WO2018059533A1 - p38αMAPK激酶抑制剂及其制备方法和应用 - Google Patents

p38αMAPK激酶抑制剂及其制备方法和应用 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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French (fr)
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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.

Abstract

公开了一类具有p38α的抑制作用的吡唑类化合物式(I)，并包含这些化合物在p38α相关疾病领域的应用，比如各种炎症以及免疫异常等疾病，此外还公开了该系列吡唑类化合物的合成及制备方法。

Description

p38αMAPK激酶抑制剂及其制备方法和应用
相关申请的引用
本申请要求于2016年09月29日向中华人民共和国国家知识产权局提交的第201610867718.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发明涉及一类具有p38α的抑制作用的吡唑类化合物，并包含这些化合物在p38α相关疾病领域的应用，比如各种炎症以及免疫异常等疾病。另外本发明还涉及该系列吡唑类化合物的合成及制备方法。
背景技术
丝裂原活化蛋白激酶(MAPK)属于丝氨酸/苏氨酸激酶家族，MAPK信号通路是真核细胞向细胞内转导细胞外信号的主要通路之一。通过蛋白质磷酸化转导外界的不同刺激信号，调控细胞的***，增殖，生存，运动和衰亡，基因转录，基因表达以及蛋白翻译等过程[Lufen Chang,Michael Karin,Nature,2001(410),37-40；Puneet Chopra,Onkar Kulkarni,Shashank Gupta,et.al,International Immunopharmacology,2010(10),467-473]。人体内的MAP激酶主要有3个亚族，即细胞外信号调节激酶ERK(extracellular signalregulated kinases)，c-Jun N-末端激酶(应激活化的蛋白激酶，stress activated protein kinases)JNK(SAPK)和p38.这些同族激酶结构相似度约为60～70％，不同之处主要在活性环区域，这个区域的蛋白序列和大小各不相同。此外，每种亚族激酶被不同的胞外信号刺激激活并做出响应[Yong Jiang,Canhe Chen,Zhuangjie Li et.al,The Journal of Biological Chemisty,1996(271),17920-17926；Sanjay Kumar,Jeffrey Boehm and John C.Lee,Nature Review,2003(2),717-726]。通常，ERKs被促有丝***和增殖信号激活，JNKs和p38MAPks被各种环境应激活化。它们都在获得细胞外信号后，被上游激酶磷酸化激活，磷酸化位点主要为丝氨酸和苏氨酸残基，活化后再分别磷酸化各自的下游底物，从而转导信号，使细胞做出响应。
p38MAPK包含四个亚型p38α，p38β，p38γ和p38δ，它们分别由不同基因编码，在人体中分布于不同组织中。p38α和p38β广泛地分布于人体各种组织中，p38γ主要分布于人体骨骼肌中而p38δ在肾脏和肺组织中大量表达。[Kana Namiki,Hirofumi Matsunaga,Kento Yoshioka,et al.,the Jounal of Biological Chemistry,2012(287),24228-24238]。这四种亚型中，p38α在各种炎症相关疾病或者炎症组织中都有很高水平的表达，与炎症的发展程度密切相关，是重要的信号分子，因此成为治疗炎性疾病的理想靶点。受到细胞外应激刺激后，p38α会激活下游激酶(比如MK2，MK3)和转录因子(比如Stat1，ATF-2)并导致生成促炎性细胞因子IL-1β，TNFα和IL-6。阻断炎症因子的生成会使各种炎症得以缓解，因此p38α成为研究热点[Bin Wu,Hui-Ling Wang,Liping Pettus,et al.,J.Med.Chem.2010(53),6398-6411]。
小分子p38α抑制剂在各种体外和体内动物模型中都显示了抑制炎症因子生成的能力，然而临床试验结果尚有各种各样的问题，还没有一个被批准上市的新药，因此开发新型口服p38α小分子抑制剂仍然具有广泛的临床需求。
文献Davies SP,et al.Biochem J,2000,351(Pt 1),95-105报道了SB202190是一个p38MAPK抑制剂；WO2003068747报道了化合物Losmapimod是一个选择性的口服p38MAPK抑制剂体；WO2005009973报道了化合物Acumapimod是一个口服p38MAPK抑制剂体。
Figure PCTCN2017104247-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物及其药学上可接受的盐，
Figure PCTCN2017104247-appb-000002
其中，
R1、R2分别独立地选自：H、卤素、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的C1-6烷基；
环B选自：5～6元杂环烷基、5～6元杂芳基；
R选自：卤素、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基、N,N’-(C1-3烷基)氨基；
所述5～6元杂芳基、5～6元杂环烷基之“杂”选自：-NH-、N、-O-、-S-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、NH2、
Figure PCTCN2017104247-appb-000003
本发明的一些方案中，上述R1、R2分别独立地选自H、F、Cl、Br、I、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的C1-3烷基。
本发明的一些方案中，上述R1、R2分别独立地选自H、F、Cl、Br、I、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2017104247-appb-000004
本发明的一些方案中，上述R1、R2分别独立地选自：H、F、Cl、Br、I、OH、NH2、CN、Me、CF3、Et、
Figure PCTCN2017104247-appb-000005
本发明的一些方案中，上述R1选自：H、F、Cl、Br、I、Me、CN、CF3。
本发明的一些方案中，上述R2选自：H、OH、NH2、CN、Me、Et、
Figure PCTCN2017104247-appb-000006
本发明的一些方案中，上述环B选自：吡咯烷基、哌啶基、吡咯基、2-吡咯啉基、2-吡唑啉基、吡唑基、咪唑基、噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基。
本发明的一些方案中，上述结构单元
Figure PCTCN2017104247-appb-000007
选自：
Figure PCTCN2017104247-appb-000008
Figure PCTCN2017104247-appb-000009
本发明的一些方案中，上述化合物选自：
Figure PCTCN2017104247-appb-000010
Figure PCTCN2017104247-appb-000011
Figure PCTCN2017104247-appb-000012
本发明还提供了一种药物组合物，其含有治疗有效量的上述化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物在制备治疗p38激酶抑制剂相关药物中的应用。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物作为P38激酶抑制剂的应用。
本发明还提供了一种治疗与p38激酶相关疾病的方法，包括给予治疗对象有效量的上述化合物或其药学上可接受的盐或上述组合物。
技术效果：
本发明包含式(I)化合物在体外酶活药效中展现良好的药效，且优于参照化合物Losmapimod(GSK)和Acumapimod(Novartis)。体外细胞LPS刺激TNFα抑制活性显著优于参照化合物Losmapimod(GSK)和Acumapimod(Novartis)。在体内类风湿性关节炎CIA模型和慢性哮喘模型中都展现了良好的治疗效果。药效与***相当，且优于参照化合物Acumapimod(Novartis)。因此本发明化合物对免疫异常，炎症抑制展现了良好的药效，有潜力用于临床研究。
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的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。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的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。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。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的 母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
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。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2017104247-appb-000013
表示一个立体中心的绝对构型，用
Figure PCTCN2017104247-appb-000014
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
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。
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)。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“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“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，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。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮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。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。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。例如，结构单元
Figure PCTCN2017104247-appb-000015
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以 外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。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。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻 吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
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。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团 或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
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；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；CDCl3代表氘代三氯甲烷；Methonal代表甲醇。
化合物经手工或者
Figure PCTCN2017104247-appb-000016
软件命名，市售化合物采用供应商目录名称。
附图说明
图1为CIA试验中，各组动物体重变化曲线。
图2A为CIA试验中，各组动物临床打分结果对比。
图2B为CIA试验中，各组动物发病率结果对比。
图2C为CIA试验中，各组动物临床打分曲线下面积结果对比。
图3为体内慢性哮喘模型实验中，各组动物潮气量结果对比。
图4为体内慢性哮喘模型实验中，各组动物最大通气量结果对比。
图5为体内慢性哮喘模型实验中，各组动物每分钟通气量结果对比。
图6为体内慢性哮喘模型实验中，各组动物呼吸频率结果对比。
图7为体内慢性哮喘模型实验中，各组动物支气管和小动脉炎症评分对比。
图8为体内慢性哮喘模型实验中，各组动物支气管评分对比。
图9为体内慢性哮喘模型实验中，各组动物小动脉炎症评分对比。
具体实施方式
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
Figure PCTCN2017104247-appb-000017
第一步
将化合物A-1(15.5g,0.102mol)溶于1,4-二氧六环(140mL)和水(140mL)中,0℃下滴加浓盐酸(36.5％,140mL),30分钟内滴加完毕,0℃下分批加入亚硝酸钠(7.78g,0.113mol)。反应液在25℃氮气保护下搅拌1小时。将二氯化锡二水合物(43.3g,0.192mol)溶于浓盐酸(36.5％,34mL),在0℃下缓慢滴加到反应液中,30分钟内滴加完毕。反应液在0℃搅拌2小时,此时有大量黄色固体析出,过滤,滤饼用1,4-二氧六环(100mL)洗涤,在室温下用220mL石油醚/乙酸乙酯(10:1)打浆10分钟,过滤,滤饼干燥后得到A-2(28.0g)。1H NMR(400MHz,DMSO-d6)δ10.27(br.s,3H),7.54-7.47(m,2H),7.27(d,J＝7.6Hz,1H),2.25(s,3H)。
第二步
将A-2(28.0g,98.1mmol)溶于1,4-二氧六环(200mL)中,加入氢氧化钠(9.81g,245mmol)的水(100mL)溶液和二碳酸二叔丁酯(23.5g,108mmol)。反应液在室温下搅拌2小时,将反应液减压浓缩,剩余物溶于水中(100mL)用1N盐酸调节pH 2～3,过滤,滤饼溶于DCM/MeOH(10:1 800mL)混合溶液,用无水硫酸钠干燥,过滤,滤液减压浓缩得到A-3(21.2g)。1H NMR(400MHz,Methonal-d4)δ7.61(s,1H),7.58(d,J＝7.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.48(br.s,1H),5.76(br.s,1H),2.28(s,3H),1.49(s,9H)。
第三步
将A-3(23.0g,103mmol),1-羟基苯并***(14.0g,104mmol),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(19.9 g,104mmol)和二异丙基乙胺(22.3g,172mmol)溶于N,N-二甲基甲酰胺(250mL)中,氮气保护下搅拌30分钟,加入环丙胺(5.92g,104mmol),反应液在室温下搅拌15.5小时。向反应液中加入水(1000mL),用乙酸乙酯萃取(700mL x 2),合并有机相,用饱和食盐水(1000mL x 2)洗涤,无水硫酸钠干燥,减压浓缩,得到的粗品用石油醚/乙酸乙酯(3:1)打浆,过滤,滤饼干燥后得到A-4(17.6g)。1H NMR(400MHz,CDCl3)δ7.33(s,1H),7.12-7.02(m,2H),6.41(br.s,1H),6.18(br.s,1H),5.70(br.s,1H),2.91-2.86(m,1H),2.23(s,3H),1.48(s,9H),0.88-0.82(m,2H),0.62-0.57(m,2H)。
第四步
将A-4(10.0g,32.7mmol)溶于甲醇(50mL),0℃下滴加盐酸甲醇溶液(4M 99.9mL),反应液室温搅拌一小时,将反应液减压浓缩得到A-5(7.90g)。1H NMR(400MHz,CDCl3)δ7.44-7.36(m,2H),7.28(d,J＝8.0Hz,1H),2.92-2.78(m,1H),2.31(s,3H),0.88-0.78(m,2H),0.69-0.62(m,2H)。
实施例1
Figure PCTCN2017104247-appb-000018
第一步
在氮气保护下将乙腈(349mg,8.52mmol)溶于四氢呋喃(10mL)中,在-78℃下滴加二异丙基氨基锂(2M四氢呋喃溶液,5.68mL,11.4mmol),反应液在-78℃下搅拌30分钟,将溶于四氢呋喃(3.00mL)的1-1(1.00g,5.68mmol)滴入到反应液中,反应液在-78℃下搅拌1.5小时,反应液升温至0℃搅拌1小时,反应液用饱和氯化铵溶液(20mL)淬灭,用乙酸乙酯(20mL x 3)萃取。合并有机相,饱和食盐水洗涤(25mL x 2),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法分离纯化(1:1石油醚/乙酸乙酯,Rf＝0.6)得到1-2(686mg)。1H NMR(400MHz,DMSO-d6)δ13.51(br.s,1H),8.52-8.50(m,1H),8.33(s,1H),7.94-7.90(m,1H),7.64(d,J＝8.8Hz,1H),4.80(s,2H)。
第二步
在氮气保护下将1-2(300mg,1.62mmol)溶于甲苯(10mL)中,加入N,N-二苯基甲脒(318mg,1.62mmol), 反应液在100℃搅拌16小时,冷却至室温,向反应液中加入水(20mL),用乙酸乙酯(20mL x 2)萃取。合并有机相,饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用薄层层析法(2:1石油醚/乙酸乙酯,Rf＝0.3)分离纯化得到1-3(133mg)。1H NMR(400MHz,DMSO-d6)δ12.50(d,J＝13.1Hz,1H),11.05(br.s,1H),8.69(d,J＝13.6Hz,1H),8.46-8.37(m,2H),8.33-8.23(m,3H),7.82(d,J＝8.0Hz,1H),7.77-7.71(m,1H),7.31-7.24(m,1H),7.23-7.17(m,1H)。
第三步
在氮气保护下将A(108mg,0.447mmol),1-3(129mg,0.447mmol)和二异丙基乙胺(116mg,0.895mmol)溶于N-甲基吡咯烷酮(5mL)中,在130℃下搅拌2小时。反应液降至室温,中加入水(20mL),用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 2),无水硫酸钠干燥,过滤,减压浓缩,剩余物用制备高效液相色谱法分离纯化,得到1(26.0mg)。1H NMR(400MHz,Methonal-d4)δ8.38(s,1H),8.26(s,1H),7.97-7.93(m,2H),7.92-7.85(m,2H),7.70(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),2.91-2.86(m,1H),2.27(s,3H),0.86-0.79(m,2H),0.69-0.63(m,2H)。MS-ESI计算值[M+H]+401,实测值401。
实施例2
Figure PCTCN2017104247-appb-000019
第一步
将2-1(600mg,3.14mmol)溶于二碳酸二叔丁酯(5mL)中,反应液加热到100℃搅拌12小时。反应液降至室温,加入水(20mL),用乙酸乙酯(30mL x 2)萃取。合并有机相,饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.7),得到2-2 (890mg)。1H NMR(400MHz,CDCl3)δ7.83-7.74(m,3H),3.89(s,3H),3.77-3.70(m,2H),2.80(t,J＝6.4Hz,2H),1.97-1.91m,2H),1.54(s,9H)。
第二步
在氮气保护下将乙腈(147mg,3.58mmol)溶于四氢呋喃(10mL)中,在-78℃下滴加二异丙基氨基锂(2M四氢呋喃溶液,2.99mL,5.97mmol),反应液在-78℃下搅拌30分钟,将溶于四氢呋喃(10mL)的2-2(870mg,2.99mmol)滴入到反应液中,反应液在-78℃下搅拌1.5小时,反应液升温至0℃搅拌1小时,反应液用饱和氯化铵溶液(20mL)淬灭,用乙酸乙酯(20mL x 3)萃取。合并有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(2:1石油醚/乙酸乙酯,Rf＝0.37)分离纯化得到2-3(725mg)。1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.4Hz,1H),7.70-7.63(m,2H),4.02(s,2H),3.80-3.70(m,2H),2.82(t,J＝6.4Hz,2H),1.98-1.92(m,2H),1.55(s,9H)。
第三步
在氮气保护下将2-3(170mg,0.566mmol)溶于甲苯(10mL)中,加入N,N-二苯基甲脒(111mg,0.566mmol),反应液在100℃反应16小时,冷却至室温,减压浓缩,剩余物用硅胶柱层析法(2:1石油醚/乙酸乙酯,Rf＝0.84)分离纯化得到2-4(152mg)。1H NMR(400MHz,CDCl3)δ8.03(d,J＝13.2Hz,1H),7.86-7.72(m,3H),7.48-7.41(m,2H),7.29(br.s,1H),7.22-7.20(m,2H),3.79-3.71(m,2H),2.84(t,J＝6.4Hz,2H),1.99-1.93(m,2H),1.55(s,9H)。
第四步
在氮气保护下将A(77.0mg,0.318mmol),2-4(151mg,0.375mmol)和二异丙基乙胺(82.3mg,0.637mmol)溶于N-甲基吡咯烷酮(10mL)中,在130℃反应2小时。向反应液中加入水(20mL),用乙酸乙酯(20mL x 1)萃取,有机相用饱和食盐水洗涤(20mL x 2),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法分离纯化(1:1石油醚/乙酸乙酯,Rf＝0.32),得2-5(64.0mg)。1H NMR(400MHz,CDCl3)δ7.87-7.78(m,3H),7.69(s,1H),7.63-7.61(m,1H),7.57(s,1H),7.40(d,J＝8.0Hz,1H),6.69(br s,1H),5.89(s,2H),3.78-3.72(m,2H),2.86-2.82(m,3H),2.22(s,3H),1.99-1.93(m,2H),1.55(s,9H),0.85-0.80(m,2H),0.62-0.55(m,2H)。
第五步
将2-5(60.0mg,0.116mmol)溶于甲醇(5mL)中,0℃下滴加盐酸甲醇溶液(4M 5mL),反应液在25℃搅拌1小时,反应液减压浓缩,用饱和碳酸氢钠水溶液调节pH～8,用二氯甲烷/甲醇(10:1)(20mL)萃取,无水硫酸钠干燥,过滤,减压浓缩,剩余物用制备高效液相色谱法分离纯化得到2(17.0mg)。1H NMR(400MHz,Methonal-d4)δ7.95-7.93(m,1H),7.90(s,1H),7.84(s,1H),7.56(d,J＝8.0Hz,1H),7.53-7.45(m,2H),6.54(d,J＝8.4Hz,1H),3.39-3.35(m,2H),2.92-2.85(m,1H),2.84-2.82(m,2H),2.24(s,3H),1.98-1.92(m,2H),0.87-0.78(m,2H),0.69-0.62(m,2H)。MS-ESI计算值[M+H]+416,实测值416。
实施例3
Figure PCTCN2017104247-appb-000020
Figure PCTCN2017104247-appb-000021
在氮气保护下将2(200mg,0.481mmol)溶于甲醇(6mL)中,加入37％甲醛水溶液(195mg,2.41mmol)和醋酸(144mg,2.41mmol),反应液在20℃搅拌10分钟,再加入氰基硼氢化钠(90.7mg,1.44mmol),反应液在20℃搅拌50分钟。向反应液中加入水(50mL),用乙酸乙酯(50mL x 3)萃取。合并有机相,饱和食盐水(80mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用制备高效液相色谱法纯化得3(12.9mg)。1H NMR(400MHz,Methonal-d4)δ7.96-7.92(m,1H),7.91(s,1H),7.84(s,1H),7.65-7.63(m,1H),7.57(d,J＝8.0Hz,1H),7.49(s,1H),6.68(d,J＝8.4Hz,1H),3.41-3.39(m,2H),3.03(s,3H),2.92-2.86(m,1H),2.86-2.81(m,2H),2.25(s,3H),2.05-1.99(m,2H),0.86-0.79(m,2H),0.69-0.63(m,2H)。MS-ESI计算值[M+H]+430,实测值430。
实施例4
Figure PCTCN2017104247-appb-000022
第一步
将4-1(27.2g,128mmol)和甲烷磺酸(250mL)加入二氯甲烷(22mL)中,0℃下,向其中缓慢加入叠氮钠 (12.8g,197mmol),反应液在20℃搅拌3小时。向反应液中加入二氯甲烷(500mL)用饱和氯化钠(2.5L)洗涤,分液，有机相用无水硫酸钠干燥,过滤,减压浓缩。得到的粗品用硅胶柱层析法(5:1石油醚/乙酸乙酯,Rf＝0.26和0.06)分离纯化纯化得到4-2(17.0g)。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.12-6.98(m,3H),2.95-2.91(m,2H),2.66-2.63(m,2H)。
第二步
将四氢铝锂(3.36g,88.4mmol)加入无水四氢呋喃(250mL)中,0℃下,缓慢滴加4-2(10.0g,44.2mol)的四氢呋喃(100mL)溶液,反应液在20℃下搅拌2小时。按顺序依次向反应液中滴加水(3.4mL),氢氧化钠溶液(1N,3.4mL)和水(10mL)并搅拌0.5小时。过滤,滤液减压浓缩得到4-3(9.10g)。1H NMR(400MHz,CDCl3):δ6.78(d,J＝8.0Hz,1H),6.70-6.67(m,1H),6.60(s,1H),3.88(s,1H),3.30-2.78(m,2H),2.71-2.68(m,2H),1.95-1.88(m,2H)。
第三步
将4-3(9.00g,42.4mmol)和二异丙基乙基胺(6.03g,46.7mmol)溶解于二氯甲烷中(150mL),0℃下,加入二叔丁基二碳酸酯(9.72g,44.5mmol)。反应液在20℃搅拌6小时。减压浓缩，粗品用硅胶柱层析法(5:1石油醚/乙酸乙酯,Rf＝0.55)分离纯化得到4-4(2.70g)。1H NMR(400MHz,CDCl3):δ7.89(s,1H),7.10-7.08(m,1H),6.94-6.92(m,1H),3.70-3.67(m,2H),2.72-2.69(m,2H),1.94-1.87(m,2H),1.54(s,9H)。MS-ESI计算值[M+H]+312和314,实测值[M+H-56]+256和258。
第四步
将4-4(10.0g,32.0mmol)和二苯基膦二茂铁二氯化钯(2.34g,3.21mmol)溶于甲醇(100mL),N,N-二甲基甲酰胺(30mL)和三乙胺(30mL)的混合溶液中,反应液在一氧化碳(50Psi),80℃下搅拌18小时。反应液降至室温,过滤,粗品用硅胶柱层析法(5:1石油醚/乙酸乙酯,Rf＝0.46)分离纯化得到4-5(60.0mg)。1H NMR(400MHz,CDCl3):δ8.34(s,1H),7.65-7.63(m,1H),7.14-7.12(m,1H),3.90(s,3H),3.74-3.71(m,2H),2.83-2.78(m,2H),1.97-1.91(m,2H),1.55(s,9H)。
第五步
参照实施例2第二步,得到4-6(1.30g)。1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.55-7.52(m,1H),7.22-7.20(m,1H),4.07(s,2H),3.76-3.73(m,2H),2.85-2.82(m,2H),1.98-1.92(m,2H),1.55(s,9H)。
第六步
参照实施例2第三步,得到4-7(1.70g)。MS-ESI计算值[M+H]+404,实测值[M+H]+404。
第七步
参照实施例2第四步,得到4-8(1.00g)。1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.98(s,1H),7.84-7.82(m,1H),7.69(s,1H),7.47-7.43(m,2H),7.19(s,1H),6.43(s,1H),5.80(s,1H),3.77-3.74(m,2H),2.87-2.82(m,2H),2.24(s,3H),1.98-1.93(m,2H),1.54(s,9H),0.87-0.83(m,2H),0.63-0.61(m,2H)。MS-ESI计算值[M+H]+516,实测值[M+H]+516。
第八步
将化合物4-8(100mg,194mmol)溶于二氯甲烷(4mL),0℃下,加入三氟乙酸(0.3mL,3.88mmol)。反应液在20℃搅拌1小时。反应液减压浓缩,剩余物用制备高效液相色谱法分离纯化得到4(50.0mg)。1H NMR (400MHz,CDCl3)δ7.87-7.83(m,2H),7.68(s,1H),7.45(s,1H),7.07-7.05(m,2H),6.92(s,1H),6.32(s,1H),5.75(s,2H),3.38-3.35(m,2H),2.90-2.82(m,3H),2.24(s,3H),2.01-1.96(m,2H),0.90-0.85(m,2H),0.63-0.61(m,2H)。MS-ESI计算值[M+H]+416,实测值[M+H]+416。
实施例5
Figure PCTCN2017104247-appb-000023
第一步
将4-8(200mg,0.388mmol)溶于甲醇(5mL)中,0℃下滴加盐酸甲醇溶液(4M 4mL),反应液在25℃搅拌1小时。反应液减压浓缩,剩余物用饱和碳酸氢钠水溶液调节pH～8,用二氯甲烷/甲醇(10:1)(20mL)萃取,无水硫酸钠干燥,过滤,减压浓缩得到4(170mg)。1H NMR(400MHz,Methonal-d4)δ7.95-7.93(m,1H),7.91-7.87(m,2H),7.85(d,J＝1.6Hz,1H),7.73(s,1H),7.59-7.57(m,2H),3.66-3.58(m,2H),3.11-3.07(m,2H),2.91-2.86(m,7.2Hz,1H),2.25(s,3H),2.24-2.19(m,2H),0.87-0.79(m,2H),0.69-0.63(m,2H)。
第二步
在氮气保护下将4(170mg,0.409mmol)溶于甲醇(6mL)中,加入甲醛水溶液(166mg,2.05mmol)和醋酸(123mg,2.05mmol),反应液在20℃搅拌10分钟,再加入氰基硼氢化钠(77.1mg,1.23mmol),反应液在20℃搅拌50分钟。向反应液中加入水(50mL),用乙酸乙酯(50mL x 3)萃取。合并有机相,饱和食盐水(80mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用制备高效液相色谱法分离纯化得到5(22.2mg)。1H NMR(400MHz,Methonal-d4)δ7.95-7.93(m,1H),7.88-7.83(m,2H),7.56(d,J＝8.0Hz,1H),7.10-7.05(m,1H),7.03-7.00(m,1H),6.98(s,1H),3.31-3.29(m,2H),2.97(s,3H),2.91-2.86(m,1H),2.86-2.82(m,2H),2.25(s,3H),2.05-1.99(m 2H),0.86-0.79(m,2H),0.69-0.63(m,2H)。MS-ESI计算值[M+H]+430,实测值430。
实施例6
Figure PCTCN2017104247-appb-000024
Figure PCTCN2017104247-appb-000025
第一步
参照实施例4第一步,得到6-2(3.60g)。1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.4Hz,1H),7.63-7.60(m,1H),7.36(s,1H),7.15(s,1H),3.63-3.59(m,2H),3.00-2.97(m,2H)。
第二步
参照实施例4第二步,得到6-3(3.60g)。1H NMR(400MHz,CDCl3)δ7.26-6.95(m,3H),3.99-3.97(m,2H),3.15-3.11(m,2H),2.75-2.72(m,2H)。MS-ESI计算值[M+H]+212和214,实测值212和214。
第三步
参照实施例4第三步,得到6-4(3.00g)。1H NMR(400MHz,CDCl3)δ7.28-6.99(m,3H),4.53(s,2H),3.63-3.62(m,2H),2.82-2.76(m,2H),1.49(s,9H)。MS-ESI计算值[M+H]+312和314,实测值312和314。
第四步
参照实施例4第四步,得到6-5(300mg)。1H NMR(400MHz,CDCl3)δ7.84-7.80(m,2H),7.20(s,1H),4.62(s,2H),3.91(s,3H),3.73-3.67(m,2H),2.90-2.87(m,2H),1.50(s,9H)。
第五步
参照实施例2第二步,得到6-6(1.3g)。1H NMR(400MHz,CDCl3)δ7.0-7.68(m,2H),7.30-7.28(m,1H),4.64(s,2H),3.69-3.67(m,2H),2.93-2.90(m,2H),1.50(s,9H)。
第六步
参照实施例2第三步,得到6-7(1.2g)。MS-ESI计算值[M+H]+404,实测值404。
第七步
参照实施例2第四步,得到6-8(1.5g)。1H NMR(400MHz,CDCl3)δ7.83-7.80(m,3H),7.70-7.30(m,4H),6.38(s,1H),5.83(s,2H),4.67(s,2H)3.73-3.72(m,2H),2.94-2.88(m,3H),2.25(s,3H),1.51(s,9H),0.89-0.84(m,2H),0.63-0.59(m,2H)。MS-ESI计算值[M+H]+516,实测值516。
第八步
参照实施例2第五步,得到6(230mg)。1H NMR(400MHz,Methonal-d4)δ7.97-7.91(m,1H),7.84(s,2H),7.61-7.56(m,2H),7.52(s,1H),7.30(d,J＝7.6Hz,1H),4.08(s,2H),3.17-3.14(m,2H),2.98-2.92(m,2H),2.91-2.86(m,7.2Hz,1H),2.25(s,3H),0.85-0.80(m,2H),0.69-0.62(m,2H)。MS-ESI计算值[M+H]+416,实测值416。
实施例7
Figure PCTCN2017104247-appb-000026
第一步
参照实施例5第二步,得到7(6.7mg)。1H NMR(400MHz,Methonal-d4)δ7.93-7.91(m,1H),7.82(s,2H),7.63-7.61(m,1H),7.58-7.52(m,2H),7.34-7.32(m,1H),3.80(s,2H),3.10-3.04(m,2H),2.91-2.88(m,2H),2.87-2.82(m,1H),2.56(s,3H),2.23(s,3H),0.84-0.78(m,2H),0.67-0.60(m,2H)。MS-ESI计算值[M+H]+430,实测值430。
实施例8
Figure PCTCN2017104247-appb-000027
Figure PCTCN2017104247-appb-000028
第一步
将乙腈(351mg,8.57mmol)溶于四氢呋喃(30mL)中,在-78℃,氮气保护下滴加二异丙基氨基锂(2M四氢呋喃溶液,8.57mL,17.1mmol),在-78℃下搅拌30分钟,在该温度下滴加8-1(1.00g,5.71mmol)的四氢呋喃(20mL)溶液,反应液在-78℃,氮气保护下搅拌1.5小时。缓慢升至室温继续搅拌1小时。反应液用饱和氯化铵溶液(50mL)淬灭,乙酸乙酯(50mL x 3)萃取,合并有机相,用饱和食盐水(50mL x 2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到8-2(1.10g)。1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.71-7.39(m,1H),7.51-7.49(m,2H),6.63-6.61(m,1H),4.77(s,2H)。
第二步
将化合物8-2(500mg,2.71mmol)和化合物B(531mg,2.71mmol)溶于无水甲苯(50mL)中,混合物在氮气保护下加热到85℃搅拌16小时。反应液冷却到室温,减压浓缩,粗品用石油醚/乙酸乙酯(20mL/5mL)打浆20分钟,过滤,滤饼真空干燥得到化合物8-3(410mg)。MS-ESI计算值[M+Na]+310,实测值310。
第三步
将化合物8-3和二异丙基乙胺(197mg,1.39mmol)溶于N-甲基吡咯烷酮(5mL)中,室温下加入化合物A(168mg,0.696mmol),反应液加热到130℃搅拌1.5小时。反应液冷却到室温,加入水(20mL),用乙酸乙酯萃取(20mL x 2),合并有机相,依次用水(50mL x 2),饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗品用制备高效液相色谱法分离纯化得到8(78.0mg)。1H NMR(400MHz,CDCl3)δ8.45(br.s,1H),8.23(s,1H),7.94(s,1H),7.77(d,J＝7.2Hz,1H),7.75-7.71(m,1H),7.71(s,1H),7.51-7.46(m,2H),7.34-7.32(m,1H),6.71-6.70(m,1H),6.33(br.s,1H),5.80(br.s,2H),2.92-2.89(m,1H),2.27(s,3H),0.89–0.86(m,2H),0.64–0.62(m,2H)。MS-ESI计算值[M+H]+400,实测值400。
实施例9
Figure PCTCN2017104247-appb-000029
Figure PCTCN2017104247-appb-000030
第一步
化合物9-1(968mg,5.53mmol)溶于冰醋酸(5mL)中,0℃下分批加入氰基硼氢化钠(1.04g,16.5mmol),反应液于室温下搅拌1小时。加入水(100mL),乙酸乙酯(100mL x 2)萃取,合并有机相,用饱和食盐水(150mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品用硅胶柱层析法(20:1二氯甲烷/甲醇,Rf＝0.42)分离纯化得到9-2(890mg)。1H NMR(400MHz,CDCl3)δ8.01-7.90(m,2H),7.90(br.s,1H),7.54(d,J＝8.0Hz,1H),3.95-3.89(m,4H),3.62-3.56(m,1H),3.30-3.22(m,1H),3.18-3.14(m,1H)。
第二步
化合物9-2(880mg,4.97mmol)溶于二氯甲烷(20mL)中,加入三乙胺(603mg,5.96mmol)和二碳酸二叔丁酯(1.30g,5.96mmol),反应液于30℃下搅拌16小时,减压浓缩。粗品经硅胶柱层析法(40:1二氯甲烷/甲醇,Rf＝0.77)分离纯化得到9-3(800mg)。1H NMR(400MHz,CDCl3)δ7.90-7.88(m,2H),7.81(s,1H),4.05(t,J＝8.4Hz,2H),3.88(s,3H),3.12(t,J＝8.4Hz,2H),1.59(s,9H)。MS-ESI计算值[M+H]+278,实测值278。
第三步
参照实施例8第一步，得到9-4(610mg)。1H NMR(400MHz,CDCl3)δ7.84-7.74(m,3H),4.08-4.02(m,4H),3.15(t,J＝8.4Hz,2H),1.58(s,9H)。
第四步
参照实施例8第二步，得到化合物9-5(780mg)。1H NMR(400MHz,CDCl3)δ12.75(d,J＝12.8Hz,1H),8.03(d,J＝12.8Hz,1H),7.92(d,J＝7.6Hz,1H),7.79(s,1H),7.46-7.42(m,2H),7.27-7.25(m,2H),7.21-7.19(m,2H),4.04(t,J＝8.8Hz,2H),3.16(t,J＝8.8Hz,2H),1.59(s,9H)。MS-ESI计算值[M+H]+390,实测值390。
第五步
参照实施例8第三步,得到化合物9-6(680mg)。1H NMR(400MHz,CDCl3)δ7.83-7.80(m,3H),7.70-7.65(m,3H),7.43(d,J＝8.0Hz,1H),6.50(br.s,1H),5.28(br.s,2H),4.05(t,J＝8.8Hz,2H),3.17(t,J＝8.8Hz,2H),2.89-2.85(m,1H),2.23(s,3H),1.59(s,9H),0.88-0.83(m,2H),0.62-0.60(m,2H)。
第六步
化合物9-6(680mg,1.36mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(1.55g,13.6mmol)和二氯甲烷(2mL),反应液室温下搅拌12小时。加入2N碳酸氢钠溶液调节pH 7～8,用二氯甲烷(50mL x 2)萃取,合并有机相,用饱和食盐水(100mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品用制备高效液相色谱法分离纯化得到10(420mg)。1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.83(d,J＝8.0Hz,1H),7.68-7.66(m,3H),7.45(d,J＝8.0Hz,1H),6.64(d,J＝8.4Hz,1H),6.37(br.s,1H),5.73(br.s,2H),4.14(br.s,1H),3.69(t,J＝8.8Hz,2H),3.13(t,J＝8.8Hz,2H),2.90-2.87(m,1H),2.25(s,3H),0.89-0.84(m,2H),0.63-0.59(m,2H)。MS-ESI计算值[M+H]+402,实测值402。
实施例10
Figure PCTCN2017104247-appb-000031
化合物9(70.0mg,0.174mmol)溶于四氢呋喃(5mL)中,加入二异丙基乙胺(24.8mg,0.191mmol)和2,2,2-三氟乙基三氟甲烷磺酸酯(44.5mg,0.191mmol),反应于70℃下搅拌12小时。加入水(15mL),乙酸乙酯(10mL x 2)萃取,合并有机相,用饱和食盐水(15mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经薄层层析法(20:1二氯甲烷/甲烷,Rf＝0.39)和制备高效液相色谱法分离纯化得到实施例10(10.0mg)。1H NMR(400MHz,Methonal-d4)δ7.91(d,J＝8.0Hz,1H),7.88(s,1H),7.82(s,1H),7.65(d,J＝8.0Hz,1H),7.60(s,1H),7.54(d,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),3.94(q,J＝9.6Hz,2H),3.73(t,J＝8.8Hz,2H),3.17(t,J＝8.8Hz,2H),2.85-2.84(m,1H),2.22(s,3H),0.81-0.79(m,2H),0.65-0.62(m,2H)。MS-ESI计算值[M+H]+484,实测值484。
实施例11
Figure PCTCN2017104247-appb-000032
Figure PCTCN2017104247-appb-000033
化合物9(60.0mg,0.149mmol)溶于甲醇(2mL)中,加入37％甲醛水溶液(60.6mg,0.747mmol)和乙酸(44.8mg,0.747mmol),室温搅拌10分钟,再加入氰基硼氢化钠(28.2mg,0.448mmol),反应液在室温搅拌50分钟。加入水(10mL),乙酸乙酯(20mL x 2)萃取,合并有机相,用饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经制备高效液相色谱法分离纯化得到11(43.0mg)。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.83(d,J＝8.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.68(s,1H),7.63(s,1H),7.45(d,J＝8.0Hz,1H),6.46(d,J＝8.4Hz,1H),6.33(br.s,1H),5.71(br.s,2H),3.52(t,J＝8.4Hz,2H),3.06(t,J＝8.4Hz,2H),2.91-2.87(m,4H),2.25(s,3H),0.88-0.85(m,2H),0.63-0.61(m,2H)。MS-ESI计算值[M+H]+416,实测值416。
实施例12
Figure PCTCN2017104247-appb-000034
第一步
化合物12-1(1.00g,6.21mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入钠氢(60％,745mg,18.6mmol),混合物在0℃搅拌20分钟,再加入碘甲烷(6.17g,43.5mmol),反应液缓慢升至室温继续搅拌40分钟。向反应液中加入饱和氯化铵溶液(50mL),用乙酸乙酯萃取(50mL x 2),合并有机相,用饱和食盐水洗涤(150mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到12-2(1.20g)。1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.81(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.22(d,J＝2.8Hz,1H),6.53(d,J＝2.8Hz,1H),3.96(s,3H),3.86(s,3H)。多一个H
第二步
参照实施例8第一步,得到化合物12-3(400mg)。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.66-7.61(m,3H),6.53(d,J＝2.8Hz,1H),4.79(s,2H),3.88(s,3H)。
第三步
参照实施例8第二步,得到化合物12-4(420mg)。MS-ESI计算值[M+H]+302,实测值302。
第四步
参照实施例8第三步,得到12(260mg)。1H NMR(400MHz,CDCl3)δ7.94-7.90(m,2H),7.84(d,J＝8.0Hz,1H),7.74-7.72(m,2H),7.72-7.67(m,1H),7.46(d,J＝8.0Hz,1H),7.24(s,1H),6.57-6.56(m,1H),6.37(br.s,1H),5.83(br.s,2H),3.89(s,3H),2.91-2.86(m,1H),2.27(s,3H),0.88–0.85(m,2H),0.64-0.60(m,2H)。MS-ESI计算值[M+H]+414,实测值414。
实施例13
Figure PCTCN2017104247-appb-000035
第一步
参照实施例12第一步,得到化合物13-2(700mg)。1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.95(d,J＝8.8Hz,1H),7.34(d,J＝8.8Hz,1H),7.12(d,J＝3.2Hz,1H),6.60(d,J＝3.2Hz,1H),3.94(s,3H),3.82(s,3H)。
第二步
参照实施例8第一步,得到化合物13-3(320mg)。1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.76(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,1H),7.50(d,J＝3.2Hz,1H),6.64(d,J＝3.2Hz,1H),4.78(s,2H),3.84(s,3H)。
第三步
参照实施例8第二步,得到化合物13-4(410mg)。MS-ESI计算值[M+H]+302,实测值302。
第四步
参照实施例8第三步,得到13(130mg)。1H NMR(400MHz,Methonal-d4)δ8.11(s,1H),7.90-7.85(m,3H),7.67(d,J＝8.0Hz,1H),7.56-7.53(m,2H),7.30(d,J＝2.8Hz,1H),6.62(d,J＝2.8Hz,1H),3.87(s,3H),2.87-2.83(m,1H),2.24(s,3H),0.81–0.79(m,2H),0.65–0.63(m,2H)。MS-ESI计算值[M+H]+414,实测值414。
实施例14
Figure PCTCN2017104247-appb-000036
第一步
化合物14-1(1.00g,5.68mmol)溶于N,N-二甲基甲酰胺(10mL)中,氮气保护下加入1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(4.02g,11.3mmol),反应液升温至80℃搅拌14小时。反应液冷至室温,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯萃取(50mL x 2),合并有机相,依次用水(50mL x 1),饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗品经硅胶柱层析法(2:1石油醚/乙酸乙酯,Rf＝0.55)分离纯化得到14-2(360mg)。1H NMR(400MHz,CDCl3)δ9.67(br.s,1H),8.49(s,1H),8.13(d,J＝8.8Hz,1H),7.43(d,J＝8.8Hz,1H),3.99(s,3H)。MS-ESI计算值[M+H]+195,实测值195。
第二步
参照实施例8第一步,得到化合物14-3(70.0mg)。1H NMR(400MHz,CDCl3)δ9.45(br.s,1H),8.30(s,1H),8.08(d,J＝8.8Hz,1H),7.51(d,J＝8.8Hz,1H),4.15(s,2H)。MS-ESI计算值[M+H]+204,实测值204。
第三步
参照实施例8第二步,得到化合物14-4(100mg)。MS-ESI计算值[M+H]+307,实测值307。
第四步
参照实施例8第三步,得到14(35mg)。1H NMR(400MHz,DMSO-d6)δ12.85(br.s,1H),8.50(d,J＝4.0Hz,1H),8.15(s,1H),7.93-7.92(m,2H),7.87-7.84(m,2H),7.62(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),6.96(s,2H), 2.88-2.85(m,1H),2.15(s,3H),0.71–0.67(m,2H),0.57–0.54(m,2H)。MS-ESI计算值[M+H]+419,实测值419。
实施例15
Figure PCTCN2017104247-appb-000037
第一步
化合物15-1(1.00g,5.68mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入碘(2.88g,11.4mmol)和氢氧化钾(1.59g,28.4mmol),反应液室温搅拌2小时。加入饱和硫代硫酸钠溶液(100mL),用乙酸乙酯萃取(50mL x 2),合并有机相,依次用水(50mL x 2),饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到15-2(1.30g)。MS-ESI计算值[M+H]+303,实测值303。
第二步
化合物15-2(850mg,2.81mmol)溶于无水二氯甲烷(20mL)中,加入化合物C(363mg,4.22mmol)和对甲苯磺酸一水合物(160mg,0.843mmol),室温搅拌12小时。加入饱和碳酸氢钠溶液(20mL),用乙酸乙酯萃取(50mL x 2),合并有机相,依次用水(50mL x 2),饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到15-3(1.10g)。1H NMR(400MHz,CDCl3)δ8.24(s,1H),8.12(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,1H),5.73-5.70(m,1H),4.04-4.01(m,1H),3.97(s,3H),3.77-3.71(m,1H),2.56-2.53(m,1H), 2.16-2.08(m,2H),1.78-1.68(m,3H)。
第三步
化合物15-3(500mg,1.29mmol)溶于N,N-二甲基甲酰胺(5mL)中,氮气保护下加入氰化锌(228mg,1.94mmol)和四(三苯基膦)钯(0)(149mg,0.129mmol),反应液加热至100℃搅拌15小时。反应液冷却至室温,加入水(50mL),用乙酸乙酯萃取(50mL x 2),合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗品经硅胶柱层析法(4:1石油醚/乙酸乙酯,Rf＝0.23)分离纯化得到化合物15-4(260mg)。1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.17(d,J＝8.8Hz,1H),7.78(d,J＝8.8Hz,1H),5.86-5.83(m,1H),3.98(s,3H),3.95-3.93(m,1H),3.80-3.77(m,1H),2.52-2.49(m,1H),2.16-2.12(m,2H),1.78-1.72(m,3H)。
第四步
参照实施例8第一步,得到化合物15-5(110mg)。1H NMR(400MHz,CDCl3)δ8.38(s,1H),8.13(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),5.89-5.86(m,1H),4.21(s,2H),3.95-3.92(m,1H),3.82-3.77(m,1H),2.50-2.48(m,1H),2.18-2.15(m,2H),1.82-1.74(m,3H)。
第五步
参照实施例8第二步,得到化合物15-6(125mg)。MS-ESI计算值[M+H]+398,实测值398。
第六步
参照实施例8第三步,得到化合物15-7(120mg)。MS-ESI计算值[M+H]+510,实测值510。
第七步
化合物15-7(120mg,0.236mmol)溶于盐酸/二氧六环溶液(4M,10mL)中,室温搅拌20小时,加入饱和碳酸氢钠溶液调节pH 7～8,用乙酸乙酯萃取(50mL x 2),合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗品经制备高效液相色谱法分离纯化得到15(8.0mg)。1H NMR(400MHz,Methonal-d4)δ8.30(s,1H),7.99-7.91(m,3H),7.85-7.83(m,2H),7.56(d,J＝8.0Hz,1H),2.87-2.85(m,1H),2.25(s,3H),0.82–0.80(m,2H),0.65–0.63(m,2H)。MS-ESI计算值[M+H]+426,实测值426。
实施例16
Figure PCTCN2017104247-appb-000038
Figure PCTCN2017104247-appb-000039
第一步
化合物16-1(500mg,2.84mmol)溶于二甲亚砜(5mL)中,加入化合物D(611mg,5.68mmol)和碳酸铯(2.78g,8.52mmol),反应液加热至80℃搅拌14小时。反应液冷却到室温,加入水(50mL),用乙酸乙酯萃取(50mL x 2),合并有机相,依次用水(50mL x 2),饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗品经硅胶柱层析法(20:1二氯甲烷/甲醇,Rf＝0.16)分离纯化得到16-2(280mg)。MS-ESI计算值[M+H]+248,实测值248。
第二步
参照实施例8第一步,得到粗品化合物16-3(300mg)。MS-ESI计算值[M+H]+257,实测值257。
第三步
参照实施例8第二步,得到化合物16-4(280mg)。1H NMR(400MHz,CDCl3)δ12.78(d,J＝12.4Hz,1H),8.51-8.50(m,1H),8.15(s,1H),8.09-8.06(m,1H),7.98(d,J＝8.8Hz,1H),7.52-7.49(m,1H),7.48-7.44(m,2H),7.30-7.27(m,1H),7.26-7.22(m,2H),4.52(t,J＝6.8Hz,2H),2.86(t,J＝6.8Hz,2H),2.32(s,6H)。
第四步
参照实施例8第三步,得到16(60.0mg)。1H NMR(400MHz,CDCl3)δ8.29(s,1H),8.16(s,1H),7.93(d,J＝8.8Hz,1H),7.91(s,1H),7.88(d,J＝8.0Hz,1H),7.72(s,1H),7.56(d,J＝8.8Hz,1H),7.47(d,J＝8.0Hz,1H),6.37(br.s,1H),5.83(br.s,2H),4.55(t,J＝6.8Hz,2H),2.91-2.86(m,3H),2.33(s,6H),2.27(s,3H),0.88–0.87(m,2H),0.64–0.61(m,2H)。MS-ESI计算值[M+H]+472,实测值472。
实施例17
Figure PCTCN2017104247-appb-000040
第一步
参照实施例14第一步,得到化合物17-2(290mg)。1H NMR(400MHz,CDCl3)δ8.44(s,1H),8.10(d,J＝8.0Hz,1H),7.33(d,J＝8.0Hz,1H),3.96(s,3H),3.95(s,3H)。
第二步
参照实施例8第一步,得到化合物17-3(260mg)。1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.05(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),4.15(s,2H),3.99(s,3H)。
第三步
参照实施例8第二步,得到化合物17-4(250mg)。MS-ESI计算值[M+H]+321,实测值321。
第四步
参照实施例8第三步,得到17(68.0mg)。1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.95(d,J＝8.4Hz,1H),7.86(s,1H),7.82(d,J＝8.0Hz,1H),7.72(s,1H),7.50(d,J＝8.4Hz,1H),7.47(d,J＝8.0Hz,1H),6.37(br.s,1H),5.85(br.s,2H),3.99(s,3H),2.91-2.88(m,1H),2.27(s,3H),0.90–0.85(m,2H),0.64–0.60(m,2H)。MS-ESI计算值[M+H]+433,实测值433。
实施例18
Figure PCTCN2017104247-appb-000041
Figure PCTCN2017104247-appb-000042
第一步
参照实施例12第一步,得到化合物18-2(2.70g)。1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.08-8.05(m,2H),7.40(d,J＝8.8Hz,1H),4.20(s,3H),3.94(s,3H)。
第二步
参照实施例8第一步,得到粗品化合物18-3(450mg)。MS-ESI计算值[M+H]+200,实测值200。
第三步
参照实施例8第二步,得到化合物18-4(480mg)。1H NMR(400MHz,CDCl3)δ12.82(br.s,1H),8.50(s,1H),8.06(s,1H),7.99(d,J＝8.8Hz,1H),7.98-7.96(m,1H),7.48-7.44(m,3H),7.28-7.27(m,1H),7.24-7.22(m,2H),4.12(s,3H)。
第四步
参照实施例8第三步,得到18(320mg)。1H NMR(400MHz,DMSO-d6)δ8.52(br.s,1H),8.31(s,1H),8.23(s,1H),7.94-7.91(m,2H),7.85-7.82(m,2H),7.77(d,J＝8.8Hz,1H),7.53(d,J＝8.0Hz,1H),6.95(br.s,2H),4.10(s,3H),2.88-2.85(m,1H),2.15(s,3H),0.71-0.68(m,2H),0.58–0.56(m,2H)。MS-ESI计算值[M+H]+415,实测值415。
实施例19&20
Figure PCTCN2017104247-appb-000043
Figure PCTCN2017104247-appb-000044
第一步
将19-1(10.0g,56.7mmol)加入到甲醇(20mL)中,0℃下滴加浓硫酸(98％,5.68g,56.8mmol)。反应液加热至65℃搅拌3小时。反应液减压浓缩得到剩余物(15g),将其中9g溶于醋酸(1000mL),加入10％钯/碳(4.50g),反应液在氢气(4MPa),室温搅拌168小时,过滤反应液,滤液减压浓缩,剩余物用碳酸氢钠水溶液调节pH～8,用二氯甲烷/甲醇(10:1)(200mL)萃取,有机相减压浓缩得到19-2(5.00g)。1H NMR(400MHz,CDCl3)δ7.50(m,1H),3.72(s,3H),2.90-2.85(m,2H),2.84-2.77(m,1H),2.74-2.58(m,2H),2.26-2.16(m,1H),2.00-1.89(m,1H)。
第二步
氮气保护下将19-2(800mg,4.44mmol)溶于N,N二甲基甲酰胺(5mL)中,0℃下加入钠氢(60％,195mg,4.88mmol),反应液在0℃下搅拌应30分钟,然后加入碘代异丙烷(1.13g,6.66mmol),反应液升至25℃搅拌1.5小时,向反应液中加入水(20mL),用二氯甲烷/甲醇(10:1)(20mL x 2)。合并有机相,用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(10:1二氯甲烷/甲醇,Rf＝0.36),分离纯化得到19-3和19-4的混合物(480mg)。1H NMR(400MHz,CDCl3)δ7.45-7.39(m,1H),4.21-4.13(m,1H),3.73(s,3H),2.95-2.81(m,2H),2.79-2.72(m,1H),2.72-2.50(m,2H),2.30-2.17(m,1H),2.00-1.83(m,1H),1.50-1.41(m,6H)。
第三步
参照实施例8第一步,得到19-5和19-6的混合物(230mg)。MS-ESI计算值[M+H]+232,实测值232。
第四步
参照实施例8第二步,得到19-7和19-8的混合物(300mg)。MS-ESI计算值[M+H]+335,实测值335。
第五步
参照实施例8第三步,得到19(20.0mg)。1H NMR(400MHz,Methonal-d4)δ8.87(s,1H),8.09(s,1H),7.91(d,J＝7.6Hz,1H),7.79(s,1H),7.54(d,J＝7.6Hz,1H),4.63-4.57(m,1H),3.63-3.59(m,1H),3.01-2.79(m,5H),2.30-2.27(m,1H),2.17(s,3H),2.03-1.93(m,1H),1.60-1.55(m,6H),0.82-0.79(m,2H),0.78-0.63(m,2H)。MS-ESI计算值[M+H]+447,实测值447。20(30.0mg)。1H NMR(400MHz,CDCl3)δ7.81-7.78(m,2H),7.67(s,1H),7.40-7.36(m,2H),7.06(br.s,1H),5.84(br.s,2H),4.21-4.14(m,1H),3.29-3.26(m,1H),2.84-2.70(m,3H),2.66-2.64(m,2H),2.25-2.18(m,4H),2.03-2.01(m,1H),1.48-1.44(m,6H),0.81-0.78(m,2H),0.60-0.56(m,2H)。MS-ESI计算值[M+H]+447,实测值447。
生物化学检测：
实验例1：体外酶活性评价
本试验目的是检测化合物对P38a/MAPK14的体外抑制活性。本试验采用的酶为人源p38α，标准底物为髓鞘碱性蛋白(MBP)(20μM)和三磷酸腺苷(ATP)(10μM)，通过检测p38α作用下从γ33P标记的ATP转移到MBP上的γ-磷酰基的量来确定底物的活性(反应式如下所示)。从10μM开始3倍稀释，检测化合物10个浓度下IC50值。从20μM开始3倍稀释，检测参照化合物SB202190的10个浓度下IC50值。
反应式：
Figure PCTCN2017104247-appb-000045
测试化合物对p38α抑制活性测试结果如表1所示。
表1：本发明化合物体外酶筛选试验结果
化合物编号 IC50(nM)
实施例1 +
实施例2 +
实施例3 +
实施例4 +
实施例5 +
实施例6 +
实施例7 +
实施例8 ++
实施例9 +
实施例10 ++
实施例11 +
实施例12 +
实施例13 +
实施例14 +
实施例15 +
实施例16 +
实施例17 +
实施例18 +
实施例19 +
实施例20 ++
Losmapimod(GSK) ++
Acumapimod(Novartis) ++
SB202190 ++
分类为：+≤10nM；10nM＜++≤50nM，
结论：本发明化合物对p38α抑制活性明显。
实验例2：体外细胞活性评价
LPS诱导小鼠脾细胞TNFα抑制活性IC50测试。
二氧化碳安乐死小鼠，分离脾脏，将脾脏磨碎后，加入红细胞裂解液孵育10分钟去除红细胞，制成单细胞悬液，细胞计数并调整细胞浓度至5x106/ml。96孔板200ul/孔体系培养，5x105细胞/孔，加入不同浓度的待测化合物和LPS(1ug/mL)共同孵育24小时，离心，收集上层清液，CBA检测TNFα水平，根据溶剂对照组和空白对照组计算抑制率及IC50。活性数据如表2所示：
表2：本发明化合物体外筛选试验结果
化合物编号 IC50
实施例11 1uM
实施例14 15.4nM
实施例17 1uM
Losmapimod(GSK) 90.9nM
Acumapimod(Novartis) 651nM
结论：本发明化合物对p38α抑制活性明显并且优于目前临床化合物Losmapimod和Acumapimod。
实验例3：体内CIA模型评价
将小鼠随机分配到不同的治疗组。第一次免疫当天记为第0天，随后的天数依序标注。DBA/1小鼠经异氟烷麻醉后，在尾部皮下注射50微升的制备好的胶原乳剂。第21天，尾部同法注射相同体积胶原乳剂。正常组的小鼠无需免疫。第28天，当平均临床评分达到1分左右时，30只小鼠按照体重和评分，重新随机分组到3个治疗组，每组10只小鼠。Dexamethasone(***)作为阳性药物0.3mpk剂量组是CIA模型中普遍使用剂量；第三组给予Dexamethasone，剂量为0.3mg/kg；第8组给予实施例14，剂量为30mg/kg。每天给药两次，共持续14天。灌胃给药体积为10ml/kg。
临床观察：从免疫前7天至免疫后第21天，每日观察DBA/1小鼠的基本健康状况及体重变化(一周记录一次)。第22天之后，每日观察小鼠健康状况，发病情况，及体重变化(一周至少记录三次)，直至实验结束。
临床评分：增强免疫后，每天观察小鼠发病情况。当小鼠开始发病之后(出现关节炎的临床症状)，根据病变的不同程度(红肿，关节变形)按照0-4分的标准进行评分，每个肢体的最高评分为4分，每只动物最高评分为16分。评分标准如表2。至少每周评分三次。
实验数据应用平均数±标准误表示(Mean±SEM)，体重用方差分析(Two-way ANOVA)，临床评分和组化评分用秩和检验(Kruskal-Wallis Test)，p<0.05认为有显著性差异。p<0.01表示非常显著差异，p<0.001表示极显著差异。
和正常组比较，各免疫组平均体重在给药后有所下降。实施例14 30mpk(b.i.d)治疗组平均体重在给药后第31天出现缓慢上升直至实验结束，与此同时Vehicle组和Dex 0.3mpk治疗组体重仍在缓慢下降，但两者不存在统计学差异，如图1所示。
第二次免疫后第6天(第一次免疫后第27天)，小鼠开始出现关节炎临床症状。空白对照组的平均临床评分稳步上升并稳定在约8分，标志着CIA模型的成功建立(图2A)。阳性对照Dexamethasone 0.3mpk组显著的抑制了平均临床评分的升高，从第33天开始，该组发病老鼠全部被治愈，并在第31天就与空白对照组出现显著差异并一直持续到试验结束；测试化合物(实施例14)组也抑制临床评分的升高，其临床评分从第33天起就稳定在0.6左右，并从第31天开始和Vehicle组出现显著性差异直至实验结束，显示出对疾病的良好的恢复效果，如图2A所示。
空白对照组在免疫后第31天发病率达到并维持在100％。所有治疗组均降低了小鼠关节炎的发病时间及发病率。阳性对照Dexamethasone 0.3mpk组的发病率从给药后就开始降低并于第33天降低至0％；测试化合物(实施例14)的发病率在第33天达到降低至30％并在这个范围内波动至实验结束，显示出对疾病良好的治愈效果，如图2B所示。通过分析每组每只动物的临床评分曲线，计算曲线下面积AUC，通过组间AUC平均值，计算各给药组相对于溶剂对照组的抑制率，结果如图2C，Dexamethason抑制率为97.1％，呈现极显著性差异(p<0.001)，实施例14给药组抑制率为87.7％，也具有极显著性差异。
结论：化合物实施例14治疗组对动物因发病造成的体重下降趋势有一定的缓解作用，但未见显著性差异。化合物实施例14治疗组小鼠发病时间有一定程度推迟，且也降低了小鼠的发病率。化合物实施例14治疗组显示出对该疾病模型的良好的治疗作用，且在31天之后的临床评分和Vehicle组相比均有统计学差异，其整体抑制率也与Vehicle组相比存在显著性差异。
实验例4：体内慢性哮喘模型评价
评估待测化合物在OVA(卵清蛋白)诱导的雌性C57BL/6小鼠慢性哮喘模型中的治疗作用。
造模方法：第1到15天免疫刺激，用OVA(卵清蛋白)和Al(OH)3的混合物高诱发C57BL/6小鼠IgE(免疫球蛋白)响应，然后继续接受低粒子质量浓度的卵清蛋白雾化刺激。
测试分组：组1(正常小鼠)，组2(模型-溶媒，口服)，组3(***-3mg/kg)，组4(模型-溶媒，雾化)，组5(Acumapimod-30mg/kg)，组6(实施例14-10mg/kg)，组7(实施例14-30mg/kg)
结果检测：体重，气道反应性，血清IgE水平，BALF细胞计数，肺组织病理研究：HE染色
实验设计：
Figure PCTCN2017104247-appb-000046
组别 老鼠个数 是否模型组 测试化合物 给药信息
组1 6 否 无 无
组2 6 是 溶媒口服 口服，1天1次
组3 6 是 *** 3mg/kg，口服，2天1次
组4 6 是 溶媒雾化 雾化，1天1次
组5 6 是 Acumapimod 30mg/kg，口服，1天2次
组6 6 是 实施例14 10mg/kg，口服，1天2次
组7 6 是 实施例14 30mg/kg，口服，1天2次
试验结果：
1.体重变化：组3***组体重轻微降低，其他组别体重未见明显降低。
2.气道反应性--潮气量：
潮气量:指静息呼吸时，每次呼出的气量。通气功能障碍时常出现浅而略快的呼吸，潮气容积减小(潮气量减少)。
模型组动物潮气量与对正常照动物相比较潮气量略微下降。
3.气道反应性—最大通气量：
最大通气量:指静息呼吸时，平均每秒钟的最大吸气和呼气量。通气功能障碍时常出现浅而略快的呼吸，最大通气量减小。
模型组动物最大通气量与对正常照动物相比较显著下降。
4.气道反应性—每分钟通气量：
每分钟通气量:指静息呼吸时，平均每分钟的通气量通气功能障碍时常出现浅而略快的呼吸，单位时间的通气量减小
模型组动物每分钟通气量与对正常照动物相比较显著下降。
5.气道反应性—呼吸频率
呼吸频率:指静息呼吸时，平均每分钟的呼吸次数。通气功能障碍时常出现浅而略快的呼吸，呼吸频率会有所改变。
本组实验动物的呼吸频率无显著性改变。
6.气道反应性—气道狭窄指数测定
气道狭窄指数:不同剂量氯化乙酰甲胆碱刺激测定气道狭窄指数。模型对照组与健康对照比较气道狭窄指数显著升高(p<0.001)。DEX治疗组与模型对照口服组相比显著性下降(p<0.001)；两种受试化合物组与模型口服对照组相比显著降低。
病理分析结果
1.支气管和小动脉炎症评分：
与模型组相比，DEX组和实施例14-10mpk组炎症评分有显著改善，两组药效相当且都优于Acumapimod组。
2.支气管炎症评分：
与模型组相比，DEX组和实施例14-10mpk组炎症评分有显著改善，两组药效相当且都优于Acumapimod组。
3.小动脉炎症评分:
与模型组相比，DEX组和实施例14-10mpk组炎症评分有显著改善，两组药效相当且都优于Acumapimod组。
结论：本发明化合物在本模型中药效明显与DEX药效相当并优于Acumapimod。

Claims (14)

  1. 式(Ⅰ)所示化合物及其药学上可接受的盐，
    Figure PCTCN2017104247-appb-100001
    其中，
    R1、R2分别独立地选自：H、卤素、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的C1-6烷基；
    环B选自：5～6元杂环烷基、5～6元杂芳基；
    R选自：卤素、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基、N,N’-(C1-3烷基)氨基；
    所述5～6元杂芳基、5～6元杂环烷基之“杂”选自：-NH-、N、-O-、-S-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合或其药学上可接受的盐，其中，R选自F、Cl、Br、I、OH、NH2、
    Figure PCTCN2017104247-appb-100002
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R1、R2分别独立地选自H、F、Cl、Br、I、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的C1-3烷基。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R1、R2分别独立地选自H、F、Cl、Br、I、OH、NH2、CN，或分别独立地选自任选被1、2或3个R取代的：Me、Et、
    Figure PCTCN2017104247-appb-100003
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R1、R2分别独立地选自：H、F、Cl、Br、I、OH、NH2、CN、Me、CF3、Et、
    Figure PCTCN2017104247-appb-100004
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R1选自：H、F、Cl、Br、I、Me、CN、CF3。
  7. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R2选自：H、OH、NH2、CN、Me、Et、
    Figure PCTCN2017104247-appb-100005
    Figure PCTCN2017104247-appb-100006
  8. 根据权利要1或2所述化合物或其药学上可接受的盐，其中，环B选自：吡咯烷基、哌啶基、吡咯基、2-吡咯啉基、2-吡唑啉基、吡唑基、咪唑基、噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2017104247-appb-100007
    选自：
    Figure PCTCN2017104247-appb-100008
    Figure PCTCN2017104247-appb-100009
  10. 根据权利要求1或2所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017104247-appb-100010
    Figure PCTCN2017104247-appb-100011
  11. 一种药物组合物，其含有治疗有效量的根据权利要求1～10任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  12. 根据权利要求1～10任意一项所述化合物或其药学上可接受的盐或根据权利要求11所述组合物在制备治 疗p38激酶抑制剂相关药物中的应用。
  13. 根据权利要求1～10任意一所述化合物或其药学上可接受的盐或根据权利要11所述组合物作为P38激酶抑制剂的应用。
  14. 一种治疗与p38激酶相关疾病的方法，包括给予治疗对象有效量的权利要求1～10任意一项所述化合物或其药学上可接受的盐或根据权利要求11所述组合物。
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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
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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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