CN117586285B - Tri-fused ring compounds - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses a tricyclic compound. Specifically, the invention discloses a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, which can be used for treating inflammatory bowel disease.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a tricyclic compound.
Background
The JAK family of cellular protein tyrosine kinases (JAK 1, JAK2, JAK3 and TYK 2) play an important role in cytokine signaling. When a cytokine binds to its receptor, the cytokine activates JAK, which then phosphorylates the cytokine receptor, thereby creating a docking site for a signal transduction molecule, notably a signal transducer and a transcription activator (STAT) family member that ultimately results in gene expression. Many cytokines are known to activate the JAK family. These cytokines include the interferon IFN family (IFN- α, IFN- β, IFN- ω, limiter (limit), IFN- γ, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single chain family (EPO, GH, PRL, TPO), the receptor tyrosine kinase (EGF, PDGF, CSF-1, HGF), and the G-protein coupled receptor (AT 1). JAK1 is expressed at different levels in all tissues. Animal studies have shown that JAK1 is essential for the development, functioning and homeostasis of the immune system. Modulation of immune activity by inhibition of JAK1 kinase activity has proven useful in the treatment of a variety of immune disorders.
Inflammatory Bowel Disease (IBD) is a chronic disease in which inflammation and ulcers are caused in the intestinal mucosa by an 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 associated with the barrier function of the epithelium of the gastrointestinal tract is induced by hypoxia-inducible factor 1 alpha (HIF-1 alpha). 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 activates transcription of several genes in response to hypoxia. In contrast, the proline residues of HIF-alpha are hydroxylated by Prolyl Hydroxylase (PHD) in an oxygen-rich environment (normoxic), and then the HIF-alpha is degraded by the proteasome pathway. There are 3 subtypes of PHD known, namely PHD1, PHD2 and PHD3.
Disclosure of Invention
The invention provides a compound which has a novel structure and can inhibit JAK1 and PHD2 simultaneously.
In a first aspect of the present invention, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
the compound of formula (I),
ring a is selected from cyclobutyl, azetidinyl or piperidinyl;
x is selected from single bond or NH.
In some embodiments of the invention, ring A is selected from、Or->The remaining variables are as defined herein.
In some embodiments of the invention, the structure of the compound of formula (I) is as follows:
。
in some embodiments of the invention, the structure of the compound of formula (I) is as follows:
。
in some embodiments of the invention, the structure of the compound of formula (I) is as follows:
。
in another aspect of the invention, the invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect of the invention, the invention provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of PHD2 and JAK1 mediated diseases.
In some aspects of the invention, the PHD2 and JAK1 mediated disease is inflammatory bowel disease.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts added with inorganic acids such as nitric acid, phosphoric acid, carbonic acid, etc., or with organic acids; such as propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, and the like; or salts formed when acidic protons present on the parent compound are replaced with metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
The compounds of formula (I) of the present invention may be prepared using synthetic methods known in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures, and other reaction conditions set forth herein are exemplary and may vary according to methods well known in the art. The compounds of the examples described in the present invention can be synthesized by the methods described in the examples using appropriate starting materials according to their specific structures, or by the methods similar to those described in the examples. The starting materials for the synthesis of the compounds of the examples of the present invention may be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources. The compounds may be further resolved as desired by methods well known in the art, such as crystallization, chromatography, etc., to give stereoisomers thereof, the resolution conditions of which are readily available to those skilled in the art by conventional means or limited experimentation. By way of further illustration, the compounds of formula (I) of the present invention may be synthesized using methods in which the solvents, temperatures and other reaction conditions in each step may be the same or similar to those described in the examples below, or using reaction conditions known in the art.
Detailed Description
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining them with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention.
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The following abbreviations extend throughout the present invention.
THF represents tetrahydrofuran, meOH represents methanol, naOH represents sodium hydroxide, na 2 SO 4 Represents sodium sulfate, DMA represents dimethylacetamide, DCM represents dichloromethane, na 2 S 2 O 4 Represents sodium dithionite, DMSO represents dimethyl sulfoxide, DIPEA represents N, N-diisopropylethylamine, NH 4 Cl represents ammonium chloride, i-PrOH represents isopropanol, etOAc represents ethyl acetate, TFA represents trifluoroacetic acid, NMP represents N-methyl-2-pyrrolidone, ts represents p-toluenesulfonyl, int represents 2-chloro-N- ((6-cyanopyridin-3-yl) methyl) -5-hydroxy-1, 7-naphthyridine-6-carboxamide (obtainable by the method of example 29 step 1 in WO 2023072257).
Example 1
Step 1:
compound 1-1 (3.28 g,9.32 mmol) was dissolved in DMA (30.0 mL), N 2 Adding 2- [ trans-4-aminocyclohexyl under atmosphere]Acetonitrile hydrochloride (1.79 g,10.257 mmol) and DIPEA (4.10 g,31.7 mmol). The mixture was reacted at 80℃for 4 hours. After cooling to room temperature, the mixture was treated with H 2 Dilution with O (200 mL)Extracted with DCM (300 mL. Times.2). The organic phase was washed with saturated brine (300 mL), na 2 SO 4 Drying, filtering and concentrating to obtain crude product 1-2, which is directly used in the next step without purification. LCMS:454.3[ M+H ]] + 。
Step 2:
compound 1-2 (500 mg,1.10 mmol), 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (470 mg,2.20 mmol), na 2 S 2 O 4 (479 mg,2.75 mmol) was added to DMSO (10 mL), meOH (10 mL) and H 2 O (5 mL), mixture in N 2 The reaction was carried out at 100℃for 16 hours. NH for mixture 4 The saturated solution (20 mL) was quenched and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (50 mL), na 2 SO 4 Drying, filtration and concentration, the crude product was purified by column chromatography (petroleum ether/etoac=10/1-1/1) to give compounds 1-3.
Step 3:
compound 1-3 (300 mg, 0.481 mmol), naOH solution (0.405 mL,1.21 mmol), tetrahydropyrrole (794 mg,1.946 mmol) were added to THF (10 mL) and MeOH (10 mL), the mixture was concentrated under N 2 The reaction was carried out under an atmosphere for 5 hours. NH for reaction 4 The saturated solution (20 mL) was quenched and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (30 mL), na 2 SO 4 Drying, filtering and concentrating to obtain the compounds 1-4. The crude product was used in the next step without purification. LCMS:463.5[ M+H ]] + 。
Step 4:
compound 1-4 (230 mg,0.497 mmol) and TFA (1 mL) were added to DCM (5 mL), and the mixture was reacted at room temperature for 2 hours and concentrated to give compound 1-5.
Step 5:
compounds 1-5 (25.0 mg,0.07 mmol), int (16.4 mg,0.05 mmol) and DIPEA (0.114 mL,0.690 mmol) were added to NMP (3 mL) and the mixture was taken under N 2 The reaction was carried out at 100℃for 16 hours. After the reaction was cooled to room temperature, it was purified by preparative liquid phase (0.1% fa) to give compound 1.LCMS:666.5[ M+H ]] + 。 1 H NMR （400 MHz，DMSO-d 6 ）δ 13.71 - 13.13（m，1H），11.88（br s，1H），9.98 - 9.66（m，1H），8.83（s，1H），8.52（br d，J = 13.5 Hz, 2H），8.34（d，J = 9.4 Hz, 1H），8.07（d，J = 1.4 Hz，2H）7.62（d，J = 9.5 Hz, 1H），7.52（t，J = 2.9 Hz，1H），6.79 （br s，1H），5.15 - 4.47（m，6H），3.67（br d，J = 11.4 Hz，1H），2.79 - 2.64（m，4H），2.25 - 1.87（m，11H），1.68 - 1.51（m，2H）。
Example 2
Step 1:
compound 1-2 (500 mg,1.10 mmol) was added to DMSO (5 mL), meOH (5 mL) and H 2 To O (2.5 mL) was added tert-butyl (cis-3-formylcyclobutyl) carbamate (439 mg,2.20 mmol) and Na 2 S 2 O 4 (479 mg,2.75 mmol). The mixture was reacted at 100℃for 12 hours. Reaction H 2 O (100 mL) was quenched, extracted with EtOAc (50 mL. Times.3), and the organic phase was washed with saturated brine (100 mL. Times.3), na 2 SO 4 Drying, filtering and concentrating to obtain the compound 2-1.LCMS:603.4[ M+H ]] + 。
Step 2:
compound 2-1 (132 mg,0.219 mmol) was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and NaOH (0.18 mL,0.547mmol, 3M) and tetrahydropyrrole (0.070 mL,0.876 mmol) were added. The mixture was reacted at room temperature for 12 hours. Reaction H 2 O (5 mL) quenching, i-PrOH/CHCl 3 (1:10, 5 mL. Times.3) extraction. Na for organic phase 2 SO 4 And (5) drying. Filtering and concentrating to obtain the compound 2-2.LCMS:449.3[ M+H ]] + 。
Step 3:
compound 2-2 (116 mg, 0.299 mmol) was added to a solution of HCl/dioxane (4.00 mL, 4M) and reacted for 2 hours. Concentrating under reduced pressure to obtain compound 2-3.LCMS:349.4[ M+H ]] + 。
Step 4:
compound 2-3 (70.0 mg,0.201 mmol) was dissolved in NMP (1 mL), int (34.1 mg,0.100 mmol) and DIPEA (166. Mu.L, 1.00 mmol) were added and the mixture was reacted at 100℃for 12 hours. Purification by preparative liquid phase (FA conditions) gave compound 2.LCMS:652.2[ M+H ]] + 。 1 H NMR (400 MHz，DMSO-d 6 ) δ 13.49 - 13.00（m，1H），11.84 - 11.79（m，1H），9.85 - 9.66（m，1H），8.76（s，1H），8.53（s，1H），8.38（br s，1H），8.21 - 8.10（m，2H），8.02 - 7.97（m，2H），7.45（br s，1H）7.02 - 6.88（m，1H），6.70（br s，1H），4.85 - 4.72（m，1H），4.63（br d，J = 6.5 Hz，2H），4.50 - 4.38（m，1H），3.84 - 3.71（m，1H），2.96 - 2.86（m，3H），2.59（br d，J = 5.8 Hz，2H） 2.39 - 2.33（m，2H），2.05 - 1.95（m，4H），1.92 - 1.85（m，2H），1.57 - 1.41（m，3H）。
Example 3
Step 1:
compound 1-2 (500 mg,1.10 mmol), tert-butyl 3-formylazetidine-1-carboxylate (408 mg,2.21 mmol) and Na 2 S 2 O 4 (384 mg,2.21 mmol) to DMSO (5.00 mL), meOH (5.00 mL) and H 2 O (2.50 mL), the mixture was reacted at 100℃for 16 hours. NH for reaction 4 The saturated solution (20 mL) was quenched and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (30 mL. Times.3), na 2 SO 4 Drying, filtering and concentrating to obtain the compound 3-1.LCMS:589.7[ M+H ]] + 。
Step 2:
compound 3-1 (319 mg, 0.540 mmol) was dissolved in THF (3 mL) and MeOH (3 mL), naOH solution (0.450 mL,1.36 mmol) and tetrahydropyrrole (0.180 mL,2.17 mmol) were added and the mixture was reacted at room temperature for 18 hours. NH for reaction 4 Quench with Cl saturated solution (20 mL) and extract with EtOAc (30 mL). The organic phase was washed with saturated brine (30 mL), na 2 SO 4 Drying, filtering and concentrating to obtain the compound 3-2.LCMS:435.4[ M+H ]] + 。
Step 3:
compound 3-2 (300 mg,0.690 mmol) was dissolved in HCl/dioxane (2 mL), and the mixture was stirred at room temperature for 1 hour and concentrated to give compound 3-3.LCMS:335.4[ M+H ]] + 。
Step 4:
compound 3-3 (300 mg,0.897 mmol) and Int (152.4 mg,0.449 mmol) were dissolved in DMSO (5 mL), DIPEA (0.74 mL,4.48 mmol) was added and the mixture was reacted at 100deg.C for 3 hours. After concentration, purification by liquid phase preparation (0.1% fa) afforded compound 3.LCMS:638.7[ M+H ]] + 。 1 H NMR (400 MHz，DMSO-d 6 ) δ 11.88（br s，1H），9.97 - 9.64（m，1H），8.76（s，1H），8.55（s，1H），8.45（br s，1H），8.35 - 8.24（m，1H），8.00（d，J = 1.1 Hz，2H），7.48（t，J = 3.1 Hz，1H），7.15 - 6.99（m，1H），6.74（br d，J = 1.1 Hz，1H），4.79 - 4.51（m，7H），2.60（br d，J = 6.0 Hz，2H），2.17 - 1.83（m，6H），1.60 - 1.40（m，2H）。
Biological test case
JAK
40nL compounds were transferred to 384 reaction plates (manufacturer: greiner, cat# 784075) using Echo 655 (Beckman, ECHO 655 SYSTEM). With 1 Xkinase reaction buffer (50 mM Hepes, 10mM MgCl) 2 0.01% Brij-35,1mM EGTA,2mM DTT) in 2 x kinase solution, transfer 2 μl of JAK1 (25 nM, manufacturer: carna, cat: 08-144) into 384 reaction plates. Centrifuge at 1000rpm for 1 min and incubate at 25℃for 10 min. A mixture of 2. Mu.L of the substrate and ATP (IRS 1: 0.05 mg/mL) and ATP (20. Mu.M, manufacturer: promega, cat. No. V915B) was prepared in the kinase reaction buffer, and after adding 2. Mu.L of the mixture of the substrate and ATP to the reaction plate, the reaction was started and centrifuged at 1000rpm for 1 minute using a centrifuge. Incubate at 25℃for 60 min. Transfer 4. Mu.L ADP-Glo to 384 assay plates, centrifuge at 1000rpm for 1 min, 25℃CIncubate for 40 min. Transfer 8. Mu.L of detection solution into 384 detection plates, centrifuge at 1000rpm for 1 min, incubate at 25℃for 40 min, and read each well of luminocene signal in ADP-Glo mode on a microplate reader (manufacturer: BMG, model: PHERAstar FSX). The read value of the negative control is set as 0% inhibition rate, the read value of the positive control is set as 100% inhibition rate, the inhibition rate of each test solution is calculated, then data analysis is carried out through GraphPad 8 software, and a nonlinear fitting formula is utilized to obtain the IC of the compound 50 (half inhibition concentration) and the results are shown in Table 1 below.
PHD2
Compounds to be tested were diluted gradient using DMSO. 40 nL/well of compound was added to 384 well reaction plates using ECHO. The test plate was sealed and centrifuged at 1000rpm for 1 minute. To 384-well reaction plates to which the above compounds were added, 4. Mu.L/well of 2 XPHD 2 enzyme working solution was added. The plate was sealed and centrifuged at 1000rpm for 1 min and incubated at 25℃for 30 min. Preparation of 2 Xsubstrate working solution (CODD peptide and. Alpha. -ketoglutarate) to 384-well reaction plates to which the above-mentioned compounds were added 4. Mu.L/well of 2 Xsubstrate working solution. The plate was sealed and centrifuged at 1000rpm for 1 min and incubated at 25℃for 30 min. The reaction was stopped by adding 4. Mu.L/well of 4 Xprepared stop solution to 384 plates. The test plate was sealed and centrifuged at 1000rpm for 1 minute. mu.L/well of 4 Xdetection working solution (AlphaScreen streptavidin donor beads, alphaScreen A protein acceptor beads and hydroxy-HIF-1α (Pro 564) (D43B 5) XP Rabbit mAb) were added to 384 assay plates. The plate was sealed and centrifuged at 1000rpm for 1 min and incubated at 25℃for 30 min. Fluorescence signals were detected on an Envision 2104 Reader, the results of which are shown in table 1 below.
TABLE 1
While specific embodiments of the invention have been described in detail, those skilled in the art will, in light of all the teachings disclosed, be able to make various modifications and alternatives to the details of the invention and such modifications are within the scope of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (8)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,ring a is selected from cyclobutyl, azetidinyl or piperidinyl;
x is selected from single bond or NH.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from、Or->
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:
4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:
5. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:
6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof,
and, a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for the treatment of PHD2 and JAK1 mediated diseases.
8. The use of claim 7, wherein the PHD2 and JAK1 mediated disease is inflammatory bowel disease.
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