Pyrrolidine derivatives, pharmaceutical compositions and their pharmaceutical applications

Abstract

This invention relates to a pyrrolidine derivative and its pharmaceutical use, and more particularly to a pyrrolidine derivative as shown in general formula (I), or its stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or cocrystals, pharmaceutical compositions comprising the thereof, and the use of the compounds or compositions of this application in the preparation of medicaments for autoimmune diseases.

Description

Technical Field

[0001] This invention relates to a pyrrolidine derivative, a pharmaceutical composition, and its application in medicine. Background Technology

[0002] Toll-like receptors (TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues. They monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), playing an important role in both innate and adaptive immunity.

[0003] TLRs belong to type I transmembrane proteins. To date, 13 members of the TLR family have been discovered, 10 of which exist in humans. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, and TLR11 are located on the cell membrane and can recognize lipids, lipoproteins, and other substances in microorganisms. TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes, and endoplasmic reticulum) and recognize nucleic acids in microorganisms.

[0004] TLR7 and TLR8 are most similar in sequence and function. Numerous studies have shown that activation of TLR7 / 8 can trigger type I interferon responses and various inflammatory reactions. In autoimmune disorders such as systemic lupus erythematosus (SLE), abnormal and persistent activation of TLR7 / 8 leads to the exacerbation of the disease state. Therefore, developing compounds with selective and potent inhibitory activity to antagonize TLR7 / 8 and inhibit overactivated immune responses holds promise as a new approach to treating autoimmune diseases. Summary of the Invention

[0005] The purpose of this invention is to provide novel pyrrolidine derivatives or stereoisomers, pharmaceutical compositions thereof, and their use in the preparation of drugs for autoimmune diseases.

[0006] One or more embodiments of the present invention provide a compound of general formula (I), or all of its stereoisomers:

[0007]

[0008] in:

[0009] R1 is selected from -CONHR4;

[0010] R4 is selected from

[0011] R2 is selected from C 1-6 Alkyl groups, wherein the alkyl groups are optionally further substituted with one or more halogens.

[0012] R3 is selected from

[0013] Furthermore, R2 can be selected from CF3.

[0014] One or more embodiments of the present invention provide a compound of general formula (I), or a stereoisomer thereof, said compound having one of the following structures:

[0015]

[0016]

[0017] One or more embodiments of the present invention provide a pharmaceutical composition comprising:

[0018] Compounds of general formula (I) or their stereoisomers;

[0019] One or more other active ingredients may be selected; and

[0020] Pharmaceutically acceptable carriers and / or excipients.

[0021] One or more embodiments of the present invention also provide the use of the compound or stereoisomer of general formula (I) and the above pharmaceutical composition in the preparation of a drug for autoimmune diseases.

[0022] One or more embodiments of the present invention also provide an intermediate for preparing a compound of general formula (I), or its stereoisomers, solvates, metabolites, prodrugs, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein the intermediate is selected from:

[0023]

[0024] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0025] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S,33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0026] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents. "Alkoxy" refers to a group formed by substituting at least one carbon atom of an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" described above.

[0027] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0028] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0029] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0030] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0031] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0032] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0033] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0034] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0035] The following embodiments illustrate the technical solutions of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0036] Intermediate A-1: ​​(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0037] (1S,5R)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0038] Intermediate A-2: (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0039] (1R,5S)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0040]

[0041] first step:

[0042] 1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester A-1.3

[0043] ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate

[0044] Under a nitrogen atmosphere, A-1.1 (10 g, 60 mmol) was dissolved in 30 mL of dichloromethane (DCM). A 14.4 g, 60 mmol solution of A-1.2 in dichloromethane (10 mL) was added dropwise under ice bath conditions, followed by a slow dropwise addition of a 10 mL solution of trifluoroacetic acid (684 mg, 6 mmol) in dichloromethane. The mixture was stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, and the mixture was extracted three times with DCM. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain the target product, ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid A-1.3 (yellow oily liquid, 15.5 g, yield 86%), which was directly used in the next reaction.

[0045] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.24(m,5H),4.19(q,2H),3.79-3.78(m,4H),1.20(t,3H).

[0046] LC-MS m / z(ESI)=300.1[M+1].

[0047] Step Two:

[0048] 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.4

[0049] ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0050] Under a nitrogen atmosphere, trimethyl sulfoxide (3.5 g, 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide. A solution of sodium hydride (633.6 mg, 15.8 mmol) in dimethyl sulfoxide (5 mL) was added in portions under ice bath conditions, and the mixture was stirred at room temperature for 30 minutes. Then, a solution of A-1.3 (4.3 g, 14.4 mmol) in dimethyl sulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60 °C for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain the target product, ethyl 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate A-1.4 (colorless oily liquid, 3.5 g, yield 78%), which was directly used in the next reaction.

[0051] 1 H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,5H),4.11(q,2H),3.66(s,2H),3.08-

[0052] 3.01(m,2H),2.86-2.82(m,1H),2.65-2.62(m,1H),1.82-1.79(m,2H),1.15(t,3H).

[0053] LC-MS m / z(ESI)=314.1[M+1].

[0054] Step 3:

[0055] 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.5

[0056] -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0057] A-1.4 (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, followed by the addition of Pd / C (681 mg, 0.64 mmol). The reaction system was replaced twice with 1 atm H2, and the temperature was raised to 60 °C for 3 h. After filtration through diatomaceous earth and rotary evaporation of the solvent, the target product, ethyl 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate A-1.5 (colorless oily liquid, 1 g, yield 88%), was obtained and used directly in the next step.

[0058] 1H NMR (400MHz, DMSO-d6) δ4.11(q,2H),3.20-2.75(m,5H),1.75(d,1H),1.48-1.47(m,1H),1.16(t,3H).

[0059] LC-MS m / z(ESI)=224.1[M+1].

[0060] Step 4:

[0061] (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.7

[0062] ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxy late

[0063] Under a nitrogen atmosphere, 5-bromoquinoline-8-carboxynitrile A-1.6 (654 mg, 2.9 mmol) was dissolved in 30 mL of 1,4-dioxane, followed by the addition of A-1.5 (804 mg, 3.5 mmol). The mixture was purged with nitrogen three times. Cesium carbonate (4.3 g, 13.05 mmol) and RuPhosPdG3 (486 mg, 0.58 mmol) were then added sequentially, followed by purging with nitrogen three times. The mixture was heated to 90 °C and reacted for 2 h. The solvent was evaporated, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated again. The crude product A-1.7 was directly added to the next step.

[0064] LC-MS m / z(ESI)=376.1[M+1],398.1[M+23].

[0065] Step 5:

[0066] 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A

[0067] 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic ac id

[0068] The crude product A-1.7 (2.02 g, 5.39 mmol) was dissolved in 10 mL of tetrahydrofuran solution. 10 mL of anhydrous lithium hydroxide (1.29 g, 53.9 mmol) aqueous solution was added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, and the mixture was extracted with ethyl acetate. The aqueous phase was retained, and the pH of the aqueous phase was adjusted to 3-4 with 2M hydrochloric acid aqueous solution. The phase was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The mixture was separated by MPLC (acetonitrile:water = 47:53) to obtain the target product, 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound A (yellow solid, 387 mg, 21%).

[0069] 1 H NMR(400MHz,DMSO-d6)δ13.26(s,1H),9.02-9.00(m,1H),8.64-8.62(m,1H),8.16( d,J=8.0Hz,1H),7.61(dd,1H),7.25(d,1H),4.05-3.77(m,4H),2.07-1.86(m,2H).

[0070] LC-MS m / z(ESI)=348.1[M+1],370.1[M+23].

[0071] Step 6:

[0072] Intermediates A-1 and A-2 of 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0073] 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic ac id

[0074] Compounds A-1 and A-2 were resolved by chiral prep-HPLC. Analytical method: Chiral column Ig-3, methanol as mobile phase, flow rate 1 mL / min, retention time of intermediate A-1 was 3.619 min, and retention time of intermediate A-2 was 4.741 min.

[0075] Example 1

[0076] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 1

[0077] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0078]

[0079] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1

[0080] (200 mg, 0.57 mmol) was dissolved in 6 mL of N,N-dimethylformamide, and then HATU (260 mg, 0.68 mmol) and DIPEA (220 mg, 1.71 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then 4-aminopyridine 1-1 (54 mg, 0.51 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 1 (pale yellow solid, 253 mg, 83%).

[0081] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.02(dd,J=4.2,1H),8.67(dd,1H),8.47(d,2H),8.19(d,1 H),7.62(dd,3H),7.27(d,1H),4.13(s,2H),4.02(d,1H),3.92(d,1H),2.10(d,1H),1.80(d,1H).

[0082] 19 F NMR(376MHz,DMSO-d6)δ-63.88.

[0083] LC-MS m / z(ESI) = 424.10 [M+1].

[0084] Example 2

[0085] (1S,5R)-N-(6-aminopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 2

[0086] (1S,5R)-N-(6-aminopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamide

[0087]

[0088] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (100 mg, 0.28 mmol) in 6 mL In N,N-dimethylformamide, HATU (94 mg, 0.33 mmol) and DIPEA (111 mg, 0.86 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, pyridine-2,6-diamine 2-1 (94 mg, 0.86 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-N-(6-aminopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 2 (pale yellow solid, 65 mg, 73%).

[0089] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.01(dd,1H),8.66(dd,1H),8.18(d,1H),7.60(dd,1H),7.36(t,1H),7. 25(d,1H),7.18(d,1H),6.21(d,,1H),5.76(s,2H),4.11(q,2H),4.01–3.87(m,2H),1.96(d,1H),1.66(d,1H).

[0090] 19 F NMR(376MHz,DMSO-d6)δ-63.70.

[0091] LC-MS m / z(ESI) = 439.10 [M+1].

[0092] Example 3

[0093] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-morpholinpyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 3

[0094] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-morpholinopyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0095]

[0096] Compound A-1 (200.0 mg, 0.58 mmol) was dissolved in 2 mL of DMF, followed by the addition of HATU (219.0 mg, 0.58 mmol) and DIPEA (159.0 mg, 1.2-0.6 mmol). The mixture was stirred at room temperature for 10 min, and then compound 3-1 (103.3 mg, 0.58 mmol) was added. The mixture was stirred at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was washed with 15 mL of water and 15 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was purified by MPLC to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(5-morpholinpyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 3 (white solid, 90 mg, 30.5%).

[0097] 1 H NMR(400MHz,DMSO-d6)δ9.03-8.98(m,1H),8.69-8.63(m,1H),8.18(d,1H),8.04(d,1H),7.90(d,1H),7.64-7.59(m,1H),7.4 7-7.41(m,1H),7.26(d,1H),4.28–4.07(m,2H),3.94(s,2H),3.82–3.64(m,4H),3.17–2.97(m,4H),2.03(d,1H),1.70(d,1H).

[0098] 19 F NMR (376MHz, DMSO-d6) δ 63.69.

[0099] LC-MS m / z(ESI) = 509.2 [M+1].

[0100] Example 4

[0101] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-morpholinpyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 4

[0102] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-morpholinopyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0103]

[0104] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (50 mg, 0.14 mmol) in 6 mL In N,N-dimethylformamide, HATU (65.7 mg, 0.173 mmol) and DIPEA (55.7 mg, 0.43 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 6-morpholinopyridine-3-amine 4-1 (28.4 mg, 0.158 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-morpholinopyridine-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 4 (pale yellow solid, 47 mg, 92%).

[0105] 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.02(dd,1H),8.67(dd,1H),8.29(d,1H),8.19(d,1H),7.76(dd,1H),7.62(dd,1H),7 .27(d,1H),6.84(d,1H),4.10(d,2H),4.05–3.95(m,2H),3.89(d,1H),3.69(t,4H),3.38(d,3H),2.10(d,1H),1.75(d,1H).

[0106] 19 F NMR(376MHz,DMSO-d6)δ-63.76.

[0107] LC-MS m / z(ESI) = 509.20 [M+1].

[0108] Example 5

[0109] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 5

[0110] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluor omethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0111]

[0112] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (100 mg, 0.28 mmol) in 6 mL In N,N-dimethylformamide, HATU (127 mg, 0.33 mmol) and DIPEA (108 mg, 0.84 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 5-(4-methylpiperazin-1-yl)pyridin-2-amine 5-1 (60 mg, 0.31 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 5 (pale yellow solid, 50 mg, 63%).

[0113] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),9.01(dd,1H),8.66(dd,1H),8.18(d,1H),8.03(d,1H),7.88(d,1H),7.60(dd,1H),7. 41(dd,1H),7.26(d,1H),4.20–4.06(m,2H),3.94(s,2H),3.14(t,4H),2.46(t,4H),2.22(s,3H),2.03(d,1H),1.69(d,1H).

[0114] 19 F NMR(376MHz,DMSO-d6)δ-63.73.

[0115] LC-MS m / z(ESI) = 522.20 [M+1].

[0116] Example 6

[0117] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-morpholinylphenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 6

[0118] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-morpholinophenyl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamide

[0119]

[0120] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (50 mg, 0.14 mmol) in 6 mL In N,N-dimethylformamide, HATU (65.7 mg, 0.173 mmol) and DIPEA (55.7 mg, 0.43 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 4-morpholinoaniline 6-1 (28.1 mg, 0.158 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(4-morpholinophenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 6 (pale yellow solid, 36 mg, 87%).

[0121] 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.45(dd,2H),7.26(d,1H),6 .91(d,2H),4.18–4.05(m,2H),4.00(d,1H),3.90(d,1H),3.72(t,4H),3.31(s,1H),3.05(t,3H),2.07(d,1H),1.72(d,1H).

[0122] 19 F NMR(376MHz,DMSO-d6)δ-63.81.

[0123] LC-MS m / z(ESI) = 508.20 [M+1].

[0124] Example 7

[0125] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(pyrrolidine-1-yl)phenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 7

[0126] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(pyrrolidin-1-yl)phenyl)-5-(trifluoromethyl)-3-az abicyclo[3.1.0]hexane-1-carboxamide

[0127]

[0128] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (100 mg, 0.28 mmol) in 6 mL In N,N-dimethylformamide, HATU (127 mg, 0.33 mmol) and DIPEA (108 mg, 0.84 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 4-(pyrrolidine-1-yl)aniline 7-1 (51 mg, 0.31 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(pyrrolidine-1-yl)phenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 7 (pale yellow solid, 70 mg, 88%).

[0129] 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.36(dd,2H),7.25(d,1H),6 .56–6.44(m,2H),4.10(q,2H),3.99(d,1H),3.89(d,1H),3.24–3.11(m,4H),2.07(d,1H),1.99–1.88(m,4H),1.70(d,1H).

[0130] 19F NMR(376MHz,DMSO-d6)δ-63.76.

[0131] LC-MS m / z(ESI) = 492.20 [M+1].

[0132] Example 8

[0133] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 8

[0134] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-5-(trifluorometh yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0135]

[0136] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (100 mg, 0.28 mmol) in 6 mL In N,N-dimethylformamide, HATU (127 mg, 0.33 mmol) and DIPEA (108 mg, 0.84 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 4-(1-methylpiperidin-4-yl)aniline 8-2 (60.3 mg, 0.31 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 8 (pale yellow solid, 60 mg, 72%).

[0137] 1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.55–7.47(m,2H),7.27(d,1H),7.23–7.16(m,2H ),4.17–4.06(m,2H),4.00(d,1H),3.91(d,1H),2.90–2.81(m,2H),2.40 (m,1H),2.19(s,3H),2.08(d,1H),2.02–1.90(m,2H),1.77–1.54(m,5H).

[0138] 19 F NMR(376MHz,DMSO-d6)δ-63.85.

[0139] LC-MS m / z(ESI) = 520.20 [M+1].

[0140] Example 9

[0141] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(pyridin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 9

[0142] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(pyridin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0143]

[0144] Dissolve (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (150 mg, 0.43 mmol) in 6 mL In N,N-dimethylformamide, HATU (196 mg, 0.51 mmol) and DIPEA (166 mg, 1.29 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 1-(pyridin-2-yl)piperidin-4-amine 9-1 (84 mg, 0.47 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(1-(pyridin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 9 (pale yellow solid, 141 mg, 8...

[0145] 5%).

[0146] 1 H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.63(dd,1H),8.16(d,1H),8.13–8.02(m,2H),7.59(dd,1H),7.51(m,1H),7.21(d,1H),6.85(d,1H),6.5 9(dd,1H),4.30–4.20(m,2H),4.00(d,1H),3.93(m,3H),3.80(d,1H),2. 91(td,2H),2.00(d,1H),1.71(td,2H),1.62(d,1H),1.48–1.32(m,2H).

[0147] 19 F NMR(376MHz,DMSO-d6)δ-63.54.

[0148] LC-MS m / z (ESI) = 507.20 [M+1].

[0149] Example 10

[0150] (1S,5R)-N-(5-(3R,4R)-3-amino-4-methoxypyrrolidine-1-yl)pyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 10

[0151] (1S,5R)-N-(5-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-2-yl)-3-(8-cyanoqui nolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0152]

[0153] first step:

[0154] (1S,5R)-N-(5-bromopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 10-2

[0155] (1S,5R)-N-(5-bromopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabi cyclo[3.1.0]hexane-1-carboxamide

[0156]

[0157] Compound A-1 (400.0 mg, 1.15 mmol) was dissolved in 2 mL of DMF, followed by the addition of HATU (438.3 mg, 1.15 mmol) and DIPEA (595.9 mg, 4.61 mmol). The mixture was stirred at room temperature for 10 min, and then 10-1 (199.4 mg, 1.15 mmol) was added. The mixture was stirred at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was washed with 15 mL of water and 15 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The mixture was separated by MPLC (acetonitrile:water 47:53) to give the crude product (1S,5R)-N-(5-bromopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 10-2 (white solid, 103 mg, 17.9%).

[0158] LC-MS m / z(ESI) = 502.1 [M+1].

[0159] Step Two:

[0160] tert-Butyl((3R,4R)-1-(6-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)pyridin-3-yl)-4-methoxypyrrolidine-3-yl)carbamate 10-4

[0161] tert-butyl((3R,4R)-1-(6-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamido)pyridin-3-yl)-4-methoxypyrrolidin-3-yl)carbamate

[0162]

[0163] Under a nitrogen atmosphere, 10⁻² (50.2 mg, 0.1 mmol) was dissolved in 10 mL of 1,4-dioxane, followed by the addition of 10⁻³ (21.6 mg, 0.1 mmol). The mixture was purged with nitrogen three times. Cesium carbonate (130.3 mg, 0.4 mmol) and Ruphos Pd G3 (8.37 mg, 0.01 mmol) were then added sequentially, and the mixture was purged with nitrogen three times. The mixture was then heated to 90 °C and reacted for 2 h. The solvent was evaporated, the product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated again to obtain crude tert-butyl((3R,4R)-1-(6-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)pyridin-3-yl)-4-methoxypyrrolidine-3-yl)carbamate 10⁻⁴, which was directly added to the next step.

[0164] LC-MS m / z(ESI) = 638.3 [M+1].

[0165] Step 3:

[0166] (1S,5R)-N-(5-(3R,4R)-3-amino-4-methoxypyrrolidine-1-yl)pyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 10

[0167] (1S,5R)-N-(5-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0168]

[0169] The crude product of 10⁻⁴ was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (126.0 mg, 1.16 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solution was evaporated to dryness. The product was separated by MPLC (acetonitrile:water 47:53) to give the target product (1S,5R)-N-(5-(3R,4R)-3-amino-4-methoxypyrrolidine-1-yl)pyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 10 (yellow solid, 30 mg, 55.9%).

[0170] 1 H NMR(400MHz,DMSO-d6)δ9.04-8.98(m,1H),8.69-8.63(m,1H),8.18(d,1H),7.88– 7.80(m,1H),7.71–7.56(m,2H),7.26(d,1H),6.99-6.92(m,1H),4.23–4.07(m,2H ),3.94(s,2H),3.75–3.65(m,1H),3.59-3.51(m,1H),3.48(d,1H),3.47-3.41(m, 1H),3.30(s,3H),3.24-3.20(m,1H),2.99-2.95(m,1H),2.03(d,1H),1.68(d,1H).

[0171] 19 F NMR (376MHz, DMSO-d6) δ 64.48.

[0172] LC-MS m / z(ESI) = 538.2 [M+1].

[0173] Example 11

[0174] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-(pyrrolidine-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 11

[0175] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0176]

[0177]

[0178] Dissolve (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid A-1 (100 mg, 0.28 mmol) in 5 ml In N,N-dimethylformamide, HATU (127 mg, 0.33 mmol) and DIPEA (180.6 mg, 1.4 mmol) were added in an ice bath and stirred at low temperature for 5 minutes. Then, 6-(pyrrolidine-1-yl)pyridin-3-amine 11-1 (86 mg, 0.31 mmol) was added and stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-(pyrrolidine-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 11 (pale yellow solid, 92 mg, 86%).

[0179] 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.02(dd,1H),8.67(dd,1H),8.24–8.14(m,2H),7.64(m,2H),7.27(d,1H),6.44( d,1H),4.16–4.06(m,2H),4.01(d,1H),3.89(d,1H),3.36-3.33(m,4H),2.10(d,1H),2.00–1.88(m,4H),1.74(d,1H).

[0180] 19 F NMR(376MHz,DMSO-d6)δ-63.73.

[0181] LC-MS m / z(ESI)=493.20.20[M+1].

[0182] Biological testing

[0183] HEK-Blue-hTLR7 / 8 / 9 cell inhibition assay

[0184] 1. HEK-Blue-hTLR7 / 8 cells (1×10⁸) 4 (cells / well), HEK-Blue-hTLR9 cells (1.5×10⁻⁶) 4 (30 μL per well) cells were seeded into 384-well cell culture plates. The plates were incubated at 37°C in a 5% CO2 incubator for 4 hours.

[0185] 2. The compounds were prepared using DMSO and diluted in DMEM medium to 10 concentrations (1:3 dilution), with final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, and 0.5 nM, respectively; R848 was prepared using DMSO and diluted in DMEM medium to final concentrations of 0.8 μM (HEK-Blue-hTLR7) and 3 μM (HEK-Blue-hTLR8); ODN2006 was prepared using endotoxin-free water and diluted in DMEM medium to final concentration of 1 μM.

[0186] 3. Cells treated with DMSO served as the blank control group. Simultaneously, cells treated with Resiquimod (R848) alone served as the positive control group for HEK-Blue-hTLR7 / 8, and cells treated with ODN2006 alone served as the positive control group for HEK-Blue-hTLR9. Cells treated with the test compound and either R848 or ODN2006 served as the test group. Each group had two parallel wells, which were incubated at 37°C in a 5% CO2 incubator.

[0187] 4. After 4 hours of incubation, remove the 384-well plates of HEK-Blue-hTLR7 / 8 from the incubator. Add R848 to each well individually, or add R848 and the diluted compound simultaneously. Incubate at 37°C in a 5% CO2 incubator for 16 hours. Then, remove the 384-well plates of HEK-Blue-hTLR9 from the incubator. Add ODN2006 to each well individually, or add ODN2006 and the diluted compound simultaneously. Incubate at 37°C in a 5% CO2 incubator for 16 hours.

[0188] 5. After culturing for 16 hours, remove the 384-well plate from the incubator, centrifuge at 1000 rpm for 1 minute, and use a multi-mode microplate reader to read the optical density value of each well at 620 nm.

[0189] 6. Calculate the cell inhibition rate = (1 - (OD620 test group - OD620 blank group) / (OD620 positive group - OD620 blank group)) × 100%, and calculate the half maximal inhibitory concentration (IC50) through curve fitting. 50 ).

[0190] The experimental results are shown in Tables 1, 2, and 3:

[0191] Table 1

[0192] compound <![CDATA[TLR7 IC 50 (nM)]]> Compound 1 32 Compound 2 27 Compound 4 17 Compound 5 2 Compound 6 9 Compound 7 12 Compound 8 1 Compound 9 19 Compound 10 4 Compound 11 9

[0193] Table 2

[0194]

[0195]

[0196] Table 3

[0197] compound <![CDATA[TLR8 IC 50 (nM)]]> Compound 5 11 Compound 8 2 Compound 10 22

[0198] Conclusion: The compounds of this invention exhibit good antagonistic activity against HEK-Blue-hTLR7 / 8 cells, showing significant antagonistic effects, while showing no significant antagonistic effect against HEK-Blue-hTLR9 cells.

[0199] In vivo inhibition experiment of IL-6

[0200] Experimental materials: Preparation of compound solutions: R848 was prepared with pure water (sterilized) to a final concentration of 25 μg / 100 μL; the test compound was prepared with sodium citrate buffer at pH 3 to a final concentration of 0.1 mg / mL.

[0201] Experimental animals: C57BL / 6 female mice, purchased from Jicui Yaokang, 6-8 weeks old.

[0202] Experimental method: C57BL / 6 female mice were randomly divided into a blank group, a control group, and an experimental group, with 8 mice in each group.

[0203] Control group: Blood was collected from mice after they were fasted for 12 hours.

[0204] Control group: Mice were fasted for 12 hours and then administered sodium citrate buffer solution with pH=3 by gavage. All other procedures were the same as those for the experimental group.

[0205] Experimental group: Mice were fasted for 12 hours and then administered the test compound (1 mg / kg) by gavage. One hour later, 25 μg of R848 (purchased from MCE) was injected intraperitoneally. Two hours later, blood was collected by enucleation. Serum was allowed to stand at room temperature for 30 minutes, followed by centrifugation for 10 minutes (3000 rpm). The supernatant was collected, and serum IL-6 concentration was measured using an IL-6 ELISA kit. The IL-6 inhibition rate was calculated based on the serum IL-6 concentrations of the control and experimental groups. Calculation formula: Inhibition rate = (C2-C3) / (C2-C1) × 100%.

[0206] C1: Serum IL-6 concentration in the blank group;

[0207] C2: Serum IL-6 concentration in the control group;

[0208] C3: Serum IL-6 concentration in the experimental group.

[0209] Table 2: In vivo inhibition experiments of IL-6

[0210] compound IL-6 inhibition rate Compound 5 ＞95％ Compound 8 ＞85％

[0211] Conclusion: The compounds of this invention have a significant inhibitory effect on IL-6.

[0212] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound of formula (I) : ###0001### (I) or a stereoisomer thereof, wherein: R1 is selected from -CONHR4; R2 is selected from CF3; R3 is selected from H, F, Cl, Br, I, and CF3; R4 is selected from H, F, Cl, Br, I, CF3, and CH3; and n is 0, 1, 2, 3, or 4.

2. A compound of formula (I) according to claim 1, or a stereoisomer thereof: ###0002### (I) wherein: R1 is selected from -CONHR4; R2 is selected from CF3; R3 is selected from H, F, Cl, Br, I, and CF3; R4 is selected from H, F, Cl, Br, I, CF3, and CH3; and n is 0, 1, 2, 3, or 4.

3. A compound according to claim 1 or 2, or a stereoisomer thereof, which is one of the following structures: ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ### R4is selected from R2is selected from C 1-6 alkyl, said alkyl being optionally further substituted by one or more halogen; R3is selected from ​ wherein ​ ​ ​ ​ ​ ​ ​ ​ 6. An intermediate for preparing a compound of general formula (I), or a stereoisomer thereof, wherein, ​

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