JAK inhibitors with high oral bioavailability

Abstract

The present invention provides a JAK inhibitor with high oral bioavailability, which is characterized by comprising a compound of the following formula I, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, or a pharma- ceutically acceptable salt thereof, as an active ingredient. The JAK inhibitor with high oral bioavailability according to the present invention can solve the problem of the low oral bioavailability of conventional JAK inhibitors, and further modify the compound to change the physicochemical properties of one or more small molecule compounds, thereby improving the in vivo cellular absorption properties of such compounds, greatly increasing the bioavailability of the drug, and enabling new administration methods and uses of such compound drugs.

Description

Cross-reference to related applications

[0001] This application claims priority to a Chinese patent application filed on August 6, 2021, bearing application number 202110901146.3, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention relates to the field of small molecule compounds, and in particular to JAK inhibitors that are useful for preventing or treating autoimmune diseases or related inflammatory skin disorders, and that have high oral bioavailability, which offers distinct advantages, especially when administered orally. [Background technology]

[0003] Since the launch of Pfizer's JAK3 inhibitor tofacitinib and Incyte's JAK1 / JAK2 inhibitor ruxolitinib, JAK inhibitors have become an important therapeutic tool and drug development direction for treating diseases such as allergic reactions and autoimmune-related inflammatory diseases, myeloproliferative diseases (MPDs), and graft-versus-host disease (GVHD).

[0004] Currently, eight JAK inhibitors are approved worldwide for oral or topical use to treat human diseases. Because the JAK family consists of four subtypes that are structurally similar but have distinct and overlapping functions, most previous JAK inhibitors have demonstrated effective inhibition of the JAK1, JAK2, and JAK3 subtypes. These JAK inhibitors have encountered problems in clinical application, such as poor therapeutic efficacy or significant side effects. For example, safety risks (such as cancer and infection) have been gradually revealed after long-term use of several commercially available oral JAK inhibitors, leading the FDA to issue a safety black box warning for marketed JAK drugs.

[0005] Currently, JAK inhibitors face the following challenges: 1) Pan-JAK inhibitors inhibit three or more JAK subtypes, particularly JAK2, which can lead to anemia and coagulation disorders, making their future prospects for oral treatment of non-malignant inflammatory diseases less optimistic. 2) Inhibiting one or two JAK subtypes, such as JAK1 or TyK2, is expected to be safer, but their specificity limits their inhibitory efficacy. 3) JAK inhibitors that inhibit one or two JAK subtypes lack sufficient bioavailability, preventing systematic oral treatment, severely limiting their clinical application. 4) There are relatively few small molecule compounds that simultaneously inhibit both TyK2 and JAK1 subtypes with high specificity, and clinical data on the application of such compounds to autoimmune diseases is scant. Summary of the Invention

[0006] The object of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a JAK inhibitor with high activity, high selectivity and high oral bioavailability.

[0007] Specifically, the present inventors have found that existing JAK inhibitors can be applied for topical administration, and that such JAK inhibitor drugs are introduced into local lesions of the skin by passive / active absorption in inflammatory skin disease model animals, suppress inflammation, treat inflammatory skin diseases, and show excellent therapeutic effects. However, such small molecule JAK inhibitors have extremely low oral bioavailability, making them unsuitable for further development as oral medications.

[0008] To solve the problem of low oral bioavailability, the present invention further modifies the compounds to change the physicochemical properties of one or more small molecule compounds, thereby improving the in vivo cellular absorption characteristics of the compounds and significantly increasing the bioavailability of the drugs, and enabling new administration methods and uses of such compound drugs. Therefore, this increases the clinical use methods for treating related diseases using JAK inhibitors that strongly inhibit JAK kinase at the cellular level in vitro and in vivo, and is an important innovative means for addressing unmet clinical needs in the field of new drug research and development. The present invention was also completed based on the above findings.

[0009] To achieve the above object, in one aspect, the present invention provides a JAK inhibitor having high oral bioavailability, characterized by comprising, as an active ingredient, a compound of the following formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

[0010] [ka] where: R1 is C or N, R2 is [ka] or [ka] wherein R4 is selected from halogen or cyano; R3 is selected from 5- or 6-membered aryl or heteroaryl that is unsubstituted or optionally substituted with at least one of halogen, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, amino, amido, and C1-C3 alkylamido.

[0011] In one embodiment of the present invention, said R4 is selected from fluoro or cyano.

[0012] In one embodiment of the present invention, said 5 or 6 membered aryl or heteroaryl is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, or pyridazinyl.

[0013] In one embodiment of the present invention, the C1-C3 alkyl is methyl, ethyl, or propyl, the C1-C3 hydroxyalkyl is hydroxymethyl, hydroxyethyl, or hydroxypropyl, and the C1-C3 alkylamide is methylformamide, dimethylformamide, ethylformamide, or methylacetamide.

[0014] In one embodiment of the present invention, R3 is any one selected from the following groups: [ka]

[0015] In another aspect, the present invention also provides the use of the compound of formula (I) as defined above, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of autoimmune diseases and associated inflammatory skin diseases.

[0016] In one embodiment of the invention, the autoimmune disease is at least one selected from rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behcet's disease, Covid-19 severe pneumonia, Reiter's syndrome, and uveitis.

[0017] In one embodiment of the present invention, the associated inflammatory skin disease is at least one selected from psoriasis, autoimmune-associated vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, and lichen sclerosus et atrophicus.

[0018] In one embodiment of the invention, the drug is an orally administered drug.

[0019] In one embodiment of the present invention, the orally administered drug is a tablet, pill, granule, capsule, lozenge, or liquid.

[0020] The functions and effects of the present invention are as follows.

[0021] The JAK inhibitors of the present invention with high oral bioavailability can overcome the drawback of the low oral bioavailability of conventional JAK inhibitors. By further modifying the compounds, the physicochemical properties of one or more small molecule compounds can be changed to improve the in vivo cellular absorption properties of such compounds, significantly increasing the bioavailability of the drug, and enabling new administration methods and uses of such compound drugs.

[0022] Specifically, the JAK inhibitors of the present invention increase the hydrolyzable metabolic groups to reduce the polarity of the compound and improve water solubility, thereby delaying the half-life of the drug substance, delaying its clearance, and increasing the blood concentration of the drug substance, thereby significantly improving the bioavailability of the drug substance, making such highly efficient JAK inhibitors orally administrable rather than orally administrable, thereby increasing the routes of drug use and correspondingly improving the therapeutic applicability of the drug. DETAILED DESCRIPTION OF THE INVENTION

[0023] Specific embodiments of the present invention will be described in detail below. Note that the specific embodiments described in this specification are used only to explain and interpret the present invention, and are not used to limit the present invention. The endpoints of the ranges and any values ​​disclosed herein should be understood not to be limited to the exact ranges or values, but to include values ​​close to those ranges or values. In the case of numerical ranges, the values ​​between the endpoints of each range, the values ​​between the endpoints of each range and the individual point values, and the values ​​between the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0024] Before describing the present invention in detail, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. In order to more fully understand the invention described herein, the following terms will be used and are defined below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as would be understood by one of ordinary skill in the art to which the present invention pertains.

[0025] In one aspect, the present invention provides a JAK inhibitor having high oral bioavailability, characterized in that it comprises, as an active ingredient, a compound of Formula I below, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: [ka] (where, R1 is C or N, R2 is [ka] or [ka] and R4 is selected from halogen (e.g. fluoro, chlorine or bromine, in particular fluoro) or cyano; R3 is selected from 5- or 6-membered aryl or heteroaryl that is unsubstituted or optionally substituted with at least one of halogen, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, amino, amido, and C1-C3 alkylamido.

[0026] In the present invention, the unsubstituted or substituted 5- or 6-membered aryl or heteroaryl may be any of various 5- or 6-membered aryl or heteroaryl groups known in the art. Furthermore, in the heteroaryl group, the heteroatom may be a heteroatom such as N, O, or S, as known to those skilled in the art, but is preferably an N atom, and the number thereof may be, for example, 1, 2, or 3. In one preferred embodiment of the present invention, the 5- or 6-membered aryl or heteroaryl may be selected from, but is not limited to, phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, or pyridazinyl.

[0027] With respect to the above substituents, the C1-C3 alkyl may be, for example, methyl, ethyl, or propyl; the C1-C3 hydroxyalkyl may be, for example, hydroxymethyl, hydroxyethyl, or hydroxypropyl; and the C1-C3 alkylamide may be, for example, methylformamide, dimethylformamide, ethylformamide, or methylacetamide, but is not limited thereto.

[0028] Furthermore, in a more preferred embodiment of the present invention, R3 may be any one selected from the following groups: [ka]

[0029] As used herein, the term "pharmaceutically acceptable" refers to a substance that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be applied to an individual without causing an undesired biological response or interacting in an undesirable manner with any of the components contained in the composition. In the present invention, "pharmaceutically acceptable salts" may include inorganic salts and organic salts, where the organic salts may include ammonium, lithium, sodium, potassium, cesium, calcium, magnesium, copper, aluminum, zinc, barium, or quaternary ammonium salts, and the inorganic salts may include, but are not limited to, arginine, t-butylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, imidazole, lysine, methylamine, pyridine, pyridine carboxylate, piperazine, triethylamine, triethanolamine, trimethylamine, or urea salts.

[0030] In another aspect, the present invention also provides the use of a compound of formula (I) above, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of autoimmune diseases and associated inflammatory skin diseases.

[0031] As used herein, the term "treatment" refers to the administration of a therapeutic agent according to a treatment regimen that achieves a desired effect of partially or completely alleviating, ameliorating, mitigating, inhibiting, delaying the onset of one or more symptoms or characteristics of a particular disease, disorder, and / or condition, delaying onset, reducing severity, and / or reducing incidence. In some embodiments, the administration of a therapeutic agent according to a treatment regimen is associated with achieving a desired effect. The treatment can be directed to subjects who do not exhibit the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment can be directed to subjects who exhibit one or more determined signs of the associated disease, disorder, and / or condition. In some embodiments, the treatment can be directed to subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, the treatment can be directed to subjects known to have one or more susceptibility factors statistically associated with an increased risk of developing the associated disease, disorder, and / or condition.

[0032] According to the present invention, the medicament manufactured for the above uses may comprise an effective amount of the compound of formula (I) of the present invention, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0033] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of a therapeutic agent that confers a therapeutic benefit on a treated subject at a reasonable benefit / risk ratio applicable to any drug treatment. Such therapeutic benefit may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication or feels an effect). In some embodiments, a "therapeutically effective amount" refers to an amount of a therapeutic agent or composition that effectively treats, ameliorates, or prevents (e.g., delays onset of) the associated disease or condition, and / or exhibits a detectable therapeutic or prophylactic effect, e.g., by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and / or reducing the severity or frequency of symptoms of the disease.

[0034] Those skilled in the art will recognize that the therapeutically effective amount of the compound of formula (I) administered will vary depending on the subject and the nature and severity of the disease, the subject's physical condition, the treatment regimen (e.g., whether a second therapeutic agent is used), and the selected route of administration. The appropriate dose can be easily determined by those skilled in the art. Furthermore, the optimal amount and duration of individual administration of the drug will be determined based on the nature and severity of the condition being treated, the form, route, and location of administration, and the age and condition of the particular subject being treated, with the physician ultimately determining the appropriate dosage. This dosage can be repeated multiple times as necessary. If side effects occur, the dosage and / or frequency can be modified or reduced based on routine clinical trials.

[0035] In the present invention, the term "pharmaceutically acceptable excipient, carrier or diluent" includes, but is not limited to, any adjuvant, carrier, excipient, flow enhancer, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending aid, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the relevant governmental authorities as acceptable for use in humans or veterinary animals.

[0036] According to the present invention, the drug produced by the use of the present invention may contain, as an active ingredient, the compound of formula (I) of the present invention, and may also contain, as another active ingredient, another drug useful for the prevention or treatment of autoimmune diseases and immune-related inflammatory skin diseases. Examples of such drugs include, but are not limited to, vitamin D derivatives, vitamin A derivatives, glucocorticoids, calcineurin inhibitors, and nonsteroidal anti-inflammatory drugs. When the drug contains multiple active ingredients, the active ingredients can be administered simultaneously, sequentially, or separately, at the discretion of a physician.

[0037] The compounds of formula (I) of the present invention can be administered to patients by various routes, including oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intrathecal, regional, or topical (e.g., mucosal) administration. The optimal route of administration in any given situation will depend on the subject and the nature and severity of the disease, as well as the subject's physical condition. In one embodiment of the present invention, a drug prepared with the compounds of formula (I) of the present invention can be administered orally. In this case, the orally administered drug may be in the form of a tablet, pill, granule, capsule, lozenge, or liquid.

[0038] The inventors' research has revealed that the compound of formula (I) of the present invention or a pharmaceutical product prepared therefrom (especially when administered orally) can achieve excellent effects when used to prevent or treat JAK-related autoimmune diseases and related inflammatory skin diseases. Specifically, the autoimmune diseases are selected from rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behçet's disease, severe COVID-19 pneumonia, Reiter's syndrome, uveitis, etc. The related inflammatory skin diseases are selected from psoriasis, autoimmune-related vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, and atrophic lichen sclerosus, etc.

[0039] The effects of specific compounds of the present invention will be described in detail below using examples. [Example]

[0040] [General synthesis method for compound 1 (TDM-181055)] [ka]

[0041] Step 1: Preparation of Compound 1 (TDM-181055) ((S)-(2,2-difluoro-N-(5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide)methyl pivalate)

[0042] To a solution of compound 1a (500 mg, 1.346 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (372 mg, 2.692 mmol) and compound 1b (608 mg, 4.039 mmol). The mixture was purged with argon gas multiple times, heated to 40 °C, and stirred overnight. The mixture was then concentrated under reduced pressure, water was added to the residue, and the solid was collected by filtration. The solid was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane = 0-30%) to give the product (TDM-181055, compound 1, 19.8 mg, 3% yield) as a yellow solid. LCMS [M+1] + =486.2.

[0043] 1 H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 5.2 Hz, 1H), 6.03 - 5.92 (m, 2H), 3.83 (s, 3H), 3.04 (s, 1H), 2.17 - 1.88 (m, 2H), 1.10 (s, 9H). [Example]

[0044] [General synthesis method for compound 2 (TDM-181065)] [ka]

[0045] Step 1: Preparation of Compound 2 (TDM-181065) (((1-(3-cyanophenyl)-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)methyl)sulfonamido)methyl pivalate)

[0046] Cesium carbonate (219.4 mg, 0.673 mmol) was added to a solution of compound 2a (150 mg, 0.337 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to 50°C and stirred for 1 hour. After cooling to room temperature, compound 2b (122.2 mg, 0.505 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. LCMS [M+H] + = 560, indicating complete reaction. Workup: The reaction mixture was poured into 70 mL of water, and the aqueous phase was extracted three times with ethyl acetate (EA) (3 x 150 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was dried. The crude product was purified by column chromatography [eluent: (D / M = 10:1) / DCM = 0-15%] to obtain the title compound (TDM-181065, compound 2, 60 mg, 31.8% yield) as a yellow solid. LCMS [M+1] + =560.2.

[0047] 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 8.6 Hz, 2H), 7.94 - 7.86 (m, 3H), 7.79 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 5.2 Hz, 1H), 5.63 (s, 2H), 4.86 (s, 2H), 3.84 (s, 3H), 1.17 (s, 9H). [Example]

[0048] [General synthesis method for compound 3 (TDM-181058)] [ka]

[0049] The compound (TDM-181058, compound 3, 90.5 mg, yield 41.13%) was obtained as a yellow solid in the same manner as in Example 2. LCMS [M+1] + =553.3.

[0050] 1 H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), 7.57 (s, 1H), 7.53 - 7.41 (m, 3H), 7.27 (ddd, J = 17.1, 11.2, 3.5 Hz, 4H), 5.60 (s, 2H), 4.79 (s, 2H), 3.83 (s, 3H), 1.17 (s, 9H). [Example]

[0051] [General synthesis method for compound 4 (TDM-181059)] [ka]

[0052] A nearly white solid (TDM-181059, Compound 4, 67 mg, 23% yield) was obtained in the same manner as in Example 2. LCMS [M+1] + =566.3.

[0053] 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.32 (d, J = 7.4 Hz, 2H), 8.09 (t, J = 5.6 Hz, 1H), 7.71 (d, J = 6.6 Hz, 2H), 7.51 (d, J = 5.2 Hz, 3H), 7.32 (d, J = 9.0 Hz, 1H), 5.74 (d, J = 10.4 Hz, 2H), 3.28 - 3.18 (m, 2H), 2.55 - 2.52 (m, 1H), 2.37 (s, 3H), 2.03 (dt, J = 13.3, 6.6 Hz, 1H), 1.87 (s, 1H), 1.19 - 1.06 (m, 12H).

Example

[0054] [General synthesis method of compound 5 (TDM-181060)]

change

[0055] Using the same method as in Example 2, a slightly white solid (TDM-181060, compound 5, 89.4 mg, yield 22%) was obtained. LCMS [M+1]+ =552.2.

[0056] 1H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.41 - 8.24 (m, 3H), 7.92 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.59 - 7.37 (m, 3H), 5.75 (d, J = 10.4 Hz, 2H), 3.31 - 3.24 (m, 2H), 2.52 (d, J = 1.9 Hz, 1H), 2.13 - 1.78 (m, 2H), 1.19 - 1.06 (m, 12H). Comparative Example 1

[0057] [Comparative Example 1: General synthesis method for compound 6 (TDM-180935)] [ka]

[0058] Step 1: Preparation of compound 6 (TDM-180935)

[0059] N,N-diisopropylethylamine (72.9 mg, 0.564 mmol) was added to a solution of 4-(6-aminopyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (compound 6a, 80 mg, 0.299 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred for 5 minutes, and then o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (170 mg, 0.449 mmol) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (compound 6b, 54 mg, 0.449 mmol) were added. The mixture was heated to 90 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove some of the solvent. Water was added to the residue, and the solution was then extracted with ethyl acetate (60 mL * 3). The organic layer was washed with saturated brine (50 mL * 5) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative separation with formic acid to obtain the compound (S)-2,2-difluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-formamide (compound 6, 21.6 mg, 19.5% yield) as a yellow solid. LCMS [M+1] + = 372.1.

[0060] 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.54 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.51 (dd, J = 14.3, 6.9 Hz, 2H), 8.22 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 5.2 Hz, 1H), 3.83 (s, 3H), 3.04 (dd, J = 22.4, 9.9 Hz, 1H), 2.05 (dt, J = 11.8, 8.0 Hz, 2H). Comparative example 2

[0061] [Comparative Example 2: General synthesis method of compound 7 (TDM-180958)] [ka]

[0062] Step 1: Preparation of Compound 7c (3-cyanobenzylaminothiocarbamate)

[0063] To a solution of compound 7a (1.78 g, 9.08 mmol) in ethanol (13 mL) was added compound 7b (690 mg, 9.08 mmol). The reaction mixture was heated to 80°C and stirred for 1 hour. LCMS [M+H] = 192 indicated complete reaction. Workup: The reaction mixture was concentrated to dryness to give the title compound (compound 3c, 1.7 g, 97.7% yield) as a white solid. LCMS [M+H] = 192.

[0064] Step 2: Preparation of Compound 7d ((3-cyanophenyl)methanesulfonyl chloride)

[0065] To a solution of N-chlorosuccinimide (4.85 g, 36.32 mmol) in acetonitrile (20 mL), 2N hydrochloric acid solution (2.5 mL) and compound 7c (1.74 g, 9.08 mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Workup: After the reaction was completed, the acetonitrile was concentrated to remove the residue, and water (15 mL) was added to precipitate a white solid. The solid was filtered and dried in an oil pump to give the title compound (compound 7d, 1.776 g, 90.7% yield) as a white solid.

[0066] Step 3: Preparation of compound 7 (TDM-180958)

[0067] Compound 7d (1 g, 4.64 mmol) was added to a solution of compound 7e (500 mg, 1.878 mmol) in anhydrous pyridine (20 mL), and the reaction mixture was heated to 80°C and reacted for 30 minutes. LCMS [M+H] + = 446, indicating that the reaction was complete. Workup: The reaction mixture was concentrated to dryness, and the crude product was passed through a column [00 eluent: (D:M=10:1) / DCM=0-50%]. The crude product was slurried with DCM / MeOH=30 / 1 to give a yellow solid, which was then purified by preparative HPLC to give the title compound, 1-(3-cyanophenyl)-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)methanesulfonamide (Compound 7, 155.4 mg, 18.6% yield).

[0068] 1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 9.46 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.93 (s, 1H), 7.84 (dt, J = 7.2, 1.6 Hz, 1H), 7.71 (s, 1H), 7.61 (ddd, J = 17.3, 10.8, 4.8 Hz, 3H), 7.32 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 5.2 Hz, 1H), 4.71 (s, 2H), 3.85 (s, 3H). LCMS[M+H] + = 446. Comparative Example 3

[0069] [Comparative Example 3: General synthesis method of compound 8 (TDM-180945)] [ka]

[0070] Step 1: Preparation of compound 8 (TDM-180945)

[0071] To a solution of compound 8a (60 mg, 0.225 mmol) in pyridine (5 mL) was added compound 8b (65.8 mg, 0.315 mmol), and the mixture was heated to 70 °C and stirred for 6 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane = 70:30) using formic acid to give the yellow title solid compound 8, TDM-180945, i.e., 1-(3-fluorophenyl)-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)methanesulfonamide (26.1 mg, 19.8% yield).

[0072] 1H NMR (400 MHz, DMSO-d6) δ10.25 (s, 1H), 9.45 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.56 (s, 1H), 7.40 (dd, J = 14.3, 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.26 - 7.15 (m, 2H), 7.11 (d, J = 7.3 Hz, 2H), 4.63 (s, 2H), 3.84 (s, 3H). LCMS [M+1]+ = 439.2. Comparative example 4

[0073] [Comparative Example 4: General synthesis method of compound 9 (TDM-180977)] [ka]

[0074] Step 1: Preparation of Compound 9b (4-amino-N-ethyl-2-methylbenzamide)

[0075] To a solution of compound 9a (1.8 g, 11.91 mmol) in N,N-dimethylformamide (80 mL) were added o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.4 g, 14.289 mmol) and N,N-diisopropylethylamine (3.8 g, 29.775 mmol), and the mixture was stirred for 5 minutes. Then, a solution of ethylamine in tetrahydrofuran (2 M) (9 mL, 18 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove part of the solvent, water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with water (150 mL * 3) and saturated brine (150 mL), dried over sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether / ethyl acetate = 0% - 50%) to give the title compound (Compound 9b, 1.32 g, 62.2% yield) as a yellow oil. LCMS [M+1]+ = 179.

[0076] Step 2: Preparation of Compound 9 ((S)-4-((4-(4-(4-(2,2-difluorocyclopropane-1-carboxamido)phenyl)pyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamide)

[0077] To a solution of compound 9c (80 mg, 0.258 mmol) in n-butanol (8 mL), compound 9b (92 mg, 0.517 mmol) and p-toluenesulfonic acid monohydrate (98 mg, 0.517 mmol) were added. The resulting mixture was heated to 110 °C and stirred for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (formic acid) to obtain the title compound TDM-180977 (compound 9, 19.4 mg, 13.3% yield) as a white solid. LCMS [M+H] = 425.2.

[0078] 1H NMR (400 MHz, DMSO) δ10.70 (s, 1H), 9.72 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 5.6 Hz, 1H), 7.81 - 7.67 (m, 4H), 7.40 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3.28 - 3.17 (m, 2H), 2.86 (ddd, J = 13.6, 10.8, 8.1 Hz, 1H), 2.37 (s, 3H), 2.14-1.93 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). Comparative example 5

[0079] [General synthesis method for compound 10 (TDM-180972)] [ka]

[0080] Step 1: Preparation of Compound 10c (4-(2-chloropyrimidin-4-yl)aniline)

[0081] Compound 10a (2 g, 9.129 mmol), compound 10b (1.36 g, 9.129 mmol), tetrakistriphenylphosphine palladium (527 g, 0.45 mmol), potassium carbonate (2.5 g, 18.258 mmol), dioxane (20 mL), and water (20 mL) were added to a three-neck flask and purged with nitrogen gas several times. The mixture was then heated to 80 °C and stirred for 45 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-60%) to afford the title compound (compound 10c, 394 mg, 21% yield) as a pale yellow solid. LCMS [M+1]+ = 206.

[0082] Step 2: Preparation of Compound 10e ((S)—N-(4-(2-chloropyrimidin-4-yl)phenyl)-2,2-difluorocyclopropane-1-carboxamide)

[0083] Compound 10c (300 mg, 1.459 mmol) and compound 10d (187 mg, 1.531 mmol) were added to a three-neck flask, and the mixture was purged with nitrogen gas several times. Then, pyridine (10 mL) and phosphorus oxychloride (335.6 mg, 2.189 mmol) were added at 0 °C. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was extracted with ethyl acetate (30 mL). The combined organic layers were washed with water (30 mL) and saturated brine (250 mL), dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-12%) to give the title compound (10e, 327.7 mg, 72.5% yield) as a yellow solid. LCMS [M+H]+ = 310.

[0084] Step 3: Preparation of Compound 1 ((S)-4-((4-(4-(4-(2,2-difluorocyclopropane-1-carboxamido)phenyl)pyrimidin-2-yl)amino)-N-ethylbenzamide)

[0085] To a solution of compound 10e (80 mg, 0.258 mmol) in n-butanol (8 mL), compound 1f (85 mg, 0.517 mmol) and p-toluenesulfonic acid monohydrate (98 mg, 0.517 mmol) were added. The resulting mixture was heated to 110 °C and stirred for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (formic acid) to obtain the title compound TDM-180972 (compound 10, 19.7 mg, 17.5% yield) as a yellow solid. LCMS [M+H] = 438.2.

[0086] 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 9.91 (s, 1H), 8.57 (d, J = 5.3 Hz, 1H), 8.28 (t, J = 5.5 Hz, 1H), 8.19 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 5.3 Hz, 1H), 3.28 (dt, J = 12.7, 6.4 Hz, 2H), 2.86 (ddd, J = 13.6, 10.8, 8.0 Hz, 1H), 2.12 - 1.94 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H).

[0087] [Rat oral PK biological explanation]

[0088] To verify whether compounds 1-5 of the present invention have significantly improved oral bioavailability compared with compounds 6-10 with similar structures, a single oral dose pharmacokinetic (PK) study was conducted in Sprague Dawley (SD) rats (weighing approximately 250-300 g) for approximately 6-8 weeks to compare the PK parameters of compounds 1-10. Briefly, the compounds were formulated into clear solutions at a concentration of 1 mg / mL in a solvent (DMA: 30% Solutol HS 15: Saline = 10:10:80 (v / v / v)), and each compound was administered orally (5 mg / kg) to three rats (n=3) in a single dose. Approximately 150 μL of whole blood was collected from each rat via the subclavian vein before administration and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration and placed in an Eppendorf tube containing EDTA-K2. Subsequently, 100 μL of whole blood was collected and added to an Eppendorf tube containing 300 μL of cyanomethane (ACN). After mixing, the plasma was centrifuged. After confirming that the sample was not hemolyzed, the plasma samples were stored in a refrigerator at -90 to -60°C and the drug concentrations in the samples were analyzed by LC-MS / MS. In all oral PK studies, rats showed no adverse reactions to any of the test compounds.

[0089] The compound concentrations in the plasma samples were measured and analyzed using an LC-MS / MS system (API4000:LC-MS-MS-001). 10 μL of the sample was mixed with 100 μL of ACN containing the standard, and then 110 μL of water was added and the mixture was shaken. Finally, 2 μL of the mixture was injected into the LC-MS / MS system.

[0090] The test results are shown below. 1) Comparative Example 1 Compound: C max = 116 ng / mL, AUC 0-t = 891 ng·h / mL. When further synthesized into the compound of Example 1, C max = 668 ng / mL, AUC 0-t =1670ng·h / mL. 2) Comparative Example 2 Compound: C max = 20.2 ng / mL, AUC 0-t= 47.4 ng·h / mL. When further synthesized into the compound of Example 2, C max = 791 ng / mL, AUC 0-t =1580ng·h / mL. 3) Comparative Example 3 Compound: C max = 85.5 ng / mL, AUC 0-t = 381 ng·h / mL. When further synthesized into the compound of Example 3, C max = 1860ng / mL, AUC 0-t =2890ng·h / mL. 4) Comparative Example 4 Compound: C max = 5.02 ng / mL, AUC 0-t = 30.7 ng·h / mL. When further synthesized into the compound of Example 4, C max = 635 ng / mL, AUC 0-t =3090ng·h / mL. 5) Comparative Example 5 Compound: C max =16.5ng / mL, AUC 0-t = 141 ng·h / mL. When further synthesized into the compound of Example 5, C max = 689 ng / mL, AUC 0-t =2710ng·h / mL.

[0091] According to the rat oral PK biological data, after further synthesis, the system exposure of the compound was significantly increased, the peak plasma drug concentration was 5-120 times higher than that of the original drug, and the AUC was 2-100 times higher, demonstrating that the oral bioavailability of the compounds in the examples of the present invention was significantly improved, and at the same time, the body clearance rate was significantly reduced.

[0092] Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the specific details in the above embodiments, and within the scope of the technical idea of ​​the present invention, the technical solution of the present invention can undergo various simple modifications that fall within the protection scope of the present invention.

[0093] It should be noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner as long as there is no contradiction, and in order to avoid unnecessary duplication, the present invention does not separately describe various possible combination methods.

[0094] Furthermore, various different embodiments of the present invention may be arbitrarily combined unless they are contrary to the concept of the present invention, and are considered to be the same as the disclosed content of the present invention.

Claims

1. A JAK inhibitor having high oral bioavailability, characterized in that it comprises, as an active ingredient, a compound of the following formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: 【Chemistry 19】 (where, R １ is C or N, R ２ teeth, 【Chemistry 20】 or 【Chemical 21】 where R ４ is selected from halogen or cyano; R ３ is unsubstituted or halogen, C １ ~C ３ Alkyl, hydroxy, C １ ~C ３ Hydroxyalkyl, amino, amide, and C １ ~C ３ and wherein the alkyl group is selected from the group consisting of 5- or 6-membered aryl or heteroaryl optionally substituted with at least one of the following: alkylamido.

2. The R ４ The JAK inhibitor of claim 1 , wherein is selected from fluoro or cyano.

3. 2. The JAK inhibitor of claim 1, wherein the 5- or 6-membered aryl or heteroaryl is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, or pyridazinyl.

4. Said C １ ~C ３ Alkyl is methyl, ethyl, or propyl, and １ ~C ３ Hydroxyalkyl is hydroxymethyl, hydroxyethyl, or hydroxypropyl, and １ ~C ３ 2. The JAK inhibitor of claim 1, wherein the alkylamide is methylformamide, dimethylformamide, ethylformamide, or methylacetamide.

5. The R ３ The JAK inhibitor of claim 1, wherein is any one selected from the following groups: 【Chemical 22】

6. 10. Use of a compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of autoimmune diseases and associated inflammatory skin diseases.

7. The use according to claim 6, wherein the autoimmune disease is at least one selected from rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behcet's disease, COVID-19 severe pneumonia, Reiter's syndrome, and uveitis.

8. 7. The use according to claim 6, wherein the associated inflammatory skin disease is at least one selected from psoriasis, autoimmune-associated vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, and lichen sclerosus et atrophicus.

9. The use according to claim 6, wherein the drug is an orally administered drug.

10. The use according to claim 9, wherein the orally administered drug is a tablet, pill, granule, capsule, lozenge, or liquid.

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