WO2018059533A1 - Inhibiteur de la p38α mapk kinase, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de la p38α mapk kinase, son procédé de préparation et son utilisation Download PDF

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WO2018059533A1
WO2018059533A1 PCT/CN2017/104247 CN2017104247W WO2018059533A1 WO 2018059533 A1 WO2018059533 A1 WO 2018059533A1 CN 2017104247 W CN2017104247 W CN 2017104247W WO 2018059533 A1 WO2018059533 A1 WO 2018059533A1
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pharmaceutically acceptable
acid
compound
acceptable salt
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PCT/CN2017/104247
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Chinese (zh)
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吴凌云
张丽
赵乐乐
黎健
陈曙辉
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南京明德新药研发股份有限公司
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • the present invention relates to a class of pyrazole compounds having an inhibitory effect on p38 ⁇ , and includes the use of these compounds in the field of p38 ⁇ -related diseases, such as various diseases such as inflammation and immune abnormalities. Further, the present invention relates to a method for synthesizing and preparing the series of pyrazole compounds.
  • Mitogen-activated protein kinase belongs to the serine/threonine kinase family, and the MAPK signaling pathway is one of the major pathways for eukaryotic cells to transduce extracellular signals into cells. Transduction of different stimuli from outside by protein phosphorylation regulates cell division, proliferation, survival, movement and decline, gene transcription, gene expression, and protein translation [Lufen Chang, Michael Karin, Nature, 2001 (410), 37 -40; Puneet Chopra, Onkar Kulkarni, Shashank Gupta, et. al, International Immunopharmacology, 2010 (10), 467-473].
  • MAP kinases There are three subfamilies of MAP kinases in human body, namely extracellular signal regulated kinases (ERK), c-Jun N-terminal kinases (stress activated protein kinases) JNK (SAPK) and P38.
  • ERK extracellular signal regulated kinases
  • SAPK stress activated protein kinases
  • P38 P38
  • the structural similarity of these homologous kinases is about 60-70%, the difference is mainly in the active loop region, and the protein sequence and size of this region are different.
  • each subfamily kinase is activated and responded by different extracellular signal stimuli [Yong Jiang, Canhe Chen, Zhuangjie Li et. al, The Journal of Biological Chemisty, 1996 (271), 17920-17926; Sanjay Kumar, Jeffrey Boehm and John C.
  • ERKs are activated by mitogenic and proliferative signals
  • JNKs and p38MAPks are activated by various environmental stresses. They are all activated by phosphorylation of the upstream kinase after obtaining extracellular signals. The phosphorylation sites are mainly serine and threonine residues. After activation, each of the downstream substrates is phosphorylated separately, thereby transducing the signal and allowing the cells to do Out of response.
  • the p38MAPK contains four subtypes, p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ , which are encoded by different genes and distributed in different tissues in humans.
  • P38 ⁇ and p38 ⁇ are widely distributed in various tissues of human body.
  • p38 ⁇ is mainly distributed in human skeletal muscle and p38 ⁇ is abundantly expressed in kidney and lung tissues. [Kana Namiki, Hirofumi Matsunaga, Kento Yoshioka, et al., the Jounal of Biological Chemistry, 2012 (287), 24228-24238].
  • p38 ⁇ is highly expressed in various inflammation-related diseases or inflammatory tissues, and is closely related to the degree of inflammation development.
  • p38 ⁇ Upon stimulation by extracellular stress, p38 ⁇ activates downstream kinases (such as MK2, MK3) and transcription factors (such as Stat1, ATF-2) and leads to the production of the pro-inflammatory cytokines IL-1 ⁇ , TNF ⁇ and IL-6. Blocking the production of inflammatory factors can alleviate various inflammations, so p38 ⁇ has become a research hotspot [Bin Wu, Hui-Ling Wang, Liping Pettus, et al., J. Med. Chem. 2010 (53), 6398-6411] .
  • Small molecule p38 ⁇ inhibitors have been shown to inhibit the production of inflammatory cytokines in a variety of in vitro and in vivo animal models. However, there are various problems in clinical trials, and no new drug approved for marketing has been developed. The p38 ⁇ small molecule inhibitor still has a wide range of clinical needs.
  • the present invention provides a compound of the formula (I) and a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from: H, halogen, OH, NH 2 , CN, or independently selected from C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
  • Ring B is selected from the group consisting of: a 5- to 6-membered heterocycloalkyl group and a 5- to 6-membered heteroaryl group;
  • R is selected from the group consisting of halogen, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, N,N'-(C 1-3 alkyl)amino;
  • hetero of the 5- to 6-membered heteroaryl group and the 5- to 6-membered heterocycloalkyl group is selected from the group consisting of: -NH-, N, -O-, -S-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 ,
  • R 1 , R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from 1, 2 or 3, respectively.
  • R 1 , R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from 1, 2 or 3, respectively.
  • R Me, Et,
  • R 1 and R 2 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, Me, CN, CF 3 .
  • R 2 is selected from the group consisting of: H, OH, NH 2 , CN, Me, Et,
  • the above ring B is selected from the group consisting of pyrrolidinyl, piperidinyl, pyrrolyl, 2-pyrrolyl, 2-pyrazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl , furyl, thienyl, pyridyl, pyrimidinyl.
  • the structural unit From:
  • the above compound is selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a p38 kinase inhibitor.
  • the present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or the above composition as a P38 kinase inhibitor.
  • the present invention also provides a method of treating a disease associated with p38 kinase comprising administering to a therapeutic subject an effective amount of the above compound or a pharmaceutically acceptable salt thereof or the above composition.
  • the present invention comprises a compound of formula (I) which exhibits good pharmacological effects in in vitro enzymatic efficacy and is superior to the reference compounds Losmapimod (GSK) and Acumapimod (Novartis).
  • Losmapimod GSK
  • Acumapimod Novartis
  • LPS stimulated TNF ⁇ inhibitory activity significantly better than the reference compounds Losmapimod (GSK) and Acumapimod (Novartis).
  • Good therapeutic effects have been demonstrated in both the in vivo rheumatoid arthritis CIA model and the chronic asthma model.
  • the efficacy is comparable to dexamethasone and is superior to the reference compound Acumapimod (Novartis). Therefore, the compound of the present invention exhibits good pharmacological effects against immune abnormalities and inflammation inhibition, and has potential for clinical research.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • Compound The parent form differs from its various salt forms by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group which can be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). Or atom.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • 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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 1 is a graph showing changes in body weight of animals in each group in the CIA test.
  • Figure 2A is a comparison of clinical scores of animals in each group in the CIA trial.
  • Figure 2B is a comparison of the incidence of animals in each group in the CIA trial.
  • Figure 2C is a comparison of the area under the clinical scoring curve for each group of animals in the CIA trial.
  • Figure 3 is a comparison of tidal volume results of animals in each group in a chronic asthma model experiment.
  • Figure 4 is a comparison of the results of maximal ventilation in each group of animals in a chronic asthma model experiment.
  • Figure 5 is a comparison of the results per minute ventilation of each group of animals in a chronic asthma model experiment in vivo.
  • Figure 6 is a comparison of respiratory frequency results of animals in each group in a chronic asthma model experiment.
  • Figure 7 is a comparison of bronchial and arteriolar inflammation scores in each group of animals in a chronic asthma model experiment.
  • Figure 8 is a comparison of bronchial scores of animals in each group in a chronic asthma model experiment.
  • Figure 9 is a comparison of arteriolar inflammation scores in each group of animals in a chronic asthma model experiment.
  • A-2 (28.0 g, 98.1 mmol) was dissolved in 1,4-dioxane (200 mL), and a solution of sodium hydroxide (9.81 g, 245 mmol) in water (100 mL) and di-tert-butyl dicarbonate ( 23.5 g, 108 mmol). The reaction solution was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure.
  • A-3 (23.0 g, 103 mmol), 1-hydroxybenzotriazole (14.0 g, 104 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (19.9 g, 104 mmol) and diisopropylethylamine (22.3 g, 172 mmol) were dissolved in N,N-dimethylformamide (250 mL), stirred under nitrogen atmosphere for 30 min, and then added with cyclopropylamine (5.92 g, 104 mmol). Stir at room temperature for 15.5 hours.
  • A-4 (10.0 g, 32.7 mmol) was dissolved in methanol (50 mL), and a solution of hydrochloric acid (4M 99.9 mL) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for one hour, and the reaction mixture was concentrated under reduced pressure to give A-5 ( 7.90g).
  • Acetonitrile (349 mg, 8.52 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and diisopropylamino lithium (2M tetrahydrofuran solution, 5.68 mL, 11.4 mmol) was added dropwise at -78 ° C. After stirring at ° C for 30 minutes, 1-1 (1.00 g, 5.68 mmol) dissolved in tetrahydrofuran (3.00 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 ° C for 1.5 hours, and the reaction mixture was warmed to 0 ° C and stirred.
  • Acetonitrile (147 mg, 3.58 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and diisopropylamino lithium (2M tetrahydrofuran solution, 2.99 mL, 5.97 mmol) was added dropwise at -78 ° C.
  • 2-2 (870 mg, 2.99 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 ° C for 1.5 hours, and the reaction mixture was warmed to 0 ° C and stirred for 1 hour.
  • Lithium tetrahydroaluminum (3.36 g, 88.4 mmol) was added to anhydrous tetrahydrofuran (250 mL), and a solution of 4-2 (10.0 g, 44.2 mol) in tetrahydrofuran (100 mL) was slowly added dropwise at 0 ° C. Stir under 2 hours.
  • Water (3.4 mL), sodium hydroxide solution (1N, 3.4 mL) and water (10 mL) were added dropwise to the reaction mixture in this order and stirred for 0.5 hour. Filtration and concentration of the filtrate under reduced pressure gave 4-3 (9.10 g).
  • the purpose of this test was to examine the in vitro inhibitory activity of the compound against P38a/MAPK14.
  • the enzyme used in this experiment was human p38 ⁇ .
  • the standard substrates were myelin basic protein (MBP) (20 ⁇ M) and adenosine triphosphate (ATP) (10 ⁇ M), which were transferred from ⁇ 33 P-labeled ATP to MBP by detecting p38 ⁇ .
  • MBP myelin basic protein
  • ATP adenosine triphosphate
  • the amount of ⁇ -phosphoryl group was used to determine the activity of the substrate (the reaction formula is shown below).
  • the IC50 value at 10 concentrations of the compound was measured by 3-fold dilution from 10 ⁇ M.
  • the IC50 value at 10 concentrations of the reference compound SB202190 was measured by 3-fold dilution from 20 ⁇ M.
  • test results of the test compound against p38 ⁇ inhibitory activity are shown in Table 1.
  • Example 1 Compound number IC50(nM) Example 1 + Example 2 + Example 3 + Example 4 + Example 5 + Example 6 + Example 7 + Example 8 ++ Example 9 + Example 10 ++ Example 11 + Example 12 + Example 13 + Example 14 + Example 15 + Example 16 +
  • the compounds of the present invention have significant inhibitory activity against p38 ⁇ .
  • LPS induces cytokine inhibitory activity of mouse spleen cells by IC50 test.
  • the carbon dioxide was euthanized, the spleen was isolated, the spleen was ground, and the red blood cells were incubated for 10 minutes to remove the red blood cells, and a single cell suspension was prepared, and the cell count was adjusted to adjust the cell concentration to 5 ⁇ 10 6 /ml.
  • the activity data is shown in Table 2:
  • the compounds of the present invention have significant inhibitory activity against p38 ⁇ and are superior to the current clinical compounds Losmapimod and Acumapimod.
  • mice were randomly assigned to different treatment groups. The first immunization day is recorded as the 0th day, and the subsequent days are marked in order. After the DBA/1 mice were anesthetized with isoflurane, 50 ⁇ l of the prepared collagen emulsion was subcutaneously injected into the tail. On the 21st day, the same volume of collagen emulsion was injected into the tail. Mice in the normal group did not need to be immunized. On day 28, when the average clinical score reached approximately 1 point, 30 mice were re-randomized into 3 treatment groups, 10 mice per group, according to body weight and score.
  • Dexamethasone (dexamethasone) as a positive drug 0.3mpk dose group is a commonly used dose in the CIA model; the third group is administered Dexamethasone at a dose of 0.3 mg/kg; the eighth group is administered with Example 14, at a dose of 30 mg/kg. It was administered twice daily for a total of 14 days. The volume of intragastric administration was 10 ml/kg.
  • mice were observed daily from 7 days before immunization to 21 days after immunization (recorded once a week). After the 22nd day, the mice were observed daily for health status, morbidity, and body weight changes (at least three times a week) until the end of the experiment.
  • Clinical score After boosting the immunization, observe the incidence of the mice every day. When the mice began to develop (the clinical symptoms of arthritis), according to the degree of disease (redness, joint deformation) according to the standard of 0-4, the highest score of each limb is 4 points, the highest for each animal The score is 16 points.
  • the scoring criteria are shown in Table 2. Score at least three times a week.
  • the experimental data were expressed as mean ⁇ standard error (Mean ⁇ SEM), weight analysis by variance (Two-way ANOVA), clinical score and histological score using the Kruskal-Wallis Test, p ⁇ 0.05 was considered significant. difference. p ⁇ 0.01 indicates a very significant difference, and p ⁇ 0.001 indicates a very significant difference.
  • Example 14 The average body weight of the 30 mpk (bid) treatment group increased slowly on the 31st day after administration until the end of the experiment, while the body weight of the Vehicle group and the Dex 0.3mpk treatment group continued to decrease slowly, but there was no statistical difference between the two groups. ,As shown in Figure 1.
  • mice On the 6th day after the second immunization (the 27th day after the first immunization), the mice began to develop clinical symptoms of arthritis.
  • the mean clinical score of the blank control group steadily increased and stabilized at approximately 8 points, indicating a successful establishment of the CIA model (Fig. 2A).
  • the positive control Dexamethasone 0.3mpk group significantly inhibited the increase in the mean clinical score. From day 33, all the mice in this group were cured, and on the 31st day, there was a significant difference from the blank control group and continued until the end of the trial.
  • test compound (Example 14) group also inhibited the increase in clinical scores, and its clinical score stabilized at around 0.6 from day 33, and there was a significant difference from the 31st day to the Vehicle group until the end of the experiment, showing A good recovery effect on the disease, as shown in Figure 2A.
  • the blank control group achieved and maintained at 100% on the 31st day after immunization. All treatment groups reduced the onset and incidence of arthritis in mice.
  • the incidence of the positive control Dexamethasone 0.3mpk group decreased from the time of administration and decreased to 0% on the 33rd day; the incidence of the test compound (Example 14) was reduced to 30% on the 33rd day and within this range. Fluctuation to the end of the experiment showed a good healing effect on the disease, as shown in Figure 2B.
  • the area under the curve AUC was calculated, and the inhibition rate of each administration group relative to the solvent control group was calculated by the average value of AUC between the groups.
  • the Dexamethason inhibition rate was 97.1%. There was a very significant difference (p ⁇ 0.001), and the inhibition rate of the administration group of Example 14 was 87.7%, which also had a very significant difference.
  • Compound treatment group 14 has a certain alleviation effect on the body weight loss caused by the disease, but no significant difference.
  • Compound Example 14 The treatment group had a certain delay in the onset time and also reduced the incidence of the mice.
  • the therapeutic effect of the test compound in the OVA (ovalbumin)-induced female C57BL/6 mouse chronic asthma model was evaluated.
  • Modeling method Immunostimulation on days 1 to 15, high-induction of C57BL/6 mouse IgE (immunoglobulin) response with a mixture of OVA (ovalbumin) and Al(OH)3, and then continued to receive low particle mass concentrations Egg albumin atomization stimulation.
  • Test group group 1 (normal mice), group 2 (model-vehicle, oral), group 3 (dexamethasone-3 mg/kg), group 4 (model-solvent, nebulized), group 5 (Acumapimod-30 mg) /kg), Group 6 (Examples 14-10 mg/kg), Group 7 (Examples 14-30 mg/kg)
  • Results body weight, airway responsiveness, serum IgE levels, BALF cell count, lung histopathology: HE staining
  • mice Whether model group Test compound Drug administration information Group 1 6 no no no Group 2 6 Yes Solvent oral Oral, once a day Group 3 6 Yes Dexamethasone 3mg/kg, orally, once every 2 days Group 4 6 Yes Solvent atomization Atomization, once a day Group 5 6 Yes Acumapimod 30mg/kg, orally, 2 times a day Group 6 6 Yes Example 14 10mg/kg, oral, 2 times a day Group 7 6 Yes Example 14 30mg/kg, orally, 2 times a day
  • Tidal volume refers to the amount of gas exhaled each time during resting breathing. When ventilation dysfunction occurs, shallow and slightly faster breathing occurs, and the tidal volume decreases (tidal volume decreases).
  • the tidal volume of the model group was slightly lower than that of the normal animals.
  • Maximum ventilation refers to the maximum inspiratory and expiratory volume per second when resting breathing. Shallow and slightly faster breathing often occurs in ventilatory dysfunction, and maximum ventilation is reduced.
  • the maximum ventilation of the model group animals was significantly lower than that of the normal animals.
  • Ventilation per minute refers to the average per minute ventilation during ventilatory ventilatory dysfunction, often with shallow and slightly faster breathing, and reduced ventilation per unit time.
  • the ventilation per minute of the model group animals was significantly lower than that of the normal animals.
  • Respiratory rate refers to the average number of breaths per minute when resting breathing. Breathing dysfunction often occurs in shallow, slightly faster breathing, and the respiratory rate changes.
  • Airway stenosis index was measured by different doses of methacholine chloride. The airway stenosis index was significantly higher in the model control group compared with the healthy controls (p ⁇ 0.001). The DEX-treated group showed a significant decrease (p ⁇ 0.001) compared with the model-controlled oral group; the two test compound groups were significantly lower than the model oral control group.
  • the inflammation scores of the DEX group and the 14-10mpk group were significantly improved, and the two groups were equally effective and superior to the Acumapimod group.
  • the inflammation scores of the DEX group and the 14-10mpk group were significantly improved, and the two groups were equally effective and superior to the Acumapimod group.
  • the inflammation scores of the DEX group and the 14-10mpk group were significantly improved, and the two groups were equally effective and superior to the Acumapimod group.

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Abstract

L'invention concerne une classe de composés de pyrazole de formule (I) ayant un effet inhibiteur de p38α, et des utilisations des composés dans le domaine des maladies associées à p38α, telles que diverses maladies inflammatoires et des anomalies immunologiques. De plus, l'invention concerne également la synthèse et le procédé de préparation de la série de composés pyrazole.
PCT/CN2017/104247 2016-09-29 2017-09-29 Inhibiteur de la p38α mapk kinase, son procédé de préparation et son utilisation WO2018059533A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065324A1 (fr) * 2018-09-26 2020-04-02 Mereo Biopharma 1 Limited Procédé de synthèse pour la préparation d'un composé hydrazine
CN110950848A (zh) * 2018-09-27 2020-04-03 徐诺药业 新型氨基吡唑类衍生物的合成与应用
US11649213B2 (en) 2018-09-26 2023-05-16 Mereo Biopharma 1 Limited Synthetic method for the preparation of a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol compound

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CN1300282A (zh) * 1998-05-05 2001-06-20 霍夫曼-拉罗奇有限公司 作为p－38map激酶抑制剂的吡唑衍生物
CN1376147A (zh) * 1999-09-22 2002-10-23 霍夫曼-拉罗奇有限公司 吡唑类衍生物
CN1832928A (zh) * 2003-06-26 2006-09-13 诺瓦提斯公司 以5元杂环为基础的p38激酶抑制剂

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CN1300282A (zh) * 1998-05-05 2001-06-20 霍夫曼-拉罗奇有限公司 作为p－38map激酶抑制剂的吡唑衍生物
CN1376147A (zh) * 1999-09-22 2002-10-23 霍夫曼-拉罗奇有限公司 吡唑类衍生物
CN1832928A (zh) * 2003-06-26 2006-09-13 诺瓦提斯公司 以5元杂环为基础的p38激酶抑制剂

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065324A1 (fr) * 2018-09-26 2020-04-02 Mereo Biopharma 1 Limited Procédé de synthèse pour la préparation d'un composé hydrazine
CN112839923A (zh) * 2018-09-26 2021-05-25 梅里奥生物制药1有限公司 用于制备肼化合物的合成方法
US11649213B2 (en) 2018-09-26 2023-05-16 Mereo Biopharma 1 Limited Synthetic method for the preparation of a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol compound
IL281636B1 (en) * 2018-09-26 2024-04-01 Mereo Biopharma 1 Ltd Synthetic method for the preparation of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid, its products and their uses
IL281636B2 (en) * 2018-09-26 2024-08-01 Mereo Biopharma 1 Ltd Synthetic method for the preparation of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid, its products and their uses
CN110950848A (zh) * 2018-09-27 2020-04-03 徐诺药业 新型氨基吡唑类衍生物的合成与应用
CN110950848B (zh) * 2018-09-27 2024-03-26 徐诺药业 新型氨基吡唑类衍生物的合成与应用

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