TWI776810B - Novel diamino pyridine derivatives - Google Patents

Abstract

The present invention describes novel diamino pyridine derivatives exhibiting JAK modulating properties. The present invention also relates to pharmaceutical compositions comprising these novel compounds, methods of using said compounds in the treatment of various diseases and disorders being susceptible to JAK modulation, and processes for preparing the compounds described hereinafter.

Description

Novel Diaminopyridine Derivatives

The present invention describes novel diaminopyridine derivatives that exhibit JAK modulating properties. The present invention also relates to pharmaceutical compositions comprising these novel compounds, methods of using these compounds for the treatment of various diseases and disorders susceptible to JAK modulation, and methods for preparing the compounds described below. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, and to its use in modulating JAK. Accordingly, the compounds of the present invention may be useful in the treatment of diseases and/or conditions susceptible to JAK modulation. Such diseases and/or disorders typically include, among others, atopic dermatitis, psoriasis, and, for example, other diseases and/or disorders as described below. The present invention further relates to pharmaceutical compositions comprising, for example, novel diaminopyridine derivatives of formula (I), methods of using these compounds for the treatment of various diseases and disorders, and methods for preparing these novel compounds.

Signal transduction by various interferon and growth factor receptors is mediated by dedicated non-receptor tyrosine kinases in the Janus kinase (JAK) family. Four members of this family (JAK 1 to JAK 3 and Tyk2) are multi-domain proteins of about 130 kDa and are highly homologous with respect to their domain structure. The catalytic kinase domain at the C-terminus is preceded by a pseudokinase domain, a Src homology 2 (SH2) domain, and an N-terminal FERM (4.1, ezrin, root protein, and prominin homology) domain. The latter is used to facilitate the interaction between JAK proteins and interleukin receptors. According to a typical signaling pathway, binding of a ligand to its cognate receptor triggers the engagement of JAK kinases that target the receptor in a series of phosphorylation events, JAK itself and STAT (Signal Transducer and Transcription Activator). One or several of the 6 representatives of the sub) family members relay the signal into the cell. Phosphorylated STATs dimerize and migrate to the nucleus where they become part of transcriptional regulatory complexes that cause transcription of response genes. The canonical JAK-STAT signaling pathway is evolutionarily conserved and active in multiple cell types, wherein the JAK-STAT signaling pathway is utilized by a variety of hormones, growth factors and interferons and their receptors. This critical signaling pathway has been elucidated over the past 25 years and has been the subject of several excellent reviews. See Cytokine receptors and the involvement of JAK kinases (from Cox and Cools, Chemistry & Biology 18, March 25, 2011). JAK inhibitors are believed to have therapeutic value in diseases with pathological amplification of JAK-dependent signaling due to their critical roles in multiple interferon pathways. Inhibition of the four JAK kinases may represent an attractive therapeutic strategy for the treatment of diseases and/or disorders associated with immune system dysregulation. Systemic inhibition of JAK signaling, as well as organ-limited inhibition, is considered to be of high therapeutic value.

其中， R₁ 為H或C₁ -C₆ 烷基；及 Hal為鹵素。The present invention relates to novel compounds of formula (I) and/or pharmaceutically acceptable salts thereof, and to their use to modulate JAK, and may further include, inter alia, the treatment of diseases and/or conditions such as allergy STDs, Respiratory Diseases (such as Asthma and Chronic Obstructive Pulmonary Disease (COPD)), Rheumatoid Arthritis, Systemic Juvenile Idiopathic Arthritis (SOJIA), Gout, Pemphigus Vulgaris, Idiopathic Thrombocytopenia Scar, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic skin inflammation, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn's disease (morbus Crohn), pancreatitis, silk Glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, Antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell mediated Lead to hyperacute or acute and chronic transplant rejection. More specifically, in Example 1, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein R ₁ is H or C ₁ -C ₆ alkyl; and Hal is halogen.

In its broadest embodiment (Example 1), the present invention relates to compounds of formula (I) and/or pharmaceutically acceptable salts thereof, as described above in the Summary of the Invention section. Embodiment 2 of the present invention relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine or fluorine. Embodiment 3 of the present invention relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine. Embodiment 4 of the present invention relates to the compound of embodiment 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R ₁ is methyl. Embodiment 5 of the present invention relates to the compound of embodiment ₁ , 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen. Embodiment 6 of the present invention relates to a compound of embodiment 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl at position ₆ of the associated bipyridine ring. Embodiment 7 of the present invention relates to the compound of embodiment 1 or 4 or a pharmaceutically acceptable salt thereof selected from 4-((2-chlorophenyl)amino)- 6-(Pyridin-2-ylamino)nicotinamide and 4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide amine. Example 8 pertains to pharmaceutical compositions comprising a therapeutically effective amount of a compound according to any one of Examples 1-7 and one or more pharmaceutically acceptable carriers. Example 9 relates to a combination comprising a therapeutically effective amount of a compound according to any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active adjuvants. Embodiment 10 relates to a method of modulating JAK activity in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound according to any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof. Example 11 relates to a compound according to any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, suitable for use as a medicament. Definitions As used herein, the term " _C1 - _C6 alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 6 carbon atoms. Unless otherwise indicated, it refers to hydrocarbon moieties having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl base, neopentyl, n-hexyl and the like. As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine; and it may especially refer to chlorine, fluorine. As used herein, the term "salt" refers to an acid or base addition salt of a compound of the present invention. "Salt" especially includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological utility and properties of the compounds of the present invention and are generally biologically or otherwise desirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amine and/or carboxyl groups or the like. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids such as acetate, chloride/hydrochloride, citrate, fumarate, tartrate, toluene Sulfonates and trifluoroacetates. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by combining the free acid forms of these compounds with a stoichiometric amount of an appropriate base such as Na, Ca, Mg or K as a hydroxide, carbonate, bicarbonate or the like ) reaction, or prepared by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or organic solvents or in a mixture of the two. Generally, where practical, it is desirable to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A listing of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and In Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structures depicted by the formulae given herein, except that one or more atoms are replaced by atoms having the selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ^15N , ^18F , respectively , ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The present invention includes various isotopically-labeled compounds as defined herein, such as those in which radioactive isotopes such ^as3H and14C are present, or those in which non ^- radioactive isotopes such ^{as2H and13C} are present compound. These isotopically-labeled compounds are suitable for use in metabolic studies ( ^using14C ), reaction kinetic studies (using, for example,2H ^{or3H )} , detection or imaging techniques (such as positrons including drug or substrate tissue distribution analysis) Emission tomography (PET) or single photon emission computed tomography (SPECT), or radiotherapy for patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I) can generally be obtained by the use of appropriate conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations. Isotopically labeled reagents were prepared in place of previously used unlabeled reagents. In addition, substitution with heavier isotopes, specifically deuterium (ie, ² H or D), may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic index Improve. It is to be understood that in this context deuterium is regarded as a substituent of the compounds of formula (I). The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent in a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation at each designated deuterium atom), respectively. deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, eg, _D2O , d6-acetone, d6 _{- DMSO} . Compounds of the present invention, ie compounds of formula (I) containing groups capable of acting as donors and/or acceptors for hydrogen bonds, may be capable of forming co-crystals with suitable co-crystal formers. Such co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting the compound of formula (I) with a co-crystal former in solution under crystallization conditions, and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004/078163. The present invention therefore further provides co-crystals comprising compounds of formula (I). As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, anti- Bacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, colors and the like and combinations thereof (see, eg, Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. The term "therapeutically effective amount" of a compound of the present invention refers to the amount of a compound of the present invention that will induce a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or ameliorating symptoms, alleviating conditions, slowing down Or delay disease progression or prevent disease, etc. In one non-limiting example, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to an individual, has the following effects: (1) effective to at least partially alleviate, inhibit, prevent and/or ameliorate A condition or disorder or disease that is (i) mediated by JAK or (ii) associated with JAK activity or (iii) characterized by JAK activity (normal or abnormal); or (2) effectively reduces or inhibits JAK or (3) effectively reduce or inhibit the expression of JAK. In another non-limiting example, the term "therapeutically effective amount" refers to an amount of a compound of the invention effective to at least partially reduce or Inhibit the activity of JAK; or effectively partially or completely reduce or inhibit the expression of JAK. As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. An individual also refers to, eg, primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human. As used herein, the term "inhibit/inhibition/inhibiting" refers to reducing or suppressing a given condition, symptom or disorder or disease, or significantly reducing the baseline activity of a biological activity or process. As used herein, the term "treat/treating/treatment" of any disease or condition refers in one embodiment to ameliorating the disease or condition (ie, slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof) . In another embodiment, "treating" refers to alleviating or improving at least one physiological parameter, including a physiological parameter that may not be discernible by a patient. In yet another embodiment, "treating" refers to modulating a disease or disorder physically (eg, stabilization of discernible symptoms), physiologically (eg, stabilization of physical parameters), or both. In yet another embodiment, "treating" refers to preventing or delaying the onset or development or progression of a disease or disorder. As used herein, an individual "requires" a treatment if the individual would benefit from the treatment biologically, medically, or in quality of life. As used herein, unless otherwise indicated herein or clearly contradicted by context, the terms "a/an", "the (the)" are used in the context of the present invention (especially in the context of the scope of claims) and similar terms should be construed to encompass both the singular and the plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or illustrative language (eg, "such as") provided herein is intended only to better clarify the invention, and not to limit the scope of the invention as otherwise claimed. Any asymmetric atom (eg, carbon or the like) of one or more compounds of the present invention may exist in a racemic or enantiomerically enriched form, eg, ( R ) configuration, ( S ) configuration or ( R , S ) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess in the ( R ) configuration or ( S ) configuration An isomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents at atoms with unsaturated double bonds are present if possible in the cis- ( Z ) - or trans- ( E ) - form. Thus, as used herein, the compounds of the present invention may be in one of the following possible forms: rotamers, tautomers, tautomers, geometric ( cis or trans ) isomers isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof. Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on physicochemical differences in the components, for example, by chromatography and /or fractional crystallization. Any resulting final product or intermediate racemate can be resolved into the optical antipodes by known methods, such as by separation of its diastereomeric salts (the salts are obtained with optically active acids or bases) and Releases optically active acidic or basic compounds. In particular, basic moieties can thus be used to resolve the compounds of the invention into their optical antipodes, for example, by fractional crystallization as salts formed with optically active acids such as tartaric acid, dibenzoyl Tartaric acid, diacetyltartaric acid, di- O , O' - p-toluyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by parachiral chromatography, such as high pressure liquid chromatography (HPLC) using parachiral stationary phases. In addition, the compounds of the present invention (including their salts) can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or be designed to form solvates with pharmaceutically acceptable solvents, including water; thus, both solvated and unsolvated forms are intended to be encompassed by the present invention. The term "solvate" refers to a molecular complex of a compound of the present invention, including pharmaceutically acceptable salts thereof, with one or more solvent molecules. Such solvent molecules are those commonly used in medical technology known to be harmless to the recipient, such as water, ethanol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or be designed to form polymorphs. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for particular routes of administration, such as oral, parenteral, and rectal administration. In addition, the pharmaceutical composition of the present invention can be prepared in solid form (including but not limited to capsules, lozenges, pills, granules, powders or suppositories) or liquid form (including but not limited to solutions, suspensions or emulsions) ). Pharmaceutical compositions may be subjected to conventional pharmaceutical procedures (such as sterilization) and/or the pharmaceutical compositions may contain conventional inert diluents, lubricants or buffers and adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, etc. agents and buffers, etc.). Pharmaceutical compositions are typically lozenges or gelatin capsules containing the active ingredient together with: a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants , such as silica, talc, stearic acid, magnesium or calcium stearic acid and/or polyethylene glycol; also for tablets c) Binders such as magnesium aluminum silicate, starch paste, gelatin , tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants such as starch, agar, alginic acid or its sodium salt, or a foaming mixture; and /or e) adsorbents, colorants, flavors and sweeteners. Tablets may be film coated or enteric coated according to methods known in the art. Suitable compositions for oral administration include an effective amount of a compound of the present invention in the form of lozenges, buccal lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or In the form of an elixir. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening, flavoring, coloring and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use can be presented in the form of hard gelatin capsules or soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, in which In soft gelatin capsules, the active ingredient is mixed with an aqueous or oily vehicle such as peanut oil, liquid paraffin or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are conveniently prepared from fatty emulsions or suspensions. Such compositions may be sterilized, and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure, and/or buffers. In addition, it may also contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% active ingredient, or about 1-50% active ingredient. Suitable compositions for transdermal administration include an effective amount of a compound of the present invention in association with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, a transdermal device is in the form of a bandage that includes a backing member, a reservoir containing a compound (optionally with a carrier), optionally delivered to the skin of the host for an extended period of time at a controlled and predetermined rate The rate-controlling barrier of the compound and the member that secures the device to the skin. Suitable compositions for topical administration (eg, to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations delivered, for example, by sprays or the like . Such topical delivery systems would be particularly suitable for transdermal administration, eg, for the treatment of skin cancer, eg, for prophylactic use in sunscreens, lotions, sprays, and the like. Therefore, it is particularly suitable for topical (including cosmetic) formulations well known in the art. Such formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. As used herein, topical administration can also involve inhalation or intranasal administration. It may suitably be delivered from a dry powder inhaler in the form of a dry powder (either alone in admixture (e.g. anhydrous admixture with lactose) or mixed component particles (e.g. with phospholipids) from a dry powder inhaler, or in the form of a nebulizer spray before use or Delivered from a pressurized container, pump, spray, nebulizer, or nebulizer without the use of a suitable propellant. The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can promote the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or lower moisture containing ingredients and lower moisture or lower humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Accordingly, anhydrous compositions are encapsulated using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, unit dose containers (eg, vials), blister packs, and tape packs. The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which a compound of the present invention as an active ingredient will decompose. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, and the like. Experimental part Abbreviations: BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)Cs ₂ CO ₃ : Cesium carbonate DMSO: Dimethyl sulfoxide g: Grams h: hours NaHMDS: Bis (trimethylsilyl) _{amide sodium} min: min MS: mass spectrum mL or ml: ml Chromatography Analytical Methods Liquid Chromatography : UPLC/MS: Waters Acquity UPLC + Waters ZQ2000 MS UV-PDA: 210 - 450 nM MS Range: 100-1200 Da Column: Acquity HSS T3 2.1 × 50 mm 1.8 µ 60 ℃ Mobile phase: A: water + 0.05% formic acid B: acetonitrile + 0.04% formic acid

Intermediate 3 synthesis 6-Chloro-4-((2-chlorophenyl)amino)nicotinamide:

To a solution of 1 (9.3 g, 48.7 mmol) and 2 (7.68 mL, 73 mmol) in THF (100 mL) was added dropwise sodium bis(trimethylsilyl)amide (NaHMDS) in THF at 0 °C (340.8 mL) of a 1M solution and the mixture was stirred at 25°C for 3 hours under nitrogen atmosphere. The mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was stirred with diethyl ether (200 mL) for 0.5 h and filtered to give 3 (12.8 g, 95% purity) as a pale yellow solid. MS: 282.0 (M+1) ⁺ ; ¹ H NMR (DMSO-d6) δ=10.84 (1 H, s), 8.60 (1 H, s), 8.35 (1 H, m), 7.80 (1 H, m ), 7.59 (2 H, m), 7.41 (1 H, m), 7.25 (1 H, m), 6.73 (1 H, s).

Synthesis of Example 1 4-((2-Chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide:

To a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) at 25 °C was added 4 (2.95 g, 31.4 mmol), _Cs2CO3 ( _{17 g} , 52.3 mmol), Pd2 (dba ) ₃ (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) and triethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassed and heated at 100°C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by combi flash using a 40 g Silicycle column (4% methanol in dichloromethane) afforded Example 1 (1.6 g, 98% purity) as an off-white solid. Retention time: 0.67 min; MS: 340.1 (M+1) ⁺ ; ¹ H NMR (DMSO-d6/D ₂ O) δ=8.52 (1 H, s), 8.11 (1 H, m), 7.72-7.62 ( 3 H, m), 7.56 (1 H, m), 7.41 (2 H, m), 7.18 (1 H, m), 6.90 (1 H, m).

Synthesis of Example 2 4-((2-Chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide:

To a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) at 25 °C was added 4 (3.39 g, 31.4 mmol), _Cs2CO3 ( _{17 g} , 52.3 mmol), Pd2 (dba ) ₃ (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) and triethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassed and heated at 100°C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by combi flash using a 40 g Silicycle column (4% methanol in dichloromethane) afforded Example 2 (2.9 g, 99.5% purity) as an off-white solid. Retention time: 0.74 min; MS: 354.2 (M+1) ⁺ ; ¹ H NMR (DMSO-d6) δ=11.00 (1 H, s), 9.74 (1 H, m), 8.59 (1 H, s), 8.09 (2 H, m), 7.70 (1 H, d), 7.59 (1 H, d), 7.52 (1 H, t), 7.43 (1 H, t), 7.40 (1 H, m), 7.17 ( 2 H, m), 6.72 (1 H, d), 2.26 (3 H, s).

Biology Section

Enzyme JAK assay. For enzymatic analysis, affinity-purified GST fusions (GST-JAK1 (866-1154), GST-JAK2 (808-1132), GST-JAK3 (811-1124), and GST-TYK2) expressing active kinase domains in insect cells (888-1187)) or purchased from Invitrogen (Carlsbad, USA). All assays were performed in 384 well microtiter plates using 8 point serial dilutions of compounds. Kinase reactions were initiated by stepwise addition of 4.5 μl per well of 2x peptide/ATP solution and 4.5 μl per well of 2x enzyme solution. The final ATP concentration used for the analysis corresponds to the KmATP determined for each enzyme individually. Assay buffer: 50 mM HEPES, pH 7.5, 1 mM DTT, 0.02% Tween20, 0.02% BSA, 0.6% DMSO, 10 mM β-glycerophosphate and 10 μM sodium orthovanadate. Other components were specifically adjusted for individual kinase assays: JAK1: 16 nM enzyme, 70 μM ATP, 2 μM peptide substrate, 12 mM MgCl ₂ . JAK2: 1.8 nM enzyme, 20 μM ATP, 2 μM peptide substrate, 9 mM MgCl ₂ . JAK3: 13 nM enzyme, 18 μM ATP, 2 μM peptide substrate, 1.5 mM MgCl ₂ . Tyk2: 3.5 nM enzyme, 35 μM ATP, 2 μM peptide substrate, 9 mM MgCl ₂ . The stop solution was 100 mM HEPES, pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA and 0.015% Brij35. The peptide matrix for JAK2 and Tyk2 assays was FITC-Ahx-KKSRGDYMTMQIG-NH2, and the peptide matrix for JAK2 and JAK3 assays was carboxyluciferin-Ahx-GGEEEEYFELVKKKK. The kinase reaction was incubated at 30°C for 60 minutes and terminated by adding 16 μl of stop solution per well. Phosphorylated and unphosphorylated peptides were separated using the Caripel microfluidic mobility shift technique on a Cariper LC3000 workstation, and the kinase activity was calculated based on the amount of phospho-peptide formed.

Determination of _IC50 data via JAK enzymatic assay:

utility part

The compounds of the present invention are generally suitable for use in the prevention or treatment of disorders or diseases in which JAKs play a role, eg for diseases or disorders selected from allergic diseases, respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), rheumatoid Arthritis, Systemic Juvenile Idiopathic Arthritis (SOJIA), Gout, Pemphigus Vulgaris, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Multiple Sclerosis, Myasthenia Gravis, Hugh Lien's syndrome, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes , Inflammatory Bowel Disease, Ulcerative Colitis, Crohn's Disease, Pancreatitis, Glomerulonephritis, Gubard's Syndrome, Hashimoto's Thyroiditis, Gray's Disease, Antibody-Mediated Transplant Rejection (AMR) , Graft-versus-host disease, B-cell-mediated hyperacute and acute or chronic transplant rejection. Preferably, the compounds of the present invention are particularly useful in the prevention and/or treatment of diseases or disorders affecting or mediated by the immune system. Dosage For the above uses, the dosage required will, of course, vary depending on the mode of administration, the particular condition to be treated, and the effect desired. Generally, a daily dose of about 0.02 mg to 25 mg per kilogram of body weight is used to obtain satisfactory systemic results. The indicated daily dose in larger mammals (eg, humans) may generally range from about 0.2 mg to about 2 g, preferably administered, for example, in divided doses up to four times a day or in delayed form . Suitable unit dosage forms for oral administration may generally contain from about 0.1 mg to 500 mg of active ingredient. Routes of Administration The compounds of the present invention can be administered by any conventional route, in particular parenteral (eg, in the form of injectable solutions or suspensions), enteral (eg, oral) route (eg, as a lozenge) dosage or capsule form), topical route (eg, in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository). Topical administration can, for example, be administered to the skin. Topical Administration Another form can be administered to the eye. Pharmaceutical compositions comprising a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. The compounds of the present invention can be administered in free form or as pharmaceutically acceptable salts. Such salts or hydrates can be prepared in a known manner and generally exhibit about the same activity as the free compounds. In light of the foregoing, the present invention also provides: (1) a compound of the present invention, or a pharmaceutically acceptable salt thereof, suitable for use as a medicine or as a medicament; (2) suitable for use as a JAK modulator, such as for the specific described above A compound of the present invention or a pharmaceutically acceptable salt thereof for any of the indications; (3) For example, a pharmaceutical composition suitable for use in any of the indications set forth above, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof; A pharmaceutically acceptable salt and one or more of its corresponding pharmaceutically acceptable diluents or carriers; (4) methods for the treatment or prevention of diseases or conditions in which JAK modulation plays a role or involves JAK modulation , such as a method for treating any of the specific indications set forth above in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof; ( 5) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug for the treatment or prevention of a disease or condition in which JAK modulation plays a role or involves JAK modulation (eg, as indicated above). Agents; 6) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition in which JAK modulation plays a role or involves JAK modulation (eg, as indicated above). Combinations Compounds of formula (I) may be administered as the sole active ingredient or in combination with other drugs (eg, as adjuvants to other drugs) such as immunosuppressive or immunomodulatory agents or other anti-inflammatory agents , eg, for the treatment or prevention of allograft or xenograft acute or chronic rejection or inflammatory or autoimmune disorders; or chemotherapeutic agents, eg, malignant cell antiproliferative agents. For example, compounds of formula (I) can be used in combination with calcineurin inhibitors (eg, cyclosporine A or FK 506) or mTOR inhibitors (eg, rapamycin). In light of the foregoing, the present invention further provides: (7) A method as defined above, comprising co-administering (eg simultaneously or sequentially) a therapeutically effective amount of: a) a compound of formula I or a pharmaceutically acceptable amount thereof and b) a second drug substance, the second drug substance (eg) suitable for any of the specific indications set forth above; (8) a combination (eg, a kit) comprising a treatment An effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a second drug substance, eg, as disclosed above. When a compound of the invention is administered in combination with, for example, other immunosuppressive/immunomodulatory, anti-inflammatory or anti-neoplastic agents as disclosed above, the dosage of the co-administered drug or agent will necessarily depend on the employed The type of co-drug or co-drug used, or the specific drug or agent used or the condition being treated, etc.

Claims (13)

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein R ₁ is H or C ₁ -C ₆ alkyl; and Hal is halogen. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine or fluorine. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine. The compound of claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof, wherein R ₁ is methyl. The compound of claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen. A compound of claims 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl at position ₆ of the associated pyridine ring. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from 4-((2-chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide; and 4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 7 and one or more pharmaceutically acceptable carriers. A combination comprising a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active adjuvants. A use of a compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating JAK activity in an individual. A use of a compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with JAK modulation in an individual in need thereof. The use of claim 11, wherein the disease or condition is selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), psoriasis, vulgaris Herpes, atopic dermatitis, contact dermatitis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, morbus Crohn's disease, antibody-mediated graft rejection (AMR) and grafts Against host disease. The use of claim 11, wherein the disease or condition is atopic dermatitis or psoriasis.