. The reaction was heated to 50°C and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by silica gel chromatography to obtain compound MC4 as a yellow solid product (1.76 g, yield 99%).
  • Step d Dissolve crude product MC4 (1.76 g, 4.5 mmol, 1.0 eq) in EtOH (20.0 mL) and add hydrazine hydrate (3 mL). The reaction was heated to 90°C and stirred for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by silica gel chromatography to obtain compound MC5 as a white solid product (1.24 g, yield 71%).
  • Step e Dissolve MC5 (610 mg, 1.56 mmol, 1.0 eq) in dioxane (10 mL) and water (1 mL), and add CNBr (497 mg, 4.69 mmol, 3.0 eq) and NaHCO3 (524 mg, 6.24 mmol, 4.0 eq). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 10% NaHCO3 solution ( 20 mL). The precipitated solid was obtained by filtration and washed with water (20 mL). The resulting solid was further dried under vacuum to give MC6 (530 mg, 78.8%) as a pale yellow solid.
  • Step f Add N-dimethylformamide dimethyl acetal (0.33 mL, 2.5 mmol, 2.0 eq) to a solution of MC6 (530 mg, 1.23 mmol, 1.0 eq) in dioxane (4 mL) at room temperature. Stir the reaction mixture at 100 °C for 2 h. After complete consumption of the starting material as monitored by TLC, concentrate the mixture under reduced pressure to obtain MC7 (600 mg, crude) as a yellow solid. The crude product itself is used in the next step without any further purification.
  • Step g Add a solution of 600 mg (crude) of dioxane (6 mL) to a sealing tube, and add methylamine (25% MeOH solution, 6 mL) and AcOH (0.220 mL). Stir the reaction mixture at 110 °C for 16 hours. After the reaction is complete, remove the solvent under reduced pressure, and purify the product by silica gel chromatography to obtain compound MC8 as a white solid product (230 mg, two-step yield 43.6%). LRMS(ESI)calcd for C 15 H 22 BrN 6 O 2 S[M+H] + 429.2,found:429.1.
  • step h intermediate MC8 (85 mg, 0.20 mmol, 1.0 eq), sodium carbonate (64 mg, 0.6 mmol, 3.0 eq), and 4-fluoro-3-pyridineboronic acid (89 mg, 0.4 mmol, 2.0 eq) were dissolved in a mixed solvent of 4 mL dioxane and 0.4 mL water. Under nitrogen protection, Pd(dppf) Cl2 (15 mg, 0.02 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product.
  • Step a 3-Bromopropanol MC123 (1 g, 7.2 mmol, 1 eq) and DMAP were dissolved in pyridine (15 mL). After the system temperature was lowered to 0 °C, p-methyl tert-butyryl chloride (955 mg, 7.92 mmol, 1.1 eq) was added dropwise, and then the temperature was raised to room temperature and the reaction was stirred for 30 min.
  • Step b MC124 (1.38 g, 6.2 mmol, 1 eq) and thiourea (567 mg, 7.44 mmol, 1.2 eq) were dissolved in ethanol (7 ml). The mixture was heated to 80 °C and stirred for 2 h. The solvent was then removed by concentration under reduced pressure. The concentrate was dissolved in DCM, filtered to remove thiourea, and the solvent was removed by rotary evaporation under reduced pressure. The concentrate was then washed with diethyl ether to remove excess MC125, and the filtered product was a white solid crude product MC125 (1.33 g, 98% yield).
  • Step c Crude MC125 was dissolved in water (0.9 mL) and acetonitrile (15 mL), the temperature was lowered to 0 °C, tert-butyl hypochlorite was added dropwise, and the reaction was stirred for 30 min. Extracted with ethyl acetate and water, the organic phase was concentrated under reduced pressure to obtain a pale yellow solid crude product MC126 (1.32 g, 88% yield).
  • step d MC91 (40 mg, 0.12 mmol, 1 eq), crude MC126 (88 mg, 0.36 mmol, 3 eq), and pyridine (28 mg, 0.36 mmol, 3 eq) were dissolved in DCM. The temperature was raised to 50 °C, and the reaction was stirred for 12 h. The solvent was then removed by rotary evaporation under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using DCM:MeOH (20:1-10:1) to obtain a brown oily liquid compound MC127 (25 mg, 37% yield). [M+H] + 559.2, found: 559.2.
  • step e MC127 (25 mg, 0.045 mmol, 1 eq), NaOH (20 mg, 0.45 mmol, 10 eq) and tetrabutylammonium hydrogen sulfate (8 mg, 0.023 mmol, 0.5 eq) were dissolved in tetrahydrofuran and stirred at room temperature for 3 h. Reduced pressure concentration was performed, and the concentrate was separated and purified by prep-HPLC to obtain a brownish-yellow solid compound 115.
  • the method for testing the QPCTL enzyme (also known as gQC or isoQC) inhibitory activity of the compound is as follows:
  • the reaction system consists of QPCTL protease, the fluorescent substrate glutamine 7-amino-4-methylcoumarin (Gln-AMC), the compound, and pyroglutamyl aminopeptidase I (PGPEP I).
  • the reaction is carried out in a black 384-well plate.
  • 12.5 ⁇ L of QPCTL protease (concentration 5.7 ng/ ⁇ L) and 2.5 ⁇ L of the compound at different concentrations are mixed and reacted in a shaker at 37°C and 100 rpm for 10 minutes.
  • the obtained fluorescence signal values were analyzed using GraphPad Prism 8.0 to obtain the inhibition rate and IC50 of the compounds, where A ⁇ 10 nM, 10 nM ⁇ B ⁇ 100 nM, 100 nM ⁇ C ⁇ 1000 nM, and D > 1000 nM.
  • the activity data are shown in Table 1 below.
  • the compound of the present invention has excellent QPCTL enzyme inhibitory activity and can be used as a glutamine cyclase inhibitor. Further research can be conducted on its anti-tumor and other therapeutic effects.
  • the method for testing the QPCT enzyme (also known as sQC) inhibitory activity of the compound is as follows:
  • the reaction system consists of QPCT protease, the fluorescent substrate glutamine 7-amino-4-methylcoumarin (Gln-AMC), the compound, and pyroglutamyl aminopeptidase I (PGPEP I).
  • the reaction is carried out in a black 384-well plate.
  • 12.5 ⁇ L of QPCT protease (concentration 3.82 ng/ ⁇ L) and 2.5 ⁇ L of the compound at different concentrations are mixed and reacted in a shaker at 37°C and 100 rpm for 10 minutes.
  • the obtained fluorescence signal values were analyzed using GraphPad Prism 8.0 to obtain the inhibition rate and IC50 of the compounds, where A ⁇ 10 nM, 10 nM ⁇ B ⁇ 100 nM, and 100 nM ⁇ C ⁇ 1000 nM.
  • the activity data are shown in Table 2 below.
  • the compound of the present invention has excellent QPCT enzyme inhibitory activity and can be used as a glutamine cyclase inhibitor. Further research will be conducted on its therapeutic effects on Alzheimer's disease and anti-tumor diseases.
  • the method for testing the cellular activity of the compound is as follows:
  • the inhibitory activity of the compounds against N-terminal pyroglutamate modification (pGlu-CD47) of CD47 cells was detected as follows: 293T cells were seeded at a density of 10,000/well in 48-well plates. After treatment with different concentrations of the compounds for 48 hours, the in vitro activity of the compounds was tested using flow cytometry (FACS). The level of N-terminal pyroglutamate modification (pGlu-CD47) of CD47 on the cell surface was detected using the CD47 flow cytometry antibody CC2C6. After treatment with the compounds, the cells were washed with PBS and resuspended in 100 ⁇ L of FACS buffer.
  • PQ912 (CAS: 1276021-65-8) and SEN177 (CAS: 2117405-13-5) are both known glutamine acyl cyclase inhibitors.
  • positive control drugs they demonstrate that the compounds of the present invention have better enzyme inhibitory activity and antitumor activity, and demonstrate that the compounds of the present invention have better drug development potential.

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Abstract

本发明公开了一种含氮杂环化合物及其应用，其具有如式(I)所示的结构。本发明的化合物抑制谷氨酰胺环化酶的效果优异，可应用于治疗肿瘤、免疫性疾病、神经性疾病、肥胖或衰老，应用前景好。

Description

一种含氮杂环化合物及其应用 技术领域
本发明涉及化学医药技术领域，涉及一种含氮杂环化合物及其应用，特别涉及一种含氮杂环化合物、其在抑制谷氨酰胺环化酶上的应用、包含含氮杂环化合物的药物组合物及其应用。
背景技术
肿瘤是导致人类死亡的重要原因，抗击癌症是人类健康面临的严峻挑战。多年来，化学治疗、放射治疗、手术和免疫疗法肿瘤治疗的常用医学手段。肿瘤免疫疗法是一种通过增强人体自然免疫防御以对抗肿瘤的治疗方法。近年来，该方法的迅速发展为人类治疗肿瘤带来了新的希望。现有的肿瘤免疫治疗药物，主要为靶向PD-1/PD-L1和CTLA-4/B7等免疫检查点的抗体药物，但是该类药物在临床上存在免疫相关毒性、药代动力学性质不佳、肿瘤治疗渗透能力弱以及适用人群窄等问题。同时肿瘤细胞可以通过诱导免疫抑制和降低自身免疫原性来实现免疫逃逸。例如，通过高表达免疫抑制信号分子与免疫细胞相互作用，如PD-L1与PD1、CD47与SIRPα的相互作用等，表达“不要吃我”信号直接抑制免疫应答，促进肿瘤细胞逃避免疫监视。
谷氨酰胺酰基环化酶(Glutaminyl cyclase，EC2.3.2.5)是一种可以催化多肽、蛋白等N端谷氨酰胺残基分子内环化反应生成焦谷氨酸(pGlu*)的酶，具有改变蛋白等N端化学结构、调节活性、增强稳定性等重要生物学功能。
焦谷氨酰化是一种翻译后修饰，其中谷氨酰胺或谷氨酸氨基酸被转化为焦谷氨酸部分。目前已知人体中有两种基因编码的酶参与催化这个N端焦谷氨酰化反应，包括谷氨酰胺酰基环化酶基因(Glutaminyl-peptide cyclotransferase，QPCT)编码的谷氨酰胺酰基环化酶/蛋白(sQC，QPCT)和谷氨酰胺酰基环化酶样基因(glutaminyl-peptide cyclotransferase like，QPCTL)编码的谷氨酰胺酰基环化酶样蛋白(gQC，QPCTL，isoQC)。
QPCT催化N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*)，释放氨。编码QPCT的基因位于染色体2p22.3。人类QPCT由361个氨基酸组成，具有N端分泌信号，QPCT最初由Messer于1963年从热带植物番木瓜(Carica papaya)的胶乳中分离(Messer，M.1963，Nature 4874，1299)。24年后，在动物垂体中发现相应的酶促活性(Busby，W.H.J.等人1987，J Biol Chem 262，8532-8536；Fischer，W.H.和Spiess，J.1987，Proc Natl Acad Sci USA 84，3628-3632)。对于哺乳动物QPCT，Gln通过QPCT转化为pGlu可以由TRH和GnRH的前体证实(Busby，W.H.J.等人1987，J Biol Chem 262，8532-8536；Fischer，W.H.和Spiess，J.1987，Proc Natl Acad Sci USA 84，3628-3632)。此外，QPCT的最初定位实验显示与其推定的催化产物共定位于牛垂体中，进一步增进所提出的在肽激素合成中的功能(Bockers，T.M.等人1995，J Neuroendocrinol 7，445-453)。据证实，重组人QPCT及来自脑提取物的QPCT酶活性均催化N端谷氨酰胺以及谷氨酸氨酸环化。最出人意料的是发现约pH 6.0有利于环化酶催化的Glu-转化，而Gln-转化为pGlu-衍生物发生在约8.0的最佳pH。因为抑制重组人QPCT和来自猪垂体提取物的QPCT-活性可以抑制pGlu-Aβ-相关肽的形成，所以酶QPCT是用于治疗阿尔茨海默病的药物开发的靶标(J Med.Chem.2017,60,2573-2590；Alzheimers Res Ther 2018,10,107)。
谷氨酰胺酰肽环转移酶样蛋白(QPCTL)亦催化N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*)，释放氨。QPCTL定位于高尔基复合体中，由染色体19q13.32编码该基因。哺乳动物QPCTL于2008年确定，包括人QPCTL和鼠QPCTL(J.Mol.Biol.2008,379,966-80)。与QPCT相比，QPCTL对几种合成底物的催化活性低2至15倍。此外，QPCT在神经元组织中的表达较高，而QPCTL的表达在不同组织和器官之间没有显着差异(FEBS J.2009,276,6522-36)。在九个不同的小鼠品系中，最高的酶促QPCT/QPCTL活性在大脑腹侧，其次是皮质和海马。QPCT敲除显着降低了小鼠大脑中的QPCT活性，尤其是在下丘脑和血浆中，尽管在肝脏和脾脏等外周器官中仍可检测到活性，这可能是QPCTL表达的结果(Int.J.Dev.Neurosci.2014,36,64-73)。QPCTL蛋白包含382个氨基酸残基，包括活性催化域(Ser53-Leu382)、跨膜域(Leu35-Trp52)、胞外域(Met1-Arg34)(J Biol Chem.286,14199-14208)。
CD47(Cluster of Differentiation 47)也被称为整合素相关蛋白，属于免疫球蛋白超家族成员，其在多种细胞表面均可以表达，包括正常细胞(如红细胞)以及多种肿瘤细胞。CD47和信号调节蛋白SIRPα(Signal Regulatory Proteinα)相互结合，从而介导细胞凋亡、增殖、免疫反应等一系列级联反应。SIRPα主要表达在单核细胞、组织亚群中的大多数巨噬细胞、粒细胞等细胞中，其在巨噬细胞上的表达比较稳定，不受炎症等因素的影响。SIRPα与CD47的N端结构域相互结合后，SIRPα的免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based Inhibitory motifs，ITIM)上的酪氨酸残基被磷酸化，磷酸酶SHP-1/SHP-2被招募和激活，进而引发下游通路分子进行去磷酸化过程，释放“别吃我”信号，抑制巨噬细胞的吞噬作用。CD47/SIRPα相互结合最终引发一系列的细胞负调控作用，包括抑制巨噬细胞和中性粒细胞的吞噬作用以及细胞毒作用，进而使肿瘤细胞逃避免疫监视。
研究发现，阻断CD47/SIRPα相互作用可以促进巨噬细胞对肿瘤细胞的吞噬，从而发挥抗肿瘤作用。临床数据也表明CD47的表达与癌症病人生存率密切相关，高表达CD47的病人往往伴随着较差的生存率以及预后表现。目前已有多个靶向CD47的抗体药物进入临床研究，在实体瘤和血液肿瘤中CD47抗体能够有效地抑制肿瘤生长，但是这类药物会产生严重不良反应。这是因为CD47在人体正常红细胞中也表达，CD47抗体除了能与肿瘤细胞表面的CD47结合，也能与红细胞表面的CD47结合，从而引起严重的红细胞毒性等副作用。此外，由于CD47表达范围广，抗体药物存在着抗原沉默效应，抗体药物需要较高剂量或者频繁给药才能实现有效治疗。因此，临床上迫切需要寻找新的CD47抑制策略，为肿瘤免疫治疗提供有效手段。
研究表明QPCTL可以在多种细胞中特异性调控CD47/SIRPα信号轴，且该调控作用依赖于QPCTL酶活性(Nat.Med.2019,25,612-619；Cell Res.2019,29,502-505)。此外，在细胞中敲除QPCTL或者使用QPCTL化学抑制剂，可以有效抑制CD47的N端焦谷氨酸化水平以及CD47/SIRPα的结合，但是对细胞表面CD47的表达无明显影响。QPCTL通过催化CD47的第19位谷氨酰胺形成焦谷氨酸，从而调控CD47和SIRPα的结合。此外，体外抗体调理细胞的吞噬作用增加和体内调理肿瘤细胞的清除增加被证明是阻断QPCTL活性或产生的影响(Nat.Med.2019,25,612-619)。在QPCTL基因敲除的小鼠中，QPCTL的缺失会促进骨髓中巨噬细胞的发育(Cell Res.2019,29,502-505)，以及增强中性粒细胞介导的肿瘤细胞杀伤作用(Nat.Med.2019,25,612-619；Cancer Sci 2021,112,3029-3040)。QPCTL是高尔基体定位蛋白，在成熟血红细胞中几乎无表达。因此，通过抑制QPCTL蛋白功能阻断CD47/SIRPα通路，有可能减少对正常红细胞CD47功能的影响，从而避免CD47抗体药物引起的严重副作用。综上所述，QPCTL是通过CD47/SIRPα通路介导的肿瘤免疫治疗的潜在靶点。
除CD47外，QPCT和QPCTL还可将其他蛋白质焦谷氨酸化。例如，已知参与阿尔茨海默病的β淀粉样蛋白会被QPCT焦谷氨酸化(Pharmacological research，2019 147,104342)，而C-C基序趋化因子配体2(CCL2)蛋白则被QPCTL焦谷氨酸化(EMBO Mol Med，2011，3,510-512)，此外，CX3CL1的N端也能被QPCT和QPCTL焦谷氨酸化(Bioscience reports，2017 37,BSR20170712)。近期有研究发现，QPCTL也能对BTN(butyrophilin)家族蛋白特别是BTN2A1、BTN3A1、BTN3A2和BTN3A3的N端发生焦谷氨酸化(Cell Mol Immunol,2024，21，362–373)。不过，由于酶特性和底物偏好的巨大重叠，不排除QPCT和QPCTL在这些目标的焦谷氨酰化过程中存在一定量的功能重叠。
然而，QPCT或QPCTL抑制剂至今无靶向药物上市。
因此，开发一种新的QPCT或QPCTL抑制剂以为肿瘤、免疫性疾病、神经性疾病、肥胖或衰老提供新的治疗方法极具现实意义。
发明内容
本发明提供了一种新的QPCT或QPCTL抑制剂为肿瘤治疗提供新的治疗方法，具体为一种含氮杂环化合物、其在抑制谷氨酰胺环化酶上的应用、包含含氮杂环化合物的药物组合物及其应用。
为了实现上述目的，本发明提供以下技术方案：
本发明提供了一种如式(I)所示的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药：
其中：
表示单键或不存在；
m为0-3中的任一整数，n为0-3中的任一整数；
X为碳原子或者氮原子；
R1为任选被一个或多个R7取代的5-10元杂芳基；
R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或C1-20烷氧基；
R4为任选被一个或多个C1-20烷基取代的5-10元杂芳基；
R5为氢原子、卤原子、羟基、C1-20烷基或C1-20烷氧基；任选地，当R5为C1-20烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-10元环状结构；
R6为氢原子或-NR8C(＝O)R9；
每一个R7各自独立地为卤原子、任选被C3-10环烷基取代的C1-20烷基、任选被C3-10环烷基取代的C1-20烷氧基或任选被C1-20烷基取代的C3-10环烷基氧基；
每一个R8各自独立地为氢原子或C1-20烷基；
每一个R9各自独立地为氢原子、C1-20烷基、C1-20卤代烷基、-NHC1-20烷基、-C1-20亚烷基-C1-20烷氧基、C3-10环烷基、5-10元杂环烷基、5-10元杂芳基或C6-10芳基；所述C3-10环烷基、5-10元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-20烷基或-C(＝O)OC1-20烷基取代；或，R8和R9相连形成5-10元环状结构。
在一些优选的实施方案中，式(I)中：
m为0或1，n为0或1；
X为碳原子或者氮原子；
R1为任选被一个或多个R7取代的5-10元含氮杂芳基；
R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或C1-10烷氧基子；
R4为任选被一个或多个C1-10烷基取代的5-10元含氮杂芳基；
R5为氢原子、卤原子、羟基、C1-10烷基或C1-10烷氧基；任选地，当R5为C1-10烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-6元环状结构；
R6为氢原子或-NR8C(＝O)R9；
每一个R7各自独立地为卤原子、C1-10烷基、任选被C3-6环烷基取代的C1-10烷基、任选被C3-6环烷基取代的C1-10烷氧基或任选被C1-10烷基取代的C3-6环烷基氧基；
每一个R8各自独立地为氢原子或C1-10烷基；
每一个R9各自独立地为氢原子、C1-10烷基、C1-10卤代烷基、-NHC1-10烷基、-C1-10亚烷基-C1-10烷氧基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基；所述C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-10烷基或-C(＝O)OC1-10烷基取代；或，R8和R9相连形成5-6元环状结构。
在一些更优选的实施方案中，式(I)中：
m为0或1，n为0或1，且m和n不同时为0；
X为碳原子或者氮原子；
R1为任选被一个或多个R7取代的吡啶基；
R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或C1-10烷氧基；
R4为任选被一个或多个C1-10烷基取代的以下基团：其中，表示结合键位；
R5为氢原子、卤原子、羟基或C1-10烷基；任选地，当R5为C1-10烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-6元环状结构；
R6为氢原子或-NR8C(＝O)R9；
每一个R7各自独立地为甲基、甲氧基、环丙基取代的甲氧基、卤原子；
每一个R8各自独立地为氢原子或C1-10烷基；
每一个R9各自独立地为氢原子、C1-10烷基、C1-10卤代烷基、-NHC1-10烷基、-C1-10亚烷基-C1-10烷氧基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基；所述C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-10烷基或-C(＝O)OC1-10烷基取代；或，R8和R9相连形成五元环状结构。
在一些实施方案中，所述化合物如式(II)所示：
其中，m、n、X、R1、R2、R3、R4、R5和R6具有如式(I)中所述的定义。
在一些实施方案中，所述化合物如式(III)所示：
其中，m、n、X、R1、R2、R3和R6具有如式(I)中所述的定义；
p为0-3中的任一整数，优选1或2。
在另一些实施方案中，所述化合物如式(IV)所示：
其中，m、n、X、R1、R2、R3、R4、R5和R6具有如式(I)中所述的定义。
在另一些实施方案中，所述化合物如式(V)所示：
在一些优选的实施方案中，所述化合物如式(VI)或者(VII)所示：
其中，m、n、X、R1、R4、R5、R8和R9具有如式(I)中所述的定义；
优选地，R4为任选被一个或两个C1-10烷基取代的以下基团：其中，表示结合键位；
优选地，R5为氢原子或卤原子。在一些优选的实施方案中，所述化合物如式(VIII)所示：
其中，m、n、X、R1、R2、R3、R5和R6具有如式(I)中所述的定义；
Z为氢原子或氮原子；
R10为氢原子、C1-10烷基或C1-10烷氧基取代的苯甲基；任选地，R5和R10相连形成5-10元环状结构；
R11为氢原子、C1-10烷基或胺基。
优选地，R10为C1-10烷基。进一步优选地，R10为C1-2烷基。其中，C1-2烷基中包括甲基、乙基、-CD3。
优选地，R11为氢原子、C1-5烷基或氨基。
在一些优选的实施方案中，R4为其中，Z、R10、R11具有如式(VIII)所述的定义。
在一些优选的实施方案中，所述R1为以下基团中的一种：
其中，表示结合键位；
每一个R12各自独立地为卤原子；
R13为甲基、甲氧基、环丙基取代的甲氧基或卤原子；
每一个R14各自独立地为C1-10烷基。
在一些具体的实施方案中，本发明的含氮杂环化合物的具体结构式为：


本发明还提供了一种药用组合物，其以上述含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药作为活性成分。在一些实施方案中，所述药用组合物含有至少一种药学上可接受的载体。本领域技术人员可根据实际需求对药用组合物进行选择以使得其中的活性成分充分发挥作用。
本发明还提供了一种药物联用形式，其包含上述含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药或者上述药用组合物，以及抗体。在一些实施方案中，所述抗体为PD-1/PD-L1抗体或CD47抗体。
本发明还提供了上述含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，或者上述药用组合物，或者上述药物联用形式在抑制谷氨酰胺环化酶上的应用。上述含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，或者上述药用组合物，或者上述药物联用形式可以作为谷氨酰胺环化酶抑制剂，能够抑制谷氨酸酰胺肽环转移酶样(QPCTL)酶和/或谷氨酰胺酰肽环转移酶(QPCT)，即能够抑制、降低或阻断QPCTL或QPCT的活性。
另外，本发明还提供了上述含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，或者上述药用组合物，或者上述药物联用形式在制备预防和/或治疗肿瘤、免疫性疾病、神经性疾病、肥胖或衰老的药物中的应用。
在一些实施方案中，所述肿瘤选自结直肠癌、肺癌、胃癌、黑色素瘤、骨髓瘤、乳腺癌、腺癌、膀胱癌和血液瘤中的至少一种。
在一些实施方案中，所述免疫性疾病选自湿疹、斑秃、银屑病、白癜风、类风湿性关节炎、红斑狼疮综合征、痤疮和化脓性汗腺炎中的至少一种。
在一些实施方案中，所述神经性疾病选自阿尔茨海默病、亨廷顿病、唐氏综合征中的神经变性、抑郁症、焦虑症、精神病和多发性硬化症中的至少一种。
以上技术方案仅为本发明的一种可行的技术方案而已，本发明的保护范围并不仅限于此，本领域技术人员可根据实际需求合理调整具体设计。
上文所述的QPCTL/QPCT活性是指在释放氨的情况下，N端谷氨酰胺残基分子环化为焦谷氨酸(pGlu*)，或者N端L-高谷氨酰胺或L-β-高谷氨酰胺分子内环化为环焦高谷氨酰胺衍生物。
EC包括QPCT和QPCTL作为谷氨酸环化酶(EC)的活性，进一步定义为EC活性。
QPCT抑制剂、谷氨酰胺酰基环化酶抑制剂是本领域技术人员公知的，具体为抑制谷氨酰胺酰基环化酶(QPCT)的催化活性或其谷氨酰环化酶(EC)活性的酶抑制剂。
QPCTL抑制剂、谷氨酰胺酰肽环转移酶样蛋白抑制剂是本领域技术人员公知的，具体为抑制谷氨酰胺酰肽环转移酶样蛋白(QPCTL)的催化活性或其谷氨酰环化酶(EC)活性的酶抑制剂。
谷氨酰胺环化酶抑制剂包括QPCT抑制剂和/或QPCTL抑制剂，起到对QPCT/QPCTL的抑制作用，具有相同或相似的药理作用效果。
QPCTL抑制的效力：鉴于与QPCTL抑制的关系，在优选的实施方案中，QPCTL抑制的IC50为10μM或更小，优选1μM或更小，甚至更优选0.1μM或更小或者0.01μM或更小，或者最优选0.001μM或更小的物质。因此，尽管本文为了方便将活性物质描述为QPCTL抑制剂，但是应当理解这样的命名不是为了将本发明的主题限于特定的作用机制。
本发明具有如下优点或者有益效果：
本发明提供了一种全新的含氮杂环化合物，该含氮杂环化合物抑制谷氨酰胺环化酶(特别是QPCTL酶和QPCT酶)效果优异，其可应用于治疗肿瘤、免疫性疾病、神经性疾病、肥胖或衰老，应用前景良好。
具体实施方式
下面结合具体的实施例对本发明作进一步的说明，但是不作为本发明的限定。
实施例1
3-(6-氟吡啶-3-基)-2-[4-(噻唑-5-基)哌啶-1-基]-苯-1-甲腈(化合物1)
3-(6-fluoropyridin-3-yl)-2-(4-(thiazol-5-yl)piperidin-1-yl)benzonitrile
化合物1合成路线如上图所示。
步骤a、将化合物MC1(111mg,0.36mmol,1.5eq)、化合物MC2(39mg,0.24mmol,1.0eq)和Na2CO3(51mg,0.48mmol,2.0eq)溶解于1，4-二氧六环(2mL)和H2O(0.2mL)的混合溶剂中，氩气保护下加入Pd(dppf)Cl2(18mg,0.024mmol,0.1eq)，体系加热至90℃后反应16小时。反应结束后冷却至室温，加入水和EA萃取，有机相减压浓缩后硅胶柱层析获得黄色油状化合物MC3(90mg,94.0％yield)。1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.65(s,1H),5.96(brs,1H),3.99-3.96(m,2H),3.54(t,J＝5.6Hz,2H),2.45-2.41(m,2H),1.38(s,9H)。
步骤b、中间体MC3(1.47g,1.0eq)溶解于MeOH(20mL)中，氩气保护下加入Pd/C(10％,200mg)，室温下用氢气置换3次体系，45℃反应过夜。当反应结束后过滤，有机相浓缩获得化合物MC4(1.2g).1HNMR(400MHz,CDCl3)δ8.62(s,1H),7.58(s,1H),4.16-4.11(m,2H),3.03-2.95(m,1H),2.79(t,J＝13.2Hz,2H),1.95-1.91(m,2H),1.63-1.51(m,2H),1.41(s,9H)。
步骤c、将中间体MC4脱Boc保护基后获得5-(哌啶-4-基)噻唑粗产物(0.20g，1.21mmol，1.0eq)溶解于DMSO(4mL)中，然后依次加入3-溴-2-氟苯腈(MC5)(0.29g，1.45mmol，1.2eq)和无水碳酸钾(0.25g，1.82mmol，1.5eq)，100℃加热搅拌16小时。TLC监测反应结束后，加入二氯甲烷和水萃取，再次用饱和食盐水和二氯甲烷萃取，收集有机相，利用SepaBean machine T200分离纯化，最后获得中间体MC6化合物0.15g。
步骤d、中间体MC6(35mg,0.10mmol,1.0eq),碳酸钠(21mg,0.2mmol,2.0eq)和4-氟-3-吡啶硼酸(34mg,0.15mmol,1.5eq)溶解在2mL二氧六环和0.2mL水的混合溶剂中，反应体系在氮气保护下加入Pd(dppf)Cl2(7mg,0.01mmol,0.1eq)，90摄氏度反应10小时。反应体系冷却至室温后用水稀释，然后用乙酸乙酯萃取。有机层浓缩后用HPLC分离制备，获得白色固体产物。
得到化合物1的数据为：1H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.26(d,J＝2.5Hz,1H),8.07-7.92(m,1H),7.83-7.63(m,2H),7.54(dd,J＝7.7,1.6Hz,1H),7.31(t,J＝7.7Hz,1H),7.20(dd,J＝8.5,2.6Hz,1H),3.26-3.20(m,1H),3.18-2.98(m,2H),2.07-1.89(m,2H),1.76-1.49(m,2H),1.35-1.28(m,2H)。LRMS(ESI)[M+H]+,found:365.2。
实施例2
3-(6-氟吡啶-3-基)-2-[4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基]-苯-1-甲腈(化合物2)
3-(6-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)benzonitrile
化合物2合成路线如上图所示。
步骤a、化合物MC7(1.05g,5.00mmol,1.0eq)、三甲基叠氮硅烷(636mg,5.5mmol,1.1eq)和CuI(48mg,0.25mmol,0.05equiv)在氩气保护下溶解于DMF(9mL)和MeOH(1mL)中，反应升温至100℃搅拌反应8h。反应结束后，加入EA(50mL)稀释，然后用水(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。浓缩物用硅胶柱层析纯化获得中间体MC8(600mg,47.6％yield).1H NMR(400MHz,CDCl3)δ7.47(s,1H),4.17-4.15(m,2H),2.97-2.82(m,3H),1.99-1.94(m,2H),1.68-1.56(m,2H),1.44(s,9H)。
步骤b、在0℃和氩气保护下，中间体MC8(30mg,0.12mmol,1.0eq)和碳酸钾(33mg,0.24mmol,2.0eq)溶解于DMF(2mL)，碘甲烷(25mg,0.18mmol,1.5eq)缓慢加入体系中，室温搅拌过夜。反应结束后，加入EA(50mL)稀释，然后用H2O(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。浓缩物用硅胶柱层析纯化获得中间体MC9(22mg,70.5％yield).1H NMR(600MHz,CDCl3)δ7.33(s,1H),4.13-4.10(m,5H),2.88-2.81(m,3H),1.95-1.91(m,2H),1.65-1.57(m,2H),1.45(s,9H)。
步骤c和步骤d、利用中间体MC9，反应如实施例1中的步骤c生成中间体MC10，然后如实施例1中的步骤d，得到化合物2的数据为：1H NMR(400MHz,MeOD-d4)δ8.24(dd,J＝2.1,1.1Hz,1H),8.07-7.95(m,1H),7.69(dd,J＝7.8,1.7Hz,1H),7.53(dd,J＝7.7,1.7Hz,1H),7.43(s,1H),7.29(t,J＝7.7Hz,1H),7.19(dd,J＝8.4,2.6Hz,1H),4.09(s,3H),3.26-3.15(m,2H),3.15-3.02(m,2H),2.83-2.66(m,1H),1.92-1.81(m,2H),1.70-1.53(m,2H)。LRMS(ESI)[M+H]+,found:363.2。
实施例3
2-[4-(1H-1,2,3-三唑-1-基)哌啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈(化合物3)
2-(4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
化合物3的合成路线如上图所示。
步骤a、在0℃和氩气保护下，化合物MC12(500mg,7.24mmol,1.0eq)溶解于DMF(5mL)中，然后缓慢加入NaH(320mg,60％,8.0mmol,1.1eq)，反应缓慢升温至室温后继续搅拌2小时，然后向体系中加入化合物MC11(2.4g,8.69mmol,1.2eq)，体系升温至60℃搅拌过夜。反应结束后，加入EA(50mL)稀释，然后用H2O(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。浓缩物用硅胶柱层析纯化获得中间体MC13(900mg,49.3％yield)。1H NMR(400MHz,CDCl3)δ7.49(brs,1H),7.45-7.43(m,1H),4.48-4.39(m,1H),4.00(d,J＝13.6Hz,2H),2.80-2.74(m,2H),1.97-1.92(m,2H),1.80-1.69(m,2H),1.23(s,9H)。
步骤b和步骤c、利用中间体MC13，反应如实施例1中的步骤c生成中间体MC14，然后如实施例1中的步骤d，得到化合物3的数据为：1H NMR(400MHz,MeOD-d4)δ8.27(dd,J＝2.1,1.2Hz,1H),8.10-7.98(m,2H),7.78(d,J＝1.2Hz,1H),7.72(dd,J＝7.7,1.6Hz,1H),7.56(dd,J＝7.7,1.7Hz,1H),7.33(t,J＝7.7Hz,1H),7.22(dd,J＝8.5,2.7Hz,1H),4.71-4.53(m,1H),3.30-3.27(m,2H),3.26-3.08(m,2H),2.17-1.98(m,4H)。LRMS(ESI)[M+H]+,found:349.2。
实施例4
2-[4-(1H-1,2,4-三唑-1-基)哌啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈(化合物4)
2-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成方法同实施例3，如上图所示路线，得到化合物4的数据为：1H NMR(400MHz,MeOD-d4)δ8.95(d,J＝15.8Hz,1H),8.03(td,J＝8.0,2.5Hz,1H),7.72(dd,J＝7.7,1.7Hz,1H),7.56(dd,J＝7.7,1.7Hz,1H),7.33(t,J＝7.7Hz,1H),7.21(dd,J＝8.5,2.5Hz,1H),4.56-4.36(m,1H),3.30-3.26(m,2H),3.24-3.06(m,2H),2.14-1.98(m,4H)。LRMS(ESI)[M+H]+,found:349.2。
实施例5
2-[4-(2H-1,2,3-三唑-2-基)哌啶-1-基]-3-(6-氟吡啶-3-基)-苯-1-甲腈(化合物5)
2-(4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成方法同实施例3，如上图所示路线，得到化合物5的数据为：1H NMR(400MHz,DMSO)δ8.28(d,J＝2.5Hz,1H),8.05(td,J＝8.2,2.5Hz,1H),7.86-7.73(m,3H),7.56(dd,J＝7.6,1.7Hz,1H),7.37-7.24(m,2H),4.68-4.48(m,1H),3.26-3.13(m,2H),3.13-2.95(m,2H),2.09-1.84(m,4H)。LRMS(ESI)[M+H]+,found:349.2。
实施例6
2-[4-(4,5-二甲基-4H-1,2,4-三唑-3-基)哌啶-1-基]-3-(6-氟吡啶-3-基)苯-1-甲腈(化合物6)
2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成方法同实施例1，合成路线如上图所示，得到化合物6的数据为：1H NMR(400MHz,MeOD-d4)δ8.28(d,J＝2.4Hz,1H),8.04(td,J＝8.0,2.8Hz,1H),7.75(dd,J＝8.0,2.0Hz,1H),7.58(dd,J＝7.6,2.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.22(dd,J＝8.4,2.8Hz,1H),3.74(s,3H),3.30-3.28(m,2H),3.17-3.07(m,3H),2.62(s,3H),1.97-1.93(m,2H),1.87-1.77(m,2H).LRMS(ESI)[M+H]+,found:377.4。
实施例7
3-(6-氟吡啶-3-基)-2-(4-(4-异丙基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯-1-甲腈(化合物7)
3-(6-fluoropyridin-3-yl)-2-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物7的数据为：1H NMR(400MHz，MeOD-d4)δ9.47(s,1H),8.56(d,J＝2.8Hz,1H),8.52(s,1H),7.82-7.76(m,2H),7.61(dd,J＝7.6,1.6Hz,1H),7.37(t,J＝8.0Hz,1H),4.82-4.74(m,1H),3.27-3.19(m,4H),1.99-1.94(m,2H),1.89-1.57(m,2H),1.58(d,J＝6.8Hz,6H).LRMS(ESI)[M+H]+,found:391.3。
实施例8
2-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯-1-甲腈(化合物8)
2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物8的数据为：1H NMR(400MHz，MeOD-d4)δ8.83(s,1H),8.29(d,J＝2.4Hz,1H),8.02(td,J＝8.0,2.4Hz,1H),7.74(dd,J＝8.0,1.6Hz,1H),7.57(dd,J＝7.6,1.6Hz,1H),7.36-7.32(m,2H),7.21(dd,J＝8.4,2.4Hz,1H),3.29-3.24(m,2H),3.16-3.11(m,2H),2.88-2.79(m,1H),1.98-1.93(m,2H),1.69-1.65(m,2H).LRMS(ESI)[M+H]+,found:348.2。
实施例9
2-(4-(4-乙基-4H-1,2,4-三唑-3-yl)哌啶-1-基)-3-(6-氟吡啶-3-基)苯-1-甲腈(化合物)
2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物9的数据为：1H NMR(600MHz,MeOD-d4)δ9.34(s,1H),8.26(s,1H),8.02(t,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.56(d,J＝7.8Hz,1H),7.33(t,J＝7.8Hz,1H),7.21(dd,J＝8.4,2.4Hz,1H),4.27(q,J＝7.2Hz,2H),3.25-3.20(m,2H),3.28(brs,2H),3.21-3.15(m,1H),1.97-1.93(m,2H),1.85(brs,2H),1.54(t,J＝7.2Hz,3H).LRMS(ESI)calcd for C21H22FN6[M+H]+377.2,found:377.3。
实施例10
3-(6-氟吡啶-3-基)-2-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)苯-1-甲腈(化合物)
3-(6-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)benzonitrile
化合物10的合成路线如上图所示：
步骤a、化合物MC32(251mg,1.2mmol,1.2eq)、CuSO4·5H2O(3mg,0.01mmol,0.01eq)、(+)-抗坏血酸钠(10mg,0.05mmol,0.05eq)和尿素(2mg,0.02mmol,0.02eq)溶解于MeOH/H2O(2mL/2mL)。苄基叠氮(133mg,1.0mmol,1.0eq)随后加入体系中，反应在室温条件下继续反应16小时。反应结束后，加入EA(50mL)稀释，然后用H2O(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。浓缩物用硅胶柱层析纯化获得中间体MC33(100mg,29.2％yield).1H NMR(600MHz,CDCl3)δ7.39-7.32(m,3H),7.27-7.23(m,2H),7.16(s,1H),5.48(s,2H),4.13-4.09(m,2H),2.93-2.83(m,3H),2.00-1.96(m,2H),1.59-1.51(m,2H),1.44(s,9H)。
步骤b、中间体MC33(40mg,0.12mmol,1.0eq)溶解于MeCN(2mL),然后加入碘甲烷(103mg,0.72mmol,6.0eq)，反应体系升温至60℃反应过夜。当反应结束后，减压浓缩，硅胶柱层析纯化获得中间体MC34(50mg,crude).1H NMR(400MHz,CDCl3)δ8.96(s,1H),7.60-7.56(m,2H),7.40-7.37(m,3H),5.90(s,2H),4.38(s,3H),4.18-4.07(m,2H),3.41-3.32(m,1H),2.92-2.80(m,2H),2.06-1.92(m,4H),1.41(s,9H)。
步骤c、中间体MC34(50mg,1.0mmol,1.0eq)和t-BuOK(29mg,2.5mmol,2.5eq)在0℃时氩气保护下溶解于MeCN(10mL)，缓慢升温至室温反应过夜。当反应结束后，减压浓缩，硅胶柱层析纯化获得中间体MC35(20mg,74.9％yield).1H NMR(600MHz,CDCl3)δ7.44(s,1H),4.00(s,3H),2.84-2.72(m,3H),1.88(d,J＝13.8Hz,2H),1.72(brs,2H),1.63-1.54(m,2H),1.47(s,9H).LRMS(ESI)calcd for C13H23N4O2[M+H]+267.2,found:267.3。
步骤d和步骤e、利用化合物MC35脱除Boc保护基后，合成方法如同实施例1中的步骤c获得中间体MC36,如同实施例1中的步骤d得到化合物10的数据为：1H NMR(400MHz,MeOD-d4)δ8.26(d,J＝2.4Hz,1H),8.04-7.99(m,1H),7.71(dd,J＝8.0,1.6Hz,1H),7.61(s,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.31(t,J＝7.6Hz,1H),7.23-7.19(m,1H),4.03(s,3H),3.26-3.14(m,4H),2.92-2.84(m,1H),1.88-1.84(m,2H),1.63-1.59(m,2H).LRMS(ESI)calcd for C20H20FN6[M+H]+363.2,found:363.3。
实施例11
3-(6-氟吡啶-3-基)-2-(4-(3-甲基-4H-1,2,4-三唑-4-yl)哌啶-1-基)苯-1-甲腈(化合物11)
3-(6-fluoropyridin-3-yl)-2-(4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)benzonitrile
化合物11的合成路线如上图所示：
步骤a、将化合物MC37(814mg,11.0mmol,1.0eq)溶解于乙腈(5mL)中，然后向体系中加入DMFDMA(1.35g,11.0mmol,1.0eq)，升温至50℃搅拌1小时。然后向体系中加入化合物MC38(1.0g,5.5mmol,0.5eq)和HOAc(1mL)，升温至100℃搅拌18小时。当反应结束后，反应体系减压浓缩，硅胶柱层析分离纯化得到中间体MC39(1.5g,52.0％yield).1H NMR(600MHz,CDCl3)δ8.00(s,1H),4.19(brs,2H),3.93-3.87(m,1H),2.77-2.73(m,2H),2.34(s,3H),1.92-1.88(m,2H),1.71-1.63(m,2H),1.35(s,9H)。
步骤b和c、利用中间体MC39，反应如实施例1中的步骤c生成中间体MC40，然后如实施例1中的步骤d，合成得到化合物11的数据为：1H NMR(600MHz,MeOD-d4)δ9.23(s,1H),8.28(s,1H),8.02(t,J＝6.6Hz,1H),7.74(d,J＝7.8Hz,1H),7.56(d,J＝7.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.21(dd,J＝9.0,2.4Hz,1H),4.43-4.37(m,1H),3.33(brs,2H),3.18(br,2H),2.72(s,3H),2.10-2.06(m,2H),1.99-1.96(m,2H).LRMS(ESI)calcd for C20H20FN6[M+H]+363.2,found:363.3。
实施例12
2-(4-(1-乙基-1H-咪唑-5-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯-1-甲腈(化合物12)
2-(4-(1-ethyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物12的数据为：1H NMR(400MHz,MeOD-d4)δ8.87(s,1H),8.28(d,J＝2.4Hz,1H),8.01(td,J＝8.0,2.4Hz,1H),7.72(dd,J＝7.6,1.6Hz,1H),7.55(dd,J＝7.6,1.6Hz,1H),7.36(s,1H),7.32(t,J＝7.6Hz,1H),7.21(dd,J＝8.4,2.4Hz,1H),4.23(q,J＝7.2Hz,2H),3.27-3.23(m,2H),3.15(brs,2H),2.89-2.81(m,1H),1.92-1.87(m,2H),1.65-1.61(m,2H),1.53(t,J＝7.2Hz,3H).LRMS(ESI)calcd for C22H23FN5[M+H]+376.2,found:376.3。
实施例13
3-(6-氟吡啶-3-基)-2-(4-(4-甲基吡啶-3-基)哌啶-1-基)苯-1-甲腈(化合物13)
3-(6-fluoropyridin-3-yl)-2-(4-(4-methylpyridin-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物13的数据为：1H NMR(400MHz,MeOD-d4)δ8.57-8.53(m,2H),8.31(s,1H),8.04(t,J＝8.0Hz,1H),7.88(d,J＝6.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.57(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.23(dd,J＝8.4,2.4Hz,1H),3.29-3.18(m,4H),3.09-3.02(m,1H),2.67(s,3H),1.84-1.70(m,4H).LRMS(ESI)calcd for C23H22FN4[M+H]+373.2,found:373.3。
实施例14
3-(6-氟吡啶-3-基)-2-(4-(3-甲基吡啶-4-基)哌啶-1-基)苯-1-甲腈(化合物14)
3-(6-fluoropyridin-3-yl)-2-(4-(3-methylpyridin-4-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物14的数据为：1H NMR(400MHz,MeOD-d4)δ8.64-8.62(m,2H),8.31(s,1H),8.04(t,J＝8.0Hz,1H),7.88(d,J＝6.0Hz,1H),7.73(d,J＝7.6Hz,1H),7.56(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),7.24(dd,J＝8.4,2.0Hz,1H),3.30-3.08(m,5H),2.55(s,3H),1.80-1.76(m,4H).LRMS(ESI)calcd for C23H22FN4[M+H]+373.2,found:373.3。
实施例15
3-(6-氟吡啶-3-基)-2-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物15)
3-(6-fluoropyridin-3-yl)-2-(4-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物15的数据为：1H NMR(600MHz，MeOD-d4)δ9.09(s,1H),8.25(d,J＝2.4Hz,1H),8.00(td,J＝7.8,2.4Hz,1H),7.73(dd,J＝7.8,1.8Hz,1H),7.58(dd,J＝7.8,1.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.19(dd,J＝9.0,2.4Hz,1H),3.98(s,3H),3.22(brs,2H),3.11(brs,2H),2.28(brs,2H),1.86-1.84(m,2H),1.48(s,3H).LRMS(ESI)[M+H]+,found:377.2。
实施例16
2-(4-氟-4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯甲腈(化合物16)
2-(4-Fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物16的数据为：1H NMR(600MHz，MeOD-d4)δ8.75(s,1H),8.27(d,J＝2.4Hz,1H),8.06(td,J＝7.8,2.4Hz,1H),7.76(dd,J＝7.8,1.2Hz,1H),7.58(dd,J＝7.8,1.2Hz,1H),7.36(t,J＝7.8Hz,1H),7.22(dd,J＝8.4,2.4Hz,1H),3.90(s,3H),3.40(brs,2H),3.20-3.17(m,2H),2.30-2.23(m,4H).LRMS(ESI)[M+H]+,found:381.2。
实施例17
3-(6-氟吡啶-3-基)-2-(6-(4-甲基-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷-3-基)苯甲腈(化合物17)
3-(6-Fluoropyridin-3-yl)-2-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物17的数据为：1H NMR(600MHz，MeOD-d4)δ8.96(s,1H),8.24(d,J＝2.4Hz,1H),7.96(td,J＝7.8,2.4Hz,1H),7.76(dd,J＝7.8,1.8Hz,1H),7.59(dd,J＝7.8,1.2Hz,1H),7.38(t,J＝7.8Hz,1H),7.24(dd,J＝8.4,3.6Hz,1H),3.89(s,3H),3.52(d,J＝9.6Hz,2H),3.38(d,J＝9.0Hz,2H),2.41-2.39(m,1H),2.27-2.25(m,2H).LRMS(ESI)[M+H]+,found:361.4。
实施例18
5-氟-3-(6-氟吡啶-3-基)-2-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲腈(化合物18)
5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物18的数据为：1H NMR(600MHz，MeOD-d4)δ9.10(s,1H),8.43(s,1H),8.20-8.16(m,1H),7.46-7.43(m,1H),7.41-7.39(m,1H),7.25-7.22(m,1H),3.96-3.92(m,5H),3.32-3.28(m,1H),3.06-3.01(m,2H),2.21-2.17(m,2H),2.06-2.01(m,2H).LRMS(ESI)[M+H]+,found:381.4。
实施例19
3-(6-氟吡啶-3-基)-2-(3-(4-甲基-4H-1,2,4-三唑-3-基)吡咯-1-基)苯甲腈(化合物19)
3-(6-fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物19的数据为：1H NMR(400MHz,MeOD-d4)δ9.42(s,1H),8.21(d,J＝2.4Hz,1H),8.01-7.96(m,1H),7.69(dd,J＝8.0,1.6Hz,1H),7.35(dd,J＝7.6,1.6Hz,1H),7.30(t,J＝7.6Hz,1H),7.17-7.13(m,1H),3.88(s,3H),3.85-3.78(m,2H),3.60-3.53(m,1H),3.43-3.30(m,2H),2.49-2.39(m,1H),2.32-2.23(m,1H).LRMS(ESI)calcd for C19H18FN6[M+H]+349.2,found:349.3。
实施例20
3-(6-氟吡啶-3-基)-2-(3-(4-甲基-4H-1,2,4-三唑-3-基)氮杂环丙烷-1-基)苯甲腈(化合物20)
3-(6-fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)azetidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物20的数据为：1H NMR(400MHz,MeOD-d4)δ9.05(s,1H),8.24(d,J＝2.4Hz,1H),8.01-7.95(m,1H),7.58(dd,J＝7.6,2.0Hz,1H),7.35(dd,J＝7.6,1.6Hz,1H),7.15(dd,J＝8.4,2.8Hz,1H),6.97(t,J＝8.0Hz,1H),4.35(t,J＝8.0Hz,2H),4.17-4.07(m,3H),3.70(s,3H).LRMS(ESI)calcd for C18H16FN6[M+H]+335.1,found:335.3。
实施例21
2-(6',7'-二氢-5'H-螺[哌啶-4,8'-[1,2,4]三唑并[4,3-a]吡啶]-1-基)-3-(6-氟吡啶-3-基)苯甲腈(化合物21)
2-(6',7'-dihydro-5'H-spiro[piperidine-4,8'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
化合物21的合成路线如上图所示：
步骤a、化合物MC60(536mg,2.0mmol,1.0eq)和Lawesson试剂(409mg,2.1mmol,1.05eq)溶解于甲苯(20mL)中，反应体系加热至回流，搅拌过夜。反应结束后，减压浓缩，硅胶柱层析分离纯化获得中间体MC61(290mg,51.1％yield).1H NMR(400MHz,CDCl3)δ8.31(s,1H),4.01(brs,2H),3.34(brs,2H),2.90(t,J＝11.6Hz,2H),2.54(t,J＝12.4Hz,2H),1.88(brs,4H),1.52-1.44(m,11H).LRMS(ESI)calcd for C14H25N2O2S[M+H]+285.2,found:285.3。
步骤b、中间体MC61(284mg,1.0mmol,1.0eq)和化合物MC62(72mg,1.2mmol,1.2eq)溶解于DCM(5mL)中，然后加入AgOBz(460mg,2.0mmol,2.0eq)和HOAc(0.17mL)，反应体系加热至回流，搅拌过夜。反应结束后，减压浓缩，硅胶柱层析分离纯化获得中间体MC63(170mg,58.0％yield).1H NMR(400MHz,CDCl3)δ8.08(s,1H),4.01(t,J＝6.0Hz,2H),3.84(brs,2H),3.61(brs,2H),2.07-1.98(m,4H),1.88-1.85(m,2H),1.63-1.57(m,2H),1.47(s,9H).LRMS(ESI)calcd for C15H25N4O2[M+H]+293.2,found:293.3。
步骤c和步骤d、利用中间体MC63脱除Boc保护基后，如实施例1合成路线中的步骤c得到中间体MC64，如实施例1合成路线中的步骤d，得到化合物21的数据为：1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.29(d,J＝2.4Hz,1H),8.08-8.02(m,1H),7.74(dd,J＝8.0,1.6Hz,1H),7.57(dd,J＝8.0,2.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.23(dd,J＝8.4,2.4Hz,1H),4.23(t,J＝6.4Hz,2H),3.25(brs,4H),2.14-2.00(m,6H),1.81-1.75(m,2H).LRMS(ESI)calcd for C22H22FN6[M+H]+389.2,found:389.3。
实施例22
2-(5',6'-二氢螺[哌啶-4,7'-吡咯并[2,1-c][1,2,4]三唑]-1-基)-3-(6-氟吡啶-3-基)苯甲腈(化合物22)
2-(5',6'-dihydrospiro[piperidine-4,7'-pyrrolo[2,1-c][1,2,4]triazol]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例21，得到化合物22的数据为：1H NMR(400MHz,MeOD-d4)δ9.23(s,1H),8.29(d,J＝2.4Hz,1H),8.06(td,J＝8.0,2.4Hz,1H),7.75(dd,J＝7.6,1.6Hz,1H),7.57(dd,J＝7.6,1.6Hz,1H),7.34(t,J＝7.6Hz,1H),7.24(dd,J＝8.4,2.4Hz,1H),4.33(t,J＝7.2Hz,2H),3.20-3.14(m,2H),2.72(t,J＝7.2Hz,4H),1.94-1.84(m,4H).LRMS(ESI)calcd for C21H20FN6[M+H]+375.2,found:375.2。
实施例23
2-(4-(4-乙基-4H-1,2,4-三唑-3-基)-4-氟哌啶-1-基)-3-(6-氟吡啶-3-基)苯甲腈(化合物23)
2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例16，得到化合物23的数据为：1H NMR(600MHz,MeOD-d4)δ9.34(s,1H),8.26(s,1H),8.02(t,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.56(d,J＝7.8Hz,1H),7.33(t,J＝7.8Hz,1H),7.21(dd,J＝8.4,2.4Hz,1H),4.27(q,J＝10.8Hz,2H),3.44-3.34(m,2H),3.18-3.15(m,2H),2.25-2.18(m,4H),1.54(t,J＝10.8Hz,3H).LRMS(ESI)calcd for C21H21F2N6[M+H]+395.2,found:395.3。
实施例24
3-(6-氟吡啶-3-基)-2-(4-羟基-4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)苯甲腈(化合物24)
3-(6-fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile
化合物24的合成路线如上图所示：
步骤a、MC71(1.32g,16.0mmol,1.0eq)溶解于THF(30mL)中，氩气保护下，体系冷却至78℃，缓慢加入n-BuLi(10mL,1.6M,1.0eq)，继续搅拌1小时。然后向体系中加入三乙基氯硅烷(2.4g,16.0mmol,1.0eq)，缓慢升温至室温后，再次冷却至-78℃，缓慢加入n-BuLi(10mL,1.6M,1.0eq)继续搅拌1小时。然后让体系升温至-15℃后再次冷却至-78℃，MC72(3.0g,15.0mmol,0.94equiv)的THF(10mL)溶液加入体系中。体系升温至室温，继续搅拌反应过夜。反应结束后，体系用EA(50mL)稀释,依次用H2O(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。硅胶柱层析分离纯化得到中间体MC73(1130mg,25.0％yield).1H NMR(400MHz,CDCl3):δ7.20(s,1H),6.69(s,1H),3.86(brs,2H),3.79(s,3H),3.27(brs,2H),1.95-1.86(m,4H),1.45(s,9H)。
步骤b和步骤c、利用中间体MC73脱除Boc保护基后，如实施例1合成路线中的步骤c得到中间体MC74，如实施例1合成路线中的步骤d得到化合物24的数据为：1H NMR(400MHz,MeOD-d4)δ8.81(s,1H),8.27(d,J＝2.4Hz,1H),8.01(td,J＝8.0,2.4Hz,1H),7.72(dd,J＝8.0,1.6Hz,1H),7.54(dd,J＝7.6,1.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(t,J＝7.6Hz,1H),7.20(dd,J＝8.4,2.4Hz,1H),3.42(brs,2H),3.06-3.00(m,2H),1.99-1.95(m,4H).LRMS(ESI)calcd for C21H21FN5O[M+H]+378.2,found:378.2。
实施例25
3-(6-氟吡啶-3-基)-2-(4-甲氧基-4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)苯甲腈(化合物25)
3-(6-fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile
化合物25的合成路线如上图所示：
步骤a、中间体MC73(300mg,1.07mmol,1.0eq)溶解于DMF(10mL)中，体系在0℃氩气保护下加入NaH(85mg,60％,2.14mmol,2.0eq)。体系升温至室温继续搅拌反应2小时，然后加入碘甲烷(303mg,2.14mmol,2.0eq)，体系升温至回流，搅拌过夜。反应结束后，体系冷却至室温，加入EA(20mL)稀释，一次用水(20mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离纯化得到中间体MC74(305mg,96.8％yield).1H NMR(400MHz,CDCl3)δ7.41(s,1H),6.89(s,1H),3.95-3.83(m,2H),3.75(s,3H),3.23-3.12(m,2H),3.00(s,3H),2.15-2.10(m,2H),1.88-1.80(m,2H),1.47(s,9H)。
步骤b和步骤c、利用中间体MC74脱除Boc保护基后，如实施例1合成路线中的步骤c得到中间体MC75，如实施例1合成路线中的步骤d得到化合物25的数据为：1H NMR(400MHz,MeOD-d4)δ8.88(s,1H),8.26(d,J＝2.0Hz,1H),8.01(td,J＝8.0,2.4Hz,1H),7.72(dd,J＝7.6,1.6Hz,1H),7.55(dd,J＝8.0,1.6Hz,1H),7.52(d,J＝1.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.19(dd,J＝8.4,2.4Hz,1H),4.00(s,3H),3.35(brs,2H),3.07(s,3H),3.05-3.00(m,2H),2.24-2.19(m,2H),1.94-1.90(m,2H).LRMS(ESI)calcd for C22H23FN5O[M+H]+392.2,found:392.3。
实施例26
3-(6-氟吡啶-3-基)-2-(4-羟基-4-(1-甲基-1H-咪唑-4-基)哌啶-1-基)苯甲腈(化合物26)
3-(6-fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例24，得到化合物26的数据为：1H NMR(600MHz,MeOD-d4)δ8.28(s,1H),8.03-7.99(m,1H),7.74(dd,J＝7.8,1.8Hz,1H),7.56(dd,J＝7.2,1.2Hz,1H),7.50(d,J＝1.8Hz,1H),7.44(d,J＝2.4Hz,1H),7.34(t,J＝7.2Hz,1H),7.21(dd,J＝8.4,2.4Hz,1H),4.06(s,3H),3.47-3.42(m,2H),3.07(d,J＝12.0Hz,2H),2.13-2.03(m,2H),1.94(d,J＝11.4Hz,2H).LRMS(ESI)calcd for C21H21FN5O[M+H]+378.2,found:378.3。
实施例27
3-(6-氟吡啶-3-基)-2-(4-甲氧基-4-(1-甲基-1H-咪唑-4-基)哌啶-1-基)苯甲腈(化合物27)
3-(6-fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例25，得到化合物27的数据为：1H NMR(600MHz,MeOD-d4)δ8.26(d,J＝2.4Hz,1H),8.04-7.99(m,1H),7.74(dd,J＝7.8,1.8Hz,1H),7.59(d,J＝1.8Hz,1H),7.57(dd,J＝7.8,1.8Hz,1H),7.53(d,J＝2.4Hz,1H),7.35(t,J＝7.2Hz,1H),7.2(dd,J＝8.4,2.4Hz,1H),4.04(s,3H),3.43-3.34(m,2H),3.14(s,3H),3.06(d,J＝13.8Hz,2H),2.30-2.26(m,2H),2.04-1.98(m,2H).LRMS(ESI)calcd for C22H23FN5O[M+H]+392.2,found:392.3。
实施例28
3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯甲胺(化合物28)
3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzamide
化合物28的合成路线如上图所示：QP5020(10mg,0.028mmol,1.0eq)和K2CO3(1.0mg,0.0072mmol,0.25eq)溶解在DMSO(1.0mL)中，室温条件下加入H2O2(3μL)，反应体系加热至50℃继续搅拌2h。反应结束后体系减压浓缩，然后通过prep-HPLC纯化(10％to 100％MeCN in H2O containing 0.1％TFA over 90min)获得化合物28(2mg,20％yield)。得到化合物28的数据为：1H NMR(400MHz,MeOD-d4)δ9.13(s,1H),8.30(s,1H),8.08-8.03(m,1H),7.45(d,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.27(t,J＝7.6Hz,1H),7.17(d,J＝8.4Hz,1H),3.86(s,3H),3.16-3.03(m,5H),1.87-1.83(m,2H),1.60(brs,2H).LRMS(ESI)calcd for C20H22FN6O[M+H]+381.2,found:381.3。
实施例29
2-(4-氟-4-(1-甲基-1H-咪唑-5-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯甲腈(化合物29)
2-(4-fluoro-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
化合物29的合成路线如上图：
步骤a、中间体MC74(10mg,0.027mmol,1.0eq)溶解于DCM(2ml)中，0℃条件下，DAST(18mg,0.11mmol,4.0eq)加入上述体系中，室温下搅拌4h。当反应结束后，体系减压旋蒸除去溶剂，利用硅胶柱层析分离纯化获得中间体MC80为白色油状液体(7mg,71.6％yield).1H NMR(400MHz,CDCl3)δ7.78(dd,J＝8.0,1.6Hz,1H),7.55(dd,J＝8.0,1.6Hz,1H),7.43(s,1H),7.05-6.99(m,2H),3.85-3.76(m,5H),3.26-3.22(m,2H),2.40-2.28(m,4H).LRMS(ESI)calcd for C16H17BrFN4[M+H]+363.1,found:363.1。
步骤b、同实施例1中合成步骤d，得到化合物29的数据为：1H NMR(600MHz,MeOD-d4)δ8.91(s,1H),8.28(d,J＝2.4Hz,1H),8.01(td,J＝7.8,2.4Hz,1H),7.75(dd,J＝7.8,2.4Hz,1H),7.65(s,1H),7.57(dd,J＝7.2,1.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.20(dd,J＝8.4,2.4Hz,1H),4.01(s,3H),3.43-3.34(m,2H),3.16-3.13(m,2H),2.29-2.25(m,2H),2.18-2.01(m,2H).LRMS(ESI)calcd for C21H20F2N5[M+H]+380.2,found:380.3。
实施例30
N-(2-氰基-4-(6-氟吡啶-3-基)-3-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丁酰胺(化合物30)
N-(2-cyano-4-(6-fluoropyridin-3-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butyramide
化合物30合成方法如上所示：
步骤a、将化合物MC81(500mg,2.325mmol,1.0eq)、丁酰氯(250mg,2.325mmol,1.0eq)和DIPEA(460μL,1.2eq)溶解于DCM(10mL)中，室温搅拌过夜。反应结束后冷却至室温，加入水和EA萃取，有机相减压浓缩后硅胶柱层析获得黄色油状化合物MC82(410mg,62.4％yield)。1H NMR(400MHz,CDCl3)δ8.22(d,J＝9.2Hz,1H),7.73(t,J＝8.0Hz,1H),7.64(s,1H),7.23(dd,J＝8.4,2.4Hz,1H),2.45(t,J＝7.2Hz,2H),1.83-1.73(m,2H),1.03(t,J＝7.2Hz,3H)。
步骤b、将中间体MC83脱Cbz保护基后获得粗产物(0.20g，1.21mmol，1.0eq)溶解于DMSO(4mL)中，然后依次加入中间体3(0.41g，1.45mmol，1.2eq)和无水碳酸钾(0.25g，1.82mmol，1.5eq)，100℃加热搅拌16小时。TLC监测反应结束后，加入二氯甲烷和水萃取，再次用饱和食盐水和二氯甲烷萃取，收集有机相，利用SepaBean machine T200分离纯化，最后获得中间体5化合物0.15g。1H NMR(400MHz,MeOD-d4)δ8.09-8.04(m,2H),7.71(d,J＝9.2Hz,1H),7.59(s,1H),3.70(s,3H),3.50-3.43(m,2H),2.96-2.88(m,1H),2.43(t,J＝7.2Hz,2H),2.33-2.29(m,2H),1.81-1.75(m,2H),1.64(s,2H),1.31-1.24(m,2H),1.03(t,J＝7.2Hz,3H)。
步骤c、中间体MC84(43mg,0.10mmol,1.0eq),碳酸钠(21mg,0.2mmol,2.0eq)和4-氟-3-吡啶硼酸(34mg,0.15mmol,1.5eq)溶解在2mL二氧六环和0.2mL水的混合溶剂中，反应体系在氮气保护下加入Pd(dppf)Cl2(7mg,0.01mmol,0.1eq)，90摄氏度反应10小时。反应体系冷却至室温后用水稀释，然后用乙酸乙酯萃取。有机层浓缩后用HPLC分离制备，获得白色固体产物。得到化合物30的数据为：1H NMR(400MHz,MeOD-d4)δ9.09(s,1H),8.27(s,1H),8.03(t,J＝8.0Hz,1H),7.54(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.23(dd,J＝8.4,2.4Hz,1H),3.88(s,3H),3.16-3.14(m,2H),2.47(t,J＝7.2Hz,2H),1.98-1.75(m,6H),1.36-1.31(m,3H),1.08(t,J＝7.2Hz,3H)。LRMS(ESI)[M+H]+,found:448.1。
实施例31
2-氟-5-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(甲磺酰)苯基)吡啶(化合物31)
2-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(methylsulfonyl)phenyl)pyridine
化合物31的合成路线如上图所示：
步骤a、1-溴-2-氟苯MC85(1.75g,10.0mmol,10.0eq)在氩气保护下溶解于四氢呋喃(30mL)中，体系降温至-78℃后，分批滴加LDA(6mL,2M,1.2eq)，维持在-78℃于1h滴加完。然后在体系中加入DMSO(1.1mL,13.0mmol,1.3eq)，-78℃搅拌反应2h。待反应结束后，体系用H2O(20mL)终止，然后用EA(50mL)和H2O(50mL)萃取，食盐水(50mL)洗涤后，用无水硫酸钠干燥，减压浓缩。所得浓缩物用硅胶柱层析PE:EA(20:1-6:1)纯化获得化合物MC86(1.4g,63.6％yield).1H NMR(400MHz,CDCl3)δ7.35(t,J＝6.8Hz,1H),7.19(t,J＝8.0Hz,1H),6.98(t,J＝8.0Hz,1H),3.82(s,3H)。
步骤b、MC86(1.40g,6.4mmol,1.0equiv)在氩气保护下溶解于DCM(30mL)中，反应体系冷却至0℃后缓慢加入m-CPBA(2.2g,30.0mmol,2.2eq)。体系缓慢回温至室温继续反应，待反应结束后，加入DCM(70mL)稀释体系，然后用饱和NaHCO3aq(500mL)和食盐水(50mL)洗涤，用无水硫酸钠干燥，减压浓缩。所得浓缩物用硅胶柱层析纯化获得白色固体化合物MC87(600mg,37.4％yield).1H NMR(400MHz,CDCl3)δ7.94-7.90(m,1H),7.88-7.83(m,1H),7.27-7.22(m,1H),3.25(s,3H)。
步骤c、利用中间体MC87和化合物MC83，如实施例1中合成路线步骤c，获得MC88(105mg,21.7％yield).1H NMR(400MHz,CDCl3)δ8.07-8.04(m,2H),7.77(dd,J＝8.0,2.4Hz,1H),7.25(t,J＝8.0Hz,1H),3.89-3.82(m,2H),3.68(s,3H),3.58(s,3H),3.16-3.11(m,2H),2.87-2.80(m,1H),2.30-2.18(m,2H),2.03-1.97(m,2H)。
步骤d、利用中间体MC88,如实施例1中合成路线步骤d，得到化合物31的数据为：1H NMR(400MHz,MeOD-d4)δ9.07(s,1H),8.25(d,J＝2.4Hz,1H),8.18(dd,J＝7.2,2.4Hz,1H),7.98(td,J＝8.0,2.4Hz,1H),7.54-7.48(m,2H),7.24(dd,J＝8.4,2.4Hz,1H),3.82(s,3H),3.41-3.34(m,5H),2.95-2.88(m,1H),2.66-2.59(m,2H),2.12-2.01(m,2H),1.92-1.88(m,2H).LRMS(ESI)calcd for C20H23FN5O2S[M+H]+416.2,found:416.3。
实施例32
2-氟-5-(2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-硝基苯)吡啶(化合物32)
2-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-nitrophenyl)pyridine
合成路线如上图所示：
步骤a、利用化合物MC83脱除Cbz保护基后获得4-(4-甲基-4H-[1,2,4]三唑-3-基)-哌啶(1.0g,6.02mmol,1.0eq)溶解在DMSO中(15mL)，碳酸钾(2.5g,18.06mmol,3.0eq)和1-溴-2-氟-3-硝基苯(MC89)(2.6g,12.04mmol,2eq)加入体系中，加热至60℃，搅拌下反应4小时。反应冷却至室温后，过滤，溶液加压浓缩，然后利用DCM和水萃取洗涤，有机相减压浓缩。硅胶柱分离纯化后获得中间体MC90共0.65g(产率30％).1H NMR(400MHz,MeOD-d4)δ8.40(s,1H),7.91(d,J＝7.6Hz,1H),7.66(dd,J＝7.6,2.4Hz,1H),7.16(t,J＝7.6Hz,1H),3.79(s,3H),3.63-3.56(m,2H),3.43-3.32(m,2H),3.17-3.08(m,1H),2.26-2.15(m,2H),2.10-2.05(m,2H)。
步骤b、中间体1-(2-溴-6-硝基苯)-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(0.65g,1.78mmol,1.0eq)、Na2CO3(0.38g,3.56mmol,2.0eq)和2-氟吡啶5-硼酸频呐醇酯(0.6g,2.67mmol,1.5eq)溶解在1,4-二氧六环(9mL)和H2O(1mL)的混合溶剂中。反应体系用氮气置换后，加入Pd(dppf)Cl2(0.13g,0.18mmol,0.1eq)，氮气保护下体系加热至90℃搅拌反应12小时.体系冷却至室温后，加水稀释，用乙酸乙酯萃取。有机相减压浓缩后柱层析分离纯化，得化合物32共0.45g(产率66％).1H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.35(d,J＝2.4Hz,1H),8.12(d,J＝8.0,2.8Hz,1H),7.71(dd,J＝8.0,1.6Hz,1H),7.53(dd,J＝7.6,1.6Hz,1H),7.37(t,J＝8.0Hz,1H),7.23-7.20(m,1H),3.83(s,3H),3.14-3.01(m,5H),1.85-1.80(m,2H),1.63-1.53(m,2H).LRMS(ESI)calcd for C19H20FN6O2[M+H]+383.2,found:383.2。
实施例33
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲酰胺(化合物33)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)formamide
化合物33的合成路线如上图所示：
步骤a、化合物33(0.6g,1.57mmol,1.0eq)和还原铁粉(0.88g,15.7mmol,10.0eq)溶解于EtOH(9mL)和H2O(1mL)混合溶剂中，然后加入NH4Cl(0.83g,15.7mmol,10.0eq)，反应体系加热至70℃继续搅拌3h。待反应结束后体系中加入DCM(20mL)稀释，过滤后减压浓缩，获得粗产物MC91(500mg)。
步骤b、室温条件下MC91(25mg,0.071mmol,1.0eq)溶解于Ac2O(0.1mL)和HCOOH(0.3mL)溶液中，体系加热至60℃搅拌反应2小时。反应结束后，减压旋蒸除去溶剂，用prep-HPLC纯化获得化合物33白色固体(14mg,51.7％yield).1H NMR(400MHz,MeOD-d4)δ9.18-9.11(m,1H),8.50(s,1H),8.26-8.20(m,1H),7.99-7.91(m,1H),7.26-7.17(m,2H),7.04-6.90(m,1H),3.85(s,3H),3.09-2.94(m,3H),2.65-2.61(m,2H),2.12-1.91(m,4H).LRMS(ESI)calcd for C20H22FN6O[M+H]+381.2,found:381.2。
实施例34
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)乙酰胺(化合物34)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)acetamide
化合物34的合成路线如上图所示：在0℃时MC91(25mg,0.071mmol,1.0eq)溶解于DCM(2.0mL)中，AcCl(8mg,0.102mmol,1.3eq)和TEA(10mg,0.102mmol,1.3eq)在搅拌时加入体系中，升温至室温后继续反应2小时。反应结束后，减压旋蒸除去溶剂，然后用prep-HPLC分离纯化获得化合物35为白色固体(10mg,35.6％yield).1H NMR(400MHz,MeOD-d4)δ8.91(brs,1H),8.21(brs,1H),7.96(brs,1H),7.24-7.16(m,3H),6.99(brs,1H),3.80(s,3H),3.06-2.95(m,3H),2.70-2.57(m,2H),2.24(s,3H),2.04-1.90(m,4H).LRMS(ESI)calcd for C21H24FN6O[M+H]+395.2,found:395.3。
实施例35
1,1,1-三氟-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺胺(化合物35)
1,1,1-trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesul fonamide
合成路线如上图所示，合成方法如化合物33，得到化合物35的数据为：1H NMR(400MHz,MeOD-d4)δ9.11(s,1H),8.26(brs,1H),8.01(brs,1H),7.39-7.17(m,4H),3.86(s,3H),3.21-2.99(m,4H),2.66(brs,1H),2.22-1.85(m,4H).LRMS(ESI)calcd for C20H21F4N6O2S[M+H]+485.1,found:485.2。
实施例36
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物36)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
化合物36的合成路线如上图所示。上述获得的MC91粗产物(30mg,0.09mmol,1.0eq)溶解于DCM(2.0mL)中，在0℃条件下加入甲基磺酰氯(16mg,0.14mmol,1.5eq)和TEA(18mg,0.18mmol,1.5eq)。反应升温至室温，搅拌反应2小时，反应结束后，减压除去溶剂，产物通过prep-HPLC进行分离纯化，获得化合物36为黄色固体产物(20mg，产率54％).1H NMR(400MHz,MeOD-d4)δ9.12(s,1H),8.22(s,1H),7.97(brs,1H),7.55-7.46(m,1H),7.26(t,J＝8.0Hz,1H),7.20-7.17(m,1H),6.95(brs,1H),3.87(s,3H),3.16(s,3H),3.10-2.99(m,3H),2.69-2.64(m,2H),2.04-1.94(m,4H).LRMS(ESI)calcd for C20H24FN6O2S[M+H]+431.2,found:431.2。
实施例37
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)环丙基磺酰胺(化合物37)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)cyclopropanesulfonamide
合成方法同实施例33，得到化合物37的数据为：1H NMR(600MHz,MeOD-d4)δ8.98(s,1H),8.22(s,1H),7.97(brs,1H),7.71-7.46(m,1H),7.25(t,J＝7.8Hz,1H),7.18(d,J＝8.4Hz,1H),6.94(brs,1H),3.81(s,3H),3.10-2.96(m,3H),2.75-2.65(m,3H),2.04-1.93(m,4H),1.16-1.07(m,4H).LRMS(ESI)calcd for C22H26FN6O2S[M+H]+457.2,found:457.3。
实施例38
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)乙基磺酰胺(化合物38)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)ethanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物38为白色固体(8mg,17％产率)，结构表征数据为：1H NMR(600MHz,MeOD-d4)δ9.11(s,1H),8.21(s,1H),7.95(brs,1H),7.56(brs,1H),7.25(t,J＝7.8Hz,1H),7.19(d,J＝7.8Hz,1H),6.92(brs,1H),3.85(s,3H),3.31-3.26(m,2H),3.09-2.99(m,3H),2.65(brs,2H),1.99-1.93(m,4H),1.39(brs,3H).LRMS(ESI)calcd for C21H26FN6O2S[M+H]+445.2,found:445.3。
实施例39
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丙基-1-磺酰胺(化合物39)N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物39的数据为：1H NMR(600MHz,MeOD-d4)δ9.03(s,1H),8.21(s,1H),7.95(brs,1H),7.56(brs,1H),7.25(t,J＝7.8Hz,1H),7.19(d,J＝8.4Hz,1H),6.92(brs,1H),3.83(s,3H),3.27(brs,2H),3.08-2.96(m,3H),2.64(brs,2H),1.98-1.87(m,6H),1.08(t,J＝7.2Hz,3H).LRMS(ESI)calcd for C22H28FN6O2S[M+H]+459.2,found:459.3。
实施例40
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)吡啶-2-磺酰胺(化合物40)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridine-2-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物40的数据为：1H NMR(600MHz,MeOD-d4)δ9.15(s,1H),8.96(s,1H),8.82-8.80(m,1H),8.25-7.88(m,3H),7.66-7.44(m,2H),7.17-7.01(m,3H),3.87(s,3H),3.32-2.54(m,5H),2.04-1.88(m,4H).LRMS(ESI)calcd for C24H25FN7O2S[M+H]+494.2,found:494.3。
实施例41
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-2-甲基丙基-1-磺酰胺(化合物41)N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-2-methylpropane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物41的数据为：1H NMR(600MHz,MeOD-d4)δ9.11(s,1H),8.21(s,1H),7.95(brs,1H),7.55(brs,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝8.4Hz,1H),6.92(brs,1H),3.85(s,3H),3.20(brs,2H),3.08-2.98(m,3H),2.64(brs,2H),2.29(brs,1H),1.98-1.93(m,4H),1.12(d,J＝7.2Hz,6H).LRMS(ESI)calcd for C23H30FN6O2S[M+H]+473.2,found:473.3。
实施例42
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丁基-1-磺酰胺(化合物42)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物42的数据为：1H NMR(600MHz,MeOD-d4)δ9.10(s,1H),8.21(s,1H),7.96(brs,1H),7.57(brs,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝7.8Hz,1H),6.92(brs,1H),3.85(s,3H),3.31-3.26(m,2H),3.09-2.98(m,3H),2.65(brs,2H),1.99-1.81(m,6H),1.49(brs,2H),0.95(brs,3H).LRMS(ESI)calcd for C23H30FN6O2S[M+H]+473.2,found:473.3。
实施例43
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丙基-2-磺酰胺(化合物43)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-2-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物43的数据为：1H NMR(600MHz,MeOD-d4)δ9.07-8.96(m,1H),8.21(s,1H),7.96-7.93(m,1H),7.60(brs,1H),7.24(t,J＝7.8Hz,1H),7.21-7.18(m,1H),6.90(brs,1H),3.81(s,3H),3.50(brs,1H),3.09-2.94(m,3H),2.69-2.63(m,2H),1.98-1.89(m,4H),1.43-1.41(m,6H).LRMS(ESI)calcd for C22H28FN6O2S[M+H]+459.2,found:459.3。
实施例44
3-氯-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丙基-1-磺酰胺(化合物44)
3-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物44的数据为：1H NMR(600MHz,MeOD-d4)δ9.02(s,1H),8.22(s,1H),7.95(brs,1H),7.56(brs,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝8.4Hz,1H),6.94(brs,1H),3.83(s,3H),3.74(s,2H),3.46(brs,2H),3.10-2.97(m,3H),2.65(brs,2H),2.31(brs,2H),1.97(brs,4H).LRMS(ESI)calcd for C22H27ClFN6O2S[M+H]+493.2,found:493.3。
实施例45
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-N-甲基甲磺酰胺(化合物45)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-N-methylmethanesulfonamide
合成方法如上图所示，化合物36(20mg,0.05mmol,1.0eq)溶解于THF(2.0mL)中，在室温条件下加入碳酸钾(14mg,0.10mmol,2.0eq)和碘甲烷(14mg,0.10mmol,2.0eq)。反应在室温下搅拌反应2小时，反应结束后，减压除去溶剂，产物通过prep-HPLC进行分离纯化，获得化合物45为白色固体产物(8mg，产率40％)。得到化合物45的数据为：1H NMR(400MHz,MeOD-d4)δ9.11(s,1H),8.29(s,1H),8.05(brs,1H),7.50-7.45(m,1H),7.29-7.26(m,2H),7.19-7.15(m,1H),3.86(s,3H),3.33(s,3H),3.09-2.96(m,7H),2.04-1.66(m,5H).LRMS(ESI)calcd for C21H26FN6O2S[M+H]+445.2,found:445.3。
实施例46
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)噻吩-2-磺酰胺(化合物46)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物46的数据为：1H NMR(600MHz,MeOD-d4)δ9.02(s,1H),8.13(brs,1H),7.89-7.79(m,2H),7.63(brs,2H),7.26-6.92(m,4H),3.82(s,3H),3.03-2.53(m,5H),1.91-1.88(m,4H).LRMS(ESI)calcd for C23H24FN6O2S2[M+H]+499.1,found:499.3。
实施例47
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲基氨-1-磺酰胺(化合物47)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物47的数据为：1H NMR(600MHz,MeOD-d4)δ9.09(s,1H),8.20(s,1H),7.94(brs,1H),7.54(d,J＝7.2Hz,1H),7.25(t,J＝7.8Hz,1H),7.19(d,J＝8.4Hz,1H),6.86(brs,1H),3.85(s,3H),3.09-2.96(m,3H),2.80-2.65(m,5H),2.04-1.93(m,4H).LRMS(ESI)calcd for C20H25FN7O2S[M+H]+446.2,found:446.3。
实施例48
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-4-甲基苯磺酰胺(化合物48)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-4-methylbenzenesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物48的数据为：1H NMR(400MHz,MeOD-d4)δ9.16(s,1H),8.10(brs,1H),7.85(brs,1H),7.72(d,J＝7.6Hz,2H),7.56(brs,1H),7.36(d,J＝8.0Hz,2H),7.16-7.13(m,2H),6.88(brs,1H),3.86(s,3H),3.00-2.49(m,5H),2.41(s,3H),1.93-1.89(m,4H).LRMS(ESI)calcd for C26H28FN6O2S[M+H]+507.2,found:507.2。
实施例49
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-2-甲氧乙基-1-磺酰胺(化合物49)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-2-methoxyethane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物49的数据为：1H NMR(600MHz,MeOD-d4)δ9.15(s,1H),8.20(s,1H),7.95(brs,1H),7.61(brs,1H),7.25(t,J＝7.8Hz,1H),7.18(d,J＝8.4Hz,1H),6.90(brs,1H),3.86(s,3H),3.84(brs,2H),3.55(brs,2H),3.27(s,3H),3.08-2.98(m,3H),2.63(brs,2H),1.99-1.93(m,4H).LRMS(ESI)calcd for C22H28FN6O3S[M+H]+475.2,found:475.2。
实施例55
N-(3-(5-(环丙基甲氧基)-6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物55)
N-(3-(5-(cyclopropylmethoxy)-6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示：步骤a、化合物90(365mg,1.0mmol,1.0eq)和还原铁粉(560mg,10.0mmol,10.0eq)溶解于EtOH(20mL)和H2O(2mL)混合溶剂中，然后加入NH4Cl(560g,10.0mmol,10.0eq)，反应体系加热至50℃继续搅拌3h。待反应结束后体系中加入DCM(200mL)稀释，过滤后减压浓缩，获得粗产物(500mg)。将粗产品(33mg,0.09mmol,1.0eq)溶解于DCM(2.0mL)中，在0℃条件下加入甲基磺酰氯(16mg,0.14mmol,1.5eq)和TEA(18mg,0.18mmol,1.5eq)。反应升温至室温，搅拌反应2小时，反应结束后，减压除去溶剂，产物通过硅胶色谱进行分离纯化，获得化合物92为黄色固体产物(20mg，产率54％).1H NMR(400MHz,MeOD-d4)δ8.58(s,1H),8.41(s,1H),8.07(s,1H),3.68(s,3H),3.64-3.57(m,2H),3.29-3.14(m,5H),2.94-2.88(m,1H),2.23-2.13(m,2H),2.04-1.99(m,2H).
步骤b、中间体N-(3-溴-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(0.735g,1.78mmol,1.0eq)、Na2CO3(0.38g,3.56mmol,2.0eq)和3-(环丙基甲氧基)-2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)吡啶(0.6g,2.67mmol,1.5eq)溶解在1,4-二氧六环(9mL)和H2O(1mL)的混合溶剂中。反应体系用氮气置换后，加入Pd(dppf)Cl2(0.13g,0.18mmol,0.1eq)，氮气保护下体系加热至90℃搅拌反应12小时.体系冷却至室温后，加水稀释，用乙酸乙酯萃取。有机相减压浓缩后柱层析分离纯化，得化合物32共0.587g(产率66％).1H NMR(400MHz,MeOD-d4)δ9.08(s,1H),7.76-7.68(m,2H),7.55-7.46(m,1H),7.26(t,J＝8.0Hz,1H),7.20-7.17(m,1H),3.98(s,3H),3.93(d,J＝7.2Hz,1H),3.86(s,3H),3.10-2.99(m,3H),2.69-2.64(m,2H),2.04-1.94(m,4H),1.28(brs,4H)0.71-0.66(m,2H),0.41-0.36(m,2H).LRMS(ESI)calcd for C24H30FN6O3S[M+H]+500.2,found:501.3。
实施例57
N-(3-(2-(叔丁基)-2H-吡唑并[3,4-b]吡啶-5-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物57)
N-(3-(2-(tert-butyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例55，得到化合物57的数据为：1H NMR(400MHz,MeOD-d4)δ9.13(s,1H),8.98(s,1H),8.51(brs,1H),8.04(s,1H),7.26(t,J＝8.0Hz,1H),7.20-7.17(m,1H),6.95(brs,1H),3.87(s,3H),3.16(s,3H),3.10-2.97(m,3H),2.68-2.65(m,2H),2.05-1.95(m,4H),1.20(s,9H).LRMS(ESI)calcd for C25H33FN8O2S[M+H]+508.2,found:509.3。
实施例65
N-(2-(4-氟-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)丁烷-1-磺酰胺(化合物65)
N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)butane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物65的数据为：LRMS(ESI)calcd for C23H29F2N6O2S[M+H]+491.2,found:491.3。
实施例67
3-氯-N-(2-(4-氟-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)丙烷-1-磺酰胺(化合物67)
3-chloro-N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)propane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物67的数据为：LRMS(ESI)calcd for C22H26ClF2N6O2S[M+H]+511.1,found:511.2。
实施例68
N-(2-(4-氟-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)噻吩-2-磺酰胺(化合物68)
N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)thiophene-2-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物68的数据为：LRMS(ESI)calcd for C23H23ClF2N6O2S2[M+H]+517.1,found:517.2。
实施例75
3,3,3-三氟-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丙烷-1-磺酰胺(化合物75)
3,3,3-trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物75的数据为：LRMS(ESI)calcd for C22H25F4N6O2S[M+H]+513.2,found:513.3。
实施例76
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)四氢-2H-吡喃-4-磺酰胺(化合物76)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物76的数据为：LRMS(ESI)calcd for C24H30FN6O3S[M+H]+501.2,found:501.4。
实施例77
4-(N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)磺胺酰基)苯甲酸甲酯(化合物77)
methyl
4-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)benzoate
合成路线如上图所示，合成方法同实施例33，得到化合物77的数据为：1H NMR(400MHz,MeOD-d4)δ9.00(s,1H),8.20-8.17(m,6H),7.53(brs,1H),7.16-7.13(m,3H),3.94(s,3H),3.82(s,3H),3.15-2.51(m,5H),1.89-1.86(m,4H).LRMS(ESI)calcd for C27H28FN6O4S[M+H]+551.2,found:551.2。
实施例78
4-氟-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)苯磺酰胺(化合物78)
4-fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物78的数据为：1H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.12-7.91(m,4H),7.55(brs,1H),7.32-7.29(m,2H),7.19-7.14(m,3H),3.83(s,3H),3.03-2.52(m,5H),2.03-1.30(m,4H).LRMS(ESI)calcd for C25H25F2N6O2S[M+H]+511.2,found:511.2。
实施例79
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-6-甲基吡啶-3-磺酰胺(化合物79)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-6-methylpyridine-3-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物79的数据为：1H NMR(400MHz,MeOD-d4)δ9.15(s,1H),8.81(brs,1H),8.24-8.12(m,2H),7.92(brs,1H),7.53-7.35(m,1H),7.22-7.15(m,4H),3.87(s,3H),3.15-2.56(m,8H),2.03-1.59(m,4H).LRMS(ESI)calcd for C25H27FN7O2S[M+H]+508.2,found:508.2。
实施例80
2-(4-氟-4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯腈(化合物80)
2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物80的数据为：1H NMR(600MHz，MeOD-d4)δ8.76(s,1H),8.28(d,J＝2.4Hz,1H),8.06(td,J＝7.8,2.4Hz,1H),7.75(dd,J＝7.8,1.2Hz,1H),7.58(dd,J＝7.8,1.2Hz,1H),7.36(t,J＝7.8Hz,1H),7.22(dd,J＝8.4,2.4Hz,1H),3.41(brs,2H),3.22-3.14(m,2H),2.30-2.23(m,4H).LRMS(ESI)calcd for C20H16D3F2N6[M+H]+384.2,found:384.2。
实施例81
N-(2-(4-氟-4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)甲磺酰胺(化合物81)
N-(2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物81的数据为：1H NMR(400MHz,MeOD-d4)δ8.53(s,1H),8.20(d,J＝1.6Hz,1H),7.97(brs,1H),7.55(brs,1H),7.26(t,J＝5.2Hz,1H),7.17(brs,1H),6.98(brs,1H),3.17(s,3H),3.06-2.70(m,4H),2.40(brs,2H),2.22-2.17(m,2H).LRMS(ESI)calcd for C20H20F2N6O2S[M+H]+452.2,found:452.2。
实施例83
3-(6-氟吡啶-3-基)-2-(4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)苯腈(化合物83)
3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物83的数据为：1H NMR(400MHz,MeOD-d4)δ9.01(s,1H),8.26(d,J＝2.4Hz,1H),8.02(td,J＝8.4,2.4Hz,1H),7.73(dd,J＝8.0,1.6Hz,1H),7.56(dd,J＝8.0,1.6Hz,1H),7.33(t,J＝8.0Hz,1H),7.20(dd,J＝8.4,2.4Hz,1H),3.27(brs,2H),3.17-3.08(m,3H),1.97-1.93(m,2H),1.83-1.79(m,2H).13C NMR(150MHz,MeOD-d4)δ164.4(d,J＝238.4Hz),159.1,154.2,148.5(d,J＝14.3Hz),145.8,144.1(d,J＝8.3Hz),137.6,136.9,135.9,135.1(d,J＝2.7Hz),126.0,119.5,111.2,110.5(d,J＝37.1Hz),52.5,32.8,32.6-31.9(m),30.8.HRMS(ESI)calcd for C20H17D3FN6[M+H]+:366.1916,found:366.1918.
实施例84
3-(5,6-二氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯并腈(化合物84)
3-(5,6-difluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物84的数据为：1H NMR(400MHz,MeOD)δ9.02(s,1H),8.05(s,1H),8.01-7.89(m,1H),7.75(dd,J＝7.6,1.6Hz,1H),7.58(dd,J＝8.0,2.0Hz,1H),7.34(t,J＝8.0Hz,1H),3.85(s,3H),3.25-3.07(m,4H),1.97(d,J＝12.4Hz,2H),1.89-1.72(m,2H).LRMS(ESI)calcd for C20H19F2N6[M+H]+381.2,found:381.3。
实施例85
3-(6-氯-5-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯并腈(化合物85)
3-(6-chloro-5-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物85的数据为：1H NMR(600MHz,MeOD)δ9.00(s,1H),8.23-8.10(m,2H),7.75(d,J＝7.2Hz,1H),7.59(d,J＝7.2Hz,1H),7.35(t,J＝7.8Hz,1H),3.85(s,3H),3.26-3.05(m,4H),2.03-1.90(m,2H),1.80(s,2H).LRMS(ESI)calcd for C20H19FClN6[M+H]+397.1,found:397.2。
实施例86
3-(6-氟-5-甲氧基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯并腈(化合物86)
3-(6-fluoro-5-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物86的数据为：1H NMR(400MHz,MeOD)δ9.08(s,1H),7.76-7.68(m,2H),7.63(dd,J＝9.6,2.0Hz,1H),7.56(dd,J＝7.6,1.6Hz,1H),7.31(t,J＝7.6Hz,1H),3.98(s,3H),3.86(s,3H),3.36(s,2H),3.22-3.07(m,2H),1.97(d,J＝11.6Hz,2H),1.92-1.76(m,2H).LRMS(ESI)calcd for C21H22FN6O[M+H]+393.2,found:393.2。
实施例87
3-(6-氟-5-甲基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯腈(化合物87)
3-(6-fluoro-5-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物87的数据为：1H NMR(600MHz,MeOD)δ9.02(s,1H),8.07(s,1H),7.88(d,J＝9.6Hz,1H),7.73(dd,J＝7.8,1.8Hz,1H),7.59-7.54(m,1H),7.34(t,J＝7.8Hz,1H),3.86(s,3H),3.28-3.06(m,4H),2.39(s,3H),1.96(d,J＝12.6Hz,2H),1.83(s,2H).LRMS(ESI)calcd for C21H22FN6[M+H]+377.3,found:377.4。
实施例88
3-(6-氟-4-甲基吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯腈(化合物88)
3-(6-fluoro-4-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物88的数据为：1H NMR(400MHz,MeOD)δ9.08(s,1H),7.99(s,1H),7.75(dd,J＝8.0,2.0Hz,1H),7.45(dd,J＝7.6,1.6Hz,1H),7.34(t,J＝8.0Hz,1H),7.11(s,1H),3.84(s,3H),3.43-3.34(m,2H),3.22-3.05(m,2H),2.99-2.86(m,1H),2.25(s,3H),1.97(d,J＝13.2Hz,1H),1.88(d,J＝13.2Hz,1H),1.81-1.69(m,1H),1.70-1.46(m,1H).LRMS(ESI)calcd for C21H22FN6[M+H]+377.3,found:377.3。
实施例89
N-(3-氰基-5-(6-氟吡啶-3-基)-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-1-甲基哌啶-4-甲酰胺(化合物89)
N-(3-cyano-5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1-methylpiperidine-4-carboxamide
合成路线如上图所示，合成方法同实施例1，得到化合物89的数据为：LRMS(ESI)calcd for C27H32FN8O[M+H]+503.2,found:503.4。
实施例90
3-(6-氟吡啶-3-基)-2-(4-(4-(4-甲氧基苄基)-4H-1,2,4-三唑-3-基)哌啶-1-基)苯腈(化合物90)
3-(6-fluoropyridin-3-yl)-2-(4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile
合成路线如上图所示，合成方法同实施例1，得到化合物90的数据为：1H NMR(600MHz,CDCl3)δ8.47(s,1H),8.16(s,1H),7.92(t,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,1H),7.43(d,J＝7.2Hz,1H),7.25-7.23(m,1H),7.11-7.09(m,3H),6.93(d,J＝7.2Hz,2H),5.10(s,2H),3.82(s,3H),3.22-3.12(m,4H),2.83(t,J＝12.0Hz,1H),1.86(brs,2H),1.73-1.70(m,2H).13C NMR(125MHz,MeOD-d4)δ164.4(d,J＝238.3Hz),161.9,159.1,154.2,148.5(d,J＝14.1Hz),145.1,144.1(d,J＝8.0Hz),137.6,136.9,135.9,135.1(d,J＝3.3Hz),131.0,126.4,126.0,119.4,115.8,111.2,110.5(d,J＝36.9Hz),55.9,52.6,50.2,33.3,31.3.HRMS(ESI)calcd for C27H26FN6O[M+H]+:469.2147,found:469.2149.
实施例91
2-(4-(4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯腈(化合物91)
2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile
合成路线如上图所示，将化合物90(24mg,0.05mmol,1.0equiv)溶解在TFA(2mL)中,反应加热至50℃并且搅拌4h.反应冷却至室温后旋干出去溶剂.所得粗品用制备液相分离纯化，得到化合物91的数据为：1H NMR(600MHz,MeOD-d4)δ8.53(brs,1H),8.25(s,1H),8.02(t,J＝7.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),7.21(d,J＝8.4Hz,1H),3.27-3.24(m,2H),3.13(brs,2H),2.98-2.93(m,1H),1.98-1.94(m,2H),1.81-1.74(m,2H).13C NMR(125MHz,MeOD-d4)δ164.4(d,J＝238.4Hz),161.5,154.3,148.4(d,J＝14.1Hz),146.0,144.2(d,J＝8.3Hz),137.6,136.8,135.9,135.1(d,J＝5.3Hz),125.9,119.5,111.1,110.4(d,J＝36.9Hz),52.6,34.8,31.5.HRMS(ESI)calcd for C19H18FN6[M+H]+:349.1571,found:349.1572.
实施例92
N-(3-(6-氟吡啶-3-基)-2-(4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物92)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物92的数据为：1H NMR(600MHz,MeOD-d4)δ8.92(s,1H),8.22(s,1H),7.96(s,1H),7.56(s,1H),7.26(t,J＝7.9Hz,1H),7.19(d,J＝7.7Hz,1H),6.94(s,1H),3.17(s,3H),3.07(m,2H),2.96(m,1H),2.63(m,2H),1.94(m,4H).LRMS(ESI)calcd for C20H21D3FN6O2S[M+H]+434.2,found:434.2.
实施例93
N-(2-(4-氟-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)甲磺酰胺(化合物93)
N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物93的数据为：1H NMR(600MHz,MeOD-d4)δ8.43(s,1H),8.20(s,1H),7.97(s,1H),7.55(brs,1H),7.26(t,J＝7.8Hz,1H),7.18-7.16(m,1H),6.98(s,1H),3.81(s,3H),3.17(s,3H),2.92(brs,4H),2.40(brs,2H),2.22-1.91(m,2H).LRMS(ESI)calcd for C20H24FN6O2S[M+H]+449.2,found:449.2.
实施例94
N-(6'-氟-4-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-[3,3'-联吡啶]-5-基)甲磺酰胺(化合物94)
N-(6'-fluoro-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,3'-bipyridin]-5-yl)methanesulfonamide
化合物94的合成路线如上图所示:
步骤a、MC53(500mg,3.01mmol,1eq)、MC104(1.07g,4.52mmol,1.5eq)和碳酸钾(541mg,3.91mmol)溶解于DMSO(5mL)中，温度升至50℃反应2h。反应用水淬灭，然后用EA和水萃取。有机相减压蒸馏，浓缩物用硅胶柱层析DCM:MeOH(40:1-10:1)纯化得到淡黄色油状液体化合MC105(580mg,53％yield).1H NMR(600MHz,CDCl3)δ8.73(s,2H),8.07(s,1H),3.68(s,3H),3.46(m,2H),3.16(t,J＝13.6Hz,2H),2.95(tt,J＝11.7,3.7Hz,1H),2.31(qd,J＝11.9,4.0Hz,2H),2.01(m,2H).
步骤b、MC105(142mg,0.39mmol,1eq)、Fe(219mg,3.9mmol,10eq)和NH4Cl(211mg,3.9mmol,10eq)溶解于乙醇(5mL)和水(1mL)中，温度升至70℃，搅拌反应2h。反应结束后，趁热过滤，减压浓缩，浓缩物溶解于DCM中，过滤除盐。滤液减压浓缩，得灰白色固体粗MC106。
步骤c、MC106(131mg,0.39mmol,1eq)、甲磺酰氯(89mg,0.78mmol,2eq)和吡啶(62mg,0.78mmol,2eq)溶解于DCM(5mL)中，温度升至50℃，搅拌反应12h。用水淬灭，EA和水萃取，有机相减压浓缩，浓缩物用硅胶柱层析DCM:MeOH(40:1-10:1)纯化得到棕色油状液体化合MC107(138mg,88％).1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.41(s,1H),8.07(s,1H),3.68(s,3H),3.57(m,2H),3.14(s,3H),2.91(m,1H),2.18(m,2H),2.01(m,2H),1.83(m,2H).
步骤d、MC108(162mg,0.39mmol,1eq)、2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶(132mg,0.59mmol,1.5eq)和碳酸钠(100mg,0.78mmol,2eq)溶解于1,4-二氧六环(5mL)和水(0.5mL)中，在氩气保护下加入Pd(dppf)Cl2。温度升至85℃，搅拌反应12h。反应液减压浓缩，浓缩物通过prep-HPLC进行分离纯化，获得黄色固体化合物94.得到化合物94的数据为：1H NMR(600MHz,MeOD)δ8.99(s,1H),8.56(s,1H),8.39(d,J＝2.8Hz,1H),8.31(s,1H),8.13(td,J＝7.6,2.7Hz,1H),7.29(dd,J＝8.4,2.6Hz,1H),3.82(s,3H),3.57(m,2H),3.26(m,2H),3.21(s,1H),3.19(s,3H),1.92(m,2H),1.84(m,2H).LRMS(ESI)calcd for C19H23FN6O2S[M+H]+432.2,found:432.2.
实施例95
N-(5-氟-3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物95)
N-(5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物95的数据为：LRMS(ESI)calcd for C20H23F2N6O2S[M+H]+449.1,found:449.2。
实施例96
N-(5-氯-3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物96)
N-(5-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物96的数据为：LRMS(ESI)calcd for C20H23ClFN6O2S[M+H]+465.1,found:465.2。
实施例97
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-5-(三氟甲基)苯基)甲磺酰胺(化合物97)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物97的数据为：1H NMR(600MHz,MeOD-d4)δ9.08(s,1H),8.27(d,J＝2.4Hz,1H),8.01(brs,1H),7.76(brs,1H),7.33(brs,1H),7.22(dd,J＝8.4,2.4Hz,1H),3.84(s,3H),3.19(s,3H),3.14-2.52(m,5H),2.04-1.92(m,4H).LRMS(ESI)calcd for C21H23F4N6O2S[M+H]+499.1,found:499.2。
实施例98
N-(3-(6-氟吡啶-3-基)-5-甲氧基-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲磺酰胺(化合物98)
N-(3-(6-fluoropyridin-3-yl)-5-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物98的数据为：LRMS(ESI)calcd for C21H26FN6O3S[M+H]+461.2,found:461.2。
实施例99
N-(3-(6-氟吡啶-3-基)-2-((1R，5S)-3-(4-甲基-4H-1,2,4-三唑-3-基)-8-氮杂双环[3.2.1]辛烷-8-基)苯基)甲磺酰胺(化合物99)
N-(3-(6-fluoropyridin-3-yl)-2-((1R,5S)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物99的数据为：1H NMR(600MHz,MeOD-d4)δ9.10(s,1H),8.23(s,1H),7.40-7.38(m,1H),7.13-7.07(m,3H),3.99(brs,2H),3.93(s,3H),3.52-3.45(m,1H),3.18(s,3H),1.90(brs,2H),1.78-1.73(m,6H).LRMS(ESI)calcd for C22H26FN6O2S[M+H]+457.2,found:457.2。
实施例100
N-(2-(4-(5-氨基-4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)甲磺酰胺(化合物100)
N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide
化合物100合成路线如上图所示。
步骤a、将化合物MC89(1.18g,5.0mmol,1.0eq)、化合物MC1(1.43g,10.0mmol,2.0eq)和K3PO4(2.12g,10.0mmol,2.0eq)溶解于DMSO(10mL)的混合溶剂中，体系加热至80℃后反应16小时。反应结束后冷却至室温，加入水和EA萃取，有机相减压浓缩后硅胶柱层析获得黄色油状化合物MC2(1.6g,93.3％yield)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.04(t,J＝8.0Hz,1H),3.73(s,3H),3.18-2.96(m,4H),2.51-2.47(m,1H),1.97-1.93(m,4H)。
步骤b、化合物MC2(1.6g,4.66mmol,1.0eq)和还原铁粉(2.8g,10.0mmol,50.0eq)溶解于EtOH(20mL)和H2O(2mL)混合溶剂中，然后加入NH4Cl(2.8g,10.0mmol,50.0eq)，反应体系加热至50℃继续搅拌3h。待反应结束后体系中加入DCM(200mL)稀释，过滤后减压浓缩，获得粗产物MC3(2.0g)。1H NMR(400MHz,CDCl3)δ6.81-6.78(m,2H),6.66(dd,J＝6.4,2.8Hz,1H),4.36(brs,3H),3.71(s,3H),3.59-3.52(m,2H),2.91-2.85(m,2H),2.48-2.39(m,1H),2.03-1.99(m,2H),1.81-1.70(m,2H)。
步骤c、将粗产品MC3(2.0g,crude)溶解于DCM(20.0mL)中，在0℃条件下加入甲基磺酰氯(773mg,6.75mmol,1.5eq)和吡啶(712mg,9mmol,2.0eq)。反应升温至50℃，搅拌反应2小时，反应结束后，减压除去溶剂，产物通过硅胶色谱进行分离纯化，获得化合物MC4为黄色固体产物(1.76g，产率99％).1HNMR(400MHz,MeOD-d4)δ7.50(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.06(t,J＝8.0Hz,1H),3.72-3.63(m,5H),3.03(s,3H),2.83-2.79(m,2H),2.48-2.40(m,1H),2.12-2.06(m,2H),1.84-1.73(m,2H)。
步骤d、将粗产品MC4(1.76g,4.5mmol,1.0eq)溶解于EtOH(20.0mL)中，加入水合肼(3mL)。反应升温至90℃，搅拌反应16小时，反应结束后，减压除去溶剂，产物通过硅胶色谱进行分离纯化，获得化合物MC5为白色固体产物(1.24g，产率71％).1H NMR(400MHz,DMSO-d6)δ9.02(brs,1H),8.48(brs,1H),7.44(d,J＝8.0Hz,1H),7.29(d,J＝7.2Hz,1H),7.15(t,J＝8.0Hz,1H),4.19(brs,2H),3.52-3.45(m,2H),3.17(s,3H),2.79-2.75(m,2H),2.22-2.15(m,1H),1.87-1.77(m,2H),1.72-1.61(m,2H)。
步骤e、将MC5(610mg,1.56mmol,1.0eq)溶解于二氧六环(10毫升)和水(1毫升)中，并加入CNBr(497mg,4.69mmol,3.0eq)和NaHCO3(524mg,6.24mmol,4.0eq)。室温下搅拌2小时后，反应混合物用10％的NaHCO3溶液(20毫升)进行淬灭。过滤获得析出的固体，并用水洗涤(20毫升)。所得固体进一步在真空下干燥以得到MC6(530mg，78.8％)，呈淡黄色固体。1H NMR(400MHz,DMSO-d6)δ7.45(d,J＝8.0Hz,1H),7.33(d,J＝7.6Hz,1H),7.17(t,J＝8.0Hz,1H),3.62-3.56(m,2H),3.22-3.18(m,4H),2.89-2.85(m,2H),2.05-1.86(m,4H)。
步骤f、在室温下向MC6(530mg，1.23mmol,1.0eq)的二氧六环(4mL)溶液中加入N-二甲基甲酰胺二甲基缩醛(0.33mL，2.5mmol,2.0eq)。将反应混合物在100℃下搅拌2h后。通过TLC监测起始材料完全消耗后，减压浓缩混合物以得到MC7(600mg，crude)成为黄色固体。粗产品本身用于下一步，无需任何进一步纯化。
步骤g、将MC7(600mg，crude)的二氧六环(6mL)溶液加入封管中，并加入甲胺(25％的MeOH溶液，6mL)和AcOH(0.220ml)。并将反应混合物在110℃下搅拌16小时。反应结束后，减压除去溶剂，产物通过硅胶色谱进行分离纯化，获得化合物MC8为白色固体产物(230mg，两步产率43.6％)。LRMS(ESI)calcd for C15H22BrN6O2S[M+H]+429.2,found:429.1。
步骤h、中间体MC8(85mg,0.20mmol,1.0eq),碳酸钠(64mg,0.6mmol,3.0eq)和4-氟-3-吡啶硼酸(89mg,0.4mmol,2.0eq)溶解在4mL二氧六环和0.4mL水的混合溶剂中，反应体系在氮气保护下加入Pd(dppf)Cl2(15mg,0.02mmol,0.1eq)，90摄氏度反应10小时。反应体系冷却至室温后用水稀释，然后用乙酸乙酯萃取。有机层浓缩后用HPLC分离制备，获得白色固体产物。得到化合物100的数据为：1H NMR(400MHz,MeOD-d4)δ8.95(s,1H),8.63-8.29(m,2H),7.58-7.42(m,2H),7.30(t,J＝7.4Hz,1H),7.01(brs,1H),3.78(s,3H),3.17-3.10(m,6H),2.92-2.68(m,2H),1.96-1.85(m,4H).LRMS(ESI)calcd for C20H25FN7O2S[M+H]+446.2,found:446.2。
实施例101
N-(2-(4-(5-氨基-4-甲基-4H-1,2,4-三唑-3-基)-4-氟哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)甲磺酰胺(化
合物101)
N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide
化合物101合成路线如上图所示。得到化合物101的数据为：LRMS(ESI)calcd for C20H24F2N7O2S[M+H]+464.2,found:464.2。
实施例102
N-(2-(4-(5-氨基-4-甲基-4H-1,2,4-三唑-3-基)-4-甲基哌啶-1-基)-3-(6-氟吡啶-3-基)苯基)甲磺酰胺(化合物102)
N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-methylpiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide
化合物102合成路线如上图所示。得到化合物102的数据为：LRMS(ESI)calcd for C21H27FN7O2S[M+H]+460.2,found:460.3。
实施例103
2-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)异噻唑烷-1,1-二氧化物(化合物103)
2-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)isothiazolidine 1,1-dioxide
化合物103合成路线如上图所示。得到化合物103的数据为：LRMS(ESI)calcd for C22H26FN6O2S[M+H]+457.2,found:457.3。
实施例106
3-氟-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丙烷-1-磺酰胺(化合物106)
3-fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide
化合物106合成路线如上图所示。得到化合物106的数据为：LRMS(ESI)calcd for C22H27F2N6O2S[M+H]+477.2,found:477.2。
实施例107
4-氯-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丁烷-1-磺酰胺(化合物107)
4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide
化合物107合成路线如上图所示。得到化合物107的数据为：LRMS(ESI)calcd for C23H29FClN6O2S[M+H]+507.2,found:507.2。
实施例108
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-3-甲基丁烷-1-磺酰胺(化合物108)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-methylbutane-1-sulfonamide
化合物108合成路线如上图所示。得到化合物108的数据为：LRMS(ESI)calcd for C24H32FN6O2S[M+H]+487.2,found:487.3。
实施例109
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)苯磺酰胺(化合物109)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide
化合物109合成路线如上图所示。得到化合物109的数据为：LRMS(ESI)calcd for C25H26FN6O2S[M+H]+493.2,found:493.2。
实施例110
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)戊烷-1-磺酰胺(化合物110)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pentane-1-sulfonamide
化合物110合成路线如上图所示。得到化合物110的数据为：LRMS(ESI)calcd for C24H32FN6O2S[M+H]+487.2,found:487.3。
实施例111
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)己烷-1-磺酰胺(化合物111)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)hexane-1-sulfonamide
化合物111合成路线如上图所示。得到化合物111的数据为：LRMS(ESI)calcd for C25H34FN6O2S[M+H]+501.2,found:501.3。
实施例112
4-氯-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)苯磺酰胺(化合物112)
4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide
化合物112合成路线如上图所示。得到化合物112的数据为：LRMS(ESI)calcd for C25H25ClFN6O2S[M+H]+527.1,found:526.8。
实施例113
4-氯-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)丁烷-1-磺酰胺(化合物113)
4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide
化合物113合成路线如上图所示。得到化合物113的数据为：LRMS(ESI)calcd for C23H29ClFN6O2S[M+H]+507.2,found:507.2。
实施例114
3-氯-N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)苯磺酰胺(化合物114)
3-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide
化合物114合成路线如上图所示。得到化合物114的数据为：LRMS(ESI)calcd for C25H25ClFN6O2S[M+H]+527.1,found:527.2。
实施例115
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-3-羟基丙烷-1-磺酰胺(化合物115)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-hydroxypropane-1-sulfonamide
化合物115的合成路线如上图所示:
步骤a、3-溴丙醇MC123(1g,7.2mmol,1eq)、DMAP溶解于吡啶(15mL)中。体系温度降至0℃后，滴加对甲基叔丁酰氯(955mg,7.92mmol,1.1eq)，随后将温度升至室温，搅拌反应30min。加入饱和NH4Cl水溶液淬灭，然后用EA(50mL)和H2O(50mL)萃取，食盐水(50mL)洗涤后，用无水硫酸钠干燥，减压浓缩的到无色油状液体化合物MC124(1.38g,86％yield).1H NMR(600MHz,CDCl3)δ4.19(t,J＝6.0Hz,2H),3.46(t,J＝6.6Hz,2H),2.18(p,J＝6.3Hz,2H),1.20(s,9H)。
步骤b、MC124(1.38g,6.2mmol,1eq)、硫脲(567mg,7.44mmol,1.2eq)溶解于乙醇(7ml)中，升温至80℃，搅拌反应2h后减压浓缩除去溶剂。用DCM溶解浓缩物，过滤除去硫脲，滤液减压旋蒸除去溶剂后，浓缩物用乙醚洗涤除去多余的MC125，过滤的到白色固体粗产物MC125(1.33g,98％yield).
步骤c、粗MC125溶解于水(0.9mL)和乙腈(15mL)中，将温度降至0℃，滴加叔丁基次氯酸酯，搅拌反应30min。用乙酸乙酯和水萃取，有机相减压浓缩，得到淡黄色固体粗产物MC126(1.32g,88％yield)。
步骤d、MC91(40mg,0.12mmol,1eq)、粗MC126(88mg,0.36mmol,3eq)和吡啶(28mg,0.36mmol,3eq)溶解于DCM中。温度升至50℃，搅拌反应12h后，直接减压旋蒸除去溶剂，所得浓缩物用硅胶柱层析DCM:MeOH(20:1-10:1)纯化得到棕色油状液体化合物MC127(25mg,37％yield).[M+H]+559.2,found:559.2.
步骤e、MC127(25mg,0.045mmol,1eq)、NaOH(20mg,0.45mmol,10eq)和四丁基硫酸氢铵(8mg,0.023mmol,0.5eq)溶解于四氢呋喃中，室温下搅拌反应3h。减压浓缩，浓缩物通过prep-HPLC进行分离纯化，获得棕黄色固体化合物115.1H NMR(400MHz,MeOD-d4)δ9.00(brs,1H),8.22(brs,1H),7.96(brs,1H),7.57(brs,1H),7.25(t,J＝7.9Hz,1H),7.19(d,J＝7.3Hz,1H),6.93(brs,1H),3.82(s,3H),3.67(m,2H),3.37(m2H),3.08(d,J＝11.4Hz,2H),2.99(s,1H),2.64(m,2H),2.03(m,2H),1.96(m,4H).LRMS(ESI)calcd for C22H28FN6O3S[M+H]+475.2,found:475.3.
实施例116
4-(N-(3-(6-氟吡啶-3-基)-2-(5-(4-甲基-4H-1,2,4-三唑-3-基)-1,2-恶氮嗪-2-基)苯基)磺胺酰基)丁酸
4-(N-(3-(6-fluoropyridin-3-yl)-2-(5-(4-methyl-4H-1,2,4-triazol-3-yl)-1,2-oxazinan-2-yl)phenyl)sulfamoyl)butanoic acid
化合物116合成路线如上图所示，合成方法如化合物115，得到化合物116的数据为：1H NMR(400MHz,MeOD-d4)δ9.02(brs,1H),8.22(brs,1H),7.96(brs,1H),7.58(brs,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝8.6Hz,1H),6.93(brs,1H),3.83(s,3H),3.32(m,4H),3.11(m,2H),3.00(s,1H),2.64(m,2H),2.51(m,2H),2.10(m,2H),1.97(m,2H).LRMS(ESI)calcd for C23H28FN6O4S[M+H]+503.2,found:503.2.
实施例117
6-(N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)磺胺酰基)己酸(化合物119)
6-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)hexanoicacid
化合物117合成路线如上图所示，合成方法如化合物115，得到化合物117的数据为：1H NMR(600MHz,MeOD-d4)δ8.92(brs,1H),8.22(brs,1H),7.97(brs,1H),7.58(brs,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝6.4Hz,1H),6.92(brs,1H),3.81(brs,3H),3.32(brs,4H),3.07(m,J＝12.5Hz,2H),2.95(s,1H),2.65(m,2H),2.27(m,2H),1.97(m,2H),1.85(m,2H),1.61(m,2H),1.50(m,2H).LRMS(ESI)calcd for C25H31FN6O4S[M+H]+503.2,found:503.2.
实施例118
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-1H-吡唑-4-磺酰胺(化合物118)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1H-pyrazole-4-sulfonamide
化合物118合成路线如上图所示，合成方法如化合物115，得到化合物118的数据为：1H NMR(600MHz,MeOD-d4)δ9.02(brs,1H),8.16(brs,1H),7.95(m,J＝54.3Hz,3H),7.65(brs,1H),7.24(brs,1H),7.18(brs,J＝8.3,2.7Hz,1H),6.93(brs,1H),3.84(s,3H),2.94(s,1H),2.78(m,2H),2.57(m,2H),1.94(m,4H).LRMS(ESI)calcd for C22H24FN8O2S[M+H]+483.2,found:483.2.
实施例119
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide
化合物119的合成路线如上图所示。上述获得的MC91粗产物(50mg,0.14mmol,1.0eq)溶解于DCM(2.0mL)中，在0℃条件下加入1-甲基-1H-吡唑-4-磺酰氯(38mg,0.21mmol,1.5eq)和Py(17mg,0.21mmol,1.5eq)。反应升温至50℃，搅拌反应12小时，反应结束后，减压除去溶剂，产物通过prep-HPLC进行分离纯化，获得化合物101为白色固体产物(30mg，产率43％)。1H NMR(400MHz,MeOD-d4)δ8.99(brs,1H),8.16(m,2H),7.91(brs,1H),7.72(brs,1H),7.61(brs,1H),7.22(brs,1H),7.16(brs,J＝8.4,2.3Hz,1H),6.91(s,1H),3.91(s,3H),3.82(s,3H),2.92(s,1H),2.79(m,2H),2.55(m,2H),1.92(m,4H).LRMS(ESI)calcd for C23H26FN6O4S[M+H]+497.2,found:497.2.
实施例120
N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)噻吩-3-磺酰胺(化合物120)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-3-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物120的数据为：1H NMR(400MHz,MeOD-d4)δ9.17(s,1H),8.13-7.88(m,2H),7.61(brs,2H),7.32-6.92(m,4H),3.86(s,3H),2.98-2.53(m,5H),2.03-1.30(m,4H).LRMS(ESI)calcd for C23H24FN6O2S2[M+H]+499.1,found:499.2。
实施例121
9-(N-(3-(6-氟吡啶-3-基)-2-(4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)磺胺酰基)-N-羟基壬酰胺
9-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)-N-hydroxynonanamide
合成路线如上图所示，合成方法同实施例33，得到化合物121的数据为：LRMS(ESI)calcd for C28H39FN7O4S[M+H]+588.3,found:589.3。
实施例122
合成路线如上图所示，合成方法同实施例33，得到化合物122的数据为：1H NMR(600MHz,MeOD)δ8.97(s,1H),8.24(s,1H),7.98(s,1H),7.59(s,1H),7.28(t,J＝7.9Hz,1H),7.21(s,1H),6.94(s,1H),3.84(s,3H),3.09(d,J＝11.8Hz,2H),2.68(s,2H),2.32(s,1H),2.12(s,2H),1.99(s,6H),1.58(d,J＝85.4Hz,6H).LRMS(ESI)calcd for C26H35FN7O4S[M+H]+546.2,found:546.3.
实施例123
合成路线如上图所示，合成方法同实施例33，得到化合物123的数据为：1H NMR(600MHz,MeOD)δ9.03(brs,1H),8.22(brs,1H),7.96(brs,1H),7.59(brs,1H),7.26(t,J＝7.9Hz,1H),7.20(brs,1H),6.93(brs,1H),3.85(s,3H),3.32(m,4H),3.08(m,3H),2.64(m,2H),2.29(m,2H),2.13(m,2H),1.99(m,2H).LRMS(ESI)calcd for C23H29FN7O4S[M+H]+518.2,found:518.2.
实施例124
N-(3-(6-氟吡啶-3-基)-2-(4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)甲基氨-1-磺酰胺(化合物124)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物124的数据为：LRMS(ESI)calcd for C23H27D3FN6O2S[M+H]+476.2,found:476.3。
实施例125
N-(3-(6-氟吡啶-3-基)-2-(4-(4-(甲基-d3)-4H-1,2,4-三唑-3-基)哌啶-1-基)苯基)噻吩-2-磺酰胺(化合物125)
N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide
合成路线如上图所示，合成方法同实施例33，得到化合物125的数据为：LRMS(ESI)calcd for C23H21D3FN6O2S2[M+H]+502.1,found:502.2。
效果例1
化合物的QPCTL酶(又称gQC或isoQC)抑制活性测试方法如下：反应体系由QPCTL蛋白酶、荧光底物谷氨酰胺7-氨基-4-甲基香豆素(Gln-AMC)、化合物、焦谷氨酰氨肽酶(pyroglutamyl aminopeptidase I，PGPEP I)组成，反应在黑色384孔板中进行。首先将12.5μL QPCTL蛋白酶(浓度5.7ng/μL)，2.5μL不同浓度的化合物混合，摇床中37℃，100rpm反应10分钟，然后加入10μL荧光底物Gln-AMC(终浓度为200μM)，摇床中37℃，100rpm反应20分钟，然后向体系中加入25μL PGPEP I(终浓度为3.97ng/μL)，摇床中37℃，100rpm反应30分钟。利用TECAN infinite 200Pro酶标仪在激发/发射波长分别为380/460nm时读取微孔板的荧光强度。所得的荧光信号值经过GraphPad Prism 8.0分析，得到化合物的抑制率和IC50，A≤10nM，10nM<B≤100nM，100nM<C≤1000nM，D>1000nM，活性数据如下表1所示：
表1.代表化合物的QPCTL活性数据

根据上述实验结果可知，本发明的化合物具有优异的QPCTL酶抑制活性，能够作为谷氨酰胺环化酶抑制剂，并进一步研究其抗肿瘤及其他疾病的治疗效果。
效果例2
化合物的QPCT酶(又称sQC)抑制活性测试方法如下：反应体系由QPCT蛋白酶、荧光底物谷氨酰胺7-氨基-4-甲基香豆素(Gln-AMC)、化合物、焦谷氨酰氨肽酶(pyroglutamyl aminopeptidase I，PGPEP I)组成，反应在黑色384孔板中进行。首先将12.5μL QPCT蛋白酶(浓度3.82ng/μL)，2.5μL不同浓度的化合物混合，摇床中37℃，100rpm反应10分钟，然后加入10μL荧光底物Gln-AMC(终浓度为200μM)，摇床中37℃，100rpm反应20分钟，然后向体系中加入25μL PGPEP I(终浓度为3.97ng/μL)，摇床中37℃，100rpm反应30分钟。利用TECAN infinite 200Pro酶标仪在激发/发射波长分别为380/460nm时读取微孔板的荧光强度。所得的荧光信号值经过GraphPad Prism 8.0分析，得到化合物的抑制率和IC50，A≤10nM，10nM<B≤100nM，100nM<C≤1000nM，活性数据如下表2所示：
表2.代表化合物的QPCT活性数据
根据上述实验结果可知，本发明的化合物具有优异的QPCT酶抑制活性，能够作为谷氨酰胺环化酶抑制剂，并进一步研究其治疗阿尔兹海默病和抗肿瘤等疾病的作用效果。
效果例3
化合物的细胞活性的测试方法如下：
化合物对细胞CD47的N端焦谷氨酸化修饰(pGlu-CD47)抑制活性检测方法如下：293T细胞以10000/孔的密度接种在48孔板中，加入不同浓度的化合物处理48小时后，采用流式细胞分析技术(FACS)进行化合物的体外活性测试。用CD47的流式抗体CC2C6检测细胞表面CD47的N端焦谷氨酸化(pGlu-CD47)水平。将化合物处理之后的细胞用PBS清洗后加入100μL FACS Buffer重悬细胞。然后加入1μL细胞流式抗体，在冰上避光孵育30分钟，FACS Buffer洗涤后再加入200μL FACS Buffer重悬细胞。用流式仪将细胞上机检测，检测所获得的平均荧光强度(MFI)利用GraphPad Prism 8.0分析，计算得到化合物的pGlu-CD47抑制率。代表化合物的活性数据如下表3所示：
表3.代表化合物的细胞活性数据

实验结果表明，本发明的化合物对293T细胞表面的CD47的N端焦谷氨酸化修饰具有较好的抑制作用，具有极高的细胞活性。
PQ912(cas：1276021-65-8)、SEN177(cas：2117405-13-5)均为已知谷氨酰胺酰基环化酶抑制剂中的一种，作为阳性对照药物，证明本发明的化合物具有更好的酶抑制活性和抗肿瘤活性，证明本发明的化合物具有更好的成药潜力。
本领域技术人员应该理解，本领域技术人员在结合现有技术以及上述实施例可以实现变化例，在此不做赘述。这样的变化例并不影响本发明的实质内容，在此不予赘述。
以上对本发明的较佳实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，其中未尽详细描述的设备和结构应该理解为用本领域中的普通方式予以实施；任何熟悉本领域的技术人员，在不脱离本发明技术方案范围情况下，都可利用上述揭示的方法和技术内容对本发明技术方案做出许多可能的变动和修饰，或修改为等同变化的等效实施例，这并不影响本发明的实质内容。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化及修饰，均仍属于本发明技术方案保护的范围内。

Claims (15)

  1. 一种如式(I)所示的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药：
    其中：
    表示单键或不存在；
    m为0-3中的任一整数，n为0-3中的任一整数；
    X为碳原子或者氮原子；
    R1为任选被一个或多个R7取代的5-10元杂芳基；
    R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
    R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或C1-20烷氧基；
    R4为任选被一个或多个C1-20烷基、胺基取代的5-10元杂芳基；
    R5为氢原子、卤原子、羟基、C1-20烷基或C1-20烷氧基；任选地，当R5为C1-20烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-10元环状结构；
    R6为氢原子或-NR8C(＝O)R9；
    每一个R7各自独立地为卤原子、C1-20烷基、任选被C3-10环烷基取代的C1-20烷基、任选被C3-10环烷基取代的C1-20烷氧基或任选被C1-20烷基取代的C3-10环烷基氧基；
    每一个R8各自独立地为氢原子或C1-20烷基；
    每一个R9各自独立地为氢原子、C1-20烷基、C1-20卤代烷基、-NHC1-20烷基、-C1-20亚烷基、-C1-20烷氧基、C3-10环烷基、5-10元杂环烷基、5-10元杂芳基或C6-10芳基；所述C1-10烷基、C3-10环烷基、5-10元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-20烷基或-C(＝O)OC1-20烷基、羧基、羟基取代；
    或，R8和R9相连形成5-10元环状结构。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，
    m为0或1，n为0或1；
    X为碳原子或者氮原子；
    R1为任选被一个或多个R7取代的5-10元含氮杂芳基；
    R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
    R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或C1-10烷氧基，
    R4为任选被一个或多个C1-10烷基、胺基取代的5-10元含氮杂芳基；
    R5为氢原子、卤原子、羟基、C1-10烷基或C1-10烷氧基；任选地，当R5为C1-10烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-6元环状结构；
    R6为氢原子或-NR8C(＝O)R9；
    每一个R7各自独立地为卤原子、C1-10烷基、任选被C3-6环烷基取代的C1-10烷基、任选被C3-6环烷基取代的C1-10烷氧基或任选被C1-10烷基取代的C3-6环烷基氧基；
    每一个R8各自独立地为氢原子或C1-10烷基；
    每一个R9各自独立地为氢原子、C1-10烷基、C1-10卤代烷基、-NHC1-10烷基、-C1-10亚烷基-C1-10烷氧基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基；所述C1-10烷基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-10烷基或-C(＝O)OC1-10烷基、羧基、羟基取代；
    或，R8和R9相连形成5-6元环状结构。
  3. 根据权利要求2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，
    m为0或1，n为0或1，且m和n不同时为0；
    X为碳原子或者氮原子；
    R1为任选被一个或多个R7取代的吡啶基；
    R2为氰基、硝基、-C(＝O)N(R8)2、-NR8C(＝O)R9、-S(＝O)2R9或-NR8S(＝O)2R9；
    R3为氢原子、卤原子、三氟甲基、-NR8C(＝O)R9或甲氧基；
    R4为任选被一个或多个C1-10烷基或者胺基取代的以下基团：其中，表示结合键位；
    R5为氢原子、卤原子、羟基或C1-10烷基；任选地，当R5为C1-10烷基时，R5的任一碳原子和R4的任一环原子相连接，形成5-6元环状结构；
    R6为氢原子或-NR8C(＝O)R9；
    每一个R7各自独立地为甲基、甲氧基、环丙基取代的甲氧基、卤原子；
    每一个R8各自独立地为氢原子或C1-10烷基；
    每一个R9各自独立地为氢原子、C1-10烷基、C1-10卤代烷基、-NHC1-10烷基、-C1-10亚烷基-C1-10烷氧基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基；所述C1-10烷基、C3-6环烷基、5-6元杂环烷基、5-10元杂芳基或C6-10芳基各自独立地任选被一个或多个卤原子、C1-10烷基或-C(＝O)OC1-10烷基、羧基、羟基取代；
    或，R8和R9相连形成五元环状结构。
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(II)所示：
    其中，m、n、X、R1、R2、R3、R4、R5和R6具有如权利要求1-3任一项中所述的定义。
  5. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(III)所示：
    其中，m、n、X、R1、R2、R3和R6具有如权利要求1-3任一项中所述的定义；
    p为0-3中的任一整数，优选1或2。
  6. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(IV)所示：
    其中，m、n、X、R1、R2、R3、R4、R5和R6具有如权利要求1-3任一项中所述的定义。
  7. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(V)所示：
    其中，X、R1、R2、R3、R4、R5和R6具有如权利要求1-3任一项中所述的定义。
  8. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(VI)或者(VII)所示：
    其中，m、n、X、R1、R4、R5、R8和R9具有如权利要求1-3任一项中所述的定义；
    优选地，R4为任选被一个或两个C1-10烷基、胺基取代的以下基团：其中，表示结合键位；
    优选地，R5为氢原子或卤原子。
  9. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述化合物如式(VIII)所示：
    其中，m、n、X、R1、R2、R3、R5和R6具有如权利要求1-3任一项中所述的定义；
    Z为碳原子或者氮原子；R10为氢原子、C1-10烷基或C1-10烷氧基取代的苯甲基；任选地，R5和R10相连形成5-10元环状结构；
    R11为氢原子、C1-10烷基或胺基。
  10. 根据权利要求9所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，其特征在于，所述R1为以下基团中的一种：
    其中，
    表示结合键位；
    每一个R12各自独立地为卤原子；
    R13为甲基、甲氧基、环丙基取代的甲氧基或卤原子；
    每一个R14各自独立地为C1-10烷基。
  11. 以下含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药：




  12. 一种药用组合物，其以根据权利要求1-11任一项所述的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药作为活性成分；优选地，所述药用组合物含有至少一种药学上可接受的载体。
  13. 一种药物联用形式，其包含根据权利要求1-11任一项所述的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药或者根据权利要求12所述的药用组合物，以及抗体；优选地，所述抗体为PD-1/PD-L1抗体或CD47抗体。
  14. 根据权利要求1-11任一项所述的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，或者根据权利要求12所述的药用组合物，或者根据权利要求10所述的药物联用形式在抑制谷氨酰胺环化酶上的应用。
  15. 根据权利要求1-11任一项所述的含氮杂环化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素标记物或前药，或者根据权利要求12所述的药用组合物，或者根据权利要求10所述的药物联用形式在制备预防和/或治疗肿瘤、免疫性疾病、神经性疾病、肥胖或衰老的药物中的应用；
    优选地，所述肿瘤选自结直肠癌、肺癌、胃癌、黑色素瘤、骨髓瘤、乳腺癌、腺癌、膀胱癌和血液瘤中的至少一种；
    优选地，所述免疫性疾病选自湿疹、斑秃、银屑病、白癜风、类风湿性关节炎、红斑狼疮综合征、痤疮和化脓性汗腺炎中的至少一种；
    优选地，所述神经性疾病选自阿尔茨海默病、亨廷顿病、唐氏综合征中的神经变性、抑郁症、焦虑症、精神病和多发性硬化症中的至少一种。
PCT/CN2025/097596 2024-05-28 2025-05-27 一种含氮杂环化合物及其应用 Pending WO2025247243A1 (zh)

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