A class of compounds that inhibit JAK and PHD

Abstract

The present invention discloses a class of compounds that inhibit JAK and PHD. Specifically, the present invention discloses a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat inflammatory bowel disease.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a class of compounds for inhibiting JAK and PHD. Background Art

[0002] The JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an important role in cytokine signal transduction. When cytokines bind to their receptors, the cytokines activate the JAKs, which then phosphorylate the cytokine receptors, thereby creating docking sites for signal transduction molecules, notably members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Many cytokines are known to activate the JAK family. These cytokines include interferon IFN family (IFN-α, IFN-β, IFN-ω, limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinase (EGF, PDGF, CSF-1, HGF), and G-protein coupled receptor (AT1). JAK1 is expressed at different levels in all tissues. Animal studies have shown that JAK1 is essential for the development, function and homeostasis of the immune system. Modulating immune activity by inhibiting JAK1 kinase activity has been shown to be useful in treating a variety of immune disorders.

[0003] Inflammatory bowel disease (IBD) is a chronic disease in which inflammation and ulcers are caused in the intestinal mucosa due to excessive immune response. IBD includes, for example, ulcerative colitis and Crohn's disease. It is known that in the pathological conditions of IBD, the expression of genes related to the barrier function of the gastrointestinal epithelium is induced by hypoxia-inducible factor 1α (HIF-1α). HIF-1α is one of the subtypes of hypoxia-inducible factor α (HIF-α). HIF-α becomes stable in a hypoxic environment (hypoxia), and then it responds to hypoxia and activates the transcription of several genes. In contrast, the proline residues of HIF-α are hydroxylated by prolyl hydroxylases (PHDs) in an oxygen-rich environment (normoxia), and then the HIF-α is degraded by the proteasome pathway. It is known that PHD has 3 subtypes, namely PHD1, PHD2 and PHD3. Summary of the invention

[0004] The invention provides a compound with a novel structure and capable of simultaneously inhibiting JAK1 and PHD2.

[0005] In one aspect of the present invention, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006]

[0007] X is selected from N or CH;

[0008] Ring A is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 halogen or C 1-6 Alkyl substitution;

[0009] Ring B is selected from 4-8 membered heterocyclic groups, wherein the 4-8 membered heterocyclic groups are optionally substituted by 1 halogen or C 1-6 Alkyl substitution;

[0010] L is selected from a single bond or -CH2-;

[0011] R 1 , R 2 , R 3 are independently selected from H, halogen or C 1-3 alkyl.

[0012] In some embodiments of the present invention, Ring A is selected from pyrazolyl, wherein the pyrazolyl is optionally substituted with 1 halogen, and the remaining variables are as defined herein.

[0013] In some embodiments of the present invention, ring A is The remaining variables are as defined in the present invention.

[0014] In some embodiments of the present invention, Ring B is selected from a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one N atom, wherein the 4-8 membered heterocyclic group is optionally substituted with 1 halogen, and the remaining variables are as defined herein.

[0015] In some embodiments of the present invention, Ring B is selected from 4-6 membered monocyclic heterocyclyl or 7-8 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl or 7-8 membered spirocyclic heterocyclyl ring is optionally substituted with 1 halogen, and the remaining variables are as defined herein.

[0016] In some embodiments of the present invention, ring B is selected from The remaining variables are as defined in the present invention.

[0017] In some embodiments of the present invention, the structural fragment Selected from

[0018] The remaining variables are as defined in the present invention.

[0019] In some embodiments of the present invention, R 1 is selected from H or F, and the remaining variables are as defined in the present invention.

[0020] In some embodiments of the present invention, R 2 is selected from H or F, and the remaining variables are as defined in the present invention.

[0021] In some embodiments of the present invention, R 3 is selected from H or CH3, and the remaining variables are as defined herein.

[0022] In some embodiments of the present invention, the structure of the compound represented by formula (I) is shown as one of the following:

[0023]

[0024]

[0025] In another aspect of the present invention, the present invention provides a pharmaceutical composition, which comprises the aforementioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0026] In another aspect of the present invention, the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for treating diseases mediated by PHD2 and JAK1.

[0027] In some embodiments of the present invention, the PHD2 and JAK1 mediated disease is inflammatory bowel disease.

[0028] The term "5-6 membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms in the ring. For example, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like can be exemplified.

[0029] Unless otherwise specified, the term "4-8 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group or partially unsaturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "4-8 membered heterocyclyl", heteroatoms may occupy the connection position of the heterocycloalkyl group to the rest of the molecule. The 4-8 membered heterocyclyl includes 4-7 membered, 5-6 membered, 4 membered, 5 membered, 6 membered, 7 membered and 6 membered heterocyclyls, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or organic acids, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0031] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

[0032] As used herein, the term “C 1-3 The term "alkyl" refers to a straight or branched monovalent alkyl group having 1 to 3 carbon atoms. Specific examples include methyl, ethyl, n-propyl and isopropyl, and various branched isomers thereof.

[0033] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0034] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of what is chemically feasible.

[0035] The compound shown in formula (I) of the present invention can be prepared using a synthetic method known in the art or using a method known in the art in combination with the method described in the present invention. The solvent, temperature and other reaction conditions given in the present invention are exemplary and can be changed according to methods well known in the art. The embodiment compounds described in the present invention can be synthesized according to the method described in the embodiment using appropriate starting materials according to their specific structure, or can be synthesized using a similar method described in the embodiment. The starting materials used to synthesize the embodiment compounds of the present invention can be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources. The compound can be further separated by methods well known in the art, such as crystallization, chromatography, etc. to obtain its stereoisomers as needed, and the separation conditions are easily obtained by those skilled in the art through conventional means or limited experiments. As a further illustration, the compound of formula (I) of the present invention can be synthesized using the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following embodiments, or reaction conditions known in the art can be used. DETAILED DESCRIPTION

[0036] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0037] The present invention is described in detail below by way of examples, but it is not intended to limit the present invention in any adverse way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0038] The following abbreviations are used throughout this disclosure.

[0039] PPh3 represents triphenylphosphine, THF represents tetrahydrofuran, MeOH represents methanol, Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium, Brettphos represents 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-11'-biphenyl, Cs2CO3 represents cesium carbonate, Na2SO4 represents sodium sulfate, DCM represents dichloromethane, K2CO3 represents potassium carbonate, DMF represents dimethylformamide, DIPEA represents N,N-diisopropylethylamine, EtOAc represents ethyl acetate, EtOH represents ethanol, NMP represents N-methyl-2-pyrrolidone, NH3·H2 O represents aqueous ammonia, DMSO represents dimethyl sulfoxide, T3P represents propylphosphonic anhydride, BnBr represents benzyl bromide, Na2CO3 represents sodium carbonate, TEA represents triethylamine, MsCl represents methanesulfonyl chloride, TsOH represents p-toluenesulfonic acid, NaHCO3 represents sodium bicarbonate, BBr3 represents boron tribromide, DIAD represents diisopropyl azodicarboxylate, Pd / C represents palladium on carbon, i-PrOH represents isopropanol, TFA represents trifluoroacetic acid, HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and PyBOP represents 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate.

[0040] Example 1

[0041]

[0042] Step 1:

[0043] Compound 1-1 (2 g, 6.382 mmol) was dissolved in DMF (30 mL), 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (0.58 g, 5.106 mmol) and Cs2CO3 (2.08 g, 6.382 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over Na2SO4, filtered and concentrated to obtain compound 1-2. LCMS: 331.2 [M+H] + .

[0044] Step 2:

[0045] Compound 1-2 (1 g, 3.027 mmol) was added to EtOH (15 mL) / H2O (3 mL), and then Fe (0.85 g, 15.136 mmol) and NH4Cl (0.97 g, 18.163 mmol) were added. The mixture was reacted at 80°C for 3 hours. The mixture was filtered and concentrated, and the crude product was purified by column chromatography (0-9% MeOH / DCM) to obtain compound 1-3. LCMS: 301.1 [M+H] + .

[0046] Step 3:

[0047] Compound 1-3 (850 mg, 2.830 mmol) was dissolved in NMP (10 mL), tert-butyl 3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (21.63 mg, 0.067 mmol), Cs2CO3 (1844.10 mg, 5.660 mmol), Pd2(dba)3 (5.42 mg, 0.007 mmol) and Brettphos (43.66 mg, 0.134 mmol) were added, and the mixture was reacted at 100° C. in N2 atmosphere for 2 hours. The reaction was quenched with water (50 mL), extracted with EtOAc (30 mL×3), and the organic phase was washed with saturated brine (30 mL×3), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM=10:90) to obtain compound 1-4. LCMS: 589.1 [M+H] + .

[0048] Step 4:

[0049] Compound 1-4 (500 mg, 0.849 mmol) was dissolved in MeOH (10 mL), 10% Pd / C (90.38 mg, 0.849 mmol) and NH3·H2O (0.1 mL) were added, and the mixture was stirred under H2 atmosphere for 1.5 hours. Filter and concentrate to obtain compound 1-5. LCMS: 455.3 [M+H] + .

[0050] Step 5:

[0051] Compound 1-5 (250 mg, 0.736 mmol) was dissolved in DMSO (3 mL), 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (501.76 mg, 1.104 mmol) and DIPEA (0.365 mL, 2.208 mmol) were added, and the mixture was stirred at 100 ° C for 16 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL×3). The organic phase was washed with saturated brine (30 mL×2) and concentrated to obtain a crude product, which was first purified by column chromatography (MeOH / DCM=5:95) and then by liquid phase preparation to obtain compound 1-6. LCMS: 758.4 [M+H] + .

[0052] Step 6:

[0053] Compound 1-6 (200 mg, 0.264 mmol) was added to HCl / EA (6 mL, 3 M), followed by HCl (0.088 mL) and reacted at room temperature for 1 hour. The mixture was filtered and washed with EtOAc (10 mL) and dried to obtain compound 1-7. LCMS: 658.3 [M+H] + .

[0054] Step 7:

[0055] (1S)-2,2-difluorocyclopropane-1-carboxylic acid (18.56 mg, 0.152 mmol) was dissolved in DMF (2 mL), and compound 1-7 (50 mg, 0.076 mmol), T3P (50% EtOAc solution, 96.75 mg,

[0056] 0.304mmol) and DIPEA (0.038mL, 0.228mmol), the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (50mL) and extracted with EtOAc (30mL×3). The organic phase was washed with saturated brine (30mL×2), filtered and concentrated, and the crude product was purified by preparative liquid phase to obtain compound 1. LCMS: 762.3[M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),9.77(s,1H),8.82(d,J=45.3Hz,2H),8 .76(s,1H),8.45(s,1H),8.28(d,J=9.5Hz,1H),8.01(s,2H),7.93(d,J=6.0H z,1H),7.82(s,1H),7.62-7.47(m,2H),6.13-6.12(m,1H),4.78-4.45(m,8H) ,4.12-4.10(m,2H),2.93-2.90(m,4H),2.13-2.11(m,2H),1.88-1.80(m,9H).

[0057] Example 2

[0058]

[0059] Prepared in a similar manner to Example 1. LCMS: 774 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),9.76(t,J=6.3Hz,1H),8.94(s,1H),8.76(s,1H),8.44(s, 1H),8.25(d,J=9.2Hz,1H),8.00(s,2H),7.95(s,1H),7.83(s,1H),7.56-7.55(m,1H),6.95(d,J =9.1Hz,1H),6.16-6.15(m,1H),4.82-4.81(m,1H),4.70-4.64(m,4H),4.31(s,2H),4.21(s,2H) ,2.99-2.97(m,2H),2.79-2.69(m,4H),2.09-1.71(m,6H),1.51-1.49(m,2H),0.95-0.94(m,2H).

[0060] Example 3

[0061]

[0062] Step 1:

[0063] Compound 3-1 (1000 mg, 5.989 mmol) was dissolved in MeOH (15 mL), TEA (2.498 mL, 17.968 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (890.05 mg, 4.193 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The reaction was quenched with DCM (100 mL) and water (50 mL). The organic phase was washed with saturated brine (50 mL), dried and concentrated to obtain compound 3-2. LCMS: 343 [M+H] + .

[0064] Step 2:

[0065] Compound 3-2 (1100 mg, 3.209 mmol) was added to HCL / EtOAc (10 mL) and stirred at room temperature for 1 hour. Filter and dry to obtain compound 3-3. LCMS: 243.2 [M+H] + .

[0066] Step 3:

[0067] (1S)-2,2-Difluorocyclopropane-1-carboxylic acid (313.88 mg, 2.571 mmol) was dissolved in DMF (6 mL), and DIPEA (2.125 mL, 12.856 mmol), T3P (50% EtOAc solution, 1363.55 mg,

[0068] 4.285mmol) and compound 3-3 (520mg, 2.143mmol), the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50mL) and extracted with EtOAc (40mL×3). The organic phase was washed with saturated brine (30×3), dried and concentrated to obtain compound 3-4. LCMS: 347.1[M+H] + .

[0069] Step 4:

[0070] Compound 3-4 (250 mg, 0.721 mmol) was dissolved in DMSO (3 mL), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (250 mg, 0.939 mmol) and TsOH (34.25 mg, 0.180 mmol) were added, and the mixture was reacted at 100 ° C for 3 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (40 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried and concentrated to obtain compound 3-5. LCMS: 577.2 [M + H] + .

[0071] Step 5:

[0072] Compound 3-5 (270 mg, 0.468 mmol) was dissolved in HCl / EtOAc (8 mL) and stirred at room temperature for 1 hour. After filtration and drying, compound 3-6 was obtained. LCMS: 477.2 [M+H] + .

[0073] Step 6:

[0074] Compound 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (47.06 mg, 0.139 mmol) was dissolved in DMF (0.5 mL), and compound 3-6 (60 mg,

[0075] 0.126mmol) and DIPEA (0.125mL, 0.755mmol), the mixture was stirred at 100℃ for 10 hours. The mixture was quenched with water (50mL) and extracted with EtOAc (40mL×3). The organic phase was washed with saturated brine (30mL×3), dried and concentrated, and then purified by preparative liquid phase to obtain compound 3. LCMS: 780[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),9.77(s,1H),9.00(s,1H),8.77(s,1H),8.45(s,1H),8.28(s,1H),8.02-8.0 1(m,3H),7.81(s,1H),7 / 54-7.52(m,2H),4.65-4.62(m,8H),4.15(s,2H),3.15-2.99(m,2H),2.02-2.00(m,12H).

[0076] Example 4

[0077]

[0078] Step 1:

[0079] Compound 4-1 (3.7 g, 12.495 mmol) was dissolved in DMF (30 mL), BnBr (3.20 g, 18.742 mmol) and K2CO3 (5.18 g, 37.485 mmol) were added, and the mixture was stirred at 75°C for 16 hours. The reaction was quenched with water (100 mL) and extracted with EtOAc (80 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (50% EtOAc / petroleum ether) to obtain compound 4-2.

[0080] Step 2:

[0081] Compound 4-2 (500 mg, 1.294 mmol) was dissolved in DMSO (6 mL), 4-hydroxypiperidine (130.89 mg, 1.294 mmol), Na2CO3 (274.41 mg, 2.589 mmol), L-proline (29.77 mg, 0.259 mmol) and CuI (98.61 mg, 0.518 mmol) were added, and the mixture was stirred at 90 ° C in N2 atmosphere for 16 hours. The reaction was quenched with water (100 mL) and extracted with EtOAc (80 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over Na2SO4, and concentrated to obtain a crude product, which was purified by reverse phase preparative column to obtain compound 4-3. LCMS: 407.2 [M+H] + .

[0082] Step 3:

[0083] Compound 4-3 (350 mg, 0.861 mmol) was dissolved in DCM (5 mL), and TEA (0.359 mL, 2.583 mmol) and MsCl (118.35 mg, 1.033 mmol) were added at 0°C. The mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with EtOAc (100 mL) and water (50 mL), and the organic phase was washed with saturated brine (30 mL), dried and concentrated to obtain compound 4-4. LCMS: 485.2 [M+H] + .

[0084] Step 4:

[0085] Compound 4-5 (2000 mg, 6.157 mmol) was added to DMSO (20 mL), and then 4-aminopyrazole (613.95 mg, 7.389 mmol) and TsOH (350.97 mg, 1.847 mmol) were added, and the mixture was reacted at 100° C. for 3 hours. After the reaction, the pH was adjusted to 7-8 with saturated NaHCO3 solution, diluted with EtOAc and water, and the organic phase was washed with saturated brine, concentrated and dried to obtain compound 4-6.

[0086] Step 5:

[0087] Compound 4-4 (373 mg, 0.748 mmol) was dissolved in DMF (6 mL), 4-6 (14.51 mg, 0.847 mmol) and Cs2CO3 (752.40 mg, 2.309 mmol) were added, and the mixture was reacted at 80°C for 16 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (40 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (0-5% MeOH / DCM) to obtain compound 4-7. LCMS: 760.4 [M+H] + .

[0088] Step 6:

[0089] Compound 4-7 (260 mg, 0.342 mmol) was added to MeOH (4 mL) and H2O (4 mL), followed by NaOH (54.74 mg, 1.369 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH was adjusted to 2-3 with HCl (1 M) solution, and then diluted with DCM and water. The organic phase was washed with saturated brine and concentrated to obtain compound 4-8. LCMS: 746.4 [M+H] + .

[0090] Step 7:

[0091] Compound 4-8 (250 mg, 0.335 mmol) was dissolved in DMF (3 mL), and DIPEA (0.166 mL, 1.006 mmol) and PyBOP (348.85 mg, 0.670 mmol) were added. After the mixture was reacted at room temperature for 10 minutes, 5-aminomethyl-2-cyanopyridine (53.55 mg, 0.402 mmol) was added and stirring was continued for 1 hour. The reaction was quenched with water (50 mL) and extracted with EtOAc (40 mL×3). The organic phase was washed with saturated brine (100 mL), dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (0-10% MeOH / DCM) to obtain compound 4-9. LCMS: 861.0 [M+H] + .

[0092] Step 8:

[0093] Compound 4-9 (280 mg, 0.325 mmol) was dissolved in DCM (3 mL), BBr3 (0.23 mL) was added at -20 °C, and then the system was slowly warmed to room temperature and the reaction was continued for 3 hours. The reaction was quenched with water and diluted with EtOAc. The organic phase was washed with saturated brine, filtered and concentrated to obtain a crude product, which was purified by column chromatography (0-10% MeOH / DCM) to obtain compound 4-10. LCMS: 771.4 [M+H]+ .

[0094] Step 9:

[0095] Compound 4-10 (170 mg, 0.221 mmol) was added to EtOAc / HCl (1 mL, 3 M) and stirred at room temperature for 1 hour. The mixture was filtered, washed with EtOAc, and dried to obtain compound 4-11. LCMS: 671.4 [M+H] + .

[0096] Step 10:

[0097] Compound (1S)-2,2-difluorocyclopropane-1-carboxylic acid (14.01 mg, 0.115 mmol) was dissolved in DMF (0.5 mL), T3P (50% EtOAc solution, 166.02 mg, 0.522 mmol), DIPEA (0.103 mL, 0.626 mmol) and 4-11 (70 mg, 0.104 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (50 mL) and extracted with EtOAc (40 mL×3). The organic phase was washed with saturated brine (30 mL), dried over Na2SO4, filtered and concentrated, and the crude product was purified by liquid phase preparation to obtain compound 4. LCMS: 775.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.10(s,1H),9.50(s,1H),8.87(s,1H),8.77(s,1H),8.35(s,1H) ,8.11-8.10(m,1H),8.01(s,2H),7.93(d,J=5.9Hz,1H),7.84(s,1H),7.69-7.68(m,1H),7 .52-7.51(m,1H),7.29(s,1H),6.13-6.12(m,1H),4.68-4.66(m,4H),4.43-4.42(m,1H),4 .16-4.15(m,3H),3.17-3.09(m,3H),2.93-2.91(m,1H),2.76(s,3H),2.14-1.65(m,11H).

[0098] Example 5

[0099]

[0100] Prepared in a similar manner to Example 3. LCMS: 748.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.36(s,1H),9.77(s,1H),8.93(s,1H),8.76(s,1H),8.43(s,1 H),8.28(d,J=9.3Hz,1H),8.00(s,2H),7.93-7.92(m,2H),7.53(d,J=9.3Hz,1H),7.19( d,J=9.2Hz,1H),6.13-6.12(m,1H),5.16(s,1H),4.66-4.64(m,4H),4.08-4.06(m,4H), 3.81-3.80(m,2H),3.20-3.19(m,2H),2.94(dd,J=27.1,12.2Hz,2H),1.85-1.80(m,7H).

[0101] Example 6

[0102]

[0103] Step 1:

[0104] Compound 6-1 (2.40 g, 10.5 mmol), 4-nitropyrazole (1.19 g, 10.5 mmol) and PPh3 (8.31 g, 31.6 mmol) were added to THF (20 mL), and then DIAD (6.237 mL, 31.6 mmol) was added under N2 atmosphere at 0°C, and the mixture was reacted at room temperature for 12 hours. The reaction was quenched with water (50 mL), extracted with EtOAc (30 mL×2), and the organic phase was dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether

[0105] / EtOAc=10 / 1-0 / 1) to obtain compound 6-2. LCMS: 267.2[Mt-Bu+H] + .

[0106] Step 2:

[0107] Compound 6-2 (1.49 g, 3.98 mmol) was dissolved in MeOH (15 mL), 10% Pd / C (0.500 g, 0.470 mmol) was added, and the mixture was reacted for 2 hours under H2 atmosphere. After the reaction, the mixture was filtered, and the residue was washed with MeOH (10 mL × 3) and concentrated to obtain compound 6-3. LCMS: 237.4 [Mt-Bu+H] + .

[0108] Step 3:

[0109] Compound 6-3 (1.10 g, 3.76 mmol) was dissolved in DCM (9 mL), TFA (3 mL, 0.342 mmol) was added, and then reacted for 2 hours. The mixture was concentrated to obtain compound 6-4.

[0110] Step 4:

[0111] Compound 6-4 (700 mg, 3.64 mmol) and 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (770 mg, 2.26 mmol) were dissolved in MeCN (10 mL) and DMF (5 mL), TEA (1.01 mL, 7.281 mmol) was added, and the mixture was stirred at 85 ° C for 2 hours. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL×2), the organic phase was dried over Na2SO4, filtered and concentrated, and the crude product was purified by reverse phase column (FA conditions) to obtain compound 6-5. LCMS: 496.4 [M+H] + .

[0112] Step 5:

[0113] Compound 6-5 (65.0 mg, 0.131 mmol) and tert-butyl 3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42.6 mg, 0.131 mmol) were added to i-PrOH (2 mL), and then TsOH (24.9 mg, 0.131 mmol) was added, and the mixture was reacted at 140° C. for 1 hour in a N2 atmosphere. After concentration, the crude product was purified by a reverse phase column (FA conditions) to obtain compound 6-6. LCMS: 784.5 [M+H] + .

[0114] Step 6:

[0115] Compound 6-6 (35.0 mg, 0.045 mmol) was dissolved in DCM (1.5 mL), then TFA (0.5 mL, 0.006 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Compound 6-7 was obtained after concentration.

[0116] LCMS: 684.3 [M+H] + .

[0117] Step 7:

[0118] Compound 6-7 (60.0 mg, 0.088 mmol) and (1S)-2,2-difluorocyclopropane-1-carboxylic acid (10.7 mg, 0.088 mmol) were dissolved in DCM (1 mL), followed by the addition of DIPEA (0.029 mL, 0.175 mmol) and HATU (40.0 mg, 0.105 mmol), and the mixture was stirred at room temperature for 2 hours. After concentration, the crude product was purified by liquid phase preparation to obtain compound 6. LCMS: 788.4 [M+H] + . 1 HNMR: (400MHz, DMSO) δ13.35 (s, 1H) 9.66-9.81 (m, 1H) 8.88-9.19 (m, 1H) 8.76 (s, 1H) 8.42 (s, 1H) 8.24 (d, J = 9.38Hz, 1H)

[0119] 8.00(d,J=1.00Hz,2H)7.85-7.96(m,2H)7.50-7.62(m,1H)7.12(d,J=9.01Hz,1H)

[0120] 6.17(t,J=6.94Hz,1H)4.88-5.00(m,1H)4.60-4.73(m,4H)4.04-4.28(m,2H)3.58-

[0121] 3.74(m,4H)3.21(dd,J=10.26,2.75Hz,2H)2.90-3.07(m,2H)2.54-2.59(m,2H)2. 18(dd,J=3.25,1.88Hz,2H)1.94-2.04(m,2H)1.80-1.92(m,3H)1.59-1.75(m,2H).

[0122] Example 7

[0123]

[0124] Prepared in a similar manner to Example 3. LCMS: 780.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.39(s,1H),9.81(s,1H),8.92(s,1H),8.77(s,1H),8.50(s,1H ),8.32(d,J=9.5Hz,1H),8.01(d,J=1.4Hz,2H),7.92(t,J=9.5Hz,2H),7.65(d,J=9.5Hz,1 H),7.56(d,J=8.0Hz,1H),6.26-6.04(m,1H),5.05-5.04(m,1H),4.97-4.78(m,1H),4.74- 4.54(m,6H),4.16-4.14(s,2H),3.28-3.10(m,3H),2.96-2.94(m,2H),2.00-1.64(m,8H).

[0125] Example 8

[0126]

[0127] Prepared in a similar manner to Example 3. LCMS: 776.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),9.75(s,1H),8.90(s,1H),8.76(s,1H),8.38( s,1H),8.23(s,1H),7.99(d,J=10.1Hz,2H),7.93(d,J=5.9Hz,1H),7.78(s,1H),7.4 8-7.47(m,2H),6.14-6.13(m,1H),4.66-4.64(m,7H),4.14-4.13(m,2H),4.01-4.00 (m,2H),3.20-3.19(m,2H),3.06-2.88(m,4H),2.10-1.62(m,7H),1.24-1.22(m,2H).

[0128] Example 9

[0129]

[0130] Prepared in a similar manner to Example 6. LCMS: 778.4 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ10.47(br s,1H),9.48(br d,J=9.0Hz,1H),8.87-8.76(m,2H),8.71(s,1H),8.59(d,J=3.9Hz,1H),8.22(s,1H),8.02(s,2H),7.17(br d,J=3.3Hz,1H),4.89-4.77(m,1H),4.72-4.61(m,3H),2.63(br d,J=5.9Hz,2H),2.40-2.33(m,1H),2.28-1.92(m,6H),1.56(d,J=6.6Hz,3H),1.50(br d,J=12.1Hz,2H).

[0131] Example 10

[0132]

[0133] Prepared in a similar manner to Example 6. LCMS: 780.4 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ13.68-13.13(m,1H),12.17-11.63(m,1H),10.08-9.92(m,1H),9.90-9.83(m,1H),8 .76(s,1H),8.52(s,1H),8.11(d,J=13.9Hz,1H),8.01(s,2H),7.98-7.94(m,1H),7.69-7.57(m,1H),6.57(br d,J=7.6Hz,1H),4.77-4.71(m,1H),4.64(br d,J=6.3Hz,4H),4.51(br d,J=13.1Hz,3H),3.31(br t,J=12.1Hz,4H),3.25-3.20(m,1H),2.20(br d,J=11.1Hz,2H),2.15-1.85(m,8H),1.72-1.58(m,2H).

[0134] Embodiment 11

[0135]

[0136] Step 1:

[0137] Compound 4-5 (2 g, 6.157 mmol) was added to a solution of HCl in EtOAc (20 mL) and stirred for 2 hours. After the reaction was completed, the mixture was concentrated to obtain compound 11-1. LCMS: 225.0 [M+H]+ .

[0138] Step 2:

[0139] Compound 11-1 (500 mg, 2.225 mmol) was dissolved in DMF (20 mL), (1S)-2,2-difluorocyclopropane-1-carboxylic acid (407.46 mg, 3.338 mmol), T3P (50% EtOAc solution, 1062.06 mg, 3.338 mmol) and DIPEA (1.103 mL, 6.676 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc and saturated brine, the organic phase was washed with saturated brine, and concentrated to give compound 11-2. LCMS: 329.0 [M+H] + .

[0140] Step 3:

[0141] Compound 11-2 (400 mg, 1.217 mmol) was dissolved in DMSO (5 mL), 4-aminopyrazole (121.32 mg, 1.460 mmol) and TsOH (41.90 mg, 0.243 mmol) were added, and the mixture was reacted at 100°C for 3 hours. The reaction was quenched with EtOAc and saturated brine, and the organic phase was washed with saturated brine. Compound 11-3 was obtained after concentration. LCMS: 376.2 [M+H] + .

[0142] Step 4:

[0143] Compound 11-3 (140 mg, 0.373 mmol) was dissolved in DMF (4 mL), and Cs2CO3 (364.55 mg, 1.119 mmol) and 1-benzyloxycarbonyl-3-methanesulfonic acid azetidine (127.69 mg,

[0144] 0.448mmol), the mixture was reacted at 100°C for 2 hours. The reaction was quenched with water (50mL), extracted with EtOAc (40mL×3), the organic phase was washed with saturated brine (30mL×3), dried over Na2SO4, filtered and concentrated to obtain compound 11-4. LCMS: 565.2[M+H] + .

[0145] Step 5:

[0146] Compound 11-4 (170 mg, 0.296 mmol) was added to MeOH (2 mL) and aqueous ammonia (0.1 mL), and 10% Pd / C (3.39 mg, 0.032 mmol) was added, and the mixture was reacted in H2 atmosphere for 2 hours. After filtration and concentration, compound 11-5 was obtained. LCMS: 431.2 [M+H] + .

[0147] Step 6:

[0148] The compound 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (60 mg, 0.177 mmol) was dissolved in DMSO (2 mL), and 11-5 (91.23 mg, 0.212 mmol) and DIPEA (0.088 mL, 0.530 mmol) were added, and the mixture was reacted at 100° C. for 3 hours. After the reaction was completed, liquid phase preparation and purification were used to obtain compound 11. LCMS: 734.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.39(s,1H),9.80(s,1H),9.02(s,1H),8.77(s,1H),8.49(s,1H),8.31(d,J=9.1Hz,1H),8.05-7.90(m,4H),7.62( s,1H),7.06(d,J=9.1Hz,1H),6.15(s,1H),5.45(s,1H),4.70-4.52(m ,6H),4.44(s,2H),4.13(s,2H),3.21-2.85(m,3H),2.05-1.57(m,6H).

[0149] Example 12

[0150]

[0151] Prepared in a similar manner to Example 3. LCMS: 798.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.48-13.26(m,1H),9.88-9.75(m,1H),9.02(d,J=5.5Hz,1H),8.76(s,1H),8. 52-8.45(m,1H),8.32(d,J=9.4Hz,1H),8.04-7.94(m,3H),7.92-7.83(m,1H),7.63(d,J=9.4Hz,1H),7. 53(d,J=9.4Hz,1H),5.13-4.99(m,1H),4.94(dt,J=4.1,9.7Hz,1H),4.86-4.76(m,1H),4.64(d,J=6.3H z,4H),4.24-4.11(m,2H),3.25-3.00(m,4H),2.21-2.13(m,1H),2.12-1.93(m,3H),1.93-1.69(m,6H).

[0152] Biological test cases

[0153] JAK

[0154] With Echo 655 (Beckman, SYSTEM) Transfer 40nL of compound to a 384 reaction plate (Manufacturer: Greiner, Catalog No.: 784075). Prepare 2× kinase solution with 1× kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01% Brij-35, 1mM EGTA, 2mM DTT), and transfer 2μL of JAK1 (25nM, Manufacturer: Carna, Catalog No.: 08-144) solution to the 384 reaction plate. Centrifuge at 1000rpm for 1 minute and incubate at 25℃ for 10 minutes. Prepare a 2× mixture of substrate (IRS1: 0.05mg / mL) and ATP (20μM, Manufacturer: Promega, Catalog No.: V915B) with kinase reaction buffer, start the reaction after adding 2μL of the mixture of substrate and ATP to the reaction plate, and centrifuge at 1000rpm for 1 minute. Incubate at 25℃ for 60 minutes. Transfer 4 μL of ADP-Glo ​​to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of the assay solution to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, incubate at 25°C for 40 minutes, and read the luminescence signal of each well in the ADP-Glo ​​mode on an ELISA reader (manufacturer: BMG, model: PHERAstar FSX). Set the reading value of the negative control to 0% inhibition rate, and the reading value of the positive control to 100% inhibition rate, calculate the inhibition rate of each test solution, and then perform data analysis using GraphPad 8 software, and use the nonlinear fitting formula to obtain the IC of the compound. 50 (half inhibitory concentration), the results are shown in Table 1 below.

[0155] PhD2

[0156] Use DMSO to make gradient dilutions of the test compound. Use ECHO to add 40nL / well of the compound to the 384-well reaction plate. Seal the experimental plate and centrifuge at 1000rpm for 1 minute. Add 4μL / well 2× PHD2 enzyme working solution to the 384-well reaction plate with the above compounds. Seal the experimental plate, centrifuge at 1000rpm for 1 minute, and incubate at 25℃ for 30 minutes. Prepare 2× substrate working solution (CODD peptide and α-ketoglutarate) and add 4μL / well 2× substrate working solution to the 384-well reaction plate with the above compounds. Seal the experimental plate, centrifuge at 1000rpm for 1 minute, and incubate at 25℃ for 30 minutes. Add 4μL / well 4× prepared stop working solution to the 384-well reaction plate to stop the reaction. Seal the experimental plate and centrifuge at 1000rpm for 1 minute. Add 4 μL / well 4× detection working solution (Alphascreen streptavidin donor beads, AlphaScreen A protein acceptor beads and hydroxy-HIF-1α (Pro564) (D43B5) Rabbit mAb) into a 384 assay plate. The assay plate was sealed, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 30 minutes. The fluorescence signal was detected on an Envision 2104 Reader. The results are shown in Table 1 below.

[0157] Table 1

[0158]

[0159]

[0160] Although the specific embodiments of the present invention have been described in detail, according to all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and these changes are within the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, X is selected from N or CH; Ring A is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 halogen or C 1-6 Alkyl substitution; Ring B is selected from 4-8 membered heterocyclic groups, wherein the 4-8 membered heterocyclic groups are optionally substituted by 1 halogen or C 1-6 Alkyl substitution; L is selected from a single bond or -CH2-; R 1 , R 2 , R 3 are independently selected from H, halogen or C 1-3 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, which is optionally substituted by 1 halogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a 4- to 8-membered heterocyclic group, said 4- to 8-membered heterocyclic group containing one N atom, said 4- to 8-membered heterocyclic group being optionally substituted by 1 halogen.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 4-6 membered monocyclic heterocyclyl or 7-8 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl or 7-8 membered spirocyclic heterocyclyl is optionally substituted by 1 halogen.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The structure of the compound represented by formula (I) is shown as one of the following:

8. A pharmaceutical composition, wherein The pharmaceutical composition comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating diseases mediated by PHD2 and JAK1.

10. The use according to claim 9, wherein: The PHD2 and JAK1 mediated disease is inflammatory bowel disease.

Images