Dihydrobenzofuran derivative, and preparation method therefor and use thereof

Abstract

Provided in the present invention are a dihydrobenzofuran derivative, and a preparation method therefor and the use thereof. Specifically, provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopically substituted compound thereof. The compound of formula (I) of the present invention has an excellent inhibitory activity on a p38a / MK2 complex. Therefore, also provided in the present invention is the use of the compound of formula (I) in the preparation of a drug for preventing or treating p38a / MK2-related diseases.

Description

Dihydrobenzofuran derivatives, preparation methods and uses thereof Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a dihydrobenzofuran derivative, a preparation method and use thereof. Background Art

[0002] The p38α-MK2 pathway, a classic inflammatory signaling pathway, is implicated in various chronic inflammatory conditions, including rheumatoid arthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, and lupus erythematosus. p38α inhibitors are commonly associated with numerous toxic side effects in clinical practice, and no drugs are currently available. Inhibition of p38α kinase inhibits the feedback control loop it participates in, leading to overactivation of upstream kinases such as TAK1 and MLK2&3, and ultimately, JNK overactivation, potentially contributing to the toxicity observed in clinical practice. Under normal conditions, TTP continuously degrades the mRNAs of proinflammatory cytokines such as TNFα, IL-6, and IL-1β, suppressing their expression. MK2, a major downstream protein substrate of p38α, is activated by phosphorylation. Activated MK2 phosphorylates the AU-rich element-binding protein TTP, reducing its stability. This ultimately leads to increased mRNA and protein expression of these proinflammatory cytokines, promoting inflammation.

[0003] MK2 is activated in both mouse arthritis models and chondrocytes from patients with osteoarthritis. Inhibiting the p38-MK2 pathway through genetic or pharmacological approaches can suppress the expression of inflammatory factors, indicating that MK2 is involved in mediating inflammatory regulation in arthritis. p38-MK2 inhibitors have the potential to treat patients with relapsed, refractory, or poorly responsive rheumatoid arthritis (RA). Aclaris Therapeutics' p38-MK2 inhibitor ATI-450 is currently in Phase IIb clinical trials for rheumatoid arthritis, but 33.3% of healthy subjects in its Phase I clinical trial experienced adverse events such as headache and dizziness, suggesting a potential risk of brain damage and side effects. Furthermore, RA is primarily prevalent in middle-aged and elderly individuals, and these adverse events may pose additional risks. Therefore, the development of novel p38-MK2 pathway inhibitors has a broader clinical need.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a p38-MK2 inhibitor compound with a novel structure, a preparation method and use thereof.

[0006] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof,

[0007] in,

[0008] Each R 1 , each R 2 , each R 3 and each R 4 Independently selected from H, halogen, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group having 1 or 2 heteroatoms selected from O, N and S, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R a replace;

[0009] R 5 、R 6 Each independently selected from H, deuterium, halogen, OH, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl and -OC 1-3 alkyl halide;

[0010] R 7 、R 8 are each independently selected from H, halogen, OH, -NR 9 R 10 、-NHCO C 1-3 Alkyl, CN, C 1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, wherein said C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R b replace;

[0011] Or, R 7 With R 8 Together they form =O, or R 7 With R 8 Together with the C atoms it is connected to, it forms C 3-6 Cycloalkyl or 4-6 membered heterocyclic group having 1 or 2 heteroatoms selected from O, N and S, wherein the C3-6 Cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R c replace;

[0012] R 9 and R 10 Independently selected from H and -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R d replace;

[0013] Or, R 9 and R 10 Together with the nitrogen atom to which they are commonly attached, they form a 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N; or a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N, wherein the 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S or the 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R e replace;

[0014] X is selected from O, S, Se and NR 11 ;

[0015] R 11 Selected from H, C 1-3 Alkyl-C(O)- and C 1-3 alkyl;

[0016] z is selected from 1, 2, 3 and 4;

[0017] m, n, p and q are independently selected from 0, 1, 2 and 3;

[0018] Each R a , each R b , each R c , each R d and each R e Independently selected from halogen, OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, and -OC 1-3 alkyl.

[0019] In some embodiments, the compound has the structure of formula (I-1):

[0020] Among them, each m, n, p, q, X, R 1 、R2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined above.

[0021] In some embodiments, each R 1 、R 2 、R 3 and R 4 independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein said CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally replaced by 1, 2 or 3 R a Replacement, R a As defined in claim 1.

[0022] In some embodiments, each R 1 independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally replaced by 1, 2 or 3 R a Replacement, R a As defined above.

[0023] In some embodiments, each R 2 independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally replaced by 1, 2 or 3 R a Replacement, R a As defined above.

[0024] In some embodiments, each R 3independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally replaced by 1, 2 or 3 R a Replacement, R a As defined above.

[0025] In some embodiments, each R 4 independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally replaced by 1, 2 or 3 R a Replacement, R a As defined above.

[0026] In some embodiments, each R 1 Independently selected from H and F.

[0027] In some embodiments, each R 2 Independently selected from H, F, Cl, Br, CH3 and cyclopropyl.

[0028] In some embodiments, each R 3 Independently selected from H, F, Cl, CH3 and cyclopropyl.

[0029] In some embodiments, each R 4 Independently selected from H, F, Cl, CN, OH, CH3 and cyclopropyl.

[0030] In some embodiments, the compound of formula (I) is a compound having formula (Ia), (Ib), or (Ic):

[0031] Among them, m, n, p, q, z, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined above.

[0032] In some embodiments, the compound of formula (I) is a compound having formula (IIa), (IIb), or (IIc):

[0033] Among them, m, n, p and q, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 As defined above.

[0034] In some embodiments, R in the compound represented by Formula I or Formula Ia or Ib or Ic or Formula II or Formula IIa or IIb or IIc is 5 and R 6 Selected from H and deuterium.

[0035] In some embodiments, in the compound represented by Formula I or Formula Ia or Ib or Ic or Formula II or Formula IIa or IIb or IIc, R 7 and R 8 independently selected from H, OH, NH2, -NHCH3, -N(CH3)2, -NHCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridine wherein -NHCH3, -N(CH3)2, -NHCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridyl are optionally substituted by 1, 2 or 3 R c replace.

[0036] In some embodiments, in the compound represented by Formula I or Formula Ia or Ib or Ic or Formula II or Formula IIa or IIb or IIc, R 7 Selected from H, C 1-3 Alkyl, R 8 is selected from OH, NH2, -NHCH3, -N(CH3)2, -NHCOCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and pyrazolyl, wherein the -NHCH3, -N(CH3)2, -NHCOCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and pyrazolyl are optionally replaced by 1, 2 or 3 R creplace.

[0037] In some embodiments, in the compound represented by Formula I or Formula Ia or Ib or Ic or Formula II or Formula IIa or IIb or IIc, R 7 Selected from H, C 1-3 alkyl, R 8 Selected from OH, NH2,

[0038] In some embodiments, the compound of Formula I is selected from the group consisting of:

[0039] In some embodiments, m, n, p, q, z, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Optionally, independently, are the corresponding groups in compounds E001-E060.

[0040] In some embodiments, m, n, p, q, z, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Optionally, independently, they are the corresponding groups in the following specific compounds.

[0041] In some embodiments, the compound is a compound with RT=3.799±0.1 in HPLC chiral resolution of E001 compound.

[0042] In some embodiments, the compound is selected from the group consisting of:

[0043] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, a stereoisomer, or an isotope thereof, and a pharmaceutically acceptable carrier.

[0044] In the third aspect of the present invention, there is provided use of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopic substitute thereof, or the pharmaceutical composition according to the second aspect of the present invention in the preparation of a medicament for preventing or treating (p38 / MK2-related) diseases. Preferably, the disease is selected from autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer (such as lymphoma) and neoplasia, preferably chronic inflammatory disorders and acute inflammatory disorders; preferably, rheumatoid arthritis, osteoarthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, and lupus erythema.

[0045] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0046] After extensive and in-depth research, numerous screenings and tests, the present inventors have provided a class of p38-MK2 inhibitor compounds with novel structures and excellent activity, on the basis of which the present invention was completed.

[0047] the term

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0049] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0050] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- includes -OCH2-.

[0051] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. "Cu-v" includes all positive integers of C atoms between u and v, such as 1, 2, 3, 4, 5, 6, 7, 8, and 9 carbon atoms.

[0052] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, an alkyl group or a portion thereof as part of another group has 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by chemical name or identified by molecular formula, all isomers having that number of carbon atoms are included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0053] "Alkoxy" refers to the group "alkyl-O-," where alkyl is as defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0054] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0055] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl having a monocycle or polycycle (including fused, bridged, and spirocyclic ring systems). The term "cycloalkyl" includes cycloalkenyl (i.e., the cyclic group has at least one double bond). Cycloalkyl used herein has 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] "Heterocyclic radical" refers to a saturated or partially unsaturated heterocyclic radical having one or more (such as 1, 2, 3 or 4) ring heteroatoms independently selected from nitrogen, oxygen and sulphur. The term "heterocyclic radical" includes heterocycloalkenyl (i.e., a heterocyclic radical having at least one double bond), bridged heterocyclic radical, fused heterocyclic radical and spiral-heterocyclic radical. The heterocyclic radical can be a monocyclic or polycyclic ring, wherein the polycyclic ring can be fused, bridged or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclic radical, regardless of connection (i.e., it can be connected to the rest of the molecule via carbon atoms or heteroatoms (such as N atoms)). As used herein, the heterocyclic radical has 5 to 10 ring atoms (i.e., 5-10 membered heterocyclic radical), 6 to 7 ring atoms (i.e., 6-8 membered heterocyclic radical), or 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic radical); wherein, there may be 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur or oxygen. The heterocyclic radical may include one or more oxo and / or thio groups. Examples of heterocyclic radicals include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolane, azetidinyl, and morpholinyl.

[0057] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) (including fused systems). As used herein, an aryl group has 6 to 10 ring carbon atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, an aryl group does not include a heteroaryl group defined below or overlaps with a heteroaryl group defined below in any way. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is a heterocyclic group.

[0058] "Heteroaryl" refers to an aromatic group having a monocyclic ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As described herein, heteroaryl includes 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), or 5 to 6 ring atoms (i.e., 5-6 heteroaryl); wherein, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, wherein the ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be attached through any ring of the fused system. Any aromatic ring with single or multiple fused rings containing at least one heteroatom is considered a heteroaryl group, regardless of attachment to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl groups do not include or overlap with aryl groups as defined above.

[0059] "Oxo" refers to the group (=O) or (O).

[0060] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0061] The term "one or more" may refer to one or more, 1, 2, 3, 4, 5 or 6.

[0062] “Hydroxy” refers to an -OH group. “Amino” refers to -NH2. “Cyano” refers to -CN. “Boc2O” refers to di-tert-butyl dicarbonate. “DCE” refers to 1,2-dichloroethane. “DCM” refers to dichloromethane. “DMA” refers to N,N-dimethylacetamide. “DMF” refers to N,N-dimethylformamide. “dppf” refers to 1,1′-bis(diphenylphosphinoferrocene). “EA” refers to ethyl acetate. “Et3N” refers to triethylamine. “EtOH” refers to ethanol. “FA” refers to formic acid. “MeCN” refers to acetonitrile. “MeLi” refers to methyllithium. “MeOH” refers to methanol. “NaBH(OAc)3” refers to sodium triacetoxyborohydride. “NCS” refers to N-chlorosuccinimide. “LiHMDS” refers to lithium bis(trimethylsilylamide). “PE” refers to petroleum ether. “TFA” refers to trifluoroacetic acid. “THF” refers to tetrahydrofuran.

[0063] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur. Additionally, the term "optionally substituted" means that any one or more hydrogen atoms on a designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0064] Indicates a connection key.

[0065] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced by a moiety other than hydrogen, provided that the normal valence of the designated atom is not exceeded. Unless otherwise specified, "substituted" may refer to the replacement of one or more hydrogen atoms on the group by a group selected from the group consisting of halogen, OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, and -OC 1-3 alkyl.

[0066] Active ingredient

[0067] The present invention provides a compound of formula I:

[0068] Among them, m, n, p, q, z, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined herein.

[0069] Also provided are pharmaceutically acceptable salts of the compounds described herein, stereoisomers thereof, or isotopic substitutes thereof.

[0070] In many cases, the compounds of the present invention are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or similar groups. "Pharmaceutically acceptable salts" include, for example, salts formed with inorganic acids or with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, specifically a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will be aware of various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trialnylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted

[0014] The present invention also provides a substituted alkenyl)amine (i.e., HN(substituted alkenyl)2), a tri(substituted alkenyl)amine (i.e., N(substituted alkenyl)3), a mono-, di- or tri-cycloalkylamine (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), a mono-, di- or tri-arylamine (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or a mixed amine, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0071] Some compounds exist in tautomer forms. Tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and no matter how the nature of the equilibrium between the tautomers is, those of ordinary skill in the art will understand that the compound comprises amides and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Similarly, compounds containing imidic acid are understood to include their amide tautomers.

[0072] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) are intended to be encompassed within the scope of the present invention. When compounds provided herein have defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), those skilled in the art will understand that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of other isomers).

[0073] Any general formula or structure provided in the application are also intended to be represented as the non-labeled form of compound and the isotope-labeled form. Isotope-labeled compound has the structure described by the general formula provided in the application, except that one or more atoms are replaced by the atom with the atomic mass or mass number of selection. The example of the isotope that can be incorporated into the compounds of this invention includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. The present invention includes multiple isotope-labeled compounds of this invention, such as those radioactive isotopes such as 3H, 13C and 14C are incorporated into compounds therein. Such isotopically labeled compounds are useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as nuclear magnetic resonance imaging (NMR), positron emission tomography (PET), or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0074] The present disclosure also includes "deuterated compounds" of Formula I in which 1 to n (where n is the number of hydrogens in the molecule) hydrogens attached to carbon atoms are replaced by deuterium. Such compounds exhibit enhanced resistance to metabolism and are therefore useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. Such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0075] Deuterium-labeled or substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution using heavier isotopes (e.g., deuterium) can provide some therapeutic advantages based on greater metabolic stability, such as increased half-life in vivo, reduced dosage requirements and / or improved therapeutic index. 18F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds of the present invention and prodrugs thereof are typically prepared by utilizing the synthetic routes described below or the steps described in the examples and preparations, wherein non-isotope-labeled reagents are replaced with readily available isotope-labeled reagents. It is understood that deuterium in this application can be considered as a substituent of a compound of formula I.

[0076] The concentration of such heavier isotopes (specifically deuterium) can be defined by an isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position is a hydrogen with its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0077] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0078] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0079] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water, such as a monohydrate.

[0080] In certain embodiments, prodrugs of the compounds described herein are provided. "Prodrug" refers to any compound that, when administered to a biological system, produces a drug substance or active ingredient due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or metabolic chemical reaction. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, ethylene glycol moieties, and the like.

[0081] Also provided herein are in vivo metabolic products of the compounds described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes.

[0082] Pharmaceutical compositions and uses

[0083] The present invention provides a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt, a stereoisomer, or an isotope thereof; and a pharmaceutically acceptable carrier.

[0084] The compounds of the present invention are capable of selectively binding to and inhibiting the p38α-MK2 complex, thereby inhibiting diseases associated with or mediated by the p38-MK2 pathway, particularly autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer, and neoplasia. Preferably, the diseases are rheumatoid arthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, lupus erythematosus, and more preferably, rheumatoid arthritis that is relapsing, refractory, or poorly responsive to existing therapies.

[0085] The compound of formula (I) can be used in combination with other drugs known to treat or improve similar conditions. Such other drugs may include one or more anti-inflammatory drugs, anti-atherosclerotic drugs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules.

[0086] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation and / or administration and / or absorption of an active agent by an individual and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the individual. Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments. Such preparations can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances that do not react harmfully with the compounds provided herein or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical carriers and excipients are suitable for use with the disclosed compounds.

[0087] In certain embodiments, the pharmaceutical compositions of the present invention may be in solid or liquid form.

[0088] Medicaments containing the active ingredients of the present invention may be in suitable oral dosage forms, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersed latex powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Medicaments for oral administration can be prepared according to known processes employed by pharmaceutical manufacturers. These compositions may include one or more agents, such as sweeteners, flavorings, colorants, and preservatives, to provide an elegant and palatable pharmaceutical formulation. Tablets contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for tablet production. Examples of such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrant agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated to delay degradation and absorption in the gastrointestinal tract, thereby maintaining activity over a longer period.

[0089] The active compound can be administered to the subject by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via an implantable cartridge. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraarticularly or intravenously.

[0090] Pharmaceutical compositions of the invention suitable for administration will typically be discrete units in solid form, such as tablets, capsules, powders, granules, patches, suppositories, pills, ointments, or in liquid form, such as liquids, injectable or infusible solutions or suspensions.

[0091] The precise amount of the compound providing a therapeutically effective amount to an individual will depend on the mode of administration, the type and severity of the disease and / or condition, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to the drug. One of ordinary skill in the art will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, the "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art based on the individual's condition, the type of condition being treated, and the amount of the compound of the invention used below, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th Edition, 2003). Preferably, the composition should be formulated so that an inhibitor dose of 0.01-100 mg / kg body weight / day can be administered to patients receiving these compositions. In certain embodiments, the compositions of the present invention provide a dosage of 0.01 mg to 50 mg. In other embodiments, a dosage of 0.1 mg to 25 mg or 5 mg to 40 mg is provided.

[0092] Examples of subjects to whom the pharmaceutical composition or therapeutic agent of the present invention can be administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0093] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, to form a pharmaceutical composition.

[0094] The present invention also provides a treatment method, which comprises the steps of administering to a subject in need of treatment the compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, or administering the pharmaceutical composition of the present invention, for selectively inhibiting the p38-MK2 pathway, or treating a disease associated with the p38-MK2 pathway (such as inflammation).

[0095] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0096] The main advantages of the present invention include:

[0097] 1. The present invention provides a class of p38-MK2 inhibitors with novel structures.

[0098] 2. The compounds of the present invention have excellent p38-MK2 inhibitory activity and can specifically inhibit the p38-MK2 pathway, thereby preventing or / treating related diseases.

[0099] 3. Compared with existing compounds, the compounds of the present invention have lower adverse reactions (such as headache and dizziness) and are more suitable for oral administration.

[0100] 4. The compounds of the present invention have good pharmacokinetic (such as longer half-life and higher bioavailability) and pharmacodynamic properties, as well as excellent drugability, and are very suitable for the preparation of drugs for preventing and / or treating p38-MK2-mediated diseases or conditions.

[0101] The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0102] Intermediate 1

[0103] Preparation of 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one (I001)

[0104] Step 1:

[0105] 2,2-Dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (I001b)

[0106] Compound I001a (30 g, 211.05 mmol) was added to a reaction flask, and THF (300 mL) was added and stirred to dissolve. The temperature was then lowered to -70°C, and LiHMDS (253 mL, 253.25 mmol, 1 M) was added dropwise. After stirring at -70°C for 1 hour, acetyl chloride (16 mL, 232.15 mmol) was added dropwise to the reaction solution. After stirring at -70°C for 0.5 hour, the reaction was completed. The reaction solution was poured into hydrochloric acid solution (20 mL, 1 M) for quenching, and extracted with EA (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound I001b (9.2 g, yield 23.67%).

[0107] MS m / z(ESI):185[M+H] + .

[0108] Step 2:

[0109] 2'-Bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (I001c)

[0110] To compound I001b (2 g, 10.86 mmol) was added 1,4-dioxane (20 mL), which was dissolved and then added 2-bromo-4-amino-5-methylpyrimidine (1.02 g, 5.43 mmol). The reaction mixture was heated to 90°C for 3 hours. 10N aqueous sulfuric acid was then added dropwise. The reaction continued for 0.5 hours until complete. The solvent was removed by concentration under reduced pressure. Water was added to precipitate a pale yellow solid. The mixture was stirred for 0.5 hours and filtered. The filter cake was washed twice with water and the solvent was removed by rotary evaporation to obtain compound I001c (1.5 g, 93.61% yield). MS m / z (ESI): 295 [M+H]. + .

[0111] Step 3:

[0112] 2'-Bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (I001d)

[0113] Compound I001c (1.5 g, 5.08 mmol) was added to DMF (15 mL). After dissolution, I002 (1.25 g, 7.62 mmol), potassium carbonate (3.51 g, 25.41 mmol), and 18-crown-6 (0.13 g, 0.51 mmol) were added. The reaction temperature was raised to 60°C for 2 hours until the reaction was complete. H2O (30 mL) was added to the reaction solution for dilution, followed by extraction with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound I001d (2 g, 93.20% yield). MS m / z (ESI): 422 [M+H] + .

[0114] Step 4:

[0115] 2'-Bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (I001)

[0116] Isopropanol (20 mL) was added to compound I001d (2 g, 4.74 mmol). After dissolution, NCS (634 mg, 4.74 mmol) and dichloroacetic acid (61 mg, 0.47 mmol) were added. The temperature was raised to 60°C for 2 hours until the reaction was complete. H2O (10 mL) was added to the reaction solution for quenching, followed by extraction with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound I001 (1.9 g, yield 87.84%). MS m / z (ESI): 456 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.4Hz,1H),8.52(s,1H),8.13-8.05(m,1H),7.81(s,1H),6.80(s,1H),5.48(d,J=1.6Hz,2H),1.96(d,J=1.2Hz,6H).

[0117] Intermediate 2

[0118] Preparation of 2-(chloromethyl)-3,5-difluoropyridine (I002)

[0119] Step 1:

[0120] Ethyl 3,5-difluoropicolinate (I002b)

[0121] Compound I002a (40 g, 251.57 mmol) was added to a reaction flask, followed by EtOH (160 mL) and stirring. SOCl2 (40 mL) was then slowly added at 0°C. The reaction was heated to 60°C and stirred for 5 hours until complete. The reaction solution was cooled and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound I002b (42 g, yield 98.36%). MS m / z (ESI): 188 [M+H] + .

[0122] Step 2:

[0123] (3,5-Difluoro-2-pyridine)methanol (I002c)

[0124] Compound I002b (40 g, 213.90 mmol) was added to a reaction flask, followed by EtOH (250 mL) and stirring. NaBH4 (19.5 g, 515.46 mmol) was slowly added at 0°C and stirred for 0.5 hours. After stirring at room temperature for 2 hours, the reaction was complete. The reaction solution was then slowly added dropwise to ammonium chloride solution (300 mL) to quench the reaction. Most of the EtOH was concentrated at 40°C, followed by DCM (300 mL) and stirring. The solid was filtered and the organic phase was separated. The mixture was extracted with DCM (300 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate. Filtration and concentration afforded compound I002c (26 g, 83.87% yield). MS m / z (ESI): 146 [M+H] + .

[0125] Step 3:

[0126] 2-(Chloromethyl)-3,5-difluoropyridine (I002)

[0127] Compound I002c (8.5 g, 52.14 mmol) and DMF (50 mg) were added sequentially to a reaction flask. DCM (20 mL) was added with stirring, and thionyl chloride (4.7 mL) was slowly added at 0°C. After warming to room temperature and stirring for 2 hours, the reaction was complete. The reaction solution was directly concentrated to obtain compound I002 (8 g, yield 66.11%). MS m / z (ESI): 164 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.53 (d, J = 2.4Hz, 1H), 8.10-7.98 (m, 1H), 4.84 (d, J = 2.1Hz, 2H).

[0128] Example Preparation

[0129] Example 1

[0130] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E001)

[0131] Step 1:

[0132] 7-Bromo-2,3-dihydrobenzofuran-3-ol (E001b)

[0133] Compound E001a (270 mg, 1.27 mmol) was added to a reaction flask at 0°C, followed by MeOH (5 mL) and NaBH4 (145 mg, 3.81 mmol). The reaction was stirred at 0°C for 0.5 hours. Ammonium chloride solution (2 mL) was added to the reaction solution to quench it. DCM (40 mL) was then added to the reaction solution for dilution. The mixture was washed with sodium chloride solution (40 mL) and extracted with DCM (40 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1) to afford compound E001b (180 mg, 66.17% yield). 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.29(d,J=7.3Hz,1H),6.78(t,J=7.7Hz,1H),5.39( dd,J=6.4,2.3Hz,1H),4.58(dd,J=10.8,6.6Hz,1H),4.48(dd,J=10.8,2.7Hz,1H),1.92(s,1H).

[0134] Step 2:

[0135] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-ol (E001c)

[0136] Compound E001b (180 mg, 0.83 mmol), pinacol diboronate (420 mg, 1.66 mmol), potassium acetate (244 mg, 2.49 mmol), and Pd(dppf)Cl2 (60 mg, 0.08 mmol) were added sequentially to a reaction flask, followed by 1,4-dioxane (8 mL). The reaction was stirred at 100°C for 3 hours. After cooling, the reaction solution was diluted with EA (50 mL), washed with sodium chloride solution (50 mL), and extracted with EA (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and concentrated to yield crude compound E001c.

[0137] Step 3:

[0138] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E001)

[0139] The entire crude product of compound E001c from step 2, compound I001 (150 mg, 0.33 mmol), sodium carbonate (105 mg, 0.99 mmol), and Pd(dppf)Cl2 (30 mg, 0.04 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (8 mL) and H2O (1 mL) were also added. The reaction was stirred at 80°C for 4 hours. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) and reverse preparative method to obtain E001 (30 mg). MS m / z (ESI): 512 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.63(s,1H),8.34(d,J=2.2Hz,1H),8.15(dd,J=21.0,7.7Hz,1H),7.86(d,J=22.6Hz,1H),7.40(d,J=7.3Hz ,1H),7.30-7.21(m,1H),7.02(t,J=7.6Hz,1H),6.31(s,1H),5.34(s,3H),4.56-4.44(m,2H),2.06(s,3H),1.94(d,J=2.4Hz,3H).

[0140] Splitting of Example 1

[0141] (S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-((R)-3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one, (S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-((S)-3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one, ( Preparation of (R)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-((R)-3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-((S)-3-hydroxy-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

[0142] Example E001 (350 mg, 0.684 mmol) was subjected to chiral separation (IB column) to give E001-P1 (92 mg, RT = 3.799), yield: 26.3%; E001-P2 (35 mg, RT = 4.337), yield: 10%; E001-P3 (47 mg, RT = 5.493), yield: 13.4%; E004-P4 (108 mg, RT = 6.993), yield: 30.9%.

[0143] E001-P1:MS m / z(ESI):512[M+H] + .

[0144] 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.33 (d, J = 2.4Hz, 1H), 8.16 (dd, J = 7.9, 1.3 Hz,1H),7.90(s,1H),7.39(dd,J=7.3,0.8Hz,1H),7.26(m,J=9.1,8.0,2.4Hz, 1H),7.01(t,J=7.6Hz,1H),6.31(s,1H),5.32(dd,J=11.9,3.1Hz,3H),4.52(d d,J=10.7,6.1Hz,1H),4.46(dd,J=10.7,2.5Hz,1H),2.05(s,3H),1.93(s,3H).

[0145] E001-P2:MS m / z(ESI):512[M+H] + .

[0146] E001-P3:MS m / z(ESI):512[M+H] + .

[0147] E001-P4:MS m / z(ESI):512[M+H] + .

[0148] HPLC chiral separation conditions:

[0149] HPLC chiral analysis method:

[0150] Example 2

[0151] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-hydroxy-3-methyl-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E002)

[0152] Step 1:

[0153] 7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-ol (E002a)

[0154] Compound E001a (500 mg, 2.35 mmol) was added to a reaction flask at 0°C, followed by ultra-dry THF (8 mL) and the slow dropwise addition of methylmagnesium bromide (3.92 mL, 3 mol / L). The reaction was stirred at room temperature for 2 hours. Ice and ammonium chloride solution (5 mL) were added to the reaction mixture to quench it. EA (50 mL) was then added to the reaction mixture for dilution. The mixture was washed with saturated sodium chloride solution (50 mL) and extracted with EA (40 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1) to afford compound E002a (30 mg, 70% purity). MS m / z (ESI): 212 [M+H] + .

[0155] Step 2:

[0156] 3-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-ol (E002b)

[0157] Compound E002a (30 mg, 70% purity), pinacol diboronate (80 mg, 0.32 mmol), potassium acetate (47 mg, 0.48 mmol), and Pd(dppf)Cl2 (24 mg, 0.032 mmol) were added sequentially to a reaction flask, followed by 1,4-dioxane (3 mL). The reaction was stirred at 95°C for 3 hours. After cooling, the reaction solution was diluted with EA (40 mL), washed with saturated sodium chloride solution (40 mL), and extracted with EA (40 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product of compound E002b, which was used directly in the next step without purification.

[0158] Step 3:

[0159] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-hydroxy-3-methyl-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E002)

[0160] The crude product of E002b, compound I001 (35 mg, 0.08 mmol), Na2CO3 (26 mg, 0.24 mmol), and Pd(dppf)Cl2 (12 mg, 0.016 mmol) were added to the reaction flask in sequence, and 1,4-dioxane (3 mL) and H2O (0.3 mL) were added. The reaction was stirred at 90°C for 3 hours. After cooling, the reaction solution was directly concentrated to obtain a crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 10:1) and preparative HPLC (E-Prep LC 012LH-40, column type: Triart C18, 250*20.0 mm ID, 5 μm, 12 nm; flowability A: 0.1% FA / H2O, flowability B: MeCN; flow rate: 20 mL / min; gradient: 75%-80%; retention time: 15-17 min, total 40 min) to obtain E002 (5.6 mg). MS m / z (ESI): 526 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.63(s,1H),8.33(d,J=2.1Hz,1H),8.12(dd,J=19.0,7.5Hz,1H),7.86(d,J=21.8Hz,1H),7.31(d,J=6.9Hz,1H),7.28-7.23(m,1 H),7.03(t,J=7.6Hz,1H),6.31(s,1H),5.34(s,2H),4.50(d,J=10.1Hz,1H ), 4.30 (d, J = 10.1Hz, 1H), 2.06 (s, 3H), 1.94 (s, 3H), 1.64 (d, J = 7.0Hz, 3H).

[0161] Example 3

[0162] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(3-oxo-2,3-dihydrobenzofuran-7-yl)-2H-[1,4'-bipyridyl]-2-one (E003)

[0163] Step 1:

[0164] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3(2H)-one (E003a)

[0165] Compound E001a (500 mg, 2.34 mmol), pinacol diboronate (888 mg, 3.51 mmol), potassium acetate (688 mg, 7.02 mmol), and Pd(dppf)Cl2 (175 mg, 0.24 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (10 mL) was added and the mixture was stirred at 100°C for 3 hours. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 9:1) to obtain compound E003a (210 mg, yield 34.42%). MS m / z (ESI): 261 [M+H] + .

[0166] Step 2:

[0167] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(3-oxo-2,3-dihydrobenzofuran-7-yl)-2H-[1,4'-bipyridinyl]-2-one (E003)

[0168] Compound E003a (210 mg, 0.80 mmol), I001 (180 mg, 0.40 mmol), sodium carbonate (85 mg, 0.80 mmol), and Pd(dppf)Cl2 (30 mg, 0.04 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (8 mL) and H2O (1 mL) were also added. The reaction was stirred at 80°C for 2 hours. After cooling, the reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) and Pre-TLC to obtain E006 (5 mg, yield 2.47%). MS m / z (ESI): 510 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.69(s,1H),8.52(d,J=7.7Hz,1H),8.34(d,J=2.3Hz,1H),7.89(s,1H),7.68(d,J=7.6Hz,1H),7.29-7 .23(m,1H),7.22(s,0.5H),7.18(s,0.5H),6.33(s,1H),5.34(d,J=1.6Hz,2H),4.71-4.60(m,2H),2.09(s,3H),1.96(s,3H).

[0169] Example 4

[0170] Preparation of 2'-(3-amino-2,3-dihydrobenzofuran-7-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-, 6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E004)

[0171] Step 1:

[0172] 7-Bromobenzofuran-3(2H)-one O-methyloxime (E004a)

[0173] Compound E001a (1.0 g, 4.7 mmol) and NH2OMe (585 mg, 7.04 mmol) were dissolved in MeOH (20 mL). Potassium carbonate (1.94 g, 14.08 mmol) was added, and the atmosphere was purged with nitrogen three times. The mixture was stirred at 70°C overnight. The reaction mixture was poured into water and extracted with EA (30 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (EA / PE = 0-3%) to obtain compound E004a (760 mg, yield 67.2%). MS m / z (ESI): 241 [M+H] + .

[0174] Step 2:

[0175] 7-Bromo-2,3-dihydrobenzofuran-3-amine (E004b)

[0176] Compound E004a (500 mg, 2.07 mmol) was dissolved in tetrahydrofuran (10 mL, 1 N) with borane, replaced with nitrogen three times, and stirred at 70°C overnight. The reaction mixture was poured into water and extracted with EA (30 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound E004b (180 mg, 40.7% yield). MS m / z (ESI): 214 [M+H] + .

[0177] Step 3:

[0178] Tert-butyl (7-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (E004c)

[0179] Compound E004b (210 mg, 0.98 mmol) was dissolved in DCM (5 mL), and Boc2O (321.17 mg, 1.47 mmol) and Et3N (297.81 mg, 2.94 mmol) were added and stirred for 3 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EA (10 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound E004c (300 mg, yield 97.33%). MS m / z (ESI): 314 [M+H] + .

[0180] Step 4:

[0181] Tert-Butyl (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (E004d)

[0182] Compound E004c (50 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL), and diboronic acid pinacol ester (70.9 mg, 0.32 mmol) and Pd(dppf)Cl2 (23.27 mg, 0.03 mmol) were added and stirred for 3 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EA (10 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain crude compound E004d (50 mg, yield 89.6%). MS m / z (ESI): 362 [M+H] + .

[0183] Step 5:

[0184] Tert-butyl (7-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl-2,3-dihydrobenzofuran-3-yl)carbamate (E004e)

[0185] Compound E004d (40 mg, 0.14 mmol) was added with 1,4-dioxane (2 mL) and H₂O (0.4 mL). After dissolution, compound I001 (62.9 mg, 0.14 mmol), sodium carbonate (44.01 mg, 0.42 mmol), and Pd(dppf)Cl₂ (20.25 mg, 0.03 mmol) were added. The mixture was heated to 100°C and stirred for 3 h until the reaction was complete. H₂O (10 mL) was added to dilute the reaction solution, which was then extracted with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford crude compound E004e (30 mg, yield: 35.47%). MS m / z (ESI): 611 [M+H] + .

[0186] Step 6:

[0187] 2'-(3-amino-2,3-dihydrobenzofuran-7-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E004)

[0188] Compound E004e (30 mg, 0.05 mmol) was dissolved in DCM (3 mL) and then TFA (1 mL) was added. After stirring for 3 h, the reaction was complete. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to 8, followed by extraction with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 20:1) and preparative HPLC (E-Prep LC 010LH-40, column type: YMC-Triart C18 250 x 20.0 mm; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN; flow rate: 16 mL / min; gradient: 10%-95%; retention time: 23.0-25.0 min, 40 min total) to afford compound E004 (3.3 mg, yield 4.43%). MS m / z(ESI):511[M+H] + . 1H NMR (400MHz, DMSO) δ8.77(s,1H),8.61(d,J=2.3Hz,1H),8.11(ddd,J=11.3,8.9,1.9Hz,2H),7.93(d,J=2.7Hz,1H),7.51(d, J=7.2Hz,1H),7.19-7.01(m,1H),6.82(s,1H),5.50(s,2H),4.89-4.65(m,2H),4.46-4.27(m,1H),2.04(s,3H),1.97(s,3H).

[0189] Example 5

[0190] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E005)

[0191] Step 1:

[0192] 7-Bromo-2,3-dihydrobenzofuran-3-carboxylic acid methyl ester (E005b)

[0193] Compound E005a (600 mg, 2.34 mmol) was added to a reaction flask, followed by MeOH (20 mL) and magnesium chips (393 mg, 16.38 mmol). After stirring at room temperature for 3 hours, the reaction mixture was diluted with EA (150 mL), washed with saturated sodium chloride solution (100 mL), and extracted with EA (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (PE:EA = 9:1) to afford compound E005b (450 mg, 40% purity). 1 H NMR (400MHz, CDCl3) δ7.27(m,1H),7.26-7.22(m,1H),6.71(t,J=7.7Hz,1H),4.96(dd ,J=9.4,6.8Hz,1H),4.70(t,J=9.6Hz,1H),4.37(dd,J=9.8,6.8Hz,1H),3.72(s,3H).

[0194] Step 2:

[0195] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-carboxylic acid methyl ester (E005c)

[0196] Compound E005b (450 mg, 40% purity), pinacol diboronate (360 mg, 1.42 mmol), potassium acetate (209 mg, 2.13 mmol), and Pd(dppf)Cl2 (81 mg, 0.11 mmol) were added sequentially to a reaction flask, followed by 1,4-dioxane (8 mL). The reaction was stirred at 95°C for 3 hours. After cooling, the reaction solution was diluted with EA (120 mL), washed with saturated sodium chloride solution (100 mL), and extracted with EA (80 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and concentrated to yield crude compound E005c.

[0197] Step 3:

[0198] 7-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-2,3-dihydrobenzofuran-3-carboxylic acid methyl ester (E005d)

[0199] The crude product of E005c, compound I001 (200 mg, 0.44 mmol), sodium carbonate (140 mg, 1.32 mmol), and Pd(dppf)Cl2 (37 mg, 0.05 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (8 mL) and H2O (0.8 mL) were also added. The reaction was stirred at 90°C for 3 hours. After cooling, the reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound E005d (120 mg, 90% purity). MS m / z (ESI): 554 [M+H] + .

[0200] Step 4:

[0201] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-7-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E005)

[0202] Compound E005d (100 mg, 0.18 mmol) was added to a reaction flask at 0°C, followed by the addition of THF (4 mL) and the slow dropwise addition of methylmagnesium bromide (0.2 mL, 3 mol / L). The reaction was stirred at room temperature for 1 hour. Ice and ammonium chloride solution (5 mL) were added to the reaction solution to quench it. DCM (50 mL) was then added to the reaction solution for dilution, followed by washing with saturated sodium chloride solution (50 mL) and extraction with DCM (40 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=10:1) and preparative HPLC (Waters 2767, column: YMC TA C18 250*21.2 mm, 5 μm, mobile phase A: 0.1% FA / H2O; mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 91%-95%; retention time: 18.0-19.5 min, total 30 min) to obtain E005 (6 mg, yield 6.00%). MS m / z (ESI): 554 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.34(d,J=2.3Hz,1H),7.64(s,1H),7.56(d,J =7.9Hz,1H),7.31-7.22(m,1H),7.09(d,J=7.5Hz,1H),6.84(t,J=7.6Hz,1H),6. 37(s,0.9H),6.10(s,0.1H),5.42(s,1H),5.36(d,J=1.5Hz,2H),5.02(s,1H),2. 31(s,0.6H),2.10(s,3H),1.93(s,3H),1.86(s,0.4H),1.43(s,3H),1.38(s,3H).

[0203] Example 6

[0204] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-5'-,6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E006)

[0205] Step 1:

[0206] 1-(7-Bromo-2,3-dihydrobenzofuran-3-yl)azetidin-3-ol (E006a)

[0207] Azetidine-3-ol (200 mg, 2.74 mmol), compound E001a (292 mg, 1.37 mmol), NaBH(OAc)3 (1.74 g, 8.20 mmol), and 5 drops of glacial acetic acid were added to a reaction flask, followed by DCE (10 mL). The mixture was stirred at room temperature for 18 h. After completion of the reaction, ice water (15 mL) was added to quench the reaction mixture, which was then extracted with DCM (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate. Filtration and concentration afforded the crude product, which was purified by pre-TLC (PE:EA = 1:1) to afford compound E006a (40 mg, yield: 10.82%). MS m / z (ESI): 270, 272 [M+H] + .

[0208] Step 2:

[0209] 1-(7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl)azetidin-3-ol (E006b)

[0210] To a reaction flask containing compound E006a (40 mg, 0.15 mmol) and pinacol diboronate (75 mg, 0.30 mmol) was added 1,4-dioxane (2 mL) and stirred to dissolve. Pd(dppf)Cl2 (11 mg, 0.015 mmol) and potassium acetate (43.6 mg, 0.44 mmol) were then added sequentially and stirred at 95°C for 3 hours. After completion of the reaction, ice water (10 mL) was added to quench the reaction mixture, followed by extraction with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration afforded crude E006b, which was used directly in the next step. MS m / z (ESI): 318 [M+H] + .

[0211] Step 3:

[0212] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-5'-,6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E006)

[0213] To a reaction flask containing crude compounds E006b and I001 (68 mg, 0.15 mmol), add 1,4-dioxane / water (5:1, 3 mL) and stir to dissolve. Then, add Pd(dppf)Cl2 (11 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 mmol) sequentially. Stir at 90°C for 2 hours. After completion of the reaction, spin dry the reaction mixture. The crude product was isolated and purified by pre-TLC (DCM:MeOH=20:1) and preparative HPLC (E-Prep LC 012LH-40, column: Triart C18 250*20.0mm ID, 5um, 12nm; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN; flow rate: 20mL / min; gradient: 45%-65%; retention time: 12.5-14.5min, total 25min) to obtain compound E006 (15mg, yield 17.65%). MS m / z (ESI): 567[M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.76(s,1H),8.61(d,J=2.3Hz,1H),8.13-8.07(m,2H),7.89(s,1H),7.40(d,J=7.2Hz,1H),7.05-7.00(m,1H),6.80(s, 1H),5.49(d,J=0.6Hz,2H),5.30(s,1H),4.50-4.39(m,2H),4.17-4.04( m,2H),3.53-3.40(m,2H),2.98-2.83(m,2H),2.03(s,3H),1.97(s,3H). 19 F NMR (376MHz, DMSO-d6) δ-120.17 (d, J = 7.1Hz), -122.38 (d, J = 7.6Hz).

[0214] Example 7

[0215] Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(3-hydroxypyrrolidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-5'-,6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E007)

[0216] Step 1:

[0217] 1-(7-Bromo-2,3-dihydrobenzofuran-3-yl)pyrrolidin-3-ol (E007a)

[0218] Compound E001a (100 mg, 0.47 mmol) and 3-pyrrolidinol (30.71 mg, 0.70 mmol) were dissolved in DCM (5 mL). NaBH(OAc)3 (211.94 mg, 1.41 mmol) was added, and the nitrogen atmosphere was replaced three times. Five drops of acetic acid were then added dropwise, and the mixture was stirred at 50°C overnight. The reaction mixture was poured into water, extracted with EA (30 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (EA / PE = 0-20%, collect all) to obtain compound E007a (40 mg, 30.0% yield). MS m / z (ESI): 284 [M+H] + .

[0219] Step 2:

[0220] 1-(7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl)pyrrolidin-3-ol (E007b)

[0221] Compound E007a (40 mg, 0.14 mmol) was dissolved in 1,4-dioxane (3 mL), and diboronic acid pinacol ester (71.53 mg, 0.28 mmol) and Pd(dppf)Cl2 (23.63 mg, 0.03 mmol) were added and stirred for 3 hours. The reaction mixture was poured into H2O (10 mL), extracted with EA (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain crude compound E007b (40 mg, yield 85.78%). MS m / z (ESI): 331 [M+H] + .

[0222] Step 3:

[0223] 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(3-hydroxypyrrolidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-5'-,6-dimethyl-2H-[1,4'-bipyridinyl]-2-one (E007)

[0224] Compound E007b (40 mg, 0.12 mmol) was added with 1,4-dioxane (2 mL) and H2O (0.4 mL). After dissolution, compound I001 (54.8 mg, 0.12 mmol), sodium carbonate (38.4 mg, 0.36 mmol), and Pd(dppf)Cl2 (17.67 mg, 0.02 mmol) were added. The temperature was raised to 100°C and stirred for 3 h until the reaction was complete. H2O (10 mL) was added to the reaction solution for dilution, followed by extraction with EA (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was then extracted with EA (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=20:1) and preparative HPLC (E-Prep LC 010LH-40, column type: YMC-Triart C18 250*20.0 mm; mobile phase A: 0.1% NH3 / H2O, mobile phase B: CH3CN; flow rate: 20 mL / min; gradient: 65%-80%; retention time: 15.0-17.0 min, 40 min total) to obtain compound E007 (2.4 mg, yield 14.25%). MS m / z (ESI): 581 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.61(d,J=2.3Hz,1H),8.15-7.96(m,2H),7.91(d,J=4.0Hz,1H),7.42(d,J=7.2Hz,1H),7.04(t ,J=7.6Hz,1H),6.81(s,1H),5.49(s,2H),4.66(dt,J=8.4,6.8Hz,2H),4.34(dd,J=9.8,6.5Hz,2H),4.14(s,1H),2.85-2.61(m,2H), 2.44-2.22(m,2H),2.03(s,3H),1.97(s,3H),1.90(dd,J=13.1,7.0Hz,1H),1.56-1.45(m,1H).

[0225] Biological test data

[0226] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on p38α / MK2 enzyme activity

[0227] The compounds were distributed into a 384-well plate using an Echo 650 (LABCYTE). 2.5 μL of pp-p38 (Thermo, PR5049C), 5 μL of MK2 (Thermo, PV3316), and 2.5 μL of ATP were added to each well of the 384-well reaction plate. The reaction was incubated at room temperature for 1 hour, and then 3 volumes of 8 M urea were added to each well to terminate the reaction. The reaction products from each well were then transferred to a 96-well nickel-plated plate (Thermo Scientific, 15142), and the amount of phosphorylated MK2 in each well was determined by ELISA. Fluorescence values ​​were read at 325 nm (Ex) / 420 nm (Em) on an Ensight (Perkin Elmer). The intensity of the fluorescence value is proportional to the amount of phosphorylated MK2.

[0228] Table 1 Test results of the inhibitory effect of the compounds of the present invention on p38α / MK2 enzyme activity

[0229] Conclusion: From the experimental results in Table 1 above, it can be seen that the compounds of the present invention have very excellent inhibitory activity against the p38a / MK2 complex.

[0230] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the expression level of TNFα in human monocytes

[0231] Cryopreserved human monocytes (TPCS) were thawed and diluted to 0.125×10 in RPMI medium containing Glutamax (10 mM HEPES, 1× Pen-Strep, 55 μM β-mercaptoethanol, 1 mM sodium pyruvate) and 10% FBS. 6 cells / mL and recovered at 37°C for 2 hours. The cell suspension was then plated on a black 384-well clear bottom plate (Corning) at a density of 5000 cells / well. The plate was pre-spotted with the test compound and serially diluted in DMSO with a final DMSO concentration of 0.1%. The plated cells were treated with the compound at 37°C for 1 hour. The cells were then stimulated with 50pg / mL of LPS (Sigma), excluding the outer row of the plate for unstimulated cell control wells. The cells were incubated at 37°C for another 4 hours, and then the cells were centrifuged to take 15μL of cell supernatant and analyzed for TNFα content using an ELISA human TNFα detection system (R&D).

[0232] Table 2 Test results of the inhibitory effect of the compounds of the present invention on the expression level of TNFα in human monocytes

[0233] Conclusion: From the experimental results in Table 2 above, it can be seen that the compounds of the present invention have significant inhibitory activity on TNFα production and can regulate inflammatory reactions and other related diseases.

[0234] Test Example 3: Pharmacokinetic Evaluation in Mice

[0235] The in vivo pharmacokinetic properties of the compounds were tested using CD-1 (ICR) mice (male, 6-8 weeks old, weighing 32-42 g, Vital River, Beijing) as follows:

[0236] The pharmacokinetic profiles of the compounds following intravenous and oral administration in rodents were tested using standard protocols. Candidate compounds were formulated as clear solutions and administered to mice as single intravenous (IV) and oral (PO) injections. The vehicle consisted of 5% DMSO + 10% Solutol + 85% ddH2O. Oral administration groups fasted overnight (10-14 hours) prior to dosing. Whole blood samples were collected within 24 hours of dosing (0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours for oral administration; 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours for intravenous administration). Blood samples were collected from the submandibular vein or other appropriate means. Approximately 30 μL of blood was collected per time point, anticoagulated with K2-EDTA, and kept on ice until centrifugation. Blood samples were centrifuged at 4°C at 6800g for 6 minutes to obtain plasma. Plasma was stored at -80°C prior to measuring blood drug concentrations. LC-MS / MS was used to quantitatively analyze the blood drug concentration and calculate the pharmacokinetic parameters, such as peak concentration (C max ), distribution volume (Vd ss ) clearance (CI), half-life (T 1 / 2 ), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.

[0237] Table 2 Pharmacokinetic data of the compounds of the present invention

[0238] Experiments have shown that the compound of the present invention has excellent pharmacokinetic properties in mice.

[0239] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, in, Each R 1 , each R 2 , each R 3 and each R 4 independently selected from H, halogen, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group having 1 or 2 heteroatoms selected from O, N and S, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R a replace; R 5 , R 6 Each independently selected from H, deuterium, halogen, OH, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl and -OC 1-3 Haloalkyl; R 7 , R 8 are each independently selected from H, halogen, OH, -NR 9 R 10 , -NHCO C 1-3 Alkyl, CN, C 1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R b replace; Or, R 7 With R 8 Together they form =O, or R 7 With R 8 Together with the C atom to which it is attached, it forms C 3-6 Cycloalkyl or a 4-6 membered heterocyclic group having 1 or 2 heteroatoms selected from O, N and S, wherein the C 3-6 Cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R c replace; R 9 and R 10 Independently selected from H and -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R d replace; Or, R 9 and R 10 Together with the N atom to which they are commonly attached, they form a 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N; or a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N, wherein the 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S or the 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 R e replace; X is selected from O, S, Se and NR 11 ; Z is selected from 1, 2, 3 and 4; R 11 Selected from H, C 1-3 Alkyl-C(O)- and C 1-3 alkyl; m, n, p and q are independently selected from 0, 1, 2 and 3; and Each R a , each R b , each R c , each R d and each R e independently selected from halogen, OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -O-halogenated C 1-3 Alkyl, and -OC 1-3 alkyl.

2. The compound according to claim 1, characterized in that Each R 1 , R 2 , R 3 and R 4 independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl, wherein said CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, cyclopropyl and cyclobutyl are each independently optionally substituted by 1, 2 or 3 R a Replacement, R a As defined in claim 1.

3. The compound according to claim 1, characterized in that The compound of formula (I) is a compound having formula (Ia), (Ib) or (Ic): Among them, m, n, p, q, z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 As defined in claim 1.

4. The compound according to any one of claims 1 to 3, characterized in that In the compound represented by Formula I or Formula Ia or Ib or Ic, R 5 and R 6 Selected from H and deuterium.

5. The compound according to any one of claims 1 to 4, characterized in that In the compound represented by Formula I or Formula Ia or Ib or Ic, R 7 and R 8 independently selected from H, OH, NH2, -NHCH3, -N(CH3)2, -NHCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridine wherein -NHCH3, -N(CH3)2, -NHCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridinyl are optionally substituted by 1, 2 or 3 R c replace.

6. The compound according to any one of claims 1 to 5, characterized in that In the compound represented by Formula I or Formula Ia or Ib or Ic, R 7 Selected from H, C 1-3 alkyl, R 8 Selected from OH, NH2, 7. The compound according to claim 1, characterized in that The compound represented by formula I is selected from the following group:

8. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope substituted product thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopic substitute thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing or treating (p38 / MK2-related) diseases, preferably, the disease is selected from autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer (such as lymphoma) and neoplasia, preferably chronic inflammatory disorders and acute inflammatory disorders; preferably rheumatoid arthritis, osteoarthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, lupus erythematosus.

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