7H-pyrrolo[2,3-D]pyrimidine JAK inhibitor

Abstract

The present invention provides crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and a method for treating dermatological conditions in non-human mammals. [Solution] A method for treating a dermatological condition is provided, comprising administering an effective amount of substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetin-3-yl)acetonitrile to a non-human mammal in need of treatment.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 837,972, filed on April 2, 2019, the content of which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to polymorphs of 2-(3-(4-(7H - pyrrolo[2,3 - d]pyrimidin - 4 - yl)- 1H - pyrazol - 1 - yl)-1-(cyclopropylsulfonyl)azetidin - 3 - yl)acetonitrile, pharmaceutical compositions, processes for preparing the same, and methods of using the same, for example, for the treatment of dermatological conditions.

Background Art

[0003] WO 2009 / 114512 pamphlet discloses the preparation of a specific JAK inhibitor, 2-(3-(4-(7H - pyrrolo[2,3 - d]pyrimidin - 4 - yl)-1H - pyrazol - 1 - yl)-1 - (cyclopropylsulfonyl)azetidin - 3 - yl)acetonitrile (Example 80), as its trifluoroacetate (Example 2) and phosphate ( Example 81).

Summary of the Invention

Problems to be Solved by the Invention

[0004] 2-(3-(4-(7H - pyrrolo[2,3 - d]pyrimidin - 4 - yl)-1H - pyrazol - 1 - yl)-1-(cyclopropylsulfonyl )azetidin - 3 - yl)acetonitrile that can be used effectively, safely and reproducibly, and that is effective on a large scale for industrial production ​​​​There is a need for methods for preparation and purification that are effective and reproducibly usable. In particular, crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl sulfonyl)azetidin-3-yl)acetonitrile that is effective, safe and reproducibly usable, and a method for preparation and purification that is effective and reproducibly usable on a large scale for industrial production is needed. In particular, there is a need for a method for preparation and purification that is effective and reproducibly usable. Specifically, substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile that is effective, safe and reproducibly usable, and a method for preparation and purification that is effective and reproducibly usable on a large scale for industrial production is needed. In particular, a method for preparation and purification that is effective and reproducibly usable on a large scale for industrial production is needed.

Means for Solving the Problems

[0005] In certain embodiments, the present disclosure provides substantially polymorphically pure crystalline Form I 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl )-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a process for making the same. In certain embodiments, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin -3-yl)acetonitrile and a process for making the same. In certain embodiments, the present disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a process for making the same. In certain embodiments, the present disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a process for making the same. Pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-( Cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and preparation thereof To provide a process for that purpose.

[0006] In certain embodiments, the disclosure is substantially polymorphic in pure form I 2-(3-(4-( 7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)- 1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and pharmaceutically The present invention provides a pharmaceutical composition comprising acceptable excipients. In certain embodiments, the present invention substantially Polymorphically pure form II 2-(3-(4-(7H-pyrolo[2,3-d]pyrimid (-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) A pharmaceutical composition comprising zethidine-3-yl)acetonitrile and a pharmaceutically acceptable excipient. Provides. In certain embodiments, this disclosure is substantially polymorphic in pure form III 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni The present invention provides a pharmaceutical composition comprising a rubbing agent and a pharmaceutically acceptable excipient.

[0007] In certain embodiments, the present disclosure relates to a method for treating a dermatological condition, which requires In non-human mammals, there is a substantially polymorphic pure form I 2-(3-(4-(7H-P Roro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cy Administer an effective dose of chloropropylsulfonyl azetidine-3-yl acetonitrile. The present disclosure provides a method including the following. In certain embodiments, the present disclosure provides a method for treating a dermatological condition. It is a law that, in non-human mammals that require it, substantially polymorphically pure form II 2 -(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole (Lu-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonite A method is provided which includes administering an effective amount of ril. In certain embodiments, this disclosure relates to the skin A method for treating dermatological conditions, which is substantially effective for non-human mammals in need. Morphologically pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti The present invention provides a method comprising administering an effective amount of (zin-3-yl)acetonitrile.

[0008] In certain embodiments, the disclosure relates to 2-(3-(4-(7H-pyrolo[2,3-d]pyrolo Midine-4-yl)-1H-pyrazole-1-yl)-1(cyclopropylsulfonyl) This provides a process for producing azetidine-3-yl)acetonitrile and its intermediates. do. [Modes for carrying out the invention]

[0009] This disclosure relates to the compound, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine -3-yl)acetonitrile, as specified herein as Form I, Form II and Form III The polymorphs and their pharmaceutical compositions, and the use of the polymorphs for, for example, the treatment of dermatological conditions. This relates to a method for producing polymorphs, a method for producing the compound and its intermediates. .

[0010] 1.Definition Unless otherwise specified, all technical and scientific terms used herein are as used by those skilled in the art. It has the same meaning as it is more commonly understood. Where there is a conflict, this definition will be included. The preferred method and materials are described below, but are the same as those described herein. Various or equivalent methods and materials may be used in the implementation or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are referenced in their entirety. More incorporated. The materials, methods and examples disclosed herein are merely illustrative. It's not limited to that.

[0011] "Include", "Include", "To have", "To possess", "To be able to", "Include The terms “possess” and their variations, when used herein, have further effect Alternatively, it shall be an open-ended transitional phrase, term, or word that does not impede structural possibilities. The singular forms of "one (a)", "one (an)", and "that" are clearly different from the context. This disclosure includes multiple references unless otherwise indicated. Even if not present, embodiments or elements shown herein are "including," "consisting of," and Other embodiments that "basically consist of" are also envisioned.

[0012] The term "approximately" is used in relation to a measurable numerical variable element. The indicated value and the experimental error of the indicated value, or within ±10 percent of the indicated value, whichever is greater. This refers to all values ​​of the variable element.

[0013] The term "acceptable excipients" is commonly used when preparing veterinary and pharmaceutical compositions. It refers to the substance used, and should be pure and nontoxic in the amount used. These are generally in the aggregate, a solid, semi-solid, or liquid substance that can be a vehicle or medium for the active ingredient. Some examples of acceptable excipients are listed in Remington's Pharmac. eutical Sciences and the Handbook of Pha Found in rmaceutical excipients, diluents, vehicles, carriers, Ointment base, binder, disintegrant, lubricant, flow enhancer, sweetener, flavoring agent, gel base, sustained release Matrix, stabilizers, preservatives, solvents, suspensions, buffers, emulsifiers, dyes, sprays, coatings Examples include fertilizers.

[0014] The term "aromatic solvent" is derived from methyl, chloro, bromo, cyano, nitro, and aceto. This refers to benzene that is optionally substituted with one or two substituents selected from the group. The term "aromatic solvent" specifically refers to nitrobenzene, chlorobenzene, and toluene. It contains xylene and acteophenone.

[0015] "C 1~5 The term "alcohol" refers to a linear or branched compound having 1 to 5 carbon atoms. Lucanol, for example methanol, ethanol, n-propanol, isopropanol, 1 -This refers to substances such as butanol, ethylene glycol, and 1,3-propanediol.

[0016] The term "C1-C4 alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms. This refers to the propyl chain, and includes methyl, ethyl, propyl, isopropyl, and butyl propyl compounds.

[0017] "C 2~8 The term "alkyl ether" refers to a linear chain having a total of 2 to 8 carbon atoms. , branched or cyclic alkyl ethers, such as dimethyl ether, diethyl ether, methyl This refers to substances such as t-butyl ether, THF, 2-methyl THF, and dioxane.

[0018] "C 3~8 The term "alkyl acetate" refers to a linear or linear acetic acid molecule having a total of 3 to 8 carbon atoms. These are branched alkyl esters, such as methyl acetate, ethyl acetate, isopropyl acetate, and ethyl acetate. This refers to substances such as chlorofluoromethyl acetate and isobutyl acetate.

[0019] "C 2~5 The term "alkylcyanide" refers to a linear chain having a total of 2 to 5 carbon atoms. or branched alkyl cyanides, such as acetonitrile, propionitrile and butyronite It refers to Lil.

[0020] "C 3~9 The term "alkylketone" refers to a group containing an oxo group and a total of 3 to 9 carbon atoms. Linear, branched, or cyclic alkyl groups having derivatives, such as acetone, methyl ethyl ketone and This refers to cyclohexanone.

[0021] "C 5~8 The term "hydrocarbon" refers to linear, branched, or cyclic saturated alkyl hydrocarbons, e.g. For example, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, methyl This refers to substances such as lucyclohexane.

[0022] The term "5-6 member heterocycle" refers to the oxygen atoms and their links R1 and R2. This refers to a monocyclic saturated ring with 5-6 members, containing boron atoms linked to oxygen atoms.

[0023] Terms such as "to crystallize," "the act of crystallization," and "crystallization" refer to complete dissolution and... This refers to a slurry process that does not include subsequent precipitation and complete dissolution. This includes processes that encompass the continuation of the crystallization process after precipitation following dissolution.

[0024] The term "dermatological condition" includes psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, Skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), a This includes skin disorders such as itching and allergic reactions, including itching associated with allergic dermatitis. nothing.

[0025] The term "effective dose" refers to the amount administered to a patient under diagnosis or treatment at the time of a single or multiple dose. The amount or dose of the compound of the present invention or a pharmaceutically acceptable salt thereof that provides the desired effect. This refers to the effective amount obtained by observing the results obtained using known techniques and under similar circumstances. This can be easily determined by the attending physician, such as a person skilled in the art. In determining the efficacy, the patient or non-human mammal species; their size, age and overall Health status; specific disease or disability involved; degree of involvement or severity of disease or disability; individual Patient response; specific compound administered; method of administration; bioavailability of the administered preparation. Characteristics of the ability; selected dosing regimen; use of concomitant medications; and other relevant circumstances, Many factors, not limited to those listed above, are considered by the diagnosing physician.

[0026] The terms “patient,” “subject,” and “non-human mammal” are used to refer to warm-blooded animals, such as dogs and cats. This refers to mice, rats, guinea pigs, rabbits, cattle, horses, sheep, goats, and pigs. Certain non-human mammals are pets or companion animals, such as dogs and cats and also mammoths. These include guinea pigs and rabbits. Preferred non-human mammals are dogs and cats. Preferably, the non-human mammal is a canid. Particularly preferred non-human mammal It is a dog.

[0027] The term "salt" refers to veterinary or pharmaceutically acceptable organic acids and bases or inorganic acids and salts. This refers to the base salt. Such salts are well known in the art, and are described in the Journal of Ph As described in Armaceutical Science, 66, 2-19 (1977). Examples include hydrochloride salts. When this term is used herein, it refers to tri Clearly exclude fluoroacetates and phosphates.

[0028] The term "substantially polymorphically pure" means more than 90%, preferably more than 97%. Polymorphic purity exceeding 99% and even more preferably exceeding 99.5% It refers to.

[0029] The terms "to treat" or "to treat" refer to the progression or worsening of existing symptoms or disorders. This refers to suppressing, delaying, stopping, or reversing the degree.

[0030] The term "water activity" is expressed in terms of p / p * Equivalent to, where p is the water vapor of water in solution. It is a partial pressure, p * This is the partial pressure of water vapor in pure water at the same temperature.

[0031] Numerical ranges cited in this specification are defined as those within the range of similar precision. The value is clearly intended. For example, for the range 92-97, in addition to 92 and 97, the number The values ​​93, 94, 95, and 96 are intended, and the numbers 92.1, 92.2, and 92.3 are within the range. A range of 92.4, 92.5, 92.6, etc., up to 97.0, is clearly intended.

[0032] 2.Compound The compound of the present invention is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine Includes crystalline forms I, II, and III of -3-yl)acetonitrile. 2-(3-(4-( 7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)- The crystalline form of 1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is To provide pharmaceutical compositions that have efficiency and reproducibility in the production of pharmaceutical formulations, as well as appropriate stability. It is desirable.

[0033] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitriles are 2-[1-cyclopropylsulfonyl-3-[4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)pyrazole-1-yl]azetidine-3-yl]aceton Tolyl and 2-(1-cyclopropylsulfonyl-3-pyrazole-1-yl-(4-( The name is 7H-pyrrolo[2,3-d]pyrimidine azetidine-3-yl)acetonitrile It is also known by its other name, and for clarity, it is the compound of the following formula (I). [ka]

[0034] In preferred embodiments, the compound of the present invention has a crystalline form I2 as described herein. -(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole (Lu-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonite It is Lil. Crystal form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti Zin-3-yl)acetonitrile is an anhydrous substance.

[0035] In another preferred embodiment, the compound of the present invention is in the crystalline form I as described herein. I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-py Razole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)azetidine It is tonitrile. Crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrrolo Midine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) Azethidine-3-yl acetonitrile is also an anhydrous substance.

[0036] In another preferred embodiment, the compound of the present invention is in the crystalline form I as described herein. II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H- Pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl) It is cetonitrile. Crystal form III 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl sulfo) Nyl)azetidine-3-yl)acetonitrile is in its hydrated form.

[0037] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto The forms of nitrile morphology I, II, and III, as well as other polymorphic forms, are characterized by X-ray diffraction. It is possible. Powder diffractometer with copper source, primary beam monochromator and position sensing detector. The peak was measured using [a specific method]. The incident beam was parallelized using a 1° divergence slit. The radiation source was operated at 40kV and 40mA. A step width of 0.02° and a step time of 37 seconds were used. Using this method, X-ray powder diffraction data was collected at 2.5° to 50°. Alternatively, a copper source was used. The peak was measured using a powder diffractometer, primary beam monochromator, and position-sensing detector. The incident beam was parallelized using a 1° divergence slit. Linear spectroscopy was performed at 40kV and 40mA. The source was manipulated. Using a process width of 0.02° and a process time of 12 seconds, the range was 1.5° to 50°. X-ray powder diffraction data was then collected.

[0038] The relative intensity of the X-ray diffraction peak may depend on other factors such as preferred orientation and particle size. This is recognized. If the influence of a preferred orientation and / or particle size is present, the peak intensity changes. However, the characteristic peak positions of the polymorphisms remain unchanged. For example, The United S tates Pharmacopoeia #24,National Formula See ry #19, pages 1843-1844, 2000. Therefore, form Form I, or Form II, or Form III 2-(3-(4-(7H-piroro[2,3-d] Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl sulfo) A sample of yl)azetidine-3-yl)acetonitrile was prepared using an agate mortar and pestle or other materials. Processing such as grinding the sample may be necessary to mitigate these factors. Differences in the relative intensity of the folded peaks indicate morphology I, morphology II, or morphology III 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl ()-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is equivalent. Therefore, it is understood that we do not exclude the patterns that can be obtained.

[0039] Furthermore, the angular position of the peaks can vary slightly for any particular crystal type. This is well known in the field of crystallography. For example, the peak position is determined by the temperature at which the sample is analyzed. This can shift due to sample displacement or variation in relative humidity. In this case, ±0.2 at 2θ. The variability of the peak position in ° does not hinder the clear identification of the crystal morphology of this disclosure, and these possibilities Take these fluctuations into account.

[0040] Morphology I, II, or III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)aze (Thidin-3-yl)acetonitrile is also characterized by differential scanning calorimetry. SC is a closed (sealed) gold crucible or an aluminum crucible with pinholes. N; Sample packing under ambient conditions or N2 flow (3-10 minutes); -50°C to 300°C in 10°C increments. This can be done at a heating rate of minutes.

[0041] Form I Crystal form I: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) -1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- (II) Acetonitrile has the following peaks at degree 2 theta (°2θ) with a relative intensity greater than about 10% of the maximum peak, I0 / I 100 %): 12.72 ° (43.1%), 14.04° (61.3%), 17.56° (20.8%), 20. 33° (87.4%), 24.50° (100%) and 25.83° (94.9%) (± 0.2° 2θ).

[0042] The present disclosure provides substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cycloprop ylsulfonyl)azetidin-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern comprising peaks at 12.72° 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern comprising peaks at 12.72° and 24.50° (±0.2° 2θ), or peaks at 20.33° and 24.50° (±0.2° 2θ), or peaks at 12.7 When used herein, "form I 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. More specifically 2° and 20.33° (±0.2° 2θ). The present disclosure provides substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern comprising peaks at 12.72° and 24.50° (±0.2° 2θ), or peaks at 20.33° and 24.50° (±0.2° 2θ), or peaks at 12.7 2° and 20.33° (±0.2° 2θ). The present disclosure provides substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo

[0043] When used herein, "form I 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The term "(rufonyl)azetidine-3-yl)acetonitrile" is "substantially polymorphic" Pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) -1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- It includes the term "acetonitrile (yl)".

[0044] Form II Crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl )-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 -Acetonitrile (I) has a relative intensity greater than approximately 10% of the peak, I0 / I 10 At a degree of 2 theta (°2θ) with 0%, the following peak was found: 5.34 °(16.2%); 10.68°(26.2%); 14.26°(20.8%); 16. 06°(13.5%); 16.39°(17.9%); 16.48°(18.6%); 1 8.26° (19.5%); 18.65° (43.4%); 19.03° (100.0%) ); 21.05° (10.2%); 21.15° (9.9%); 21.45° (9.0%) );21.76°(20.5%);22.45°(9.6%);22.68°(22.5 %); 23.23°(11.1%); 23.72°(12.3%); 24.90°(11 0.7%); 25.08°(9.2%); 26.75°(30.7%); and 31.18° (10.1%); (±0.2°2θ).

[0045] This disclosure applies to 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 19.03°, 21.05°, 21.76° X-ray powder diffraction pattern containing peaks at 22.68° or 26.75° (±0.2°²θ) Form II, characterized by turns, is essentially polymorphically pure 2-(3-(4-( 7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)- We provide 1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. More specifically, this disclosure relates to the P-force at 18.65° and 10.68° (±0.2°²θ). Does it include the 'k', or does it include peaks at 18.65° and 21.76° (±0.1°²θ)? , or including peaks at 18.65° and 22.68° (±0.1°²θ), or 26 The X-ray powder diffraction pattern includes peaks at 0.75° and 21.76° (±0.2°²θ). Thus, it is characterized by a substantially polymorphic pure form II 2-(3-(4-(7H-P Roro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cy We provide chloropropylsulfonyl azetidine-3-yl acetonitrile.

[0046] When used herein, "Form II 2-(3-(4-(7H-Pyrro[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl The term "sulfonyl azetidine-3-yl acetonitrile" is "substantially polymorphic" In pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- The term includes "3-yl)acetonitrile".

[0047] Form III Crystal form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-Iyl)acetonitrile has a relative intensity greater than approximately 10% of the maximum peak, I0 / I1 00 It was found that the following peaks were present at a degree of 2 theta (°2θ) with a %): 11. 08°(62.3%); 12.32°(15.9%); 13.28°(13.7%); 1 4.06° (15.3%); 14.73° (32.8%); 17.86° (16.9%) ;18.06°(46.4%);18.27°(18.1%);18.51°(35.2 %); 18.91° (10.9%); 20.36° (15.8%); 21.48° (12 0.7%); 22.24°(26.9%); 22.69°(100%); 23.40°(1 0.2%; 24.76° (18.8%); 25.48° (55.4%); 25.97° (12.6%); 26.70° (12.5%); and 28.04° (12.8%); (± 0.2°2θ)°.

[0048] This disclosure applies to 11.08°, 14.73°, 18.06°, 18.27°, and 18.51°. , 22.24°, 22.69°, 24.76°, 25.48° or 28.04° (±0. Characterized by an X-ray powder diffraction pattern including a peak at 2°2θ), substantially multi Morphologically pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti This disclosure provides 11.08° and 2 Includes a peak at 2.69° (±0.2°²θ), or 14.73° and 22.69°. It includes a peak at °(±0.2°2θ), or at 22.69° and 25.48°(±0. Includes a peak at 2°²θ, or at 11.08° and 18.06° (±0.2°²θ) It includes a peak at 11.08° and 25.48° (±0.2°²θ). Form II, characterized by an X-ray powder diffraction pattern containing a substantially polymorphic and pure form II. I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-py Razole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)azetidine Tonitrile is provided.

[0049] When used herein, "Form III 2-(3-(4-(7H-Pyrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop The term "(sulfonyl)azetidine-3-yl)acetonitrile" is "substantially polymorphic Pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetide The term includes "(n-3-yl)acetonitrile".

[0050] Those skilled in the art will recognize that the compound may exist as a tautomer. We intend that all tautomer biological forms of the hybrid are within the scope of this disclosure.

[0051] The compounds of the present invention have at least one atom of the main atomic mass having the same number of atoms, All isotope variations are replaced by atoms with atomic masses different from the primary atomic mass. This also includes isotope variations (e.g., deuterium, 2 By using H), metabolic rate This may allow for improved qualitative analysis. Furthermore, specific isotopic variations of the compounds of the present invention The spectroscopy is a radioactive isotope that may be useful in drug and / or substrate tissue distribution studies (e.g., Tritium, 3 H or 14 C) can be incorporated. 11 C, 18 F, 15 O and 13 N etc. Substitution with positron emission isotopes is useful in positron emission tomography (PET) tests. could be.

[0052] 3. Process for creating crystal forms Morphology I process Crystal form I: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) -1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- Acetonitrile (I) can be prepared by crystallization under controlled conditions. This disclosure is substantially Polymorphically pure crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrim Zin-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) A process for producing azetidine-3-yl)acetonitrile, and an antisol The process also involves crystallizing a mixture of acetone and heptane as a vent. Provided. In a preferred embodiment, form I 2-(3-(4-(7H-pyrolo[2,3-d Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfate) Honyl azetidine-3-yl acetonitrile is generally stored under vacuum at approximately 40°C to approximately 8°C. It can also be obtained by dehydrating a morphological III sample, such as by heating it at a temperature of 0°C.

[0053] Morphological II process Crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl )-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 -Acetonitrile is a solvent or mixture of solvents that crystallizes under controlled conditions. It can be prepared by crystallization. This disclosure relates to a substantially polymorphic pure crystalline form II 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing a solution that further contains water and has a water activity of less than 0.7 The process also includes crystallization from a mixture of a medium or solvent. In fact, the appropriate solvent is Each C has a water activity of less than approximately 0.7. 1~5 Alcohol, C 2~8 Alkyl ether , C 2~8 Alkyl acetate, C 2~5 Alkylcyanide, C 3~9 Alkyl ketones and aromas It is selected from the group consisting of group solvents.

[0054] In a preferred embodiment, the present disclosure relates to a substantially polymorphic pure crystalline form II 2-(3- (4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1- (Iyl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing a solvent further containing water and having a water activity of less than 0.5. Alternatively, the process also includes crystallization from a mixture of solvents.

[0055] The use of antisulfants may be advantageous. When used in connection with this, "antisulfants" "Tisolvent" is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile refers to a solvent in which its solubility is significantly lower than that of the selected solvent. Preferably, if an antisolvent is used, it is miscible with the selected solvent. Therefore, an antisolvent may be used, while the selected antisolvent is at the desired level. Care must be taken not to increase water activity beyond the limit.

[0056] In effect, the crystalline form II is polymorphically pure: 2-(3-(4-(7H-pyrrolo[2,3-d Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfate) The water activity of honyl)azetidine-3-yl)acetonitrile is temperature-dependent. It is understood that the higher temperature of the final crystallization stage allows for greater water activity resistance. Therefore, a water activity of approximately 0.7 is obtained at a final crystallization temperature higher than approximately 40°C. It is effective.

[0057] Since the amount recovered increases with lower temperatures, in preferred embodiments, this disclosure is substantially polymorphic. Pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti A process for producing zinc-3-yl acetonitrile, wherein the moisture content is less than 0.5 The process also includes crystallization from an active solvent or mixture of solvents. Generally, A water activity of approximately 0.5 is effective at the final crystallization temperature below approximately 25°C.

[0058] Preferred solvents are C, each having a water activity of less than approximately 0.7. 1~5 Alcohol and C 2~5 A solvent is selected from the group consisting of alkyl cyanides. A more preferred solvent is each C has a water activity of less than approximately 0.5. 1~5 Alcohol and C 2~5 Alkylcyanide Selected from the following group.

[0059] In certain embodiments, the present disclosure relates to a substantially polymorphic pure crystalline form II 2-(3-( 4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl Prepare 1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process that further contains water and has a water activity of less than 0.7 in acetonitrile. We also offer a process that includes crystallization.

[0060] In another specific embodiment, the present disclosure relates to a substantially polymorphic pure crystalline form II 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing water containing acetonitrile, which further contains water having a water activity of less than 0.5. We also offer a process that includes crystallization from the material.

[0061] This disclosure relates to a substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclop The process for producing ropyrsulfonyl azetidine-3-yl acetonitrile The process also includes crystallization from acetonitrile containing water. Care must be taken to avoid the formation of undesirable hydrated crystal forms. Therefore, water A further preferred embodiment for crystallization from acetonitrile is 92-97 acetonitrile Using a v / v ratio of tonitrile to water of 8-3; more preferably 95-97 acetonitrile Crystallization occurs from acetonitrile containing water in a v / v ratio of 5 to 3. 96:4 (v / v) acetonitrile / water is most preferred at temperatures below approximately 20°C. It was found to have product efficiency.

[0062] Therefore, the substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopro A better way to produce pyrsulfonyl azetidine-3-yl acetonitrile The process involves adding water to acetonitrile in a v / v ratio of approximately 96 to 4 parts water. This includes crystallization from tonitrile.

[0063] Selectively, crystallization occurs in morphology II 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl sulfo) Seeding can be performed using yl)azetidine-3-yl)acetonitrile.

[0064] Crystallization by precipitation and slurrying techniques from solution is within the scope of this process. The plan is to melt the crystallization process at a rate of 0.2°C / min to 0.02°C / min, where complete dissolution is involved. Slow cooling is preferable. Crystallization to obtain Form II does not require complete dissolution. No. A slurry process may be used. The slurry is processed without complete dissolution. It can be formed by further, or complete, dissolution followed by treatment after the initial precipitation. Slurry In the process, the volume should be sufficient to provide a free-flowing slurry. The volume of the medium is not critical, but for convenience, it should be kept to a minimum. The solvent used is water. The activity levels must take into account the water, including the water that may be released from the hydrated starting material. Selectively, the slurry crystallization process is morphological II 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclop Seeding may be performed using propylsulfonyl azetidine-3-yl acetonitrile. ru.

[0065] In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- Non-form II containing 3-yl)acetonitrile is a slurry at a temperature of approximately 50°C or higher and Crystallization occurs through optional cooling, and the final product is recovered. In another embodiment, non-morphological II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitriles are crystallized from a solvent by slurry at temperatures around room temperature. Selectively, Crystallization is morphology II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- Seeding can be performed using 3-yl)acetonitrile. Such slurry processes This generally takes 2 to 14 days.

[0066] Morphological III process Crystal form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile is crystallized from a solvent or a mixture of solvents under controlled conditions. It can be prepared by crystallization. This disclosure describes a substantially polymorphic pure crystalline form III 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni A process for producing water, further containing water and having a water activity greater than 0.9 The process also includes crystallization from a solvent or mixture of solvents. In fact, a suitable solvent The medium is water, C, each having a water activity greater than approximately 0.9. 1~5 Alcohol, C 2~8 Alkyl acetate, C 2~5 Alkyl cyanides and C 3~9 Select from the group consisting of alkyl ketones It will be selected.

[0067] The use of antisulfants may be advantageous. When used in connection with this, "antisulfants" "Tisolvent" is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile is a solvent that is significantly less soluble compared to the selected solvent. Preferably, if an antisolvent is used, it is miscible with the selected solvent. That is the case.

[0068] While an antisulfur is used, the selected antisulfur lowers the desired level. Care must be taken to avoid rotating the water and reducing its water activity.

[0069] A preferred solvent is C with a water activity greater than approximately 0.9. 1~5 A group consisting of alcohols It will be selected.

[0070] Crystallization from solution and slurry techniques are intended to be within the scope of this process. If crystallization involves complete dissolution, cool slowly at a rate of 0.2°C / min to 0.02°C / min. It is preferable to do so. Crystallization to obtain form III does not require complete dissolution. A slurry process may be used. The slurry is processed without complete dissolution, or It can be formed by complete dissolution followed by treatment after the initial precipitation. The volume should be sufficient to provide a free-flowing slurry. The volume of the solvent is Although not critical, for convenience, it should be kept at the minimum amount. Optionally, slurry crystals The chemical transformation process is morphological III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)aze Seeding can be performed using thidine-3-yl)acetonitrile.

[0071] In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- Non-form III containing 3-yl)acetonitrile is greater than 0.9 at temperatures around room temperature. It is crystallized by slurry from a solvent with high water activity. Optionally, crystallization is performed in a specific form. State III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1 H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Seeding can be performed using acetonitrile. Such slurry processes are generally This takes 2 to 10 days.

[0072] Preferably, in order to avoid conversion to form I under vacuum at a temperature below 20°C, Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl (L) When drying acetonitrile, care must be taken.

[0073] 4.Synthesis method This disclosure is as shown in Scheme A: 2-(3-(4-(7H-pyrolo[2,3-d Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfate) This provides a process for producing honyl)azetidine-3-yl)acetonitrile. [ka]

[0074] In Scheme A, step 1, the compound of formula (1) is converted to the compound of formula (2) in the presence of a suitable catalyst. The compound of formula (3) is obtained by reacting with the compound. The compound of formula (1) is obtained when X is tosylate, to Selected from the group consisting of lyflate, chloro, bromo, and iodine, with Pg as the protecting group. In fact, compounds of formula (1) in which X is bromo or chloro are preferred, and chloro is Even more preferable. Various protecting groups are suitable. The selection of an appropriate protecting group is by those skilled in the art. This can be easily determined. The chemistry of the protecting group is, for example, TWGreene and PG. .M.Wuts,Protective Groups in Organic Syn thesis, 3rd Ed., Wiley&Sons, Inc., New York( It can be found in 1999). For example, to give just a few examples, t-BOC, 2-(trimethic Lucilyl)ethoxymethyl and N-pivaloyloxymethyl are useful. In fact, t- A BOC group is preferred. In the compound of formula (2), R1 and R2 are independently hydrogen and C 1~ Selected from the group consisting of 6 alkyl groups; or R1 and R2 are oxygen atoms to which they are linked. Together with the atoms and boron atoms, optionally 1, 2, 3, or 4 C atoms 1~4 Alki It forms a 5-6 member heterocycle substituted with a 1x group. This is recognized by those skilled in the art. Thus, the reaction shown in step 1 is the well-known Suzuki reaction. Various suitable catalysts can be used. It is possible. Both nickel and palladium catalysts are useful, but palladium catalysts are preferred. Many suitable palladium(O) and palladium(II) catalysts are known in the art. For example, tetrakis(triphenylphosphine)palladium(0), tetrakis (Triphenylphosphine)palladium(II) chloride, 4,5-bis(diphenylphosphine) Sphino)-9,9-dimethylxanthene and dichloromethane [1,1'-bis(dife) The mixture is 1:1 ylphosphinoferrocene dichloropalladium(II).

[0075] This reaction generally takes place in a solvent containing a wide variety of organic solvents. The solvent contains water. It may have. For example, suitable solvents include 1,4-dioxane, THF, and 1-butanol. , 1,2-dimethoxyethane (DME), 2-propanol, toluene or ethanol Examples include palladium or a combination thereof. Typical palladium catalysts have a pH of approximately 0.01 to approximately 0. It is used in an amount of 0.1 equivalent.

[0076] This reaction takes place in the presence of a base. Both organic and inorganic bases can be used, for example Alkali metal carbonates and alkali metal bicarbonates, as well as bases such as cesium carbonate, are used. This reaction generally takes place at temperatures of approximately 40°C to 100°C and typically lasts 1 to 18 hours. It is required.

[0077] 5. Pharmaceutical Compositions This disclosure relates to 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl The present invention provides a pharmaceutical composition comprising acetonitrile or a salt thereof and an acceptable excipient. In a more accurate embodiment, the present disclosure relates to crystalline form I, or form II, or form III 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and The present disclosure provides a pharmaceutical composition comprising, and acceptable excipients. In another preferred embodiment, the present disclosure This is the crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- A pharmaceutical composition comprising 3-yl)acetonitrile and at least one acceptable excipient. Provided. In another preferred embodiment, the present disclosure provides substantially polymorphic pure crystalline form II. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto The present invention provides a pharmaceutical composition comprising a nitrile and at least one acceptable excipient.

[0078] The compounds of the present invention can be administered alone or in the form of a composition. In fact, the compounds of the present invention This is usually in the form of a composition, i.e., a mixture with at least one acceptable excipient. It is administered as follows. The proportion and properties of any acceptable excipients are selected from the compounds of the present invention. Based on its characteristics, the selected route of administration, and standard techniques in the fields of veterinary medicine and pharmacy, It will be decided.

[0079] In providing treatment for subjects requiring such treatment, the compounds of the present invention This compound can be administered in any form and via any route that makes it bioavailable.

[0080] The compounds of the present invention can be administered by various routes, including orally, particularly in the form of tablets and capsules. The compounds of the present invention can be administered subcutaneously and intramuscularly via parenteral routes, particularly by inhalation. Into veins, into arteries, percutaneously, into the nasal cavity, into the rectum, into the vagina, into the eyes, locally, sublingually via local delivery, for example, a catheter It can be administered via a stent or other means.

[0081] Those skilled in the art will know the specific characteristics of the selected compound, the problem or condition to be treated, and the problem or Depending on the stage of the condition and other relevant circumstances, the appropriate form and route of administration can be easily selected. The pharmaceutical composition of the present invention can be, for example, in the form of tablets, capsules, cachets, paper, medicinal candies, Wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, liquid medicines, dissolving It can be administered to patients in the form of a liquid or suspension.

[0082] In one embodiment, the composition is administered orally, for example, in the form of tablets or capsules or by oral administration. Applicable to liquid formulations, such as solutions or suspensions. In one embodiment, the composition It is suitable for oral administration, such as in chewable formulations, and is suitable for oral administration. In terms of administration, this composition is a liquid or semi-solid formulation suitable for parenteral administration, such as a solution or It is a suspension or paste.

[0083] The compositions disclosed herein are prepared in a manner well known in the fields of veterinary medicine and pharmaceuticals, and contain active ingredients. The present invention comprises at least one of the compounds of the present invention. The amount of the compounds of the present disclosure depends on the particular form. It may vary and, conveniently, can be the weight of a unit dose from 1% to approximately 50%. The product is preferably prescribed in unit dose form, and each dose is generally about 0.25 mg to about Contains 10 mg of the compound of the present invention. One or more units to affect the treatment dose. The dosage form may be selected.

[0084] 6.How to use This disclosure relates to a method for treating a dermatological condition in a non-human mammal that requires such treatment. The present invention provides a method comprising administering an effective amount of the compound of the present invention to a person.

[0085] In certain embodiments, this disclosure relates to dermatological conditions [e.g., skin disorders, e.g., psoriasis (e.g.)] For example, psoriasis vulgaris, atopic dermatitis, skin rash, skin irritation, skin sensitization (for example, contact dermatitis) Dermatitis or allergic contact dermatitis, including itching associated with allergic dermatitis. A method for treating itching and allergic reactions in non-human mammals that require it. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton The present invention provides a method comprising administering an effective amount of trill or a salt thereof. Preferred non-human mammary glands The object is a dog. In certain embodiments, the dog is at least 9 months old or at least 1 It is two months old.

[0086] In preferred embodiments, this disclosure relates to dermatological conditions [e.g., skin disorders, e.g., psoriasis ( For example, psoriasis vulgaris, atopic dermatitis, skin rash, skin irritation, skin sensitization (for example, contact dermatitis) Dermatitis or allergic contact dermatitis, including itching associated with allergic dermatitis A method for treating itching and allergic reactions in non-human mammals that require it. Crystal morphology I, or morphology II, or morphology III 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop This includes administering an effective dose of acetonitrile (sulfonyl)azetidine-3-yl)acetonitrile. The law is provided. The preferred non-human mammal is the dog. In certain embodiments, the dog is They are at least 9 months old or at least 12 months old.

[0087] In particularly preferred embodiments, the disclosure relates to dermatological conditions [e.g., skin disorders, e.g., dry skin]. dermatitis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact (Touch dermatitis or allergic contact dermatitis), including itching associated with allergic dermatitis. A method for treating itching and allergic reactions, etc., which is necessary for non-human infants In mammals, crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti The present invention provides a method comprising administering an effective amount of din-3-yl)acetonitrile. The non-human mammal is the dog. In certain embodiments, the dog is at least 9 months old or It is at least 12 months old.

[0088] In a particularly preferred embodiment, the disclosure relates to dermatological conditions [e.g., skin disorders, e.g.]. For example, psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (for example) For example, contact dermatitis or allergic contact dermatitis, and allergic dermatitis. A method for treating itching, including pruritus and allergic reactions, and for which it is not necessary. In human mammals, there is a substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyro Ro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cytoyl) Administer an effective dose of rospropylsulfonyl azetidine-3-yl acetonitrile. The present invention provides a method including the following. A preferred non-human mammal is a dog. In a particular embodiment, The dog must be at least 9 months old or at least 12 months old.

[0089] In certain embodiments, the present disclosure is a method for treating atopic dermatitis, which does not require In non-human mammals, the key ingredient is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine. -4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)aze The present invention provides a method comprising administering an effective amount of thidine-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure is a method for treating atopic dermatitis, and For non-human mammals that require this, crystalline morphology I, or morphology II, or morphology III 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile The present invention provides a method comprising administering an effective amount of [a substance]. In a particularly preferred embodiment, the present disclosure provides [a method]. A method for treating atopic dermatitis, wherein a crystalline form is used in non-human mammals that require it. State II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H -Pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl) The present invention provides a method comprising administering an effective amount of acetonitrile. A particularly preferred implementation In form, this disclosure relates to a method for treating atopic dermatitis, which requires non-atopic dermatitis. In mammals, a substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo [2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclo Administer an effective dose of propylsulfonyl azetidine-3-yl acetonitrile. A method is provided that includes [a]. A preferred non-human mammal is a dog. In a particular embodiment, [a] Nu is at least 9 months old or at least 12 months old.

[0090] In certain embodiments, the disclosure relates to a method for treating itching associated with allergic dermatitis. And for non-human mammals that need it, 2-(3-(4-(7H-pirolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop Administer an effective amount of acetonitrile (sulfonyl)azetidine-3-yl)acetonitrile or its salt. The present invention provides a method including the following. In a preferred embodiment, the present invention relates to allergic dermatitis. A method for treating itching, in non-human mammals that require it, crystalline form I, Or form II, or form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrim Zin-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) The present invention provides a method comprising administering an effective amount of azetidine-3-yl)acetonitrile. In a particularly preferred embodiment, the present disclosure addresses pruritus associated with allergic dermatitis. A method that is used in non-human mammals that require it, crystalline form II 2-(3-(4-( 7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)- Inject an effective amount of 1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile The present disclosure provides a method that includes giving. In a particularly preferred embodiment, the present disclosure provides an allergen. A method for treating itching associated with gynecomastia, which is necessary for non-human mammary glands In the substance, there is a substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl A method comprising administering an effective amount of sulfonyl azetidine-3-yl acetonitrile. The preferred non-human mammal is the dog. In certain embodiments, the dog is small. They must be at least 9 months old or at least 12 months old.

[0091] The effective dose may be, for example, in the range of 0.5 mg to 100 mg. The specific amount will be determined by those skilled in the art. These dosages can be determined by the following criteria for patients with a mass of approximately 0.5 kg to approximately 80 kg. Based on this, however, the diagnostician will determine the appropriate dose for subjects whose mass falls outside this weight range. It may be determined. The effective amount can be, for example, in the range of 0.1 mg to 1.2 mg / kg patient, 0.3 mg to 1.0 mg / kg patient or 0.4 mg to 0.6 mg / kg patient. The dosing regimen can be, for example, daily, twice daily, weekly or monthly dosing.

[0092] In certain embodiments, the disclosure provides 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof for use in the treatment of dermatological conditions [such as, for example, skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus including pruritus associated with allergic dermatitis, and allergic reactions, etc.] in non-human mammals. Preferred non-human mammals are dogs. In certain embodiments, the

[0093] dog is at least 9 months old or at least 12 months old. In preferred embodiments, the disclosure provides crystalline form I, or form II, or form III of 2-(3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile for use in the treatment of dermatological conditions [such as, for example, skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), pruritus including pruritus It is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old. He is of a certain age.

[0094] In particularly preferred embodiments, this disclosure relates to dermatological conditions in non-human mammals [e.g., For example, skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, and skin irritations. , skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic skin For use in the treatment of itching, including itching associated with inflammation and allergic reactions, etc. Crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl (L) Provides acetonitrile. Preferred non-human mammal is dog. Specific implementation In this state, the dog is at least 9 months old or at least 12 months old.

[0095] In a particularly preferred embodiment, the present disclosure relates to dermatological conditions in non-human mammals. [For example, skin disorders, e.g., psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rash, skin Skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergy For use in the treatment of itching, including itching associated with genital dermatitis, and allergic reactions. The substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3- d] Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl Provides ruhonyl)azetidine-3-yl)acetonitrile. Preferred non-human mammals. is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 It is 1 month old.

[0096] In certain embodiments, the disclosure relates to the treatment of atopic dermatitis in non-human mammals. For use, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) -1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- The present invention provides acetonitrile (I) or a salt thereof. In preferred embodiments, the present invention relates to non-human Crystal form I or form II for use in the treatment of atopic dermatitis in mammals. , or form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile is provided. In a particularly preferred embodiment, the disclosure provides non-human acetonenitrile. Crystal form II 2-(3-( 4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl We provide acetonitrile (L)-1-(cyclopropylsulfonyl)azetidine-3-yl) In a particularly preferred embodiment, the present disclosure relates to atopic dermatitis in non-human mammals. For use in the treatment of dermatitis, substantially polymorphic pure crystalline form II 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl We provide )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. The preferred non-human mammal is the dog. In certain embodiments, the dog is at least The person is 9 months old or at least 12 months old.

[0097] In certain embodiments, this disclosure relates to allergic dermatitis in non-human mammals. For use in the treatment of pruritus, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is provided. In preferred embodiments, (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is provided. In preferred embodiments, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. In particularly preferred embodiments, the present disclosure provides crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. In even more particularly preferred embodiments, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. Preferred non-human mammals are dogs. In certain embodiments, the dog is at least 9 months old or at least 12 months old. In certain embodiments, the present disclosure provides a dermatological condition in non-human mammals [e.g., skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. Preferred non-human mammals are dogs. In certain embodiments, the dog is at least 9 months old or at least 12 months old. In certain embodiments, the present disclosure provides a dermatological condition in non-human mammals [e.g., skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin

[0098] In certain embodiments, the present disclosure provides a dermatological condition in non-human mammals [e.g., skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, rash, skin irritation, skin Sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic dermatitis For the manufacture of drugs for the treatment of itching, including associated itching and allergic reactions. , 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Provides the use of nitriles or salts thereof. The preferred non-human mammal is the dog. In this embodiment, the dog is at least 9 months old or at least 12 months old.

[0099] In preferred embodiments, this disclosure relates to dermatological conditions in non-human mammals [e.g., Skin disorders, such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin Skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic dermatitis For the manufacture of drugs for the treatment of itching, including associated itching and allergic reactions. Crystal morphology I, or morphology II, or morphology III 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopro The use of (pyrusulfonyl)azetidine-3-yl)acetonitrile is provided. Preferred non The human mammal is a dog. In certain embodiments, the dog is at least 9 months old or young At least 12 months old.

[0100] In particularly preferred embodiments, this disclosure relates to dermatological conditions in non-human mammals [e.g., For example, skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, and skin irritations. , skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic skin Manufacturing of drugs for the treatment of itching, including itching associated with inflammation, and allergic reactions. For this purpose, crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetide The use of 1-3-yl)acetonitrile is provided. The preferred non-human mammal is the dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old. .

[0101] In a particularly preferred embodiment, the present disclosure relates to dermatological conditions in non-human mammals. [For example, skin disorders, e.g., psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rash, skin Skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergy Drugs for the treatment of itching, including itching associated with genital dermatitis, and allergic reactions. For manufacturing, substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo [2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclo The use of propylsulfonyl azetidine-3-yl acetonitrile is provided. The non-human mammal is the dog. In certain embodiments, the dog is at least 9 months old or It is at least 12 months old.

[0102] In certain embodiments, this disclosure relates to the treatment of atopic dermatitis in non-human mammals. For the manufacture of the drug, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azeti The use of din-3-yl)acetonitrile or a salt thereof is provided. In a preferred embodiment, This disclosure relates to the manufacture of agents for the treatment of atopic dermatitis in non-human mammals. Crystal morphology I, or morphology II, or morphology III 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop The use of (sulfonyl)azetidine-3-yl)acetonitrile is provided. Particularly preferred In embodiments, the present disclosure relates to a drug for the treatment of atopic dermatitis in non-human mammals. For the manufacture of the crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrim Zin-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) The use of azetidine-3-yl)acetonitrile is provided. More particularly preferred embodiments Therefore, this disclosure relates to the manufacture of agents for the treatment of atopic dermatitis in non-human mammals. For this purpose, the substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop The use of (sulfonyl)azetidine-3-yl)acetonitrile is provided. Preferred non-hyaluronic acid The mammal is a dog. In certain embodiments, the dog is at least 9 months old or less At least 12 months old.

[0103] In certain embodiments, this disclosure relates to allergic dermatitis in non-human mammals. For the manufacture of drugs for the treatment of pruritus, 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl The use of sulfonyl azetidine-3-yl acetonitrile or a salt thereof is provided. In a particular embodiment, this disclosure relates to the treatment of allergic dermatitis in non-human mammals. Crystal form I, or form II, or form III for the manufacture of drugs for the treatment of itching 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton The use of trills is provided. In a particularly preferred embodiment, the disclosure applies to non-human mammals. For the manufacture of a drug for the treatment of itching associated with allergic dermatitis, crystalline form I I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-py Razole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)azetidine The use of tonitrile is provided. In a particularly preferred embodiment, the disclosure provides a non-human milking For the manufacture of drugs for the treatment of pruritus associated with allergic dermatitis in animals, Substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl sulfo) Provides the use of yl)azetidine-3-yl)acetonitrile. Preferred non-human infant feeding The object is a dog. In certain embodiments, the dog is at least 9 months old or at least 1 It is two months old. [Examples]

[0104] The following examples are provided to illustrate the present invention and are not limiting in any way.

[0105] Example 1 2-[1-Cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl acetonitrile 2-(1-cyclopropylsulfonylazetidine-3-ylidene)acetonitrile (8 50g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (874g) was mixed in acetonitrile (2.6L). Add 1,8-diazabicyclo[5.4.0]undec-7-ene (65g) to the mixture. The mixture was heated to 70°C. After 2.5 hours, the reaction mixture was cooled to ambient temperature for approximately 2 hours. Slowly add water (5.2L) to this mixture over approximately 1 hour, and let the mixture steep for approximately 3 hours. The mixture was stirred for a considerable time. The formed solid was collected by filtration and vacuum-dried at 45°C for approximately 24 hours. Dry the mixture, then 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetra [methyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine -3-yl]acetonitrile was obtained.

[0106] Example 2 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Potassium phosphate (829g) was combined with water (1L) and cooled to ambient temperature. THF(2 L) was added. 4-chloropyrrolo[2,3-d]pyrimidine (200g) was added, and Then, di-tert-butyl dicarbonate (344g) was added. The reaction mixture was heated to ambient temperature. The mixture was stirred at 2°C for 24 hours. Nitrogen gas was sprayed onto the reaction mixture for 60 minutes. 2-[1- Cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2- [Dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]aceton Add Toryl (562g) and Pd-134 (6.6g), and raise the reaction temperature to 60°C. After about 2 hours, the aqueous layer was separated, silicathiol (40g) was added, and the reaction mixture was heated to 60°C. The mixture was stirred for 18 hours. The reaction mixture was filtered at 60°C, and the filtrate was stirred for 10-2 hours. Cool to 0°C to obtain solid matter, recover it by filtration, rinse with cold THF, and then 4 Dry under vacuum at 0-50°C for 2 hours, then tert-butyl 4-[1-[3-(Sy Anomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4 -yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (540g) was obtained.

[0107] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropyl obtained above [Sulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyri Midine-7-carboxylate (540g) is mixed with n-butanol (3L) and water (770ml) Combine with L) and heat to 90°C. After 6 hours, the reaction mixture was cooled to 80°C within 30 minutes, and then... Stir at 80°C for 30 minutes, then cool to 20°C for 6 hours, and then at 10-20°C for 1 Stir for 6 hours to obtain a solid, filter it, and obtain 460g of the title compound (as a wet cake). I obtained it.

[0108] Example 3 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile Potassium phosphate (829g) was combined with water (1L) and cooled to ambient temperature. THF(2 L) was added. 4-chloropyrrolo[2,3-d]pyrimidine (200g) was added, and Then, di-tert-butyl dicarbonate (344g) was added. The reaction mixture was heated to ambient temperature. The mixture was stirred at 2°C for 24 hours. Nitrogen gas was sprayed onto the reaction mixture for 60 minutes. 2-[1- Cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2- [Dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]aceton Add Toryl (562g) and Pd-134 (6.6g), and raise the reaction temperature to 60°C. After about 2 hours, the aqueous layer was separated, silicathiol (40g) was added, and the reaction mixture was heated to 60°C. The mixture was stirred for 18 hours. The reaction mixture was filtered at 60°C, and then the filtrate was stirred for 10-20 hours. It is cooled to °C to obtain a solid, which is recovered by filtration, rinsed with cold THF, and then 4 Dry under vacuum at 0-50°C for 2 hours, then tert-butyl 4-[1-[3-(Sy Anomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4 -yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (525g) was obtained.

[0109] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropyl obtained above [Sulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyri Midine-7-carboxylate (540g) is mixed with n-butanol (3L) and water (770ml) Combine with L) and heat to 90°C. After 6 hours, the reaction mixture was cooled to 80°C within 30 minutes, and then... Stir at 80°C for 30 minutes, then cool to 20°C over 6 hours, and then at 10-20°C. Stir for 16 hours to obtain a solid, filter it, and extract the title compound (as a wet cake) 454 g was obtained.

[0110] Example 4 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II Combine the wet cakes (approximately 907g) from Examples 2 and 3 in acetonitrile (4L). The mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 20°C for 6 hours, and then to 20°C. The mixture was stirred for 12 hours. The solids were collected by filtration, rinsed with acetonitrile, and then rinsed for 50-60 minutes. The compound was dried under vacuum at °C for 24 hours to obtain the title compound (695 g).

[0111] Example 5 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (104.1 mg) was combined with acetone (8 mL) and heated to 55°C for 30 minutes. Next, the reaction mixture was cooled to a temperature of 30°C at a rate of 0.02°C / min, and then at a rate of 0.1°C / min. The mixture was cooled to a temperature of 5°C, during which time heptane (12 mL) was added at a rate of 2.94 mL / hour. Simultaneously, it is added to obtain a solid, which is recovered by filtration and dried to obtain the title compound (79 I obtained 0.5 mg.

[0112] Example 6 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (152.4 mg) with acetonitrile (8.1 mL) and heat to 80°C. After 30 minutes, the reaction mixture was cooled to a temperature of 5°C at a rate of 0.05°C / min to obtain a solid. The compound was then recovered by filtration and dried to obtain the title compound (93.4 mg).

[0113] Example 7 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (157.8 mg) in acetonitrile / water 96:4 (v / v) (4.2 mL) The mixture was then heated to 80°C. After 30 minutes, the reaction mixture was heated to 5°C at a rate of 0.05°C / min. It is cooled to obtain a solid, which is recovered by filtration and dried to obtain the title compound (89.4m). g) was obtained.

[0114] Example 8 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (5g) with acetonitrile / water 96:4 (v / v) (100mL), 8 The mixture was heated to 0°C. After approximately 75 minutes, the reaction mixture was cooled to 70°C at a rate of 0.20°C / min. Next, add the crystal species (0.25g twice) and heat to 8°C at a rate of 0.05°C / min. Cooling was continued until a solid was obtained. After about 6 hours, the solid was collected by filtration, dried, and then laid flat. The target compound (4.88 g) was obtained.

[0115] Example 9 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (20.6 mg) is mixed with 4:1 (v / v) methanol, which has a water activity of approximately 0.5. Combine with water (0.3 mL), stir at 25°C for 4 days, and then add 4:1 (v / v) methanol. Add water (0.5 mL), continue stirring at 25°C for 6 days, then filter and centrifuge (3 The solid was collected using a 0.2 μm PVDF film at 5000 rpm for several minutes, and the title compound was identified. I obtained it.

[0116] Example 10 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (10g) with acetonitrile / water 96:4 (v / v) (250mL), The mixture was heated to 72°C. After approximately 60 minutes, the reaction mixture was cooled to 65°C at a rate of 0.20°C / min. Next, add the crystal species (0.10g) and heat at a rate of 0.035°C / min to a temperature of 35°C. The cooling is continued to obtain a solid, and then the material is cooled to a temperature of 5°C at a rate of 0.125°C / min. A solid was obtained. After about 3 hours, the solid was recovered by filtration and dried, and the title compound (8.5 1g was obtained.

[0117] Example 11 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (70.3 mg) with 0.2 mL of 9:1 (v / v) acetone / water and stir. It was heated to 60°C. Then, a further 9:1 (v / v) acetone / water mixture was slowly added in total. Approximately 1.6 mL was added. The temperature was maintained at 60°C for 1.5 hours, and then the mixture was heated at 0.05°C / min. The mixture was cooled to 10°C at a certain rate and held at 10°C for 2 hours and 45 minutes to obtain a solid. The solid was then filtered. The compound was recovered by centrifugation (2 minutes, 5000 rpm) to obtain the title compound.

[0118] Example 12 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (149.8 mg) with acetonitrile (8.0 mL) and heat to 80°C. After 30 minutes, the reaction mixture was cooled to a temperature of 55°C at a rate of 0.02°C / min. Next, The mixture is cooled at a rate of 0.1°C / min over a range of 55°C to 5°C, and simultaneously from 55°C Over the same duration as a 5°C cooling gradient, a total of 12 units were injected at a rate of 1.44 mL / hour. mL of isopropyl acetate is added to obtain a solid, which is then collected by filtration and dried. The title compound (94.2 mg) was obtained.

[0119] Example 13 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (208.5 mg) with 0.2 mL of 3:1 (v / v) methanol / water. The mixture was heated to 60°C while stirring. Further 3:1 (v / v) methanol / water was added slowly. A total of approximately 23.2 mL was added. The temperature was maintained at 60°C for 30 minutes, and then the mixture was diluted to 0.0 The mixture was cooled to 10°C at a rate of 5°C / min and held at 10°C for 20 minutes to obtain a solid. The compound was recovered by filtration to obtain the title compound.

[0120] Example 14 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (60 mg) is mixed with 2 mL of 5:1(v / v)1-bronze, which has a water activity of approximately 0.9. Combine with tanol / water, stir at room temperature for 10 days, then filter and centrifuge (2 minutes, 5000°C). The solid material was recovered using rpm (0.2 μm PTFE film) to obtain the title compound.

[0121] Example 15 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (33 mg) is mixed with 0.4 mL of 3:2 (v / v) solution, which has a water activity of approximately 0.7. Combine with tanol / water, stir at approximately 20°C for 14 days, then filter and centrifuge (2 minutes, 44 minutes). The solid material was recovered using a 0.2 μm PTFE film at 00 rpm to obtain the title compound.

[0122] Example 16 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.4 mg) with acteophenone (1 mL) and stir at room temperature for 10 days. Next, the material is solidified by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0123] Example 17 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (59.9 mg) with butyronitrile (2 mL) and stir at room temperature for 10 days. Next, the solid was obtained by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0124] Example 18 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.3 mg) with cyclohexanone (1.5 mL) and leave at room temperature for 10 days. Stirring, then filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) The solid material was recovered, and the title compound was obtained.

[0125] Example 19 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.9 mg) with dioxane (2 mL), stir at room temperature for 10 days, and then... The solids are then separated by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The sample was recovered, and the title compound was obtained.

[0126] Example 20 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.0 mg) with ethyl formate (1.5 mL) and stir at room temperature for 10 days. Next, the solid was obtained by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0127] Example 21 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (59.4 mg) with methyl acetate (1.5 mL) and stir at room temperature for 10 days. Next, the solid was obtained by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0128] Example 22 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.5 mg) with nitrobenzene (2 mL) and stir at room temperature for 10 days. Next, the solid was obtained by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0129] Example 23 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.5 mg) with anisole (0.6 mL) and stir at 40°C for 6 days. Next, the solid was obtained by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0130] Example 24 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (59.8 mg) with ethyl formate (0.6 mL) and stir at 40°C for 6 days. Next, the material is solidified by filtration and centrifugation (2 minutes, 5000 rpm, 0.22 μm PVDF membrane). The material was recovered, and the title compound was obtained.

[0131] Example 25 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.5 mg) with isopropyl acetate (0.6 mL) and incubate at 40°C for 6 days. Stirring, then filtering and centrifuging (2 minutes, 5000 rpm, 0.22 μm PVDF membrane) Further solid material was recovered to obtain the title compound.

[0132] Example 26 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.4 mg) with isopentanol (1 mL) and stir at 40°C for 6 days. Next, the material is solidified by filtration and centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0133] Example 27 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.4 mg) with methyl isobutyl ketone (1 mL) and incubate at 40°C for 6 days. Stirring is performed, followed by filtration and centrifugation (2 minutes, 5000 rpm, 0.22 μm PTFE membrane). The solid material was recovered, and the title compound was obtained.

[0134] Example 28 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (60.6 mg) is mixed with 3:1 (v / v) ethanol, which has a water activity of approximately 0.7. Combine with water (0.9 mL), stir at 40°C for 6 days, then filter and centrifuge (2 minutes, 5 The solid material was recovered using a 0.22 μm PVDF film at 000 rpm to obtain the title compound.

[0135] Example 29 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (69.7 mg) with 1-propanol (10.8 mL) and stir while It was heated to 60°C. Dimethyl 1-propanol / DMSO was added to a mixture of approximately 85:15 (v / v) Chil sulfoxide (2 mL) was slowly added. The temperature was maintained at 60°C for approximately 1.5 hours. Then, the mixture is cooled to 10°C at a rate of 0.05°C / min and held at 10°C for 7.5 hours. Next, add 1-propanol (5 mL), then stir the mixture at 5°C for 10 days until solids are removed. The compound was obtained by collecting the sample by filtration and then obtaining the title compound.

[0136] Example 30 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (70.6 mg) with ethyl acetate saturated with water (0.2 mL) and stir. Heat to 60°C, then add ethyl acetate (7.2 mL) and heat at 60°C for approximately 1.5 hours. Stirring intermittently, then the mixture is cooled to 10°C at a rate of 0.05°C / min, followed by filtration and centrifugation. The solid was collected using a 0.2 μm PTFE film at 5000 rpm for 2 minutes, and the title compound was identified. I obtained it.

[0137] Example 31 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (199.6 mg) with ethyl acetate saturated with water (2.0 mL) and heat in a room. Stir at warm temperature for 2 days, then filter and centrifuge (2 minutes, 5000 rpm, 0.2 μm PTF). The solid material was recovered using film E, and the title compound was obtained.

[0138] Example 32 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill form I By drying under vacuum at 60°C for approximately 69 hours, 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile Form III was obtained, and the title compound was acquired.

[0139] Example 33 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.3 mg) with ethanol (1 mL), stir at 5°C for 7 days, and then... The solids are then separated by filtration and centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The sample was recovered, and the title compound was obtained.

[0140] Example 34 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.4 mg) with methanol (1 mL), stir at 5°C for 7 days, and then... The solids are then separated by filtration and centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The sample was recovered, and the title compound was obtained.

[0141] Example 35 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.0 mg) with isopropanol (1 mL) and stir at 5°C for 7 days. Next, the material is solidified by filtration and centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The material was recovered, and the title compound was obtained.

[0142] Example 36 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.3 mg) with 1-butanol (2 mL) and stir at 5°C for 7 days. Next, the material was solidified by filtration and centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The material was recovered, and the title compound was obtained.

[0143] Example 37 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (59.6 mg) with ethanol (1 mL), stir at 60°C for 5 days, then proceed to... The solids are then filtered and centrifuged (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The compound was recovered, and the title compound was obtained.

[0144] Example 38 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (59.9 mg) with methanol (1 mL), stir at 60°C for 5 days, then proceed... The solids are then filtered and centrifuged (2 minutes, 5000 rpm, 0.45 μm PVDF membrane). The compound was recovered, and the title compound was obtained.

[0145] Example 39 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.1 mg) with isopropanol (1.5 mL) and incubate at 60°C for 5 days. Stirring, then filtration and centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) Further solid material was recovered to obtain the title compound.

[0146] Example 40 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (60.6 mg) with 1-butanol (1.5 mL) and stir at 60°C for 5 days. Mix, then filter and centrifuge (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) The solid material was recovered, and the title compound was obtained.

[0147] Example 41 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (10.4 mg) with acetonitrile (0.5 mL) and stir at 20°C for 1 day. Mix, then filter and centrifuge (1 minute, 4500g rcf, 0.2μm PTFE membrane). Further solid material was recovered to obtain the title compound.

[0148] Example 42 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (10.3 mg) with acetone (0.5 mL) and stir at 20°C for 1 day. Next, the material is solidified by filtration and centrifugation (2 minutes, 4000g rcf, 0.2μm PTFE membrane). The material was recovered, and the title compound was obtained.

[0149] Example 43 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (20.6 mg) is mixed with 4:1 (v / v) methanol, which has a water activity of approximately 0.5. Combine with water (0.4 mL), stir at 25°C for 4 days, then further 4:1 (v / v) Add methanol / water (0.5 mL), stir at 25°C for 6 days, then filter and centrifuge ( The solid material was collected using a 0.2 μm PVDF film at 5000 rpm for 3 minutes, and the title compound was identified. I obtained it.

[0150] Example 44 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Combine nitrile (539.9 mg) with 1:1 (v / v) ethanol / acetone (18 mL). Mix, stir at 60°C for 45 minutes, then cool to 5°C at a rate of 0.05°C / min, and solidify. The resulting compound was obtained, recovered by filtration, dried under vacuum at 40°C, and the title compound was obtained. I got it.

[0151] Example 45 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (256.1 mg) in a 7:3 (v / v) acetone / isopropyl acetate (13.5 Combine with (mL), stir at 60°C for 1 hour, then cool to 5°C at a rate of 0.02°C / min. Then, a solid is obtained, which is recovered by filtration, dried under vacuum at 40°C, and then labeled. I obtained a suitable product.

[0152] Example 46 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (60 mg) is mixed with 5:1(v / v)1-butanol, which has a water activity of approximately 0.9. Combine with water (2 mL), stir at room temperature for 10 days, then filter and centrifuge (2 minutes, 500°C). The solid material was recovered using a 0.2 μm PTFE film (0 rpm) to obtain the title compound.

[0153] Example 47 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazo (Il-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceton Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile (60.1 mg) is mixed with 1:1 (v / v) acetonite, which has a water activity of approximately 0.9. Combine with Lil / water (0.9 mL), stir at 40°C for 6 days, then filter and centrifuge (2 minutes). The solid material was recovered using a 0.2 μm PTFE film at 5000 rpm, and the title compound was obtained. .

[0154] Example 48 Control of pruritus and skin lesions associated with allergic dermatitis in dogs This study aims to control itching and skin lesions associated with allergic dermatitis in dogs. Therefore, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H -Pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl) Acetonitrile was evaluated.

[0155] As shown below, morphology II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)aze Oral tablets containing thidine-3-yl)acetonitrile were prepared. Crystal form II 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni Ingredients: cellulose, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dehydrate, oxidized starch An oral tablet blend containing a pigment and magnesium stearate was prepared. The Lend material was compressed to obtain crystalline form II in 2.4 mg, 3.6 mg, 5.4 mg, and 16 mg. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto A tablet core containing nitrile and a placebo core were obtained. Water and Opadry 20A1 The tablet core was coated with a mixture containing 50011 Red, thereby allowing testing to be performed. The final oral tablet was obtained.

[0156] [Table 1]

[0157] Regarding the control of pruritus and skin lesions associated with allergic dermatitis in dogs, 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni To evaluate the efficacy of daily administration of the drug, a four-group, blinded, randomized, placebo-controlled trial was conducted. The study was conducted. Participants were randomized to one of the following treatment groups: API-containing tablets, 0.25 ~0.40 mg / kg body weight; API-containing tablets, 0.40~0.60 mg / kg body weight; AP Tablets containing I: 0.60-0.80 mg / kg body weight; and placebo tablets: 0.0 mg / kg body weight.

[0158] The dogs enrolled in this study received the treatment once a day for approximately 28 days. Baseline Data (clinical history, concomitant medications, weight, physical examination, and assessment of pruritus and atopic dermatitis) The following were collected for each dog at the time of registration (Day 0): further health assessment, physical examination, and weight measurement. , evaluation of pruritus and atopic dermatitis and hematological, serological, and pharmacokinetic (PK) analysis Blood samples were collected according to a standard test protocol.

[0159] The primary variable regarding effectiveness was the response to treatment. Treatment response was the smallest response within the first 7 treatment days. At least 70% (i.e., at least 5 of the first 7 treatment days) Self-reported itchiness: More than 2 units above baseline on the Visual Analog Scale (VAS). This was defined as a decrease in [the relevant factor]. Due to the perceived lack of effectiveness, the test was performed within the first 7 days of treatment. Dogs from which treatment was discontinued were considered to have undergone unsuccessful treatment. Treatment efficacy was achieved in at least 50% of the dogs. The minimum effective dose was defined in the protocol as the appropriate dosage.

[0160] Table 2 shows 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1 H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl The maximum dose of acetonitrile (0.60-0.80 mg / kg) is 0.2935 (95 The response rate was statistically significantly higher than the placebo response rate (with a confidence interval of 0.1571, 0.4808). It has a response rate of 0.7188 (95% confidence intervals 0.5331, 0.8512); (logit This indicates that the p-value for comparison (on the scale) is 0.0006. Therefore, the maximum dose The group (0.6-0.8 mg / kg) achieved the primary endpoint for treatment response. Administering 0.6-0.8 mg / kg once daily showed a significant improvement in itching from the first dose. Furthermore, this group showed a significant improvement in lesion scores on day 28 of this trial. Low dose (0.2 Estimated marginal mean for 4-0.4 mg / kg and medium dose (0.4-0.6 mg / kg) The response rate was also higher than that of the placebo group. This result indicates a fixed effect term and 0 Based on a general linear mixed model using VAS scores. Using the covariance structure of the variance components. The dam effect is fitted to the site and site treatment, and the complex symmetrical covariance structure is applied to individual dogs. It was fitted to it.

[0161] [Table 2]

[0162] 8. Typical Embodiments For completeness, various aspects of this disclosure are presented in the following numbered clauses.

[0163] Clause 1.12.72° (43.1%), 14.04° (61.3%), 17.56° ( 20.8%, 20.33° (87.4%), 24.50° (100%), and 25.83 The X-ray powder diffraction pattern, which includes a peak at °(94.9%)(±0.2°2θ), is particularly distinctive. Characterized, substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl Sulfonyl azetidine-3-yl acetonitrile.

[0164] Clause 2. Substantially polymorphic pure crystalline 2-(3-(4-(7H-pyro Ro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cytoyl) Ropropylsulfonyl)azetidine-3-yl)acetonitrile and pharmaceutically acceptable A pharmaceutical composition containing an excipient.

[0165] Clause 3. Substantially polymorphic pure crystalline 2-(3-(4-(7H-pyro Ro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cytoyl) Process for preparing rospropylsulfonyl azetidine-3-yl acetonitrile A process comprising crystallization from acetone and heptane.

[0166] Clause 4. Substantially polymorphic pure crystalline 2-(3-(4-(7H-pyro Ro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cytoyl) Process for preparing rospropylsulfonyl azetidine-3-yl acetonitrile It is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl A process comprising drying the hydrated crystalline form of acetonitrile.

[0167] Article 5. Methods for treating dermatological conditions in non-human mammals that require such treatment. , substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop This includes administering an effective dose of acetonitrile (sulfonyl)azetidine-3-yl)acetonitrile. Law.

[0168] Article 6. The dermatological condition shall be selected from the group consisting of atopic dermatitis and pruritus. The method described in Article 5.

[0169] Article 7. Non-human mammals are dogs, as described in Article 6.

[0170] Clauses 8.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 1 6.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68° Alternatively, the X-ray powder diffraction pattern, which includes a peak at 26.75° (±0.2°²θ), is particularly useful. Characterized, substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl Sulfonyl azetidine-3-yl acetonitrile.

[0171] X-ray powder containing peaks at clauses 9.18.65° and 10.68° (±0.2°²θ). Characterized by diffraction patterns, substantially polymorphically pure crystalline 2-(3-(4- (7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl) -1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0172] X-ray powder containing peaks at clauses 10.18.65° and 21.76° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0173] X-ray powder containing peaks at 11.18.65° and 22.68° (±0.2°²θ) Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0174] X-ray powder containing peaks at 12.26.75° and 21.76° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0175] Clause 13. Substantially polymorphic pure crystalline 2-(3) as described in any one of Clauses 8-12 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and A pharmaceutical composition comprising pharmaceutically acceptable excipients.

[0176] Clause 14. Substantially polymorphic pure crystalline 2-(3) as described in any one of Clauses 8-12 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for production, wherein each C has a water activity of less than approximately 0.7. 1~5 a Lecol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylcyani D, C3~9 A solvent or mixture of solvents selected from the group consisting of alkyl ketones and aromatic solvents. A process that includes crystallization from a compound.

[0177] Clause 15. Substantially polymorphic pure crystalline 2-(3) as described in any one of Clauses 8-12 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for production, wherein each C has a water activity of less than approximately 0.5. 1~5 a Lecol, C 2~8 Alkyl ethers, C acetate 2~8 Alkyl, C 2~5 Alkylcyani D, C 3~9 A solvent or mixture of solvents selected from the group consisting of alkyl ketones and aromatic solvents. A process that includes crystallization from a compound.

[0178] Clause 16. Substantially polymorphic pure crystalline 2-(3) as described in any one of Clauses 8-12 -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for production, comprising crystallizing from acetonitrile having a water activity of less than 0.7. A process that includes doing so.

[0179] Article 17. Substantially polymorphic pure crystalline 2-(3) as described in any one of Articles 8-12. -(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for production, comprising crystallizing from acetonitrile having a water activity of less than 0.5. A process that includes doing so.

[0180] Article 18. Methods for treating dermatological conditions that require the treatment of non-human mammals. In addition, the crystalline 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropyl A method comprising administering an effective amount of sulfonyl azetidine-3-yl acetonitrile. .

[0181] Article 19. The dermatological condition shall be selected from the group consisting of atopic dermatitis and pruritus. The method described in Article 18.

[0182] Clause 20. Non-human mammal is a dog, as described in Clause 19.

[0183] Clauses 21.11.08°, 14.73°, 18.06°, 18.27°, 18.51° , 22.24°, 22.69°, 24.76°, 25.48° or 28.04° (±0. Characterized by an X-ray powder diffraction pattern including a peak at 2°2θ), substantially multi Morphologically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile.

[0184] X-ray powder containing peaks at clauses 22.11.08° and 22.69° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0185] X-ray powder containing peaks at clauses 23.14.73° and 22.69° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0186] X-ray powder containing peaks at clauses 24.22.69° and 25.48° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0187] X-ray powder containing peaks at 25.11.08° and 18.06° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0188] X-ray powder containing peaks at 26.11.08° and 25.48° (±0.2°²θ). Characterized by its final diffraction pattern, it is a substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl )-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0189] Article 27. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[0190] Article 28. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing C, each having a water activity of more than approximately 0.9 1~ 5. Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkyl Anido and C 3~9 From a solvent or mixture of solvents selected from the group consisting of alkyl ketones A process that includes crystallization.

[0191] Article 29. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing a C having a water activity of more than approximately 0.9 1~5 Arco A process comprising crystallization from a solvent or mixture of solvents selected from the group consisting of . .

[0192] Article 30. Methods for treating dermatological conditions that require the treatment of non-human mammals. In addition, the crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop This includes administering an effective dose of acetonitrile (sulfonyl)azetidine-3-yl)acetonitrile. Law.

[0193] Clause 31. The dermatological condition shall be selected from the group consisting of atopic dermatitis and pruritus. , the method described in Article 30.

[0194] Clause 32. Non-human mammal is a dog, as described in Clause 31.

[0195] Clause 33.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68 X-ray powder diffraction patterns containing peaks at ° or 26.75° (±0.2°²θ) Characterized as substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cycloprop Acetonitrile (Azetidine-3-yl) acetonitrile.

[0196] X-ray powder containing peaks at 34.18.65° and 10.68° (±0.2°²θ). A substantially polymorphically pure crystal as described in Clause 33, characterized by its final diffraction pattern. Sex 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile.

[0197] X-ray powder containing peaks at clauses 35.18.65° and 21.76° (±0.2°²θ). A substantially polymorphically pure crystal as described in Clause 33, characterized by its final diffraction pattern. Sex 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile.

[0198] X-ray powder containing peaks at clauses 36.18.65° and 22.68° (±0.2°²θ). A substantially polymorphically pure crystal as described in Clause 33, characterized by its final diffraction pattern. Sex 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile.

[0199] X-ray powder containing peaks at 37.26.75° and 21.76° (±0.2°²θ). A substantially polymorphically pure crystal as described in Clause 33, characterized by its final diffraction pattern. Sex 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyramidyl Zole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)aceto Nitrile.

[0200] Article 38. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[0201] Article 39. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing C, each having a water activity of less than approximately 0.7. 1~5 Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylcia Nido, C 3~9 A solvent selected from the group consisting of alkyl ketones and aromatic solvents or a solvent A process that involves crystallization from a mixture.

[0202] Article 40. Substantially polymorphic pure crystalline 2-( described in any one of Articles 33-37) 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing C, each having a water activity of less than approximately 0.5. 1~5 Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylcia Nido, C 3~9 A solvent selected from the group consisting of alkyl ketones and aromatic solvents or a solvent A process that involves crystallization from a mixture.

[0203] Article 41. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing a product, wherein crystallization is performed from acetonitrile having a water activity of less than 0.7. A process that includes doing something.

[0204] Article 42. Substantially polymorphic pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile A process for producing a product, wherein crystallization is performed from acetonitrile having a water activity of less than 0.5. A process that includes doing something.

[0205] Article 43. Methods for treating dermatological conditions that require the treatment of non-human mammals. , 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-py Razole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)azetidine A method comprising administering an effective amount of tonitrile or a salt thereof.

[0206] Clause 44. Control of itching associated with allergic dermatitis and control of atopic dermatitis. A method that is used in non-human mammals that require it, 2-(3-(4-(7H-pyrolo[ 2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclop Administer an effective dose of rosin sulfonyl azetidine-3-yl acetonitrile or its salt. A method that includes doing so.

[0207] Article 45. A method for treating itching associated with allergic dermatitis, which is necessary In non-human mammals, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetide A method comprising administering an effective amount of 1-3-yl)acetonitrile or a salt thereof.

[0208] Article 46. Methods for treating the clinical symptoms of atopic dermatitis, which are not necessary for treating non-atopic dermatitis. In mammals, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) -1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- A method comprising administering an effective amount of acetnitrile or a salt thereof.

[0209] Article 47. A non-human mammal is a dog, as described in any one of Articles 43-46. .

[0210] Clause 48. The dog is at least 12 months old, as described in Clause 47.

[0211] Clause 49. The effective dose is 0.6 to 0.8 mg / kg, any one of Clauses 43 to 48. Methods used.

[0212] Clause 50. Administration to non-human mammals shall be once daily, as specified in any one of Clauses 43-49. Methods used.

[0213] Clause 51.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl (l) Acetonitrile is crystalline, as described in any one of the provisions of 43 to 50.

[0214] Clause 52.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile is crystalline form I, crystalline form II, crystalline form III, or any of them. A combination of the methods described in any one of the clauses 43 to 51.

[0215] Clause 53.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile is available at 5.34°, 10.68°, 14.26°, 16.06°, and 16 0.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, X-ray powder diffraction pattern containing peaks at 22.68° or 26.75° (±0.2°²θ) Characterized by , virtually polymorphic, pure crystalline 2-(3-(4-(7H-p Roro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cy Clopropylsulfonyl azetidine-3-yl acetonitrile, clauses 43-5 The method described in any one of item 1.

[0216] Clause 54.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile showed peaks at 18.65° and 10.68° (±0.2°²θ). Characterized by the X-ray powder diffraction pattern, substantially polymorphic and pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni The method described in any one of the clauses 43 to 51.

[0217] Clause 55.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile showed peaks at 18.65° and 21.76° (±0.2°²θ). Characterized by the X-ray powder diffraction pattern, substantially polymorphic and pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni The method described in any one of the clauses 43 to 51.

[0218] Clause 56.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile showed peaks at 18.65° and 22.68° (±0.2°²θ). Characterized by the X-ray powder diffraction pattern, substantially polymorphic and pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni The method described in any one of the clauses 43 to 51.

[0219] Clause 57.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile showed peaks at 26.75° and 21.76° (±0.2°²θ). Characterized by the X-ray powder diffraction pattern, substantially polymorphic and pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetoni The method described in any one of the clauses 43 to 51.

[0220] Clause 58.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl (L) Oral dosage form containing acetonitrile or a salt thereof.

[0221] Clause 59.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Oral dosage form containing acetonitrile (L)

[0222] Clause 60. Crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-i (Lu)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine- An oral dosage form containing 3-yl)acetonitrile.

[0223] Clause 61.2.4mg, 3.6mg, 4.8mg, 5.4mg, 6.4mg, 8.5mg g, 15 mg, or 16 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)aze An oral dosage form containing thidine-3-yl)acetonitrile.

[0224] Clause 62.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetide Form I, form II, or form III of acetonitrile (n-3-yl), or combinations thereof. The oral dosage form specified in any one of clauses 58 to 61.

[0225] Clause 63.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl Acetonitrile is available at 5.34°, 10.68°, 14.26°, 16.06°, and 16 0.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, X-ray powder diffraction pattern containing peaks at 22.68° or 26.75° (±0.2°²θ) Characterized by , virtually polymorphic, pure crystalline 2-(3-(4-(7H-p Roro[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cy Clopropylsulfonyl azetidine-3-yl acetonitrile, clauses 58-6 The oral dosage form described in any one of item 2.

[0226] Clause 64. The oral dosage form shall consist of microcrystalline cellulose, pregelatinized starch, and dicalcium phosphate. Dehydrate, oxide pigment, or magnesium stearate, or any combination thereof. Oral dosage forms as described in any one of clauses 58 to 63, including combinations.

Claims

1. ５．３４°、１０．６８°、１４．２６°、１６．０６°、１６．３９°、１６．４８ °, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or Characterized by powder X-ray diffraction patterns including a peak at 26.75° (±0.2°²θ). It can be obtained, a substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d (Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfate) An effective amount of honyl azetin-3-yl acetonitrile is administered to non-human infants requiring treatment. Treatment methods for dermatological conditions, including administration to animals.

2. The substantially polymorphic, pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d] Limidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) Azetin-3-yl acetonitrile is rated at 10.68° and 18.65° (±0. Characterized by a powder X-ray diffraction pattern including a peak at 2°2θ), as described in claim 1. Method of loading.

3. The substantially polymorphic, pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d] Limidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) Azetin-3-yl acetonitrile is found at 18.65° and 21.76° (±0. Characterized by a powder X-ray diffraction pattern including a peak at 2°2θ), as described in claim 1. Method of loading.

4. The substantially polymorphic, pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d] Limidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) Azetin-3-yl acetonitrile is found at 18.65° and 22.68° (±0. Characterized by a powder X-ray diffraction pattern including a peak at 2°2θ), as described in claim 1. Method of loading.

5. The substantially polymorphic, pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d] Limidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl) Azetin-3-yl acetonitrile is found at 26.75° and 21.76° (±0. Characterized by a powder X-ray diffraction pattern including a peak at 2°2θ), as described in claim 1. Method of loading.

6. Any of Claims 1 to 5, wherein the dermatological condition is atopic dermatitis or pruritus. The method described in item 1.

7. The method according to claim 6, wherein the non-human mammal is a dog.

8. Formula (I): The substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d (Pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfate) Honyl)azetin-3-yl)acetonitrile (where the above 2-(3-(4-(7H- Pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-( The crystalline form of cyclopropylsulfonyl azetin-3-yl acetonitrile is 5.3 ４°±０．２°、１０．６８°±０．２°、１４．２６°±０．２°、１６．０６°±０ ．２°、１６．３９°±０．２°、１６．４８°±０．２°、１８．２６°±０．２°、 １８．６５°±０．２°、２１．０５°±０．２°、２１．７６°±０．２°、２２．６ At least one peak at 8°±0.2° or 26.75°±0.2°(2θ) Characterized by the X-ray diffraction pattern of the included powder, where the X-ray powder diffraction pattern is C (Determined by a diffractometer using uKα rays).

Images