WO2022253333A1 - Composés amides et leur application - Google Patents

Composés amides et leur application Download PDF

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WO2022253333A1
WO2022253333A1 PCT/CN2022/096978 CN2022096978W WO2022253333A1 WO 2022253333 A1 WO2022253333 A1 WO 2022253333A1 CN 2022096978 W CN2022096978 W CN 2022096978W WO 2022253333 A1 WO2022253333 A1 WO 2022253333A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
added
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PCT/CN2022/096978
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English (en)
Chinese (zh)
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王建非
杨广文
奥志华
孙继奎
胡世尘
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022253333A1 publication Critical patent/WO2022253333A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of amide compounds and applications thereof, in particular to compounds represented by formula (P) and 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 interferons. 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 (P) or a pharmaceutically acceptable salt thereof,
  • T, Y, Y 1 , Y 2 and Y 3 are selected from N and CH, said CH is optionally substituted by 1 halogen, C 1-3 alkyl and C 1-3 alkoxy;
  • R 11 is selected from C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN, and the C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN are optionally replaced by 1, 2 or 3 Halogen substitution;
  • R 12 is selected from N(R 2 ) 2 and C(R 2 ) 3 ;
  • 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 ;
  • Ring B does not exist
  • Ring B is selected from C 5-10 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 5-10 cycloalkyl, 5- 10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R c ;
  • s 0, 1 or 2;
  • n and m are independently selected from 0, 1, 2 and 3;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R is selected from F, Cl, Br, I and OH
  • 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 halogens;
  • Hetero in the 3-6 membered heterocycloalkane, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl means that 1, 2 or 3 are independently selected from Atoms or atomic groups of 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 ;
  • Ring B does not exist
  • ring B is selected from 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R c ;
  • n and m are independently selected from 0, 1, 2 and 3;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R is selected from F, Cl, Br, I and OH
  • 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 halogens;
  • Hetero in the 5-6 membered heteroaryl represents 1, 2 or 3 atoms or atomic groups independently selected from N, O, S and NH.
  • T is selected from N and CH, and other variables are as defined in the present invention.
  • T is selected from N, and other variables are as defined in the present invention.
  • n is selected from 0 and 1, and other variables are as defined in the present invention.
  • 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 halogens, and other variables are as in this invention defined.
  • 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.
  • each of the above R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are 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 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.
  • the aforementioned Y, Y 1 , Y 2 and Y 3 are selected from CH, and other variables are as defined in the present invention.
  • R 12 is selected from NH 2 , NHCH 3 , NHCD 3 , CH 2 CH 3 and CH 2 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-mentioned E is selected from NH, -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-, Other variables are as defined herein.
  • 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 ;
  • Ring B does not exist
  • Ring B is selected from a 5-membered heteroaryl optionally substituted by 1, 2 or 3 R ;
  • n and m are independently selected from 0, 1 and 2;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R and R are independently selected from H, D, F, Cl, Br and I;
  • R c is independently selected from H, F, Cl, Br and C 1-3 alkyl, said C 1-3 alkyl is 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.
  • 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.
  • 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 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 CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R b , 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-mentioned E is selected from -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-, Other variables are as defined herein.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • T1 is selected from N and CH;
  • R 1 , R 2 , E, T 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 above compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides following experimental method:
  • 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 lines were Ba/F3-FL-TYK2-E957D and Ba/F3-TEL-TYK2.
  • Ba/F3-FL-TYK2-E957D cells can stably express exogenously introduced human TYK2-E957D gene, and the TYK2-E957D gene sequence contains JH1 and JH2 domains;
  • Ba/F3-TEL-TYK2 cells can stably express exogenous
  • the introduced human TEL-TYK2 gene, the TEL-TYK2 gene sequence only includes the JH1 domain of TYK2.
  • 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 were analyzed with GraphPad Prism software, and the nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated accordingly.
  • 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; while for the JAK1 signaling pathway, JAK1 is 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; The inhibitory activity of the downstream STAT5 phosphorylation can be used to obtain the half inhibitory concentration IC 50 of the compound on the activity of the JAK2 signaling pathway; for the JAK3 signaling pathway, the JAK3 signaling
  • 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 cells were centrifuged at 320 g for 3 min, and 200 ⁇ L of staining solution was added to each well to wash once.
  • pSTAT1 (stimulated by IL-6 and IFN ⁇ ) or pSTAT5 (stimulated by IL-2) in CD4 positive cells by flow cytometry; detect the fluorescence intensity of pSTAT5 (stimulated by GM-CSF) in CD33 positive cells.
  • the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.
  • 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 the salts of the compounds of the present invention, which are prepared from the compounds with specific substituents found in the present invention and relatively non-toxic acids or bases.
  • 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 the molecules.
  • 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 diastereomeric 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. from 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 solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond in 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.
  • C2-4alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-4 alkenyl includes C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; the C 2-4 alkenyl can be monovalent, divalent or multivalent. Examples of C alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
  • C2-4 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, the carbon-carbon triple bond can be located anywhere in the group.
  • the C 2-4 alkynyl includes C 2-3 , C 4 , C 3 and C 2 alkynyl and the like. It may be monovalent, divalent or polyvalent. Examples of C alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 5-10 cycloalkyl means a saturated cyclic hydrocarbon group composed of 5 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include Spiral, parallel and bridged rings.
  • the C 5-10 cycloalkyl group includes C 5-8 or C 5-6 and the like; it may be monovalent, divalent or multivalent.
  • Examples of C 5-10 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] dicyclodecane Wait.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolid
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • the 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-membered, 6-membered and 8-membered heterocycloalkyl groups and the like.
  • Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • C 6-10 aromatic ring and “C 6-10 aryl” in the present invention can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means that the A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It can be monovalent, divalent or multivalent, and the C 6-10 aryl group includes C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10 membered heteroaryl” means that there are 5 to 10 rings
  • the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, 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
  • 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.
  • G-1-2 (0.25g, 1.32mmol, 1eq) was dissolved in MeOH (7.5mL), methylamine (410.78mg, 3.97mmol, 30% purity, 3eq), sodium cyanoborohydride (249.36mg, 3.97mmol, 3eq), acetic acid (262.12mg, 4.36mmol, 249.64 ⁇ L, 3.3eq) were stirred at room temperature 25°C for 1.5 hours.
  • the phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through SFC (column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m; mobile phase: CO 2 -isopropanol containing 0.1% ammonia; gradient: containing 0.1 % ammonia water isopropanol 52%-52%, 9min) separation and purification to obtain WX-002A and WX-002B.
  • SFC column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m
  • mobile phase CO 2 -isopropanol containing 0.1% ammonia
  • gradient containing 0.1 % ammonia water isopropanol 52%-52%, 9min
  • Example 6 Referring to the synthesis steps of Example 6, replace 6-2 in Step 2 with the fragment G-1 in the table below to synthesize the compounds in Table 4 below.
  • Dissolve compound 7-1 (15g, 125.92mmol, 1eq) in acetic acid (30mL), add fuming nitric acid (8.73g, 138.52mmol, 6.23mL, 1.1eq) dropwise at 50°C, the temperature should not be higher than 70°C, stir 4hr.
  • the reaction solution was slowly added to ice water (90 mL), solids were precipitated and filtered.
  • Trifluoroacetic acid salt 35mg, 71.35 ⁇ mol, 1eq
  • triethylamine 28.88mg, 285.38 ⁇ mol, 39.72 ⁇ L, 4eq
  • dichloromethane 1.5mL
  • - Acryloyl chloride 7.75 mg, 85.61 ⁇ mol, 6.98 ⁇ L, 1.2 eq
  • reaction solution was added to aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was separated by preparative high-performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: A (water, ammonium bicarbonate) and B (acetonitrile; gradient: B%: 20%-55%, 8min), Compound WX-008 was obtained.
  • 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.
  • WX-003A 0.51 WX-004B 0.39 WX-005 0.27 WX-006 0.43 WX-007 0.12 WX-008 0.16 WX-009 0.49
  • the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.

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Abstract

L'invention concerne une classe de composés amides et une application de ceux-ci. L'invention concerne en particulier des composés représentés par la formule (P) et un sel pharmaceutiquement acceptable de ceux-ci.
PCT/CN2022/096978 2021-06-02 2022-06-02 Composés amides et leur application WO2022253333A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
WO2020086616A1 (fr) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
WO2020092196A1 (fr) * 2018-10-30 2020-05-07 Bristol-Myers Squibb Company Composés hétérocycliques à substitution amide pour le traitement d'états pathologiques liés à la modulation d'il-12, il-23 et/ou ifn-alpha
WO2020156311A1 (fr) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 Inhibiteur de dérivé de pyridazine, son procédé de préparation et son utilisation
CN111718332A (zh) * 2019-03-19 2020-09-29 北京赛特明强医药科技有限公司 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
WO2020086616A1 (fr) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
WO2020092196A1 (fr) * 2018-10-30 2020-05-07 Bristol-Myers Squibb Company Composés hétérocycliques à substitution amide pour le traitement d'états pathologiques liés à la modulation d'il-12, il-23 et/ou ifn-alpha
WO2020156311A1 (fr) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 Inhibiteur de dérivé de pyridazine, son procédé de préparation et son utilisation
CN111718332A (zh) * 2019-03-19 2020-09-29 北京赛特明强医药科技有限公司 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用

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