7H-Pyrrolo[2,3-D]pyrimidine JAK-inhibitors

Abstract

To provide a method for treating dermatologic conditions of a nonhuman mammal.SOLUTION: A method for treating dermatologic conditions includes administering an effective amount of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetine-3-yl)acetonitrile, which is characterized by a powder X-ray diffraction pattern including peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75°(±0.2°2θ), to a nonhuman mammal that needs treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed on April 2, 2019, the contents of which are incorporated herein by reference in their entirety. Priority is claimed to U.S. Provisional Patent Application No. 62 / 837,972, filed on the 4th.

[0002] The present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Polymorphs of acetonitrile, pharmaceutical compositions and processes for preparing the same, and and methods of using same for the treatment of dermatological conditions. [Background technology]

[0003] WO 2009 / 114512 describes the compound 2-(3-(4-(7H -pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- (Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile (Example 80) Certain JAK inhibitors, including as trifluoroacetate salts (Example 2) and as phosphate salts ( Its preparation is disclosed in Example 81). Summary of the Invention [Problem to be solved by the invention]

[0004] 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyls (sulfonyl)azetidin-3-yl)acetonitrile and its large-scale effectiveness for industrial production There is a need for methods for preparation and purification that can be used efficiently and reproducibly. Effective, safe, and reproducibly usable crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl ((arylsulfonyl)azetidin-3-yl)acetonitrile and large-scale production for industrial use There is a need for methods for preparation and purification that can be used effectively and reproducibly. In particular, substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and for preparation and purification that can be used effectively and reproducibly on a large scale for industrial production. There is a need for a method for [Means for solving the problem]

[0005] In certain embodiments, the present disclosure provides a 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 In certain embodiments, the present disclosure provides a process for making a substantially polymorphic Highly pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin The present invention provides a method for producing acetonitrile (3-phenyl-3-yl) acetonitrile and a process for making the same. In embodiments, the present disclosure provides a 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 its preparation Provide a process for

[0006] In certain embodiments, 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 and pharmaceutical and an acceptable excipient. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising substantially Polymorphically Pure Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidinyl) (4-phenyl-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)a PHARMACEUTICAL COMPOSITIONS COMPRISING (ZETIDINYL-3-YL)ACETONITRILE AND PHARMACEUTICALLY ACCEPTABLE EXCIPIENTS - Patent application In certain embodiments, the present disclosure provides a substantially polymorphically pure Form III 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

[0007] In certain embodiments, the present disclosure provides a method for treating a dermatological condition, comprising administering to a subject in need thereof and administering to a non-human mammal a substantially polymorphically pure Form I 2-(3-(4-(7H-pi (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl)- administering an effective amount of (chloropropylsulfonyl)azetidin-3-yl)acetonitrile In certain embodiments, the present disclosure provides a method for treating a dermatological condition, comprising: 2. A method for administering substantially polymorphically pure Form II 2 to a non-human mammal in need thereof. -(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazoline (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonite In certain embodiments, the present disclosure provides a method for treating a skin condition comprising administering an effective amount of a steroid hormone to a subject. 1. A method of treating a dermatological condition, comprising administering substantially multiple Statistically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering an effective amount of (diazin-3-yl)acetonitrile to a patient suffering from a rheumatoid arthritis.

[0008] In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrrolidine). (4-amino-1H-pyrazol-1-yl)-1(cyclopropylsulfonyl) A process for making azetidin-3-yl)acetonitrile and intermediates thereof is provided. do. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure provides the compound 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4- (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine -3-yl)acetonitrile, identified herein as Form I, Form II and Form III and pharmaceutical compositions thereof and the use of the polymorphs for the treatment of, for example, dermatological conditions. methods for preparing the compounds, methods for preparing polymorphs, and methods for preparing the compounds and intermediates thereof .

[0010] 1.Definition Unless otherwise defined, all technical and scientific terms used herein are understood to be within the skill of the art. In case of conflict, the terms herein, including definitions, shall have the same meaning as more commonly understood. Preferred methods and materials are described below, but are equivalent to those described herein. Similar or equivalent methods and materials can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only. , but not limited to.

[0011] "including," "including," "having," "having," "can," "include" The term "having" and variations thereof, as used herein, refers to an additional function. or an open-ended transitional phrase, term or word that does not preclude structural possibilities. The singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. The present disclosure includes multiple references unless expressly stated otherwise. The embodiments or elements set forth herein may be "comprised," "consisting," and "consisting" of any of the above, even if they are not. Other embodiments "consisting essentially of" are also contemplated.

[0012] The term "about," when used in connection with a measurable numerical variable, means the The values ​​shown and within experimental error of the values ​​shown or within ±10 percent of the values ​​shown, whichever is wider This refers to all values ​​of a variable element that is a part of the variable.

[0013] The term "acceptable excipient" refers to any substance commonly used in preparing veterinary and pharmaceutical compositions. These refer to substances used in the manufacture of pharmaceuticals that should be pure and non-toxic in the amounts used. a solid, semi-solid or liquid substance that can be a vehicle or medium for the active ingredient in the aggregate. Some examples of acceptable excipients are listed in Remington's Pharmacy eutical Sciences and the Handbook of Pha Found in pharmaceutical excipients, diluents, vehicles, carriers, Ointment base, binder, disintegrant, lubricant, glidant, sweetener, flavoring, gel base, sustained release Matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coatings Examples include steroids.

[0014] The term "aromatic solvents" is a term that refers to the aromatic groups methyl, chloro, bromo, cyano, nitro, and aceto. "Benzene" refers to benzene optionally substituted with one or two substituents selected from the group consisting of: The term "aromatic solvents" specifically refers to nitrobenzene, chlorobenzene, toluene , xylene and acteophenone.

[0015] "C 1~5 The term "alcohol" refers to a straight or branched chain alcohol having 1 to 5 carbon atoms. Alcohols, such as methanol, ethanol, n-propanol, isopropanol, 1 -butanol, ethylene glycol, 1,3-propanediol, etc.

[0016] The term "C1-C4 alkyl" refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms. It refers to alkyl chains, including methyl, ethyl, propyl, isopropyl, butyl, etc.

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

[0018] "C 3~8 The term "alkyl acetate" refers to a straight or short chain of acetic acid having a total of 3 to 8 carbon atoms. branched alkyl esters, such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, This refers to ethyl acetate, isobutyl acetate, etc.

[0019] "C 2~5 The term "alkyl cyanide" refers to a straight-chain alkyl group having a total of 2 to 5 carbon atoms. or branched alkyl cyanides, such as acetonitrile, propionitrile and butyronite He points to Lil.

[0020] "C 3~9 The term "alkyl ketone" refers to a ketone having an oxo group and a total of 3 to 9 carbon atoms. linear, branched or cyclic alkyl groups having alkyl groups such as acetone, methyl ethyl ketone and It 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 cyclohexane, etc.

[0022] The term "5- to 6-membered heterocycle" refers to the oxygen atom to which R1 and R2 are attached and the ring structure thereof. It refers to a 5-6 membered monocyclic saturated ring containing boron to which an oxygen atom is attached.

[0023] Terms such as "crystallize," "crystallization," and "crystallization" refer to complete dissolution and subsequent Refers to a slurry process that does not involve subsequent precipitation and complete dissolution. This includes the continuation of the crystallization process after precipitation following solution.

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

[0025] The term "effective amount" refers to the amount of a dose that is effective in a patient under diagnosis or treatment upon single or multiple administration to the patient. the amount or dosage of the compound of the present invention or a pharmaceutically acceptable salt thereof that provides the desired effect in An effective amount is determined by the use of known techniques and observing results obtained under similar circumstances. The beneficial effect on the patient can be readily determined by the attending diagnostician, such as one skilled in the art. In determining the effective dose, the species of the patient or non-human mammal; its size, age and overall health status; the specific disease or disorder involved; the degree of involvement or severity of the disease or disorder; the patient's response; the specific compound administered; the mode of administration; the bioavailability of the administered preparation the characteristics of the patient's ability to Many factors, including but not limited to, are considered by the attending diagnostician.

[0026] The terms "patient," "subject," and "non-human mammal" refer to warm-blooded animals, e.g., dogs, cats, This refers to animals such as mice, rats, guinea pigs, rabbits, cows, horses, sheep, goats and pigs. Particular non-human mammals are pet or companion animals, such as dogs and cats and also horses. Preferred non-human mammals include dogs and cats. Preferably, the non-human mammal is a canine. Particularly preferred non-human mammals is a dog.

[0027] The term "salt" refers to veterinarily or pharmaceutically acceptable organic acids and bases or inorganic acids and salts. Such salts are well known in the art and are described in the Journal of Ph Armaceutical Science, 66, 2-19 (1977) An example is the hydrochloride salt. As used herein, this term refers to the trichloride salt. Fluoroacetates and phosphates are specifically excluded.

[0028] The term "substantially polymorphically pure" means greater than 90%, preferably greater than 97% polymorphically pure. , more preferably greater than 99% and even more preferably greater than 99.5% polymorphic purity Refers to...

[0029] The terms "treating" or "treating" refer to the treatment of an existing condition or disorder, including the progression or severity of the condition. "To inhibit, slow, stop or reverse the progression of an illness."

[0030] The term "water activity" refers to p / p * where p is the water vapor in the solution is the partial pressure, and p * is the partial pressure of water vapor for pure water at the same temperature.

[0031] For recitation of numerical ranges herein, each number therebetween to the same degree of precision is Values ​​are explicitly contemplated. For example, for a range of 92 to 97, the numbers 92 and 97 are used in addition to the numbers Values ​​93, 94, 95 and 96 are contemplated, as are numbers 92.1, 92.2, 92.3 within the range. , 92.4, 92.5, 92.6 etc. to 97.0 are expressly contemplated.

[0032] 2.Compound The compound of the present invention is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4- (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine 2-(3-(4-( 7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- The crystalline form of 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is In order to provide a pharmaceutical composition with efficient and reproducible production of pharmaceutical formulations and suitable stability, This is desirable.

[0033] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile is 2-[1-cyclopropylsulfonyl-3-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonyl tolyl and 2-(1-cyclopropylsulfonyl-3-pyrazol-1-yl-(4-( 7H-Pyrrolo[2,3-d]pyrimidineazetidin-3-yl)acetonitrile It is also known by the name, for clarity, a compound of formula (I) below: [ka]

[0034] In a preferred embodiment, the compound of the present invention is in crystalline form I2 as described herein. -(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazoline (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonite Crystalline Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti Diazin-3-yl)acetonitrile is an anhydrous compound.

[0035] In another preferred embodiment, the compound of the present invention is in crystalline form I as described herein. I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyridin-4-yl)- (cyclopropylsulfonyl)azetidin-3-yl)azetidin-1-yl Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrrolo[2,3-d]pyrrolonitrile) (4-amino-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) )Azetidin-3-yl)acetonitrile is also anhydrous.

[0036] In another preferred embodiment, the compound of the present invention is in crystalline form I as described herein. II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- (pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)a Acetonitrile. Crystalline Form III 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) Nyl)azetidin-3-yl)acetonitrile is the hydrated form.

[0037] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile Forms I, II and III and other polymorphic forms were characterized by X-ray diffraction. A powder diffractometer equipped with a copper source, a primary beam monochromator and a position sensitive detector The peak was measured using a 1° divergence slit to collimate the incident beam. The source was operated at 40 kV and 40 mA. A step width of 0.02° and a step time of 37 seconds were used. X-ray powder diffraction data were collected from 2.5° to 50° using a microscope equipped with a copper source. Peaks were measured using a powder diffractometer, a primary beam monochromator, and a position sensitive detector. A 1° divergence slit was used to collimate the incident beam. The source was operated from 1.5° to 50° using a step width of 0.02° and a step time of 12 seconds. X-ray powder diffraction data were collected.

[0038] The relative intensities of X-ray diffraction peaks may depend on other factors such as preferred orientation and grain size. It is recognized that when preferred orientation and / or grain size effects are present, the peak intensities change. However, the characteristic peak positions of the polymorphs remain unchanged. tates Pharmacopoeia #24,National Formula See ry #19, pages 1843-1844, 2000. Therefore, the form Form I, Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) A sample of (3-(3-amino-3-phenyl)azetidin-3-yl)acetonitrile was prepared using an agate mortar and pestle or other suitable Processing to reduce these factors, such as crushing the sample, may be necessary. The difference in the relative intensities of the folding peaks indicates whether the compound is Form I, Form II, or Form III. -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl )-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile It is understood that this does not exclude patterns that may be obtained from the above.

[0039] Furthermore, for any particular crystal type, the angular position of the peaks may vary slightly. It is well known in the art of crystallography. For example, peak positions vary depending on the temperature or may shift due to sample displacement or fluctuation in relative humidity. In this case, ±0.2 in 2θ The peak position variability of 10° does not preclude unambiguous identification of the crystalline forms of the present disclosure, and these possible Take into account the variations that occur.

[0040] Form I, II or III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)aze D)dithidin-3-ylacetonitrile can also be characterized by differential scanning calorimetry. The SC is a closed (sealed) gold crucible or an aluminum pan with a pinhole. Sample filling under ambient conditions or N2 flow (3-10 min); -50°C to 300°C (10°C / The heating rate may be as fast as 1000 s.p.m.

[0041] Form I Crystalline Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- Acetonitrile exhibits a relative intensity (I / I) greater than approximately 10% of the maximum peak. 100 %) was found to have the following peaks at degrees two theta (°2θ): 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 the following: 12.72°, 14.04°, 17.56°, 20.33°, 24.50° or by an X-ray powder diffraction pattern containing a peak at 25.83° 2θ (±0.2° 2θ). Substantially polymorphically pure Form I 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropanediol) More specifically, the present invention provides a compound comprising (hydroxyl-sulfonyl)azetidin-3-yl)acetonitrile. The present disclosure includes peaks at 12.72° and 24.50° (±0.2° 2θ), or contains peaks at 20.33° and 24.50° (±0.2° 2θ), or 12.7 The X-ray powder diffraction pattern included peaks at 20.33° and 20.2° (±0.2° 2θ). Substantially polymorphically pure Form I 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropanediol) (3-(propylsulfonyl)azetidin-3-yl)acetonitrile.

[0043] As used herein, "Form I 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyls The term "substantially polymorphic (azetidin-3-yl)acetonitrile" refers to Pure Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- The term "(methyl)acetonitrile" is used herein.

[0044] Form II Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl )-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 (-yl)acetonitrile (relative intensity of about 10% of the maximum peak, I / I 10 0%) was found to have the following peak at degrees two theta (°2θ): 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] The present disclosure provides: 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 including peaks at 22.68°, 26.75°, or 22.68° (±0.2° 2θ) Substantially polymorphically pure Form II 2-(3-(4-( 7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. More specifically, the present disclosure provides peaks at 18.65° and 10.68° (±0.2° 2θ). or the 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 included peaks at 0.75° and 21.76° (±0.2° 2θ). Substantially polymorphically pure Form II 2-(3-(4-(7H-pi (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl)- (chloropropylsulfonyl)azetidin-3-yl)acetonitrile.

[0046] As used herein, "Form II 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl The term "substantially polymorphic" refers to "a substantially polymorphic (azetidin-3-yl)acetonitrile." Highly pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile.

[0047] Form III Crystalline Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile (relative intensity, I0 / I1, greater than approximately 10% of the maximum peak) 00 %) was found to have the following peaks at degrees two theta (°2θ): 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 .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] The present disclosure provides the following: 11.08°, 14.73°, 18.06°, 18.27°, 18.51° , 22.24°, 22.69°, 24.76°, 25.48° or 28.04° (±0. substantially polymorphous, characterized by an X-ray powder diffraction pattern including peaks at 2° 2θ Statistically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti In particular, the present disclosure provides a compound having a 11.08° and 2 2.69°; (±0.2° 2θ), or including peaks at 14.73° and 22.69° 2θ) or 22.69° and 25.48° (±0. 2° 2θ) or 11.08° and 18.06° (±0.2° 2θ) or peaks at 11.08° and 25.48° (±0.2° 2θ) a substantially polymorphically pure Form II characterized by an X-ray powder diffraction pattern comprising: I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyridin-4-yl)- (cyclopropylsulfonyl)azetidin-3-yl)azetidin-1-yl To provide trinitrile.

[0049] As used herein, "Form III 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl The term "substantially polymorphic" refers to "(azetidin-3-yl)sulfonyl" or "(azetidin-3-yl)acetonitrile." Pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin The term "(benzo-3-yl)acetonitrile" is used herein.

[0050] One skilled in the art will recognize that compounds may exist as tautomers. All tautomeric forms of the compounds are contemplated as being within the scope of the disclosure.

[0051] The compounds of the present invention have at least one atom of the major atomic mass having the same atomic number, but All isotopic variants that are replaced by atoms with atomic masses different from the main atomic mass Isotopic variations (e.g., deuterium, 2 H) to stabilize metabolism Furthermore, it may be possible to obtain a specific isotopic variation of the compound of the present invention. The fusion may incorporate radioisotopes (e.g., Tritium, 3 H or 14 C) may be incorporated. 11 C. 18 F, 15 O and 13 N etc. Substitution of benzophenone with positron-emitting isotopes is useful in positron emission tomography (PET) studies. could be.

[0052] 3. Process for creating crystalline forms Form I Process Crystalline Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- The acetonitrile may be prepared by crystallization under controlled conditions. Polymorphically pure crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidinyl)methyl) (4-in-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) A process for making (azetidin-3-yl)acetonitrile, comprising: A process involving crystallization from a mixture of acetone and heptane as a vent is also proposed. In a preferred embodiment, Form I 2-(3-(4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) (Hydroxy)azetidin-3-yl)acetonitrile is generally heated under vacuum at about 40°C to about 8 It may also be obtained by dehydration of a Form III sample, such as by heating at a temperature of 0°C.

[0053] Form II Process Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl )-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 (-yl)acetonitrile can be obtained under controlled conditions by crystallization from a solvent or mixture of solvents. The present disclosure provides a substantially polymorphically pure crystalline Form II 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A process for making a solution further containing water and having a water activity of less than 0.7. The present invention also provides a process involving crystallization from a solvent or mixture of solvents. C, each with a water activity of less than about 0.7 1~5 Alcohol, C 2~8 Alkyl ether , C 2~8 Alkyl acetate, C 2~5 Alkyl cyanide, C 3~9 Alkyl ketones and fragrances The solvent is selected from the group consisting of aromatic solvents.

[0054] In a preferred embodiment, the present disclosure provides a substantially polymorphically pure crystalline Form II 2-(3- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1- (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 1. A process for producing a solvent having a water activity of less than 0.5, further comprising water. Alternatively, a process comprising crystallization from a mixture of solvents is also provided.

[0055] The use of an antisolvent may be advantageous. "Tisorbent" is a compound of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile indicates a solvent in which the solubility is significantly lower than that of the selected solvent. Preferably, if an antisolvent is used, it is miscible with the selected solvent. While antisolvents may be used, the antisolvent selected must be at a desired level. Care must be taken not to increase the water activity above the normal range.

[0056] Substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) The water activity of (phenyl)azetidin-3-yl)acetonitrile is temperature dependent. It is understood that the higher temperature of the final crystallization stage can tolerate higher water activity. Therefore, a water activity of about 0.7 results in a temperature of the final crystallization state above about 40°C. It is valid.

[0057] Since recovery is greater at lower temperatures, in preferred embodiments, the present disclosure provides substantially polymorphic Pure Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti A process for making diphenyl ether (diphenyl ether-3-yl)acetonitrile, comprising less than 0.5% water Also provided are processes involving crystallization from an active solvent or mixture of solvents. A water activity of about 0.5 is effective at temperatures in the final stage of crystallization below about 25°C.

[0058] Preferred solvents are C , each having a water activity of less than about 0.7. 1~5 Alcohol and C 2~5 Even more preferred solvents are selected from the group consisting of alkyl cyanides, C with a water activity of less than about 0.5 1~5 Alcohol and C 2~5 Alkyl cyanide? is selected from the group consisting of:

[0059] In certain embodiments, the present disclosure provides a substantially polymorphically pure crystalline Form II 2-(3-( 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl Preparation of (cyclopropylsulfonyl)-1-azetidin-3-yl)acetonitrile 2. A process for producing acetonitrile, the process further comprising the step of: Also provided is a process comprising crystallizing from

[0060] In another specific embodiment, the present disclosure provides a substantially polymorphically pure crystalline Form II 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A process for making acetonitrile, further comprising water having a water activity of less than 0.5. Also provided is a process comprising crystallizing the compound from a solution of the compound.

[0061] 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-(cyclopropanediol) a process for making (propylsulfonyl)azetidin-3-yl)acetonitrile; Also provided is a process comprising crystallizing from acetonitrile further containing water. Care must be taken to avoid the formation of undesirable hydrated crystal forms. A preferred embodiment for crystallization from acetonitrile further comprises 92-97 acetonitrile. Use a v / v ratio of acetonitrile to water of 8 to 3; more preferably 95 to 97. It is crystallized from acetonitrile containing additional water in a v / v ratio of acetonitrile to water of 5:3. The use of (v / v) acetonitrile / water is actually the most preferred solution at temperatures below about 20°C. It was found that the product had high efficiency.

[0062] Thus, substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cycloproline) An even more preferred method for making (pyrsulfonyl)azetidin-3-yl)acetonitrile is A preferred process is to use an acetonitrile solution containing additional water in a v / v ratio of about 96 acetonitrile to about 4 water. This involves crystallizing from nitrile.

[0063] Optionally, the crystallization is carried out to obtain Form II 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) The reaction can be seeded with (azetidin-3-yl)acetonitrile.

[0064] Precipitation from solution and crystallization by slurry techniques are considered to be within the scope of this process. If the crystallization involves complete dissolution, it is contemplated that the rate may be between 0.2°C / min and 0.02°C / min. It is preferable to cool slowly. Crystallization to obtain Form II requires complete dissolution. A slurry process can be used. The slurry can be processed without complete dissolution. It can be formed by dissolution or by complete dissolution followed by treatment after the initial precipitation. In the process, the volume should be sufficient to provide a free-flowing slurry. The volume of solvent is not critical but should be kept to a minimum for convenience. The molecular activity must take into account water, including water that may be released from hydrated starting materials. Optionally, the slurry crystallization process produces Form II 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropanediol) (3-(4-hydroxybenzoyl)sulfonyl)azetidin-3-yl)acetonitrile do.

[0065] In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- Non-Form II containing (3-yl)acetonitrile is obtained by subjecting the slurry and Optionally, cooling allows crystallization and the final product is recovered. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile is crystallized from the solvent by slurry at a temperature around room temperature. Crystallization revealed Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl-2-pyrimidin-4-yl)-2-methyl-2-pyrimidin-4-yl. (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile. Generally, it takes 2 to 14 days.

[0066] Form III Process Crystalline Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- (3-yl)acetonitrile can be obtained under controlled conditions by crystallization from a solvent or mixture of solvents. The present disclosure provides a substantially polymorphically pure crystalline Form III 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A process for making a jelly further containing water and having a water activity greater than 0.9. The present invention also provides a process for crystallization from a solvent or mixture of solvents containing a suitable solvent. The solvents are water, C, and HCl, each having a water activity greater than about 0.9. 1~5 Alcohol, C 2~8 Alkyl acetate, C 2~5 Alkyl cyanide and C 3~9 alkyl ketones It is selected.

[0067] The use of an antisolvent may be advantageous. "Tisorbent" is a compound of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile is significantly less soluble than the selected solvent. Preferably, if an antisolvent is used, it is miscible with the selected solvent. is.

[0068] While antisolvents are used, the antisolvent selected may not be below the desired level. Care must be taken not to reduce the water activity by rotating.

[0069] Preferred solvents are C , ... 1~5 From the group consisting of alcohols are selected.

[0070] Crystallization from solution and slurry techniques are contemplated within the scope of the present process. If crystallization involves complete dissolution, cool slowly at a rate of 0.2 °C / min to 0.02 °C / min. Crystallization to obtain Form III does not require complete dissolution. A slurry process can be used. The slurry can be 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. , is not critical, but should be kept to a minimum for convenience. Optionally, slurry crystallization The polymerization process leads to Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)aze The mixture can be seeded with acetonitrile (3-thiazol-3-yl).

[0071] In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- Non-form III containing (3-yl)acetonitrile has a pH greater than 0.9 at temperatures around room temperature. Optionally, the crystallization is performed by slurry crystallization from a solvent having a low water activity. Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) can be seeded with acetonitrile. Such a slurry process is generally It takes 2 to 10 days.

[0072] Preferably, to avoid conversion to Form I under vacuum at temperatures below 20°C, Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (l) Care must be taken when drying acetonitrile.

[0073] 4.Synthesis method The present disclosure provides a 2-(3-(4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) The present invention provides a process for making phenyl)azetidin-3-yl)acetonitrile. [ka]

[0074] In Scheme A, step 1, a compound of formula (1) is converted into a compound of formula (2) in the presence of a suitable catalyst. The compound of formula (1) is reacted with a compound of formula (3) where X is a tosylate, a trimethylsilyl group, or a methyl group. Pg is a protecting group selected from the group consisting of riflate, chloro, bromo and iodo; In fact, compounds of formula (1) in which X is bromo or chloro are preferred, with chloro being preferred. Even more preferred are various protecting groups. The selection of an appropriate protecting group is within the skill of the art. Protecting group chemistry can be readily determined, for example, by TW Greene and PG .M.Wuts,Protective Groups in Organic Syn thesis, 3rd Ed., Wiley&Sons, Inc., New York( 1999). For example, t-BOC, 2-(trimethylsilyl) In fact, t-(methylsilyl)ethoxymethyl and N-pivaloyloxymethyl are useful. The compound of formula (2) is preferably a BOC group, wherein R1 and R2 are independently hydrogen and C 1~ 6 alkyl; or R1 and R2 are selected from the group consisting of the oxygen to which they are connected. and optionally 1, 2, 3 or 4 C atoms together with the boron atoms. 1~4 Archi It forms a 5- to 6-membered heterocyclic ring substituted with a methyl group. As such, the reaction shown in step 1 is the well-known Suzuki reaction. A variety of suitable catalysts are available. Both nickel and palladium catalysts are useful, but palladium catalysts are preferred. Many suitable palladium(0) 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(diphenyl) (Nylphosphino)ferrocene]dichloropalladium(II) (1:1).

[0075] This reaction is generally carried out in a solvent, which includes a wide variety of organic solvents. For example, suitable solvents include 1,4-dioxane, THF, and 1-butanol. , 1,2-dimethoxyethane (DME), 2-propanol, toluene or ethanol Typical palladium catalysts include those having a palladium content of about 0.01 to about 0 Used in an amount of 0.1 equivalent.

[0076] The reaction is carried out in the presence of a base. Both organic and inorganic bases can be used, such as For example, bases such as alkali metal carbonates and alkali metal bicarbonates and cesium carbonate are used. This reaction is generally carried out at a temperature of about 40°C to about 100°C for 1 to 18 hours. It requires.

[0077] 5. Pharmaceutical Compositions The present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl The present invention provides a pharmaceutical composition comprising acetonitrile or a salt thereof and an acceptable excipient. In a preferred embodiment, 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-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile In another preferred embodiment, the present disclosure provides a pharmaceutical composition comprising: is crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- and at least one acceptable excipient. In another preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A pharmaceutical composition is provided that includes 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. is usually in the form of a composition, i.e., in a mixture with at least one acceptable excipient. The proportion and nature of any acceptable excipient may be adjusted to suit the selected compound of the invention. Depending on the characteristics of the compound, the route of administration chosen and standard practices such as those in the veterinary and pharmaceutical fields, It is decided.

[0079] In effecting treatment of a subject in need of such treatment, the compounds of the present invention: The compounds may be administered in any form and by any route that makes them bioavailable.

[0080] The compounds of the present invention may be administered by a variety of routes, including orally, particularly via tablets and capsules. The compounds of the present invention can be administered parenterally, especially by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, ophthalmically, topically, sublingually and buccal, intraperitoneally, intraadipose, intrathecal and via local delivery, e.g., catheter The drug may be administered via a catheter or stent.

[0081] Those skilled in the art will appreciate the particular characteristics of the compound selected, the disorder or condition to be treated, the disorder or Depending on the stage of the condition and other relevant circumstances, the appropriate form and route of administration can be readily selected. The pharmaceutical compositions of the present invention can be in the form of, for example, tablets, capsules, cachets, papers, lozenges, Oblates, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, liquid medicines, solutions It can be administered to patients in the form of liquids and suspensions.

[0082] In one embodiment, the composition is administered orally, e.g., as a tablet or capsule or as a In one embodiment, the composition is adapted for use in a liquid formulation, such as a solution or suspension. The formulation is adapted for oral administration, such as a chewable formulation, and is adapted for oral administration. In embodiments, the compositions are liquid or semi-solid formulations adapted for parenteral administration, such as solutions or is a suspension or paste.

[0083] The compositions of the present disclosure may be prepared in a manner well known in the veterinary and pharmaceutical arts and contain as an active ingredient The amount of the compound of the present disclosure will depend on its particular form. This may vary depending on the individual dosage form and may conveniently be between 1% and about 50% of the weight of the unit dosage form. The compositions are preferably formulated in a unit dosage form, each dosage generally ranging from about 0.25 mg to about 100 mg. Contains 10 mg of a compound of the invention. One or more units may be used to affect the treatment dose. The mode of administration can be selected.

[0084] 6.How to use The present disclosure provides a method for treating a dermatological condition in a non-human mammal in need thereof. and administering to said patient an effective amount of a compound of the present invention.

[0085] In certain embodiments, the present disclosure provides a method for treating dermatological conditions [e.g., skin disorders, such as psoriasis (e.g., skin irritation (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis), dermatitis or allergic contact dermatitis), including itching associated with allergic dermatitis 1. A method for treating pruritus and allergic reactions in a non-human mammal in need thereof, comprising: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide The present invention provides a method for treating a mammalian animal, the method comprising administering an effective amount of riboflavin or a salt thereof to the mammal. In certain embodiments, the dog is at least 9 months old or at least 1 He is 2 months old.

[0086] In a preferred embodiment, the present disclosure provides a method for treating dermatological conditions [e.g., skin disorders such as psoriasis ( psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), including itching associated with allergic dermatitis 2. A method for treating pruritus and allergic reactions in a non-human mammal in need thereof. , 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-(cyclopropyl a method for treating a rhodamine-induced ... A preferred non-human mammal is a dog. In a particular embodiment, the dog is At least 9 months of age or at least 12 months of age.

[0087] In particularly preferred embodiments, the present disclosure provides a method for treating a dermatological condition [e.g., a skin disorder, e.g., dry skin]. dermatitis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact Allergic contact dermatitis, including pruritus associated with allergic dermatitis 1. A method for treating pruritus and allergic reactions in a non-human mammal in need thereof. In mammals, crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti The present invention provides a method for treating a rheumatoid arthritis, comprising administering an effective amount of (diazin-3-yl)acetonitrile to a patient suffering from a rheumatoid arthritis. In certain embodiments, the non-human mammal is a dog. In certain embodiments, the dog is at least 9 months of age or older. are at least 12 months old.

[0088] In further particularly preferred embodiments, the present disclosure provides a method for treating dermatological conditions [e.g., skin disorders, e.g., For example, psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), which may accompany allergic dermatitis and allergic reactions, including itching, in a patient in need thereof. In a human mammal, substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyro[ (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl) administering an effective amount of (isopropylsulfonyl)azetidin-3-yl)acetonitrile; In a particular embodiment, the method comprises: The dog is at least 9 months of age or at least 12 months of age.

[0089] In certain embodiments, the present disclosure provides a method for treating atopic dermatitis, comprising administering to a subject a In a non-human mammal, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)aze and administering an effective amount of acetonitrile or a salt thereof to a patient. In a preferred embodiment, the present disclosure provides a method for treating atopic dermatitis, crystalline Form I, or Form II, or Form III 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile In a particularly preferred embodiment, the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering an effective amount of: A method for treating atopic dermatitis, comprising administering to a non-human mammal in need thereof a crystalline form Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl) In a further particularly preferred embodiment, the method comprises administering an effective amount of acetonitrile. In one embodiment, the present disclosure provides a method for treating atopic dermatitis in a non-human rheumatoid arthritis patient in need thereof. In mammals, substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolomethyl)-2-methyl-2-propanol [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo[2,3-d]pyrimidin-4-yl] ... administering an effective amount of (propylsulfonyl)azetidin-3-yl)acetonitrile; A preferred non-human mammal is a dog. In certain embodiments, The animals are at least 9 months of age or at least 12 months of age.

[0090] In certain embodiments, the present disclosure provides a method for treating itching associated with allergic dermatitis. and administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl and administering an effective amount of (azetidin-3-yl)sulfonylacetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides a method for treating allergic dermatitis. 1. A method for treating pruritus caused by crystalline Form I, comprising administering to a non-human mammal in need thereof, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidinyl) (4-in-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) The method includes administering an effective amount of (azetidin-3-yl)acetonitrile. In particularly preferred embodiments, the present disclosure provides a method for treating itching associated with allergic dermatitis. 2. A method for administering crystalline Form II 2-(3-(4-( 7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- An effective amount of 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is administered. In a further particularly preferred embodiment, the present disclosure provides a method comprising administering an allele EP 1 137 263 A1 2 Description

[0010] A method for treating pruritus associated with allergic dermatitis in a non-human mammal in need thereof. The compound is a substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl A method comprising administering an effective amount of sulfonyl)azetidin-3-yl)acetonitrile. A preferred non-human mammal is a dog. In a particular embodiment, the dog is At least 9 months of age or at least 12 months of age.

[0091] The effective amount may be, for example, in the range of 0.5 mg to 100 mg. The specific amount can be determined by a person skilled in the art. These dosages can be determined for patients weighing about 0.5 kg to about 80 kg. Although based on this, diagnosticians may determine the appropriate dose for subjects whose mass falls outside this weight range. The effective amount can be determined, for example, from 0.1 mg to 1.2 mg / kg of patient, from 0.3 mg to The dosage regimen may be 1.0 mg / kg or in the range of 0.4 mg to 0.6 mg / kg. Dimene can be administered, for example, daily, twice daily, weekly, or monthly.

[0092] In certain embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, e.g., Skin disorders such as psoriasis (e.g. plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin Sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic dermatitis 2-(3) for use in the treatment of pruritus, including associated pruritus, and allergic reactions, etc. -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or provides salts thereof. A preferred non-human mammal is a dog. In certain embodiments, The animals are at least 9 months of age or at least 12 months of age.

[0093] In preferred embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, e.g., Skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rashes, skin irritations, Skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic dermatitis crystalline forms for use in the treatment of pruritus, including associated pruritus, and allergic reactions, etc. Form I, Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) A preferred non-human mammal is In certain embodiments, the dog is at least 9 months old or at least 12 months old. Age.

[0094] In particularly preferred embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, such as For example, skin disorders such as psoriasis (e.g., plaque psoriasis), 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]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl A preferred non-human mammal is a dog. In some embodiments, the dog is at least 9 months of age or at least 12 months of age.

[0095] In a further particularly preferred embodiment, the present disclosure provides a method for treating a dermatological condition in a non-human mammal. [For example, skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, Skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergy For use in the treatment of itching, including itching associated with allergic dermatitis, and allergic reactions Substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyls The present invention provides a method for treating a mammalian animal, comprising administering to a mammal a compound of formula (I) of formula (II ... In certain embodiments, the dog is at least 9 months old or at least 12 months old. He is months old.

[0096] In certain embodiments, the present disclosure provides a method for treating atopic dermatitis in a non-human mammal. For use in 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- In a preferred embodiment, the present disclosure provides a method for the preparation of a non-human acetylcholinesterase inhibitor (e.g., a hydroxybenzoate) or a salt thereof. Crystalline Form I or Form II for use in the treatment of atopic dermatitis in a mammal or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- In a particularly preferred embodiment, the present disclosure provides a method for the preparation of a non-human mammalian cell line comprising administering to the mammalian cell line (a mammalian cell line, a ... Crystalline Form II 2-(3-( for use in the treatment of atopic dermatitis in mammals 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile In a further particularly preferred embodiment, the present disclosure provides a method for treating atopic dermatitis in a non-human mammal. 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 A preferred non-human mammal is a dog. In a particular embodiment, the dog comprises at least 9 months of age or at least 12 months of age.

[0097] In certain embodiments, the present disclosure provides a method for treating allergic dermatitis associated with non-human mammals. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrrolidine)) for use in the treatment of acute pruritus (4-amino-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) )azetidin-3-yl)acetonitrile or a salt thereof. The present disclosure relates to the use of rheumatoid arthritis inhibitors in the treatment of pruritus associated with allergic dermatitis in non-human mammals. For use in crystalline Form I, Form II, or Form III 2-(3-(4-(7H-pyridinyl)-2-methyl-2-propanol (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl)- Particularly preferred is (chloropropylsulfonyl)azetidin-3-yl)acetonitrile. In a preferred embodiment, the present disclosure provides a method for treating allergic dermatitis associated with non-human mammals. Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl A particularly preferred embodiment of the present invention is (sulfonyl)azetidin-3-yl)acetonitrile. In embodiments, the present disclosure provides a method for treating itching associated with allergic dermatitis in non-human mammals. Substantially polymorphically pure crystalline form II 2-(3-(4-(7H) for use in the treatment of -pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- (Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. The preferred non-human mammal is a dog. In a specific embodiment, the dog is at least 9 months old. or at least 12 months of age.

[0098] In certain embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, e.g., Skin disorders such as psoriasis (e.g. plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin Sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic dermatitis for the manufacture of a medicament for the treatment of itching, including associated itching, and allergic reactions, etc. , 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The present invention provides the use of a nitrile or a salt thereof. A preferred non-human mammal is a dog. In embodiments, the dog is at least 9 months old or at least 12 months old.

[0099] In preferred embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, e.g., Skin disorders, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rashes, skin irritations, 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, etc. Crystalline Form I, Form II, or Form III 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cycloproline) The use of (pyrsulfonyl)azetidin-3-yl)acetonitrile is provided. The human mammal is a dog. In a particular embodiment, the dog is at least 9 months old or younger. At least 12 months of age.

[0100] In particularly preferred embodiments, the present disclosure provides a method for treating dermatological conditions in non-human mammals, such as For example, skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rashes, and skin irritations. , skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic skin Manufacture of drugs for the treatment of itching, including itching associated with inflammation, and allergic reactions, etc. Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin The present invention provides the use of (benzo-3-yl)acetonitrile in a non-human mammal. In certain embodiments, the dog is at least 9 months old or at least 12 months old. .

[0101] In a further particularly preferred embodiment, the present disclosure provides a method for treating a dermatological condition in a non-human mammal. [For example, skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, Skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergy of drugs for the treatment of itching, including itching associated with allergic dermatitis, and allergic reactions, etc. Substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolomethyl)-2-methyl-2-propanol) [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo[2,3-d]pyrimidin-4-yl] ... The use of (propylsulfonyl)azetidin-3-yl)acetonitrile is preferred. In certain embodiments, the non-human mammal is a dog. In certain embodiments, the dog is at least 9 months of age or older. are at least 12 months old.

[0102] In certain embodiments, the present disclosure provides a method for treating atopic dermatitis in a non-human mammal. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azeti In a preferred embodiment, the present invention provides the use of (diazin-3-yl)acetonitrile or a salt thereof, The present disclosure relates to a method for the manufacture of a medicament for the treatment of atopic dermatitis in a non-human mammal. , 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-(cyclopropyl Particularly preferred is the use of (azetidin-3-yl)sulfonylacetonitrile. In embodiments, the present disclosure provides a medicament for the treatment of atopic dermatitis in a non-human mammal. for the preparation of crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidinyl) (4-in-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) Further particularly preferred embodiments provide for the use of azetidin-3-yl)acetonitrile. The present disclosure relates to a method for the manufacture of a medicament for the treatment of atopic dermatitis in a non-human mammal. Substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl The present invention provides a method for the preparation of a compound having a non-hydroxybenzoic acid, a compound having a non-hydroxybenzoic acid, and a compound having a non-hydroxybenzoic acid. In certain embodiments, the dog is at least 9 months old or younger. At least 12 months of age.

[0103] In certain embodiments, the present disclosure provides a method for treating allergic dermatitis associated with non-human mammals. 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl The present invention provides the use of sulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides a method for treating allergic dermatitis associated with non-human mammals. Crystalline Form I, or Form II, or Form III for the manufacture of a medicament for the treatment of pruritus 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide In a particularly preferred embodiment, the present disclosure provides for the use of ribozyme in non-human mammals. Crystalline Form I for the preparation of a medicament for the treatment of itching associated with allergic dermatitis I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyridin-4-yl)- (cyclopropylsulfonyl)azetidin-3-yl)azetidin-1-yl In a further particularly preferred embodiment, the present disclosure provides for the use of thiazolinone in non-human mammals. For the manufacture of a medicament for the treatment of itching associated with allergic dermatitis in animals, Substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) The present invention provides a method for the preparation of a non-human mammalian animal using a hydroxybenzoate (azetidin-3-yl)acetonitrile. In certain embodiments, the dog is at least 9 months old or at least 1 He is 2 months old. [Example]

[0104] The following examples are offered to illustrate the present invention and not to limit it in any way.

[0105] Example 1 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl ]Acetonitrile 2-(1-cyclopropylsulfonylazetidin-3-ylidene)acetonitrile (8 50g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (874 g) in acetonitrile (2.6 L). 1,8-diazabicyclo[5.4.0]undec-7-ene (65 g) was added and the mixture The mixture was heated to 70° C. After 2.5 hours, the reaction mixture was cooled to ambient temperature over approximately 2 hours. Water (5.2 L) was slowly added to the mixture over approximately 1 hour, and the mixture was stirred for approximately 3 hours. The solid that formed was collected by filtration and dried in vacuo at 45° C. for about 24 hours. After drying, 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl- Methyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidine 4-(3-yl)acetonitrile was obtained.

[0106] Example 2 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Potassium phosphate (829 g) was combined with water (1 L) and cooled to ambient temperature. THF (2 4-Chloropyrrolo[2,3-d]pyrimidine (200 g) was added, followed by Di-tert-butyl dicarbonate (344 g) was added and the reaction mixture was allowed to stand at ambient temperature. The mixture was stirred at 40°C for 24 hours. Nitrogen gas was sparged through the reaction mixture for 60 minutes. Cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl]acetonide Tolyl (562 g) and Pd-134 (6.6 g) were added, and the reaction temperature was increased to 60°C. After about 2 hours, the aqueous layer was separated, silica thiol (40 g) was added, and the reaction was heated to 60°C. The reaction mixture was filtered at 60°C, and the filtrate was stirred for 10-2 hours. Cooling to 0°C gave a solid which was collected by filtration, rinsed with cold THF, and then Dry under vacuum at 0-50°C for 2 hours to obtain tert-butyl 4-[1-[3-(cyclohexyl)methyl]-4-(methylphenyl)-2-(4- ... Anomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazole-4 -yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (540 g) was obtained.

[0107] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropyl Sulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrrolo[2,3-d]pyrazole Imidin-7-carboxylate (540 g) was dissolved in n-butanol (3 L) and water (770 m L) and heated to 90° C. After 6 hours, the reaction was cooled to 80° C. within 30 minutes, and then The mixture was stirred at 80°C for 30 minutes, then cooled to 20°C over 6 hours and stirred at 10-20°C for 1 hour. Stir for 6 hours to obtain a solid, which was filtered to give 460 g of the title compound (as wet cake). obtained.

[0108] Example 3 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile Potassium phosphate (829 g) was combined with water (1 L) and cooled to ambient temperature. THF (2 4-Chloropyrrolo[2,3-d]pyrimidine (200 g) was added, followed by Di-tert-butyl dicarbonate (344 g) was added and the reaction mixture was allowed to stand at ambient temperature. The mixture was stirred at 40°C for 24 hours. Nitrogen gas was sparged through the reaction mixture for 60 minutes. Cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl]acetonide Tolyl (562 g) and Pd-134 (6.6 g) were added, and the reaction temperature was increased to 60°C. After about 2 hours, the aqueous layer was separated, silica thiol (40 g) was added, and the reaction was heated to 60°C. The reaction mixture was filtered at 60°C, and the filtrate was stirred for 10-20 minutes. Cooling to °C gave a solid which was collected by filtration, rinsed with cold THF, and then Dry under vacuum at 0-50°C for 2 hours to obtain tert-butyl 4-[1-[3-(cyclohexyl)methyl]-4-(methylphenyl)-2-(4- ... Anomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazole-4 -yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (525 g) was obtained.

[0109] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropyl Sulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrrolo[2,3-d]pyrazole Imidin-7-carboxylate (540 g) was dissolved in n-butanol (3 L) and water (770 m L) and heated to 90° C. After 6 hours, the reaction was cooled to 80° C. within 30 minutes, and then The mixture was stirred at 80°C for 30 minutes, then cooled to 20°C over 6 hours and stirred at 10-20°C. Stir for 16 hours to obtain a solid which was filtered to give the title compound (as wet cake) 454 I got g.

[0110] Example 4 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II Combine the wet cakes (approximately 907 g) from Examples 2 and 3 in acetonitrile (4 L). The reaction mixture was cooled to 20° C. over 6 hours and then stirred at 60° C. for 2 hours. The mixture was stirred at rt for 12 h. The solid was collected by filtration, rinsed with acetonitrile, and Drying under vacuum at °C for 24 hours gave the title compound (695g).

[0111] Example 5 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (104.1 mg) was combined with acetone (8 mL) and heated to 55°C for 30 minutes. After that, the reaction mixture was cooled to a temperature of 30°C at a rate of 0.02°C / min, and then cooled to a temperature of 30°C at a rate of 0.1°C / min. The mixture was cooled to 5°C by adding heptane (12 mL) at a rate of 2.94 mL / hour. Simultaneous addition gave a solid which was collected by filtration and dried to give the title compound (79 0.5mg) was obtained.

[0112] Example 6 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (152.4 mg) was combined with acetonitrile (8.1 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled to 5°C at a rate of 0.05°C / min to obtain a solid. It was collected by filtration and dried to give the title compound (93.4 mg).

[0113] Example 7 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (157.8 mg) was dissolved in acetonitrile / water 96:4 (v / v) (4.2 mL). The mixture was combined and heated to 80° C. After 30 minutes, the reaction mixture was cooled to 5° C. at a rate of 0.05° C. / min. The mixture was cooled to rt to give a solid which was collected by filtration, dried and the title compound (89.4 m g) was obtained.

[0114] Example 8 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (5 g) was combined with acetonitrile / water 96:4 (v / v) (100 mL) and After about 75 minutes, the reaction mixture was cooled to 70° C. at a rate of 0.20° C. / min. Then, crystal seeds (0.25 g in two portions) were added and the temperature was raised to 8°C at a rate of 0.05°C / min. The cooling was continued to obtain a solid. After about 6 hours, the solid was collected by filtration, dried, and The title compound (4.88 g) was obtained.

[0115] Example 9 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (20.6 mg) was dissolved in 4:1 (v / v) methanol with a water activity of approximately 0.5. The mixture was stirred at 25°C for 4 days and then further diluted with 4:1 (v / v) methanol. Aqueous / water (0.5 mL) was added and stirring was continued at 25°C for 6 days, followed by filtration and centrifugation (3 The solid was collected by filtration through a 0.2 μm PVDF membrane (5000 rpm, 1 min, 5 min) to obtain the title compound. obtained.

[0116] Example 10 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (10 g) was combined with acetonitrile / water 96:4 (v / v) (250 mL), After approximately 60 minutes, the reaction mixture was cooled to a temperature of 65°C at a rate of 0.20°C / min. Then crystal seeds (0.10 g) were added and the temperature was increased to 35°C at a rate of 0.035°C / min. Continue cooling at 0.125°C / min to obtain a solid, then cool to a temperature of 5°C at a rate of 0.125°C / min, After about 3 hours, the solid was collected by filtration and dried to give the title compound (8.5%). 1g) was obtained.

[0117] Example 11 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (70.3 mg) was combined with 0.2 mL of 9:1 (v / v) acetone / water and stirred. The mixture was heated to 60°C while stirring. Additional 9:1 (v / v) acetone / water was slowly added until the total volume was 100%. Approximately 1.6 mL was added. The temperature was held at 60°C for 1.5 hours, and then the mixture was stirred at 0.05°C / min. The mixture was cooled to 10°C at a rate of 10°C and kept at 10°C for 2 hours and 45 minutes to obtain a solid. The solid was filtered. The precipitate was collected by centrifugation (2 min, 5000 rpm) to give the title compound.

[0118] Example 12 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (149.8 mg) was combined with acetonitrile (8.0 mL) and heated 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. The reaction mixture was cooled at a rate of 0.1°C / min over a range of 55°C to 5°C, and simultaneously A total of 12 mL / hour was added at a rate of 1.44 mL / hour over the same duration as the 5°C cooling gradient. mL of isopropyl acetate was added to give a solid which was collected by filtration, dried and The title compound (94.2 mg) was obtained.

[0119] Example 13 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (208.5 mg) was combined with 0.2 mL of 3:1 (v / v) methanol / water; Heat to 60° C. with stirring. Add additional 3:1 (v / v) methanol / water slowly A total of approximately 23.2 mL was added. The temperature was held 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. Collection by filtration gave the title compound.

[0120] Example 14 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (60 mg) was dissolved in 2 mL of 5:1 (v / v) 1-bromobenzoate with a water activity of approximately 0.9. The mixture was combined with ethanol / water and stirred at room temperature for 10 days, then filtered and centrifuged (2 min, 5000 The solid was collected by filtration (rpm, 0.2 μm PTFE membrane) to give the title compound.

[0121] Example 15 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (33 mg) was dissolved in 0.4 mL of 3:2 (v / v) methacrylate with a water activity of approximately 0.7. The mixture was combined with ethanol / water and stirred at about 20°C for 14 days, then filtered and centrifuged (2 min, 44 The solid was collected by centrifugation at 1000 rpm using a 0.2 μm PTFE membrane to give the title compound.

[0122] Example 16 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.4 mg) was combined with acteophenone (1 mL) and stirred at room temperature for 10 days. and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane). The product was collected to give the title compound.

[0123] Example 17 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (59.9 mg) was combined with butyronitrile (2 mL) and stirred at room temperature for 10 days. , and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to separate the solids. The product was collected to give the title compound.

[0124] Example 18 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.3 mg) was combined with cyclohexanone (1.5 mL) and incubated at room temperature for 10 days. Stir and then filter by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane). The solid was collected to give the title compound.

[0125] Example 19 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.9 mg) was combined with dioxane (2 mL) and stirred at room temperature for 10 days. The solids were separated by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane). Recovery gave the title compound.

[0126] Example 20 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.0 mg) was combined with ethyl formate (1.5 mL) and stirred at room temperature for 10 days. , and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to separate the solids. The product was collected to give the title compound.

[0127] Example 21 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (59.4 mg) was combined with methyl acetate (1.5 mL) and stirred at room temperature for 10 days. , and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to separate the solids. The product was collected to give the title compound.

[0128] Example 22 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.5 mg) was combined with nitrobenzene (2 mL) and stirred at room temperature for 10 days. , and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to separate the solids. The product was collected to give the title compound.

[0129] Example 23 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.5 mg) was combined with anisole (0.6 mL) and stirred at 40°C for 6 days. , and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to separate the solids. The product was collected to give the title compound.

[0130] Example 24 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (59.8 mg) was combined with ethyl formate (0.6 mL) and stirred at 40°C for 6 days. Then, the solid was filtered by centrifugation (2 min, 5000 rpm, 0.22 μm PVDF membrane). The product was collected to give the title compound.

[0131] Example 25 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.5 mg) was combined with isopropyl acetate (0.6 mL) and heated at 40°C for 6 days. Stir and then filter using a centrifuge (2 min, 5000 rpm, 0.22 μm PVDF membrane). More solid was collected to give the title compound.

[0132] Example 26 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.4 mg) was combined with isopentanol (1 mL) and stirred at 40°C for 6 days. and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane). The product was collected to give the title compound.

[0133] Example 27 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.4 mg) was combined with methyl isobutyl ketone (1 mL) and heated at 40°C for 6 days. Stir for 1 minute, then filter using a centrifuge (2 minutes, 5000 rpm, 0.22 μm PTFE membrane). The solid was collected by distillation to give the title compound.

[0134] Example 28 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (60.6 mg) was dissolved in 3:1 (v / v) ethanol with a water activity of approximately 0.7. The mixture was combined with 0.9 mL of water and stirred at 40°C for 6 days, then filtered and centrifuged (2 min, 5 min). The solid was collected by centrifugation at 1000 rpm using a 0.22 μm PVDF membrane) to give the title compound.

[0135] Example 29 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (69.7 mg) was combined with 1-propanol (10.8 mL) and stirred. The mixture was heated to 60°C. Dimethyl methacrylate was added to a mixture of 1-propanol and DMSO at a ratio of approximately 85:15 (v / v). Dimethyl sulfoxide (2 mL) was added slowly. The temperature was maintained at 60°C for approximately 1.5 hours. The mixture was then cooled to 10°C at a rate of 0.05°C / min and held at 10°C for 7.5 hours. 1-Propanol (5 mL) was then added, and the mixture was then stirred at 5° C. for 10 days, and the solid which was collected by filtration to give the title compound.

[0136] Example 30 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (70.6 mg) was combined with ethyl acetate saturated with water (0.2 mL) and stirred. Then, ethyl acetate (7.2 mL) was added and the mixture was stirred at 60°C for about 1.5 hours. The mixture was then cooled to 10°C at a rate of 0.05°C / min and then filtered by centrifugation ( The solid was collected by filtration (2 min, 5000 rpm, 0.2 μm PTFE membrane) and the title compound was obtained. obtained.

[0137] Example 31 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (199.6 mg) was combined with ethyl acetate saturated with water (2.0 mL) and The mixture was stirred at room temperature for 2 days, and then filtered by centrifugation (2 min, 5000 rpm, 0.2 μm PTF The solid was collected using a filter (E membrane) to give the title compound.

[0138] Example 32 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form I 2-( ... 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Form III was obtained to give the title compound.

[0139] Example 33 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.3 mg) was combined with ethanol (1 mL) and stirred at 5°C for 7 days, then The solids were filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) Recovery gave the title compound.

[0140] Example 34 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.4 mg) was combined with methanol (1 mL) and stirred at 5°C for 7 days, then The solids were filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) Recovery gave the title compound.

[0141] Example 35 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.0 mg) was combined with isopropanol (1 mL) and stirred at 5°C for 7 days. Then, the solid was filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane). The product was collected to give the title compound.

[0142] Example 36 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.3 mg) was combined with 1-butanol (2 mL) and stirred at 5° C. for 7 days. The solid was then filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane). The product was collected to give the title compound.

[0143] Example 37 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (59.6 mg) was combined with ethanol (1 mL) and stirred at 60°C for 5 days, and then The solids were filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane). was collected to give the title compound.

[0144] Example 38 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (59.9 mg) was combined with methanol (1 mL) and stirred at 60°C for 5 days, and then The solids were filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane). was collected to give the title compound.

[0145] Example 39 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.1 mg) was combined with isopropanol (1.5 mL) and heated at 60°C for 5 days. Stir and then filter using a centrifuge (2 min, 5000 rpm, 0.45 μm PVDF membrane). More solid was collected to give the title compound.

[0146] Example 40 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (60.6 mg) was combined with 1-butanol (1.5 mL) and stirred at 60°C for 5 days. The mixture was stirred and then filtered by centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane). The solid was collected to give the title compound.

[0147] Example 41 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (10.4 mg) was combined with acetonitrile (0.5 mL) and stirred at 20°C for 1 day. Stir and then filter using a centrifuge (1 minute, 4500g rcf, 0.2µm PTFE membrane). More solid was collected to give the title compound.

[0148] Example 42 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile The nitrile (10.3 mg) was combined with acetone (0.5 mL) and stirred at 20°C for 1 day. The solids were then filtered by centrifugation (2 min, 4000 g rcf, 0.2 μm PTFE membrane). The product was collected to give the title compound.

[0149] Example 43 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (20.6 mg) was dissolved in 4:1 (v / v) methanol with a water activity of approximately 0.5. / water (0.4 mL) and stirred at 25° C. for 4 days, then further 4:1 (v / v) Methanol / water (0.5 mL) was added and stirred at 25 °C for 6 days, followed by filtration, centrifugation ( The solid was collected by filtration through a 0.2 μm PVDF membrane at 5000 rpm for 3 minutes, and the title compound was obtained. obtained.

[0150] Example 44 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (539.9 mg) was mixed with 1:1 (v / v) ethanol / acetone (18 mL). The mixture was stirred at 60°C for 45 minutes, then cooled to 5°C at a rate of 0.05°C / min, and allowed to solidify. A solid was obtained which was collected by filtration and dried under vacuum at 40°C to give the title compound. Got it.

[0151] Example 45 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (256.1 mg) was dissolved in 7:3 (v / v) acetone / isopropyl acetate (13.5 mL), stirred at 60°C for 1 hour, then cooled to 5°C at a rate of 0.02°C / min. A solid was obtained, which was collected by filtration and dried under vacuum at 40°C to give the title compound. A compound was obtained.

[0152] Example 46 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (60 mg) was dissolved in 5:1 (v / v) 1-butanol with a water activity of approximately 0.9. Combine with water (2 mL), stir at room temperature for 10 days, then filter and centrifuge (2 min, 500 The solid was collected by filtration through a 0.0 rpm, 0.2 μm PTFE membrane) to give the title compound.

[0153] Example 47 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo (cyclopropyl-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonide Trill Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile (60.1 mg) was dissolved in 1:1 (v / v) acetonitrile with a water activity of approximately 0.9. The mixture was combined with ethanol / water (0.9 mL), stirred at 40°C for 6 days, and then filtered and centrifuged (2 min The solid was collected by centrifugation at 5000 rpm using a 0.2 μm PTFE membrane to give the title compound. .

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

[0155] Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine) -4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)aze An oral tablet containing 2-(2-thiazol-3-yl)acetonitrile was prepared. (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Calcium phosphate dehydrate, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dehydrate, oxidized An oral tablet blend containing a food pigment and magnesium stearate was prepared. The blend was compressed to obtain 2.4 mg, 3.6 mg, 5.4 mg, and 16 mg of crystalline Form II. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyra (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Tablet cores containing nitrile and placebo cores were obtained. The tablet cores were coated with a mixture containing 50011 Red, thereby providing The final oral tablet was obtained.

[0156] [Table 1]

[0157] Control of itching and skin lesions associated with allergic dermatitis in dogs (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A four-arm, blinded, randomized, placebo-controlled trial was conducted to evaluate the efficacy of daily administration of rivaroxaban. Subjects were randomized to one of the following treatment groups: API-containing tablets, 0.25 ~0.40mg / kg body weight; API-containing tablets, 0.40-0.60mg / kg body weight; AP I-containing tablets, 0.60–0.80 mg / kg body weight; and placebo tablets, 0.0 mg / kg body weight.

[0158] Dogs enrolled in this study were treated once daily for approximately 28 days. Data (clinical history, concomitant medications, weight, physical examination, and assessment of pruritus and atopic dermatitis) was collected for each dog at enrollment (day 0). Further health assessment, physical examination, and weight measurement , evaluation of pruritus and atopic dermatitis, and hematology, serum chemistry, and pharmacokinetic (PK) analyses Blood samples were collected according to standard testing protocols.

[0159] The primary efficacy variable was treatment response. Treatment response was defined as the number of patients with at least one of the first 7 treatment days. 10 units on at least 70% of treatment days (i.e., at least 5 of the first 7 treatment days) Self-assessed itch visual analogue scale (VAS) decrease of 2 units or more from baseline Patients were defined as a decrease in the ability to tolerate the study within the first 7 days of treatment due to a perceived lack of efficacy. Dogs that discontinued were considered treatment failures. At least 50% of dogs achieved a treatment response. The minimal effective dose was defined in the protocol as the dose at which the

[0160] Table 2 shows the 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl The maximum dose of acetonitrile (0.60-0.80 mg / kg) was 0.2935 (95 %CI 0.1571, 0.4808) was statistically significantly higher than the placebo response rate With a response rate of 0.7188 (95% confidence limits 0.5331, 0.8512); (logit The p-value for the comparison (on the scale) is 0.0006. The 0.6-0.8 mg / kg group achieved the primary endpoint for treatment success. Once-daily administration of 0.6-0.8 mg / kg showed significant improvement in pruritus from the first dose. However, this group showed a significant improvement in lesion scores on day 28 of the study. Estimated marginal means for the 4-0.4 mg / kg and intermediate doses (0.4-0.6 mg / kg) Response rates were also higher than placebo rates. This result was based on fixed-effect terms for treatment and 0 Based on a general linear mixed model using daily VAS scores. Dam effects were fitted to site and site-treatment, and a compound symmetric covariance structure was fitted to individual dogs. It was made to fit.

[0161] [Table 2]

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

[0163] Article 1.12.72°(43.1%), 14.04°(61.3%), 17.56°( 20.8%), 20.33° (87.4%), 24.50° (100%) and 25.83 It was characterized by an X-ray powder diffraction pattern containing peaks at 94.9% (±0.2° 2θ) Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl Sulfonyl)azetidin-3-yl)acetonitrile.

[0164] Clause 2. The substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolidone)) according to clause 1. (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl) (isopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable and an excipient.

[0165] Clause 3. The substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolidone)) according to clause 1. (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl) Process for making (isopropylsulfonyl)azetidin-3-yl)acetonitrile A process comprising crystallizing from acetone and heptane.

[0166] Clause 4. The substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolidone)) according to clause 1. (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl) Process for making (isopropylsulfonyl)azetidin-3-yl)acetonitrile 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (l) A process comprising drying a hydrated crystalline form of acetonitrile.

[0167] Clause 5. A method of treating a dermatological condition in a non-human mammal in need thereof, comprising administering , the substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl a method for treating a rhodamine-induced ... Law.

[0168] Clause 6. The dermatological condition is selected from the group consisting of atopic dermatitis and pruritus; Clause 5 Method.

[0169] Clause 7. The method of clause 6, wherein the non-human mammal is a dog.

[0170] Articles 8.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 1 6.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68° or 26.75° (±0.2° 2θ) Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl Sulfonyl)azetidin-3-yl)acetonitrile.

[0171] Article 9.1 X-ray powder containing peaks at 8.65° and 10.68° (±0.2° 2θ) 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.

[0172] Article 10. X-ray powder containing peaks at 18.65° and 21.76° (±0.2° 2θ) 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.

[0173] Article 11. X-ray powder containing peaks at 18.65° and 22.68° (±0.2° 2θ) 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.

[0174] Article 12. X-ray powder containing peaks at 26.75° and 21.76° (±0.2° 2θ) 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.

[0175] Clause 13. The substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

[0176] Clause 14. The substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 1. A process for making C, each of which has a water activity of less than about 0.7. 1~5 a Lucor, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylcyani C3~9 A solvent or mixture of solvents selected from the group consisting of alkyl ketones and aromatic solvents. A process involving crystallization from a mixture.

[0177] Clause 15. The substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 1. A process for making C, each of which has a water activity of less than about 0.5. 1~5 a Lucor, C 2~8 Alkyl ether, acetic acid C 2~8 Alkyl, C 2~5 Alkylcyani C 3~9 A solvent or mixture of solvents selected from the group consisting of alkyl ketones and aromatic solvents. A process involving crystallization from a mixture.

[0178] Clause 16. The substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A process for preparing acetone by crystallization from acetonitrile having a water activity of less than 0.7. The process involves:

[0179] Clause 17. The substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A process for preparing acetone by crystallization from acetonitrile having a water activity of less than 0.5. The process involves:

[0180] Clause 18. Method of treating a dermatological condition in a non-human mammal in need thereof 2,3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl A method comprising administering an effective amount of sulfonyl)azetidin-3-yl)acetonitrile. .

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

[0182] Clause 20. The method of clause 19, wherein the non-human mammal is a dog.

[0183] Articles 21.11.08°, 14.73°, 18.06°, 18.27°, 18.51° , 22.24°, 22.69°, 24.76°, 25.48° or 28.04° (±0. substantially polymorphous, characterized by an X-ray powder diffraction pattern including peaks at 2° 2θ Statistically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile.

[0184] X-ray powder containing peaks at 22.11.08° and 22.69° (±0.2° 2θ) 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.

[0185] X-ray powder containing peaks at 23.14.73° and 22.69° (±0.2° 2θ) 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.

[0186] X-ray powder containing peaks at 24, 22, 69° and 25, 48° (±0.2° 2θ) 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.

[0187] Article 25.1 X-ray powder containing peaks at 11.08° and 18.06° (±0.2° 2θ) 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.

[0188] X-ray powder containing peaks at 26.11.08° and 25.48° (±0.2° 2θ) 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.

[0189] Clause 27. A substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

[0190] Clause 28. The substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and C, each having a water activity greater than about 0.9. 1~ 5 Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkyl Anid and C 3~9 from a solvent or mixture of solvents selected from the group consisting of alkyl ketones A process involving crystallization.

[0191] Clause 29. A substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 1. A process for making a C having a water activity greater than about 0.9. 1~5 Arco a process comprising crystallizing the compound from a solvent or mixture of solvents selected from the group consisting of alcohols .

[0192] Clause 30. Method of treating a dermatological condition in a non-human mammal in need thereof 21 to 26, the crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl a method for treating a rhodamine-induced ... Law.

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

[0194] Clause 32. The method of Clause 31, wherein the non-human mammal is a dog.

[0195] Articles 33.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68 by an X-ray powder diffraction pattern containing peaks at 26.75° (±0.2° 2θ) or 26.75° (±0.2° 2θ) Characterized, substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropyl (arylsulfonyl)azetidin-3-yl)acetonitrile.

[0196] Article 34. X-ray powder containing peaks at 18.65° and 10.68° (±0.2° 2θ) 34. The substantially polymorphically pure crystal of claim 33, characterized by a diffraction pattern 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl] ... (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile.

[0197] Article 35. X-ray powder containing peaks at 18.65° and 21.76° (±0.2° 2θ) 34. The substantially polymorphically pure crystal of claim 33, characterized by a diffraction pattern 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl] ... (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile.

[0198] Article 36. X-ray powder containing peaks at 18.65° and 22.68° (±0.2° 2θ) 34. The substantially polymorphically pure crystal of claim 33, characterized by a diffraction pattern 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl] ... (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile.

[0199] X-ray powder containing peaks at 37, 26, 75° and 21, 76° (±0.2° 2θ) 34. The substantially polymorphically pure crystal of claim 33, characterized by a diffraction pattern 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl] ... (1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Nitrile.

[0200] Clause 38. The substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

[0201] Clause 39. The substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and C, each having a water activity of less than about 0.7. 1~5 Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylsia Nido, C 3~9 a solvent or solvents selected from the group consisting of alkyl ketones and aromatic solvents; A process involving crystallization from a mixture.

[0202] Clause 40. A substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and C, each having a water activity of less than about 0.5. 1~5 Alcohol, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, C 2~5 Alkylsia Nido, C 3~9 a solvent or solvents selected from the group consisting of alkyl ketones and aromatic solvents; A process involving crystallization from a mixture.

[0203] Clause 41. A substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 2. A process for preparing a compound comprising crystallizing the compound from acetonitrile having a water activity of less than 0.7. The process involves:

[0204] Clause 42. A substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 2. A process for preparing a compound comprising crystallizing the compound from acetonitrile having a water activity of less than 0.5. The process involves:

[0205] Article 43. A method for treating a dermatological condition in a non-human mammal in need thereof. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrimidin-4-yl)- (cyclopropylsulfonyl)azetidin-3-yl)azetidin-1-yl The method comprises administering an effective amount of thiazolinone or a salt thereof.

[0206] Article 44. Control of itching associated with allergic dermatitis and control of atopic dermatitis A method comprising administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropanediol) an effective amount of (propylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is administered. The method includes:

[0207] Article 45. A method for the treatment of itching associated with allergic dermatitis, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin A method comprising administering an effective amount of (benzo-3-yl)acetonitrile or a salt thereof.

[0208] Article 46. A method for treating the clinical symptoms of atopic dermatitis, comprising administering to a non-human resident in need thereof In mammals, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- A method comprising administering an effective amount of (a)-(methyl)acetonitrile or a salt thereof.

[0209] Clause 47. The method according to any one of clauses 43 to 46, wherein the non-human mammal is a dog. .

[0210] Clause 48. The method of clause 47, wherein the dog is at least 12 months old.

[0211] Clause 49. Any one of clauses 43 to 48, wherein the effective amount is 0.6 to 0.8 mg / kg. The method described below.

[0212] Article 50. Administration to a non-human mammal is once a day. Any one of Articles 43 to 49. The method described below.

[0213] Article 51. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (k) The method according to any one of clauses 43 to 50, wherein the acetonitrile is crystalline.

[0214] Article 52. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (l) Acetonitrile is crystalline form I, crystalline form II, crystalline form III or any of them. 52. The method of any one of clauses 43 to 51, which is a combination.

[0215] Article 53. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile is 5.34°, 10.68°, 14.26°, 16.06°, 16 .39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, X-ray powder diffraction pattern including peaks at 22.68° or 26.75° (±0.2° 2θ) Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyridinyl)phenyl)- ... (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl)- (chloropropylsulfonyl)azetidin-3-yl)acetonitrile, 1. The method according to any one of claims 1 to 10.

[0216] Article 54. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile gives peaks at 18.65° and 10.68° (±0.2° 2θ). Substantially polymorphically pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method according to any one of clauses 43 to 51,

[0217] Article 55. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile gives peaks at 18.65° and 21.76° (±0.2° 2θ). Substantially polymorphically pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method according to any one of clauses 43 to 51,

[0218] Article 56.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile gives peaks at 18.65° and 22.68° (±0.2° 2θ). Substantially polymorphically pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method according to any one of clauses 43 to 51,

[0219] Article 57. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile has peaks at 26.75° and 21.76° (±0.2° 2θ). Substantially polymorphically pure crystalline 2- (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method according to any one of clauses 43 to 51,

[0220] Article 58. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (l) An oral dosage form containing acetonitrile or its salt.

[0221] Article 59. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl (l) An oral dosage form containing acetonitrile.

[0222] Article 60. Crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) (1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile.

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

[0224] Article 62. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin Form I, Form II or Form III of (benzo-3-yl)acetonitrile or a combination thereof 62. The oral dosage form of any one of clauses 58 to 61, wherein the oral dosage form is a combination of

[0225] Article 63. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl Acetonitrile is 5.34°, 10.68°, 14.26°, 16.06°, 16 .39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, X-ray powder diffraction pattern including peaks at 22.68° or 26.75° (±0.2° 2θ) Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyridinyl)phenyl)- ... (2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclohexyl)- (chloropropylsulfonyl)azetidin-3-yl)acetonitrile, 2. An oral dosage form according to any one of claims 1 to 11.

[0226] Article 64. Oral dosage forms are made of microcrystalline cellulose, pregelatinized starch, and dicalcium phosphate. dehydrate, oxide pigment, or magnesium stearate, or any combination thereof 64. The oral dosage form of any one of clauses 58 to 63, further comprising a combination.

Claims

1. 1. A method for treating a dermatological condition in a non-human mammal, comprising administering to the non-human mammal in need thereof an effective amount of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile in a substantially polymorphically pure crystalline form, characterized by an X-ray powder diffraction pattern comprising peaks at 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).

2. 10. The method of claim 1, wherein the dermatological condition is atopic dermatitis or pruritus.

3. The method of claim 2, wherein the non-human mammal is a dog.

4. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile in a substantially polymorphically pure crystalline form, characterized by a powder X-ray diffraction pattern containing peaks at 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).

5. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile in a substantially polymorphically pure crystalline form, characterized by a powder X-ray diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, and 26.75° (±0.2° 2θ).

6. A substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, characterized by a powder X-ray diffraction pattern containing peaks at 10.68° and 18.65° (±0.2° 2θ).

7. A substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, characterized by a powder X-ray diffraction pattern containing peaks at 18.65° and 21.76° (±0.2° 2θ).

8. A substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, characterized by a powder X-ray diffraction pattern containing peaks at 18.65° and 22.68° (±0.2° 2θ).

9. A substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, characterized by a powder X-ray diffraction pattern containing peaks at 26.75° and 21.76° (±0.2° 2θ).

10. 10. A pharmaceutical composition comprising the substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile of any one of claims 4 to 9 and a pharmaceutically acceptable excipient.

11. An oral pharmaceutical composition comprising 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 according to any one of claims 4 to 9.

12. An oral pharmaceutical composition comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile in a substantially polymorphically pure crystalline form.

13. 1. An oral pharmaceutical composition comprising 2.4 mg, 3.6 mg, 4.8 mg, 5.4 mg, 6.4 mg, 8.5 mg, 15 mg, or 16 mg of a substantially polymorphically pure crystalline form of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

14. The crystalline form is Form I, Form II, or Form III, or a combination thereof, and Form I is characterized by a powder X-ray diffraction pattern comprising peaks at 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). Form II is characterized by a powder X-ray diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2° 2θ), and Form III is characterized by a powder X-ray diffraction pattern containing peaks at 11.08° (62.3%), 12. 32° (15.9%), 13.28° (13.7%), 14.06° (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° (12.7%), 22.24° (26.9%) 14. The oral pharmaceutical composition of claim 12 or 13, characterized by an X-ray powder diffraction pattern comprising peaks at: 22.69° (100%), 23.40° (10.2%), 24.76° (18.8%), 25.48° (55.4%), 25.97° (12.6%), 26.70° (12.5%), and 28.04° (12.8%), (±0.2° 2θ)°.

15. The 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.7°.

15. The oral pharmaceutical composition of any one of claims 11 to 14, which is 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 characterized by an X-ray powder diffraction pattern including a peak at 5° (±0.2° 2θ).

16. 16. The oral pharmaceutical composition of any one of claims 11 to 15, further comprising microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dehydrate, oxide pigments, or magnesium stearate, or any combination thereof.

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