WO2022253335A1 - 含磺酰基的芳基类化合物及其应用 - Google Patents
含磺酰基的芳基类化合物及其应用 Download PDFInfo
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- WO2022253335A1 WO2022253335A1 PCT/CN2022/097000 CN2022097000W WO2022253335A1 WO 2022253335 A1 WO2022253335 A1 WO 2022253335A1 CN 2022097000 W CN2022097000 W CN 2022097000W WO 2022253335 A1 WO2022253335 A1 WO 2022253335A1
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- Prior art keywords
- compound
- added
- pharmaceutically acceptable
- crude product
- alkyl
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
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- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel sulfonyl-containing aryl compounds and applications thereof, in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof.
- JAK is a class of non-receptor tyrosine kinases with four subtypes, JAK1, JAK2, JAK3, and TYK2.
- the JAK-STAT signaling pathway mediated by them is related to cell proliferation, differentiation, apoptosis, and immune regulation.
- JAK-STAT is an essential pathway for immune response, and when inflammation occurs, overactivation of JAK will in turn promote disease progression.
- JAK1, JAK2 and TYK2 widely exist in various tissues and cells in the body, and JAK3 mainly exists in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes.
- JAK1 has become a target for diseases such as immunity, inflammation, and cancer
- JAK2 has become a target for blood system-related diseases
- JAK3 has become a target for autoimmune diseases.
- Popular target TYK2 has also become a target in diseases such as autoimmunity and inflammation.
- the four members of the JAK family have different functions. If they lack selectivity, they may interfere with a variety of normal signal transduction and cause a variety of toxic and side effects, which also limits the first generation of non-selective JAK inhibitors (such as ruxolitinib). , Tofacitinib, etc.) clinical application range.
- non-selective JAK inhibitors such as ruxolitinib. , Tofacitinib, etc.
- the five JAK inhibitors approved by the FDA all carry a black-box warning. In addition to target-related toxicity, many of them may be caused by off-target.
- JAK2 a member of the JAK family, plays an important role in mediating the signaling of pro-inflammatory cytokines, including IL-12, IL-23 and type I interferon. Th17 and Th1 cells are differentiated and formed under the activation of IL-12 and IL-23, and drive the release of a series of pro-inflammatory factors, further aggravating the inflammatory response.
- BMS-986165 an oral allosteric inhibitor of TYK2 developed by BMS, has a unique mechanism of action. Unlike other JAK inhibitors, it acts on the pseudokinase region of TYK2 JH2, achieving high kinase selectivity (>1000 times). It beat the oral standard drug Apremilast in the Phase III clinical trial of psoriasis, and it was safe and well tolerated. This reflects that highly selective TYK2 inhibitors have great potential for clinical application in the treatment of psoriasis and other targets, and have great clinical application value.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T is selected from N and CH optionally substituted by 1 halogen
- R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
- R 2 is selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R b ;
- R 3 is selected from F, Cl, Br, I and C 1-3 alkyl
- Ring B is selected from 5-membered heteroaryl optionally substituted by 1, 2 or 3 Rc ;
- R and R are independently selected from H, D, F, Cl, Br and I;
- Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
- each R is selected from F, Cl, Br and I;
- Hetero in the 5-membered heteroaryl represents 1, 2 or 3 atoms or atomic groups independently selected from N, O, S and NH.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T is selected from N and CH optionally substituted by 1 halogen
- R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
- R 2 is selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R b ;
- R 3 is selected from F, Cl, Br and C 1-3 alkyl
- Ring B is selected from 5-membered heteroaryl optionally substituted by 1, 2 or 3 Rc ;
- R and R are independently selected from H, D, F, Cl, Br and I;
- each R is selected from H, F, Cl, Br and C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
- each R is selected from F, Cl, Br and I;
- Hetero in the 5-membered heteroaryl represents 1, 2 or 3 atoms or atomic groups independently selected from N, O, S and NH.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T is selected from N and CH optionally substituted by 1 halogen
- R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
- R 2 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R ;
- R 3 is selected from F, Cl, Br and C 1-3 alkyl
- Ring B is selected from 5-membered heteroaryl optionally substituted by 1, 2 or 3 Rc ;
- R and R are independently selected from H, D, F, Cl, Br and I;
- each R is independently selected from H, F , Cl, Br and C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
- each R is selected from F, Cl, Br and I;
- the 5-membered heteroaryl group contains 1, 2 or 3 atoms or atom groups independently selected from N, O, S and NH.
- each of the above-mentioned R c is independently selected from H, F, Cl, Br, I and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R, and other variables are as in this invention defined.
- R c is independently selected from H, F, Cl, Br and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
- each R c mentioned above is independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
- R c is independently selected from H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
- R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are independently and optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
- R 1 is selected from OCH 3 , and other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 and OCH 3 , and the CH 3 and OCH 3 are independently optionally substituted by 1, 2 or 3 R b , and other variables are as described in the present invention definition.
- R 2 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are independently and optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 and CD 3 , and other variables are as defined in the present invention.
- R 2 is selected from CD 3 , and other variables are as defined in the present invention.
- the above ring B is selected from said Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
- the above ring B is selected from Other variables are as defined herein.
- the above compound or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , R 3 and R c are as defined in the present invention.
- the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
- the compound of the present invention has a good inhibitory effect on TYK2JH2 pseudokinase; the compound of the present invention has strong inhibitory activity on the proliferation of Ba/F3 cells transfected with human TYK2-E957D gene; the compound of the present invention has higher selectivity and excellent Pharmacokinetic properties.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
- the compounds of the invention may exist in particular geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
- diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of each other.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
- the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- any variable eg, R
- its definition is independent at each occurrence.
- said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
- substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
- linking group listed does not indicate its linking direction
- its linking direction is arbitrary, for example,
- the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
- any one or more sites of the group can be linked to other groups through chemical bonds.
- connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
- the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
- the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
- the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
- halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- the term "5-membered heteroaryl” and “5-membered heteroaryl ring” in the present invention can be used interchangeably.
- the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
- a 5-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole group, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4 -thiazo
- the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
- SXRD single crystal X-ray diffraction
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
- the solvent used in the present invention is commercially available.
- reaction solution was concentrated to dryness, then dichloromethane (30mL) was added, and then concentrated to dryness, then added into dichloromethane (150mL), deuterated methylamine hydrochloride (3.37g, 47.76mmol, 0.95eq) was added, and After cooling down to 0°C, DIPEA (19.49g, 150.83mmol, 26.27mL, 3eq) was added and reacted at 20°C for 16hr.
- the crude product was separated by preparative high-performance liquid chromatography (chromatographic column: Phenomenex luna C18 80*40mm*3 ⁇ m; mobile phase: A (water, containing 0.04% hydrochloric acid) and B (acetonitrile); gradient: B%: 28%-48%, 7min) to obtain compound WX-002 hydrochloride.
- reaction solution was extracted and separated with ethyl acetate (50 mL) and water (50 mL), and the organic phase was washed once with saturated brine and then concentrated to obtain a crude product.
- TR-FRET fluorescence resonance energy transfer
- HEPES pH7.5 the final concentration is 20mM
- MgCl 2 the final concentration is 10mM
- Brij-35 the final concentration is 0.015%
- DTT the final concentration is 2mM
- BSA the final concentration is 50 ⁇ g/mL.
- the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.
- Adenosine Tri-Phosphate is a common energy carrier in various life activities in nature, and is the smallest unit of energy storage and transfer.
- CellTiter-Glo TM Live Cell Detection Kit uses luciferase as the detection substance, and luciferase needs the participation of ATP in the process of luminescence.
- Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the cell proliferation can be detected.
- the cell line is Ba/F3-FL-TYK2-E957D, which can stably express the exogenously introduced human TYK2-E957D gene.
- Cell lines were cultured in an incubator with culture conditions of 37 °C, 5% CO2 . Passage regularly, and take cells in logarithmic growth phase for plating.
- the cell viability rate should be over 90%.
- Adding drugs to the compound detection cell plate Take 5 ⁇ L of 20 ⁇ compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 ⁇ L of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO was 0.1%.
- the SpectraMax Paradigm readout yields the corresponding RLU of fluorescence per well.
- Inhibition Rate (Inh%) 100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%.
- the inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the data was analyzed with GraphPad Prism software, and the dose-effect curve was obtained by fitting the data with nonlinear S-curve regression, and the IC50 value was calculated accordingly. The data are shown in Table 3.
- the compound of the present invention has strong inhibitory activity on the proliferation of Ba/F3 cells transfected with human TYK2-E957D gene.
- the purpose of this experiment is to detect the inhibitory effect of compounds on cytokine-activated JAK-STAT signaling pathway in human peripheral blood mononuclear cells (PBMC).
- PBMC peripheral blood mononuclear cells
- the TYK2 signaling pathway is activated by IFN ⁇ stimulation, and the inhibitory activity of the compound on its downstream STAT1 phosphorylation can be detected, and the half inhibitory concentration IC 50 of the compound on the activity of the TYK2 signaling pathway can be obtained;
- JAK1 can be activated by IL-6 stimulation Signaling pathway, detecting the inhibitory activity of the compound on its downstream STAT1 phosphorylation, the half inhibitory concentration IC 50 of the compound on the activity of the JAK1 signaling pathway can be obtained.
- PBMC Human Peripheral Blood Mononuclear Cells
- Culture medium 1640 culture medium + 10% fetal bovine serum + 1% double antibody + 1% non-essential amino acids (percentages are volume ratios)
- PBMCs frozen in liquid nitrogen were thawed in a water bath at 37° C., culture medium was added, and centrifuged at 320 g for 3 min.
- the compound of the present invention exhibits higher inhibitory activity on the TYK2 signaling pathway stimulated and activated by IFN ⁇ ; at the same time, it exhibits a weaker inhibitory activity on the JAK1 signaling pathway activated by IL-6 stimulation, showing a higher inhibitory activity. selectivity.
- Drug preparation the compounds were formulated into clear solutions with corresponding solvents for administration in IV (intravenous injection) and PO (gastric administration) groups.
- the vehicle is 10% DMSO + 10% solutol + 80% (10% HP- ⁇ -CD aqueous solution).
- the administration method is cassette dosing, and the dosage of each compound is: IV 0.5mg/kg; PO dosage is 2mg/kg.
- Table 5 The results of pharmacokinetic parameters are shown in Table 5:
- the compound of the present invention exhibits excellent pharmacokinetic properties after administration to mice.
- mice take male SD rats as the tested animals, apply LC/MS/MS method to measure single intravenous injection (IV) and gavage (PO) after giving the compound, the drug concentration of the compound in the blood plasma at different times, research the present invention Pharmacokinetic behavior of the compound in mice, and evaluate its pharmacokinetic characteristics.
- IV intravenous injection
- PO gavage
- Drug preparation the compounds were formulated into clear solutions with corresponding solvents for administration in IV (intravenous injection) and PO (gastric administration) groups.
- the vehicle is 10% DMSO + 10% solutol + 80% (10% HP- ⁇ -CD aqueous solution).
- the results of pharmacokinetic parameters are shown in Table 7:
- the compound of the present invention exhibits excellent pharmacokinetic properties after administration to rats.
Abstract
一种新的含磺酰基的芳基类化合物及其应用,具体公开了式(I)所示化合物或其药学上可接受的盐。
Description
本申请主张如下优先权:
CN202110613891.8,申请日:2021年06月02日;
CN202110875437.X,申请日:2021年07月30日;
CN202210317221.6,申请日:2022年03月28日。
本发明涉及新的含磺酰基的芳基类化合物及其应用,具涉及式(I)所示化合物或其药学上可接受的盐。
JAK是一类非受体酪氨酸激酶,共有JAK1、JAK2、JAK3、TYK2四种亚型,它们介导的JAK-STAT信号通路与细胞的增殖、分化、凋亡以及免疫调节有关。JAK-STAT是免疫反应所必需的通路,而在炎症发生时,JAK被过度激活又会反过来促进疾病进展。JAK1、JAK2和TYK2广泛存在于体内各种组织和细胞中,JAK3主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布,JAK1已成为免疫、炎症和癌症等疾病的靶点;JAK2已成为血液***相关疾病的靶点;JAK3已成为自身免疫性疾病的热门靶点;TYK2也成为自身免疫和炎症等疾病的靶点。
JAK家族4个成员功能各不相同,如果缺乏选择性,很可能会干扰多种正常信号传导,引起多种毒副作用,这也限制了第一代非选择性JAK抑制剂(例卢可替尼、托法替尼等)的临床应用范围。FDA批准的5款JAK抑制剂,全部带有黑框警告,除靶点相关毒性外,很多可能是由脱靶造成。
开发高选择性JAK抑制剂是降低毒副作用的重要手段,但是JAK家族四个亚型同源性高达40%~70%,开发高选择性的JAK抑制剂难度大,暂无高选择性的JAK抑制剂上市。TYK2是JAK家族一员,在介导促炎性细胞因子(包括IL-12,IL-23和I型干扰素)的信号传导中起重要作用。Th17及Th1细胞在IL-12及IL-23激活下分化形成,并驱动一系列促炎因子的释放,进一步加剧炎症反应。这些细胞因子与银屑病、炎症性肠病(IBD)和***性红斑狼疮(SLE)等多种炎症和自身免疫性疾病的发病机制有关。BMS公司开发的口服TYK2别构抑制剂BMS-986165作用机制独特,与其它JAK抑制剂不一样的是,它作用于TYK2 JH2假激酶区域,实现了激酶高选择性(>1000倍)。它在银屑病临床三期实验中击败口服标准药物阿普斯特(Apremilast),而且安全耐受性较好。这体现了高选择性TYK2抑制剂在治疗银屑病等靶点方面具有巨大的临床应用潜力,具有重大的临床应用价值。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
T选自N和CH,所述CH任选被1个卤素取代;
R
1选自C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
a取代;
R
2选自H、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
b取代;
R
3选自F、Cl、Br、I和C
1-3烷基;
环B选自5元杂芳基,所述5元杂芳基任选被1、2或3个R
c取代;
R
a和R
b分别独立地选自H、D、F、Cl、Br和I;
各R
c分别独立地选自H、F、Cl、Br、I和C
1-3烷基,所述C
1-3烷基任选被1、2或3个R取代;
各R选自F、Cl、Br和I;
所述5元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
T选自N和CH,所述CH任选被1个卤素取代;
R
1选自C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
a取代;
R
2选自H、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
b取代;
R
3选自F、Cl、Br和C
1-3烷基;
环B选自5元杂芳基,所述5元杂芳基任选被1、2或3个R
c取代;
R
a和R
b分别独立地选自H、D、F、Cl、Br和I;
各R
c选自H、F、Cl、Br和C
1-3烷基,所述C
1-3烷基任选被1、2或3个R取代;
各R选自F、Cl、Br和I;
所述5元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
T选自N和CH,所述CH任选被1个卤素取代;
R
1选自C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
a取代;
R
2选自C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
b取代;
R
3选自F、Cl、Br和C
1-3烷基;
环B选自5元杂芳基,所述5元杂芳基任选被1、2或3个R
c取代;
R
a和R
b分别独立地选自H、D、F、Cl、Br和I;
各R
c独立地选自H、F、Cl、Br和C
1-3烷基,所述C
1-3烷基任选被1、2或3个R取代;
各R选自F、Cl、Br和I;
所述5元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的原子或原子团。
在本发明的一些方案中,上述各R
c分别独立地选自H、F、Cl、Br、I和CH
3,所述CH
3任选被1、2或3个R取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
c独立地选自H、F、Cl、Br和CH
3,所述CH
3任选被1、2或3个R取代,其他变量如本发明所定义。
在本发明的一些方案中,上述各R
c分别独立地选自H、F、Cl、Br、I、CH
3、CH
2F、CHF
2和CF
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
c独立地选自H、F、Cl、Br、CH
3、CH
2F、CHF
2和CF
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
1选自CH
3和OCH
3,所述CH
3和OCH
3分别独立地任选被1、2或3个R
a取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
1选自OCH
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
2选自H、CH
3和OCH
3,所述CH
3和OCH
3分别独立地任选被1、2或3个R
b取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
2选自CH
3和OCH
3,所述CH
3和OCH
3分别独立地任选被1、2或3个R
b取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
2选自H、CH
3和CD
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
2选自CD
3,其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
在本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自:
其中,
T、R
1、R
2、R
3和R
c如权本发明所定义。
本发明提供了下式所示化合物或其药学上可接受的盐,
技术效果
本发明化合物对TYK2JH2假激酶具有良好的抑制作用;本发明化合物对转染人TYK2-E957D基因的Ba/F3细胞的增殖具有较强的抑制活性;本发明化合物具有较高的选择性和优异的药代动力学性质。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除非另有说明,术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和 反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有说明,用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型,用直形实线键
和直形虚线键
表示立体中心的相对构型,用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
或直形虚线键
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用 放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当一个取代基数量为0时,表示该取代基是不存在的,比如-A-(R)
0表示该结构实际上是-A。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时,这种取代基可以与这个环上的任意原子相键合,例如,结构单元
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,
中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,当某一基团具有一个或多个可连接位点时,该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的,且可连接位点存在H原子时,则连接化学键时,该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连;
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连;
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连;
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这4种连接方式,即使-N-上画出了H原子,但是
仍包括
这种连接方式的基团,只是在连接1个化学键时,该位点的H会对应减少1个变成相应的一价哌啶基。
除非另有规定,环上原子的数目通常被定义为环的元数,例如,“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定,术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
除非另有规定,术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定,术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定,本发明术语“5元杂芳基”与“5元杂芳环”可以互换使用,术语“5元杂芳基”表示由5个 环原子组成的具有共轭π电子体系的单环基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子。其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)
p,p是1或2)。5元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基的实例包括但不限吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词:aq代表水;eq代表当量、等量;DCM代表二氯甲烷;PE代表石油醚;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;DMF代表N,N-二甲基甲酰胺;Boc代表叔丁氧羰基是一种胺保护基团;r.t.代表室温;O/N代表过夜;THF代表四氢呋喃;Boc
2O代表二叔丁基二碳酸酯;TFA代表三氟乙酸;HCl代表盐酸;mp代表熔点;Pd(dppf)Cl
2代表[1,1′-双(二苯膦基)二茂铁]二氯化钯;Pd(dppf)Cl
2.CH
2Cl
2代表[1,1′-双(二苯膦基)二茂铁]二氯化钯二氯甲烷复合物;TEA代表三乙胺;Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽;Pd
2(dba)
3代表三(二亚苄基丙酮)二钯;EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;HOBt代表1-羟基苯并***;HATU代表2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯;NMP代表N-甲基吡咯烷酮;DIPEA代表N,N-二异丙基乙胺;SEM代表2-(三甲硅烷基)乙氧甲基。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1
步骤1:化合物A-1的合成
将化合物A-1-1(10g,49.49mmol,1eq),双联频哪醇硼酸酯(18.85g,74.24mmol,1.5eq),乙酸钾(14.57g,148.48mmol,3eq)溶于1,4-二氧六环(200mL)中,置换氮气三次后加入Pd(dppf)Cl
2.CH
2Cl
2(2.02g,2.47mmol,0.05eq),在100℃搅拌2hr。向反应液中加入水(200mL),用乙酸乙酯(100mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚=0~25%),得到化合物A-1。
1HNMR(400MHz,CDCl
3)δ:7.13-7.11(m,1H),6.93(t,J=15.2,7.6Hz,1H),6.88-6.85(m,1H),3.81(s,3H),1.36(s,12H);LCMS m/z=250.1[M+H]
+。
参考例2
步骤1:化合物A-2-2的合成
将化合物A-2-1(20g,135.17mmol,1eq)溶于NMP(200mL)中,0℃加入钠氢(6.49g,162.20mmol,60%纯度,1.2eq),搅拌0.5小时后,加入2-(三甲硅烷基)乙氧甲基氯(27.04g,162.20mmol,28.71mL,1.2eq),自然升至15℃搅拌16hr。向反应液中加入饱和氯化铵水溶液(50mL)后加入乙酸乙酯(200mL*2)和水(200mL*2)萃取,有机相用饱和食盐水(200mL*2)清洗后用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物A-2-2。
1HNMR(400MHz,CDCl
3)δ:8.13(s,1H),5.44(s,2H),3.66-3.62(m,2H),0.94-0.90(m,2H),-0.02(s,9H);LCMS m/z=278.0[M+H]
+。
步骤2:化合物A-2的合成
将化合物A-2-2(5g,17.97mmol,1eq),化合物A-1(4.48g,17.97mmol,1eq),碳酸钾(4.97g,35.94mmol,2eq)溶于1,4-二氧六环(50mL)和水(30mL)中,置换氮气三次后加入Pd(dppf)Cl
2(1.31g,1.80mmol,0.1eq),在90℃搅拌14hr。向反应液中加入水(100mL),用乙酸乙酯(50mL*2)萃取,有机相用无 水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~50%),得到化合物A-2。
1HNMR(400MHz,CDCl
3)δ:8.31(s,1H),7.38-7.36(m,1H),7.01(t,J=15.2,7.6Hz,1H),6.87-6.83(m,1H),5.58(s,2H),3.78(s,3H),3.74-3.69(m,2H),0.98-0.94(m,2H),-0.01(s,9H);LCMS m/z=321.1[M+H]
+。
参考例3
步骤1:化合物A-3-2的合成
将化合物A-3-1(20g,96.61mmol,1eq)溶于乙腈(100mL)和水(15mL)中,加入溴化锂(25.17g,289.84mmol,7.28mL,3eq)和DIPEA(37.46g,289.84mmol,50.48mL,3eq),在20℃搅拌反应3hr。将反应液过滤,滤饼用乙腈(50mL)淋洗,得到滤饼化合物A-3-2。LCMS m/z=192.9[COOH+1]
+。
步骤2:化合物A-3的合成
将化合物A-3-2(10g,50.27mmol,1eq)溶于DCM(150mL)中,然后加入草酰氯(8.93g,70.38mmol,6.16mL,1.4eq),然后加入DMF(183.72mg,2.51mmol,193.39μL,0.05eq),在20℃下反应4hr。然后将反应液浓缩干,再加入二氯甲烷(30mL),再浓缩干,然后加入二氯甲烷(150mL)中,加入氘代甲胺盐酸盐(3.37g,47.76mmol,0.95eq),然后降温至0℃后,加入DIPEA(19.49g,150.83mmol,26.27mL,3eq),在20℃下反应16hr。反应完成后,向反应液中加入水(150mL),萃取分液,然后水相再用二氯甲烷(150mL)萃取一次,合并有机相,用饱和食盐水洗涤一次,无水硫酸钠干燥,过滤,浓缩得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~20%),得到化合物A-3。LCMS m/z=209.0[M+1]
+。
参考例4
步骤1:化合物A-4-2的合成
将化合物A-4-1(1g,6.15mmol,1eq)溶于DMF(6mL)中,加入碳酸钾(849.91mg,6.15mmol,1eq),碘甲烷(872.86mg,6.15mmol,382.83μL,1eq),在15℃下搅拌3hr。向反应液中加入水(5mL)和乙酸乙酯(10mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物A-4-2。
1HNMR(400MHz,CDCl
3)δ:7.14-7.10(m,1H),6.99-6.95(m,1H),6.92-6.88(m,1H),2.31(s,3H)。
步骤2:化合物A-4的合成
将化合物A-4-2(0.5g,2.83mmol,1eq)溶于DCM(10mL)中,加入间氯过氧苯甲酸(1.03g,5.07mmol,85%纯度,1.79eq),在15℃下搅拌4hr。向反应液中加入饱和碳酸氢钠水溶液(10mL)后静置分液,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物A-4。HNMR(400MHz,CDCl
3)δ:8.10-7.99(m,2H),7.38-7.33(m,1H),3.09(s,3H);LCMS m/z=209.0[M+H]
+。
实施例1
合成路线:
步骤1:化合物1-3的合成
将化合物A-2(0.15g,468.08μmol,1eq)溶于异丙醇(1.5mL)中,加入醋酸锌(171.76mg,936.15μmol,2eq),化合物A-3-2(108.40mg,561.69μmol,1.2eq),水(0.5mL),在65℃搅拌15hr。向反应液中加入水2mL,搅拌,过滤,收集滤饼,得到化合物1-3。
1HNMR(400MHz,DMSO-d
6)δ:12.11(s,1H),8.83(s,1H),7.75(d,J=7.2Hz,1H),7.68(d,J=8.4Hz,1H),7.34-7.30(m,2H),5.59(s,2H),3.72(s,3H),3.69-3.65(m,3H),0.88(t,J=16.0,8.0Hz,2H),-0.05(s,9H);LCMS m/z=477.1[M+H]
+。
步骤2:化合物1-4的合成
将化合物1-3(3.76g,7.38mmol,1eq,0.5Zn),环丙基甲酰胺(6.28g,73.77mmol,10eq),碳酸铯(7.21g,22.13mmol,3eq),Xantphos(426.86mg,737.71μmol,0.1eq)溶于1,4-二氧六环(75.2mL)中,氮气置换三次后加入Pd2(dba)3(675.54mg,737.71μmol,0.1eq),120℃搅拌2hr。与另一批次(500mg)一起后处理,向反应液中加入3mol/L稀盐酸调至pH=3,加入二氯甲烷(50mL*2)和水(50mL*2)萃取,用无水硫酸钠干燥后过滤,滤液减压浓缩,得到化合物1-4。LCMS m/z=526.2[M+H]
+。
步骤3:化合物1-5的合成
将化合物1-4(5g,4.76mmol,纯度:50%,1eq)溶于NMP(50mL)和乙腈(25mL)中,加入N-甲基咪唑(1.17g,14.27mmol,1.14mL,3eq),EDCI(1.28g,6.66mmol,1.4eq),HOBt(321.34mg,2.38mmol,0.5eq),氘代甲胺盐酸盐(335.48mg,4.76mmol,1eq,HCl),65℃下搅拌1hr。向反应液中加入水(100mL*2)和乙酸乙酯(100mL*2)萃取后,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~100%),得到化合物1-5。
1HNMR(400MHz,CDCl
3)δ:11.19(s,1H),9.45(s,1H),8.32(s,1H),8.23(s,1H),8.02(s,1H),7.86(dd,J=8.0,1.6Hz,1H),7.53(d,J=8.0Hz,1H),7.31-7.29(m,1H),5.58(s,2H),3.83(s,3H),3.74-3.70(m,2H),1.13-1.09(m,2H),1.01-0.90(m,5H),0.08(s,9H);LCMS m/z=542.3[M+H]
+。
步骤4:化合物1-6的合成
将化合物1-5(1.2g,2.22mmol,1eq)溶于TFA(24mL)中,在15℃下搅拌1hr。向反应液中加入饱和碳酸氢钠水溶液(500mL)调至pH=8后加入水(200mL)和二氯甲烷(1000mL*5)和乙醇(300mL*5)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物1-6,粗品未经纯化直接用于下一步反应。
1HNMR(400MHz,DMSO-d
6)δ:14.19-14.02(m,1H),11.35-11.32(m,1H),11.00(s,1H),9.15(d,J=14.8Hz,1H),8.16-8.09(m,2H),7.81-7.68(m,1H),7.59-7.50(m,1H),7.37-7.27(m,1H),3.72(s,3H),1.40-1.23(m,1H),0.87-0.81(m,4H);LCMS m/z=412.2[M+H]
+。
步骤5:化合物WX-001的合成
将化合物1-6(30mg,72.92μmol,1eq),化合物2-溴-1-氟-4-(甲基磺酰基)苯(20.30mg,80.21μmol,1.1eq),碳酸铯(59.39mg,182.29μmol,2.5eq)溶于DMF(2mL)和水(0.2mL)中,氮气置换三次后加入碘 化亚铜(2.78mg,14.58μmol,0.2eq),100℃搅拌13hr。向反应液中加入水(10mL),用乙酸乙酯萃取两次,每次5mL,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经过制备硅胶薄层色谱层析板纯化(石油醚∶乙酸乙酯=0∶1),得到化合物WX-001。
1HNMR(400MHz,CDCl
3)δ:11.09(s,1H),9.76(s,1H),8.79(s,1H),8.37(d,J=2.0Hz,1H),8.27(s,1H),8.08-8.05(m,2H),7.93-7.90(m,2H),7.59(dd,J=8.0,1.2Hz,1H),7.32(t,J=8.0,4.0Hz,1H),3.89(s,3H),3.15(s,3H),1.89-1.82(m,1H),1.13-1.09(m,2H),0.93-0.89(m,2H);LCMS m/z=644.1[M+H]
+。
实施例2
合成路线:
步骤1:化合物WX-002盐酸盐的合成
将化合物1-6(0.1g,121.53μmol),化合物2-氟-1-氟-4-(甲基磺酰基)苯(23.36mg,121.53μmol),碳酸铯(98.99mg,303.82μmol)溶于DMF(2mL)和水(0.5mL)中,加入碘化亚铜(4.63mg,24.31μmol),在100℃搅拌2hr。向反应液中加入水(3mL),用乙酸乙酯萃取两次,每次6mL,有机相用无水硫酸钠干燥后过滤,滤液浓缩得到粗品。粗品经制备硅胶薄层色谱层析板纯化(二氯甲烷∶甲醇=10∶1)得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex luna C18 80*40mm*3μm;流动相:A(水,含0.04%盐酸)和 B(乙腈);梯度:B%:28%-48%,7min)得到化合物WX-002盐酸盐。
1HNMR(400MHz,CD
3OD)δ:9.17(d,J=2.4Hz,1H),8.32-8.29(m,1H),8.12-8.08(m,2H),8.04-8.02(m,1H),7.67(dd,J=8.0,1.6Hz,1H),7.47(d,J=8.0Hz,1H),6.86(s,1H),3.88(s,3H),3.24(s,3H),1.84-1.78(m,1H),1.16-1.06(m,4H);LCMS m/z=584.2[M+H]
+。
实施例3
合成路线:
步骤1:化合物WX-003盐酸盐的合成
将化合物1-6(80mg,178.61μmol,1eq),化合物A-4(48.45mg,232.20μmol,1.3eq)溶于DMF(4mL)中,加入碳酸铯(174.59mg,535.84μmol,3eq),在100℃下搅拌2hr。向反应液中加入水(10mL)和乙酸乙酯(20mL*3)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:20%-50%,8min),得到化合物WX-003盐酸盐。
1HNMR(400MHz,CD
3OD)δ:9.12(s,1H),8.33(d,J=1.6Hz,1H),8.15-8.12(m,1H),8.05-8.01(m,2H),7.65(dd,J=7.6,1.6Hz,1H),7.45-7.41(m,1H),7.22-7.14(m,1H),3.84(s,3H),3.26(s,3H),1.88-1.80(m,1H),1.12-1.03(m,4H);LCMS m/z=600.2[M+H]
+。
实施例4
合成路线:
步骤1:化合物4-2的合成
将化合物4-1(20g,98.99mmol,1eq)和三甲基硅乙炔(99.26g,1.01mol,140.00mL,10.21eq)加入到N,N-二甲基乙酰胺(400mL)中,然后加入碘化亚铜(7.54g,39.59mmol,0.4eq)和Pd(PPh
3)
2Cl
2(6.95g,9.90mmol,0.1eq),置换N
2后,加入二异丙胺(220.67g,2.18mol,308.20mL,22.03eq),在105℃下反应24 hr。将反应液减压浓缩,粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~30%),得到化合物4-2。LCMS m/z=220.1[M+H]
+。
步骤2:化合物4-3的合成
将化合物4-2(8g,21.88mmol,60%纯度,1eq)加入到MeOH(120mL)中,然后加入碳酸钾(9.07g,65.65mmol,3eq),在20℃下反应1hr。将反应液过滤,滤液浓缩干得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~50%),得到化合物4-3。
1HNMR(400MHz,CD
3OD)δ:6.88-6.86(m,2H),6.77-6.74(m,1H),3.95(s,3H),3.88(s,2H),3.27(s,1H);LCMS m/z=148.1[M+H]
+。
步骤3:化合物4-4的合成
将化合物4-3(581.51mg,3.95mmol,1eq)和化合物1-溴-2-氟-4-甲砜基苯(1g,3.95mmol,1eq)加入到二甲基亚砜(25mL)和水(5mL)中,然后加入N,N-二甲基环己烷-1,2-二胺(84.30mg,592.68μmol,0.15eq)、碘化亚铜(75.25mg,395.12μmol,0.1eq)和抗坏血酸钠(78.28mg,395.12μmol,0.1eq),最后加入叠氮化钠(385.30mg,5.93mmol,1.5eq),在25℃下反应24hr。将反应液用乙酸乙酯(50mL)和水(50mL)萃取分液,有机相用饱和食盐水洗涤一次后浓缩得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~50%),得到化合物4-4。
1HNMR(400MHz,CD
3OD)δ:8.70-8.69(m,1H),8.43-8.39(m,1H),7.98-7.95(m,2H),7.66(dd,J=8.0,0.4Hz,1H),7.09(t,J=8.0,1H),6.83-6.81(m,1H),3.75(s,3H),3.15(s,3H);LCMS m/z=363.0[M+H]
+。
步骤4:化合物4-5的合成
将化合物4-4(214mg,590.54μmol,1eq)和化合物A-3(148.14mg,708.65μmol,1.2eq)加入到THF(10mL)中,降温至0℃后加入双(三甲基硅基)胺基锂(1M,1.48mL,2.5eq),在20℃下反应2hr。向反应液中加入饱和氯化铵水溶液(10mL)和乙酸乙酯(10mL)萃取分液,水相再用乙酸乙酯(10mL),合并有机相,用饱和氯化钠水溶液洗涤一次,有机相用无水硫酸钠干燥,浓缩得化合物4-5。LCMS m/z=535.1[M+H]
+。
步骤5:化合物WX-004的合成
将化合物4-5(90mg,126.18μmol,75%纯度,1eq)和环丙基甲酰胺(214.76mg,2.52mmol,20eq)加入到1,4-二氧六环(8mL)和NMP(1.6mL)中,然后加入碳酸铯(123.33mg,378.53μmol,3eq)和Pd
2(dba)
3(17.33mg,18.93μmol,0.15eq),置换N
2后,加入Xantphos(10.95mg,18.93μmol,0.15eq),置换N
2后,在120℃反应5hr。反应完成后,向反应液中加入水(10mL)和乙酸乙酯(10mL)萃取分液,水相再用乙酸乙酯(10mL),合并有机相,用饱和氯化钠水溶液洗涤,有机相用无水硫酸钠干燥,浓缩得粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex C18 80*40mm*3μm;流动相:A(水,含0.04%碳酸铵)和B(乙腈);梯度:B%:30%-60%,8min),得到化合物WX-004。
1HNMR(400MHz,DMSO-d
6)δ:11.35(s,1H), 11.01(s,1H),9.18(s,1H),8.98(s,1H),8.29-8.24(m,1H),8.15(s,1H),8.04-8.00(m,2H),7.52-7.39(m,1H),7.37-7.35(m,1H),4.06(s,1H),3.70(s,3H),3.39(s,3H),2.10-2.00(m,1H),0.83-0.81(m,4H);LCMS m/z=584.2[M+H]
+。
实施例5
合成路线:
步骤1:化合物5-2的合成
将化合物5-1(1g,4.15mmol,1eq),化合物2-氟-4-(甲磺酰基)苯硼酸(905.04mg,4.15mmol,1eq),碳酸铯(4.06g,12.45mmol,3eq)溶于二氧六环(20mL)和水(4mL)中,氮气置换三次后加入Pd(dppf)Cl
2.CH
2Cl
2(339.02mg,415.14μmol,0.1eq),在100℃搅拌2hr。向反应液中加入水(10mL)和乙酸乙酯(20mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品通过硅胶柱层析分离纯化(乙酸乙酯/石油醚=0~50%),得到化合物5-2。LCMS m/z=334.0[M+H]
+。
步骤2:化合物3的合成
将化合物5-2(530mg,1.59mmol,1eq),化合物A-1(395.10mg,1.59mmol,1eq),碳酸钾(438.40mg,3.17mmol,2eq)溶于1,4-二氧六环(24mL)和水(8mL)中,氮气置换三次后加入Pd(dppf)Cl
2.CH
2Cl
2(116.05mg,158.60μmol,0.1eq),在90℃搅拌2hr。向反应液中加入水(10mL)和乙酸乙酯(20mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品通过硅胶柱层析分离纯化(乙酸乙酯/石油醚=0~75%),得到化合物5-2。LCMS m/z=377.1[M+H]
+。
步骤3:化合物5-3的合成
将化合物5-2(300mg,797.01μmol,1eq),化合物A-3(166.61mg,797.01μmol,1eq)溶于THF(30mL)中,加入双(三甲基硅基)胺基锂(1M,2.39mL,3eq),在15℃搅拌1hr。向反应液中加入水(10mL)后加入乙酸乙酯(20mL),有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:15%-45%,8min),向机分液里加饱和NaHCO
3溶液,调pH=7~8,然后使用二氯甲烷(20mL*2)萃取,有机相使用饱和食盐水(20mL)洗涤一次,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物5-3。LCMS m/z=549.2[M+H]
+。
步骤4:化合物WX-005盐酸盐的合成
将化合物5-3(83mg,151.19μmol,1eq),环丙甲酰胺(321.66mg,3.78mmol,25eq),碳酸铯(147.78mg,453.56μmol,3eq)溶于二氧六环(8mL)中,氮气置换三次后加入氯(2-二环己基膦基-2‘,4’,6‘-三异丙基-1,1’-联苯基)[2-(2’-氨基-1,1’-联苯)]钯(11.90mg,15.12μmol,0.1eq),在120℃搅拌2hr。向反应液中加入水(5mL)和乙酸乙酯(10mL*2)萃取两次,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:20%-50%,8min),得到化合物WX-005盐酸盐。
1HNMR(400MHz,CD
3OD)δ:8.05-7.98(m,4H),7.63(dd,J=8.0,1.2Hz,1H),7.43(t,J=8.0Hz,1H),6.86(s,1H),3.99(d,J=1.6Hz,3H),3.83(s,3H),3.26(s,3H),1.85-1.80(m,1H),1.16-1.06(m,4H);LCMS m/z=598.3[M+H]
+。
实施例6
合成路线:
步骤1:化合物6-1的合成
将化合物A-3-2(7g,35.19mmol,1eq)溶于DCM(105mL)中,然后加入草酰氯(6.25g,49.27mmol,4.31mL,1.4eq),然后加入DMF(128.60mg,1.76mmol,135.37μL,0.05eq),在20℃下反应3hr。然后将反应体系浓缩,再加入二氯甲烷(80mL),再浓缩,然后加入二氯甲烷(105mL)中,加入甲胺盐酸盐(2.26g,33.43mmol,0.95eq),然后降温至0℃后,加入DIPEA(13.64g,105.57mmol,18.39mL,3eq),在20℃下反应10hr。反应完成后,向体系中加入水(80mL),萃取分液,然后水相再用二氯甲烷(100mL)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到化合物6-1。LCMS m/z=206.0[M+1]
+。
步骤2:化合物6-2的合成
将化合物6-1(1.45g,7.02mmol,1.5eq),化合物A-2(1.5g,4.68mmol,1eq)溶于THF(30mL)中,加入双(三甲基硅基)胺基锂(1M,14.04mL,3eq),在25℃搅拌1hr。向反应液中加入饱和氯化铵水溶液(20 mL),再加入水(10mL),用乙酸乙酯(20mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品,得到化合物6-2。LCMS m/z=490.2[M+H]
+。
步骤3:化合物6-3的合成
将化合物6-2(2.47g,5.04mmol,1eq),环丙甲酰胺(4.29g,50.41mmol,10eq),碳酸铯(4.93g,15.12mmol,3eq),Xantphos(291.65mg,504.05μmol,0.1eq)溶于二氧六环(49.4mL)中,氮气置换三次后加入Pd
2(dba)
3(461.57mg,504.05μmol,0.1eq),120℃搅拌3hr。向反应液中加入水(50mL),用乙酸乙酯(50mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚=0~80%)得到化合物6-3。
1HNMR(400MHz,CDCl
3)δ:10.99(s,1H),9.39(s,1H),8.32(s,1H),8.21(s,1H),8.14-8.11(m,1H),7.83-7.80(m,1H),7.54-7.52(m,1H),7.29(s,1H),5.57(s,2H),3.80(s,3H),3.74-3.69(m,2H),3.04(d,J=5.2Hz,3H),1.76-1.72(m,1H),1.28-1.24(m,2H),0.94-0.89(m,4H),-0.01(s,9H);LCMS m/z=539.2[M+H]
+。
步骤4:化合物6-4的合成
将化合物6-3(3g,5.57mmol,1eq)溶于TFA(30mL)中,25℃搅拌1hr。将反应液浓缩,加入二氯甲烷(200mL),然后加入饱和碳酸氢钠水溶液(100mL),调至pH=8后静置分液,有机相用饱和食盐水(100mL)洗涤后用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物6-4。LCMS m/z=409.0[M+H]
+。
步骤5:化合物WX-006盐酸盐的合成
将化合物6-4(0.5g,1.22mmol,1eq)溶于DMF(5mL)中,加入碳酸铯(797.77mg,2.45mmol,2eq),化合物A-4(127.71mg,612.13μmol,0.5eq),在100℃搅拌2hr。向反应液中加入水(5mL)和乙酸乙酯(10mL*3)萃取,有机相用无水硫酸钠干燥过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:20%-50%,8min),得固体WX-006盐酸盐。
1HNMR(400MHz,CDCl
3)δ:11.10(s,1H),8.86(s,1H),8.60(m,1H),8.22-8.21(m,2H),8.16-8.15(m,1H),8.04-8.03(m,2H),7.94-7.92(m,1H),7.60-7.58(m,1H),7.35-7.31(m,1H),3.90(s,3H),3.15(s,3H),3.06(d,J=5.2Hz,3H),1.68-1.63(m,1H),1.14-1.10(m,2H),0.96-0.92(m,2H);LCMS m/z=597.1[M+H]
+。
实施例7
合成路线:
步骤1:化合物7-1的合成
将化合物A-3-2(623.88mg,3.12mmol,1eq),化合物A-2(1g,3.12mmol,1eq)溶于THF(20mL)中,加入双(三甲基硅基)胺基锂(1M,9.36mL,3eq),25℃搅拌1hr。向反应液中加入饱和氯化铵水溶液(20mL),然后用入乙酸乙酯(20mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到化合物7-1。LCMS m/z=477.1[M+H]
+。
步骤2:化合物7-2的合成
将化合物7-1(1.3g,2.73mmol,1eq),环丙甲酰胺(3.48g,40.88mmol,15eq),碳酸铯(2.66g,8.18mmol,3eq),Xantphos(157.70mg,272.54μmol,0.1eq)溶于二氧六环(13mL)中,氮气置换三次后加入 Pd
2(dba)
3(249.57mg,272.54μmol,0.1eq)120℃搅拌2hr。向反应液中加入水(10mL),然后用二氯甲烷(25mL*3)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(甲醇/二氯甲烷=0~10%),得到化合物7-2。LCMS m/z=526.2[M+H]
+。
步骤3:化合物7-3的合成
将化合物7-2(1.4g,2.66mmol,1eq),DIPEA(361.45mg,2.80mmol,487.12μL,1.05eq),HATU(1.06g,2.80mmol,1.05eq)溶于DMF(14mL)中,搅拌5min后加入氨水(12.74g,90.88mmol,14mL,25%纯度,34.12eq),在25℃搅拌1hr。向反应液中加入水(14mL),用乙酸乙酯(20mL)萃取,有机相用饱和食盐水(20mL)洗涤后用无水硫酸钠过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(甲醇/二氯甲烷=0~10%),得到化合物7-3。LCMS m/z=525.2[M+H]
+。
步骤4:化合物7-4的合成
将化合物7-3(0.5g,953.02μmol,1eq)溶于TFA(7.70g,67.53mmol,5mL,70.86eq)中,在25℃搅拌1hr。向反应液中加入饱和碳酸氢钠水溶液(50mL),调至pH=8,然后用二氯甲烷(100mL*2)萃取,合并有机相,用无水硫酸钠干燥后浓缩。得到化合物7-4。LCMS m/z=395.0[M+H]
+。
步骤5:化合物WX-007盐酸盐的合成
将化合物7-4(0.145g,367.66μmol,1eq)溶于DMF(5mL)中,加入碳酸铯(239.58mg,735.32μmol,2eq),化合物A-4(38.35mg,183.83μmol,0.5eq),在100℃搅拌2hr。向反应液中加入水(5mL),用乙酸乙酯(10mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:15%-35%,8min),得到化合物WX-007盐酸盐。
1HNMR(400MHz,CD
3OD)δ:9.13(s,1H),8.32(d,J=2.0Hz,1H),8.15-8.13(m,1H),8.09-8.02(m,2H),7.67-7.64(m,1H),7.49-7.43(m,1H),6.82(s,1H),3.83(s,3H),3.26(m,3H),1.85-1.77(m,1H),1.16-1.06(m,4H);LCMS m/z=583.0[M+H]
+。
实施例8
合成路线:
步骤1:化合物WX-008盐酸盐的合成
将化合物6-4(0.25g,612.13μmol,1eq)溶于DMF(2.5mL)中,加入碳酸铯(398.89mg,1.22mmol,2eq),化合物1,2-二氟-4-(甲磺酰基)苯(58.82mg,306.06μmol,0.5eq),100℃搅拌2hr。向反应液中加入水(3mL),用乙酸乙酯(6mL*3)萃取后有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna C18 80*40mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:26%-44%,7min),得到化合物WX-008盐酸盐。
1HNMR(400MHz,CDCl
3)δ:11.12(s,1H),8.90(d,J=2.8Hz,1H),8.47(s,1H),8.40-8.36(m,1H),8.23(s,1H),8.18-8.17(m,1H),7.96-7.91(m,3H),7.60(dd,J=7.6,1.2Hz,1H),7.33(t,J=8.0Hz,1H),3.92(s,3H),3.14(s,3H),3.07(d,J=5.2Hz,3H),1.66-1.61(m,1H),1.14-1.08(m,2H),0.98-0.91(m,2H);LCMS m/z=581.1[M+H]
+。
实施例9
合成路线:
步骤1:化合物WX-009盐酸盐的合成
将化合物7-4(0.145g,367.66μmol,1eq)溶于DMF(5mL)中,加入碳酸铯(239.58mg,735.32μmol,2eq),化合物1,2-二氟-4-(甲磺酰基)苯(35.33mg,183.83μmol,0.5eq),在100℃搅拌2hr。向反应液中加入水(5mL),用乙酸乙酯(10mL*2)萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离(色谱柱:Phenomenex Luna 80*30mm*3μm;流动相:A(水,含0.04%盐酸)和B(乙腈);梯度:B%:20%-45%,8min),得到化合物WX-009盐酸盐。
1HNMR(400MHz,CD
3OD)δ:9.17(d,J=3.2Hz,1H),8.33-8.29(m,1H),8.11-8.01(m,3H),7.68-7.65(m,1H),7.47-7.42(m,1H),7.12-7.08(m,1H),3.87(s,3H),3.24(m,3H),1.86-1.81(m,1H),1.12-1.03(m,4H);LCMS m/z=567.1[M+H]
+。
生物测试数据
实验例1:化合物对TYK2 JH2假激酶抑制活性
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对TYK2 JH2假激酶的抑制作用。
1实验试剂
表1:实验试剂信息
试剂名称 | 供应商 | 存储条件 |
TYK2/JAK1 | Bioduro | -80℃ |
Tracer | Bioduro | -80℃ |
Tb antibody | Cisbio | -80℃ |
HEPES | Invitrogen | 4℃ |
MgCl2 1M | Sigma | 常温 |
Brij L23 solution(Brij-35) | Sigma | 常温 |
DTT | Sigma | -20℃ |
BSA | Sigma | 4℃ |
2实验方法
1)准备1X实验工作液
HEPES pH7.5,终浓度为20mM;MgCl
2,终浓度为10mM;Brij-35,终浓度为0.015%;DTT,终浓度为2mM;BSA,终浓度为50μg/mL。
2)实验操作步骤:
a)用DMSO溶解化合物到10mM的存储浓度。
b)在化合物稀释板子中配备200倍于终浓度的化合物浓度,按照27倍倍比稀释法,从最高浓度点稀释,共4个浓度点,并转移到Echo板中。
c)用Echo仪器将化合物从Echo板脉冲到384实验板,使得化合物变成3倍倍比稀释矩阵,11个浓度点。
d)加5μL 3X TYK2 JH2激酶到384实验板中。
e)加5μL 3X Tb到384实验板中。
f)加5μL 3X Tracer到384孔实验板中。
g)离心30秒,室温孵育60分钟。
h)Envision酶标仪(PerkinElmer)495/520荧光信号值。
3)数据分析
使用XL-Fit软件进行数据分析,得出化合物IC
50。结果如表2:
表2:激酶半数抑制浓度IC
50(nM)
受试品 | TYK2 JH2 |
WX-001 | 0.15 |
WX-002盐酸盐 | 0.11 |
WX-004 | 0.38 |
WX-006盐酸盐 | 0.05 |
WX-007盐酸盐 | 0.06 |
WX-008盐酸盐 | 0.07 |
WX-009盐酸盐 | 0.07 |
结论:本发明化合物对TYK2 JH2假激酶具有良好的抑制作用。
实验例2:化合物对Ba/F3-FL-TYK2-E957D细胞增殖的抑制活性
三磷酸腺苷(Adenosine Tri-Phosphate,ATP)是自然界中各种生命活动中共用的能量载体,是能量储存和转移的最小单位。CellTiter-Glo
TM活细胞检测试剂盒采用萤光素酶作检测物,发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo
TM试剂,测量发光值,光信号和体系中ATP量成正比,而ATP又和活细胞数正相关。因此通过使用CellTiter-Glo试剂盒检测ATP含量,可以检测出细胞的增殖情况。本测试中,细胞系为Ba/F3-FL-TYK2-E957D,此细胞系能够稳定表达外源导入的人TYK2-E957D基因。
IC
50测定过程:
1)细胞培养
将细胞系在培养条件37℃,5%CO
2的培养箱中进行培养。定期传代,取处于对数生长期的细胞用于铺板。
2)化合物存储板制备
a)用DMSO将待测化合物配置成10mM溶液,再用DMSO将待测化合物稀释至0.3或1mM。
b)制备1000×化合物存储板(管):用DMSO从最高浓度3倍梯度稀释至最低浓度,9个浓度。
c)20×化合物工作液的配制:在平底的96孔透明药板中加入49μL细胞培养液,从1000×化合物存储板中吸取1μL化合物加入96孔透明药板的细胞培养液中。在溶媒对照中加入1μL DMSO。加入化合物或DMSO后用排枪吹打混匀。
3)细胞铺板与给药
a)用台盼兰进行细胞染色并计数活细胞,要求细胞活率90%以上。
b)在化合物检测细胞板中每孔加入95μL细胞悬液(2000cells/well),在Min对照孔中加入不含细胞(含0.1%DMSO)的培养液。
c)化合物检测细胞板加药:取5μL的20×化合物工作液按表1所示加入到细胞培养板中。在Max对照中加入5μL DMSO-细胞培养液混合液。DMSO终浓度为0.1%。
d)将培养板在37℃,5%CO2培养箱中培养72小时。
4)CellTiter-Glo发光法细胞活性检测
以下步骤按照Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行。
a)将CellTiter-Glo缓冲液融化并放置至室温。
b)将CellTiter-Glo底物放置至室温。
c)在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物,从而配制CellTiter-Glo工作液。
d)缓慢涡旋震荡使充分溶解。
e)取出细胞培养板放置10分钟使其平衡至室温。
f)在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液。
g)将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。
h)培养板在室温放置10分钟以稳定发光信号。
i)在SpectraMax Paradigm读板器上检测发光信号。
5)数据处理
SpectraMax Paradigm读数得出对应的每孔荧光值RLU。
细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理:
Inhibition Rate(Inh%)=100-(RLU
Drug-RLU
Min)/(RLU
Max-RLU
Min)*100%。在EXCEL中计算不同浓度化合物对应的抑制率,然后用GraphPad Prism软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值,数据见表3。
表3:细胞半数抑制浓度IC
50(nM)
化合物 | Ba/F3-FL-TYK2-E957D |
WX-001 | 0.4 |
WX-002盐酸盐 | 1.1 |
WX-003盐酸盐 | 0.2 |
WX-004 | 7.6 |
WX-005盐酸盐 | 5.6 |
WX-006盐酸盐 | 1.0 |
WX-007盐酸盐 | 2.2 |
WX-008盐酸盐 | 3.5 |
WX-009盐酸盐 | 5.1 |
结论:本发明化合物对转染人TYK2-E957D基因的Ba/F3细胞的增殖具有较强的抑制活性。
实验例3:化合物对人PBMC细胞TYK2和JAK1信号通路的抑制活性
本实验目的是在人外周血单个核细胞(PBMC)中检测化合物对细胞因子激活的JAK-STAT信号通路的抑制作用。其中通过IFNα刺激激活TYK2信号通路,检测化合物对其下游STAT1磷酸化的抑制活性, 可得出化合物对TYK2信号通路活性的半数抑制浓度IC
50;而对于JAK1信号通路,通过IL-6刺激激活JAK1信号通路,检测化合物对其下游STAT1磷酸化的抑制活性,可得出化合物对JAK1信号通路活性的半数抑制浓度IC
50。
1主要试剂及仪器
1)细胞:人外周血单个核细胞(PBMC)(供应商:赛笠生物)
2)试剂:见表4。
表4:主要试剂及来源
名称 | 供应商 |
1640培养基 | Gibco |
非必需氨基酸 | Gibco |
胎牛血清 | 依科赛 |
双抗(青霉素、链霉素) | Millipore |
人白细胞介素6(IL-6) | Absin |
人干扰素α(IFNα) | pbl assay science |
人CD4抗体 | Biolegend |
人pSTAT1抗体 | BD |
染色液 | Biolegend |
固定液 | BD |
破膜液 | BD |
磷酸缓冲液(DPBS) | Corning |
3)仪器
流式细胞仪:品牌:BD;型号:Fortessa
2试剂配制
培养液:1640培养液+10%胎牛血清+1%双抗+1%非必需氨基酸(百分比均为体积比)
3实验步骤
a)将于液氮中冻存的PBMC在37℃水浴中解冻,加入培养液,320g离心3min。
b)培养液重悬细胞后计数,用培养液将细胞浓度调整为5×10
5个/mL,然后将细胞悬液接种至两个96孔圆底板,每孔200μL。37℃、5%CO
2条件下孵育90min。
c)加入不同浓度的待测化合物(2μM起始,5倍梯度稀释,共8个浓度),37℃、5%CO
2孵育30min。
d)在其中一个圆底板中加入IL-6(终浓度20ng/mL),37℃、5%CO
2孵育15min。
e)在另一个圆底板中加入IFNα(终浓度1000U/mL),37℃、5%CO
2孵育15min。
f)细胞320g离心3min,每孔加入200μL染色液洗一次。
g)每孔加入50μL含有人CD4抗体的染色液,4℃染色30min。染色液洗两次。
h)每孔加入100μL固定液,4℃固定15min。染色液洗一次。
i)每孔加入100μL破膜液,4℃破膜20min。染色液洗两次。
j)每孔加入50μL含有人pSTAT1抗体的染色液,室温染色15min。染色液洗两次。
k)150μL染色液重悬细胞。
l)用流式细胞仪检测CD4阳性细胞中pSTAT1的荧光强度。
4数据分析
使用Flowjo软件进行数据分析,得出化合物IC
50。结果见表5:
表5:细胞半数抑制浓度IC
50(nM)
结论:本发明化合物在人PBMC细胞中,对IFNα刺激激活的TYK2信号通路展现了较高的抑制活性;同时对IL-6刺激激活的JAK1信号通路展现了较弱的抑制活性,展现了较高的选择性。
实验例4:化合物在小鼠体内的cassette药代动力学测试
实验目的:以雄性ICR小鼠为受试动物,应用LC/MS/MS法测定单次静脉注射(IV)及灌胃(PO)给予化合物后,不同时刻血浆中化合物的药物浓度,研究本发明的化合物在小鼠体内的药代动力学行为,评价其药动学特征。
药物配制:化合物均以相应溶媒配成澄清溶液用于IV(静注)和PO(灌胃)组给药。溶媒为10%DMSO+10%solutol+80%(10%HP-β-CD水溶液)。给药方法为盒式给药法(cassette dosing),每个化合物的给药剂量为:IV 0.5mg/kg;PO剂量为2mg/kg。药代动力学参数结果见表5:
表6:小鼠体内药代动力学测试结果
结论:本发明化合物的小鼠给药后展现了优异的药代动力学特性。
实验例5:化合物在大鼠体内的药代动力学测试
实验目的:以雄性SD大鼠为受试动物,应用LC/MS/MS法测定单次静脉注射(IV)及灌胃(PO)给予化合物后,不同时刻血浆中化合物的药物浓度,研究本发明的化合物在小鼠体内的药代动力学行为,评价其药动学特征。
药物配制:化合物均以相应溶媒配成澄清溶液用于IV(静注)和PO(灌胃)组给药。溶媒为10%DMSO+10%solutol+80%(10%HP-β-CD水溶液)。药代动力学参数结果见表7:
表7:大鼠体内药代动力学测试结果
结论:本发明化合物的大鼠给药后展现了优异的药代动力学特性。
Claims (12)
- 式(I)所示化合物或其药学上可接受的盐,其中,T选自N和CH,所述CH任选被1个卤素取代;R 1选自C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代;R 2选自H、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代;R 3选自F、Cl、Br、I和C 1-3烷基;环B选自5元杂芳基,所述5元杂芳基任选被1、2或3个R c取代;R a和R b分别独立地选自H、D、F、Cl、Br和I;各R c分别独立地选自H、F、Cl、Br、I和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R取代;各R选自F、Cl、Br和I;所述5元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,各R c分别独立地选自H、F、Cl、Br、I和CH 3,所述CH 3任选被1、2或3个R取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,各R c分别独立地选自H、F、Cl、Br、I、CH 3、CH 2F、CHF 2和CF 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1选自CH 3和OCH 3,所述CH 3和OCH 3分别独立地任选被1、2或3个R a取代。
- 根据权利要求4所述化合物或其药学上可接受的盐,其中,R 1选自OCH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 2选自H、CH 3和OCH 3,所述CH 3和 OCH 3分别独立地任选被1、2或3个R b取代。
- 根据权利要求6所述化合物或其药学上可接受的盐,其中,R 2选自H、CH 3和CD 3。
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