Crystalline forms of wild type kit inhibitors

Abstract

Various polymorph forms of Compound (I) represented by the following formula are disclosed. Pharmaceutical compositions comprising the same, methods of treating disorders and disorders mediated by wild type c-kit kinase using the same, and methods for making the polymorph forms of Compound (I) are also disclosed.

Description

[0001] CRYSTALLINE FORMS OF WILD TYPE KIT INHIBITORS

[0002] RELATED APPLICATION

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 656,413, filed on June 5, 2024, the entire teachings of which are incorporated herein by reference in their entirety.

[0004] BACKGROUND OF THE INVENTION

[0005] Mast cells are a part of the immune system. They are a main driver of allergic inflammatory responses and are present throughout the body in connective and vascularized tissues, most prominently along surface boundaries with exposure to the external environment: in the skin, the respiratory tract and the gastrointestinal tract. Dysfunctional mast cell activity has been implicated in the pathophysiology of a broad range of allergic and other inflammatory disorders including urticaria, asthma and gastrointestinal disorders.

[0006] For many who suffer from allergic conditions, inhibition of mast cell derived mediators, including histamines, leukotrienes, and prostaglandins, has resulted in insufficient therapeutic value to-date given that many mast cell-driven disorders involve multiple pro- inflammatory mediators. One such mast-cell driven disorder is chronic urticaria, which is defined as the occurrence of wheals, angioedema, or both for more than 6 weeks. The international urticaria guideline classifies the disease as chronic spontaneous urticaria (CSU, also called chronic idiopathic urticaria), without a definite eliciting factor involved, or as chronic inducible urticaria (CIndU), where defined and definite eliciting factors reproducibly trigger signs and symptoms and are required for their occurrence. The point prevalence of chronic urticaria is approximately 0.5% to 1%. Chronic urticaria is unpredictable in its course and duration, and it may persist for several years in many patients. Chronic urticaria is a disabling condition that leads to substantial deterioration in quality of life. Furthermore, psychosocial factors, such as anxiety, depression, somatization, interpersonal sensitivity, insomnia, and stressful life events, are present in many of the patients with chronic urticaria. In addition, care of patients with chronic urticaria is time-consuming and costly. No curative treatment exists for chronic urticaria, and all currently recommended treatment options are intended only to control and prevent the symptoms of chronic urticaria.

[0007] Wild-type c-kit plays a central role in mast cell survival, proliferation, and activation. Recently in clinical trials, c-kit inhibition has shown positive responses in mast cell mediated diseases. For example, c-kit inhibition in chronic inducible urticaria and chronic spontaneous urticaria has been shown to be an effective treatment in a phase I trial (inducible) and phase 1 and 2 (spontaneous) using a monoclonal antibody, and a c-kit small molecule inhibitor has also shown modulation of tryptase, a mast cell mediator, in normal healthy volunteers and in a phase 1 trial of chronic inducible urticaria the inhibitor has been shown to be an effective treatment. There is need for treatments to target mast cells directly through highly selective inhibition of c-kit to achieve broad symptomatic relief across a range of mast cell mediated diseases.

[0008] International Application No. PCT / US2023 / 081773, the entire teachings of which are incorporated herein by reference, discloses compounds for inhibiting wild type c-kit kinase. The structure of one of the inhibitors disclosed therein, referred to herein as “Compound (I)” is shown below:

[0009] The successful development of pharmaceutically active agents, such as Compound (I), typically requires the identification of a solid form with properties that enable ready isolation and purification following synthesis, that are amendable to large scale manufacture, that can be stored for extended periods of time with minimal absorption of water, decomposition or transformation into other solid forms, that are suitable for formulation and that can be readily absorbed following administration to the subject (e.g., are soluble in water and in gastric fluids).

[0010] SUMMARY OF THE INVENTION

[0011] It has now been found that the free base of Compound (I) can be crystallized under well-defined conditions to afford crystalline Forms A and O. Described herein is the synthesis and characterization of the polymorph Forms A and O of the free base of Compound (I). Form A is the more favored form kinetically, as Form A was obtained from most crystallization studies. However, Form O was found to be the most thermodynamically stable form. Both Form A and Form O are anhydrates and demonstrate favorable solid state properties. Form A and Form O exhibit good thermal behavior with a high melting point onset ( >170 °C). However, Form A is more easily obtained from large scale reactions and demonstrates improved solubility compared to Form O at room temperature and above.

[0012] Another aspect of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and Form A or Form O of Compound (I). In one embodiment, the composition is for treating a disease or disorder mediated by wild type c-kit kinase. In another embodiment, the composition is for inhibiting wild type c-kit kinase.

[0013] Another aspect of the disclosure is a method of treating a subject suffering from a disease or disorder mediated by wild type c-kit kinase. The method comprises administering to the subject an effective amount of Form A or Form O of Compound (I), or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and Form A or Form O of Compound (I).

[0014] Another aspect of the disclosure is a method of inhibiting wild type c-kit kinase in a subject in need thereof. The method comprises administering to the subject in need thereof an effective amount of Form A or Form O of Compound (I), or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and Form A or Form O of Compound (I).

[0015] Another aspect of the disclosure is the use of Form A or Form O of Compound (I), or a pharmaceutical composition comprising Form A or Form O of Compound (I) and a pharmaceutically acceptable carrier or excipient in the manufacture of a medicament for the treatment of medical condition mediated by wild type c-kit kinase.

[0016] Another aspect of the disclosure is the use of Form A or Form O of Compound (I), or a pharmaceutical composition comprising Form A or Form O of Compound (I) and a pharmaceutically acceptable carrier or excipient in the manufacture of a medicament for inhibiting wild type c-kit kinase in a subject in need thereof.

[0017] Another aspect of the disclosure is Form A or Form O of Compound (I), or a pharmaceutically composition comprising Form A or Form O of Compound (I) and a pharmaceutically acceptable carrier or excipient for the treatment of a medical condition mediated by wild type c-kit kinase.

[0018] Another aspect of the disclosure is Form A or Form O of Compound (I), or a pharmaceutically composition comprising Form A or Form O of Compound (I) and a pharmaceutically acceptable carrier or excipient for inhibiting wild type c-kit kinase in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION

[0019] FIG 1 A shows the X-ray Powder Diffraction (XRPD) pattern of crystalline Form A of Compound (I).

[0020] FIG IB shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of crystalline Form A of Compound (I).

[0021] FIG 1C shows the coupled Thermogravimetric Analysis-Differential Scanning Calorimetry Analysis (TGA / DSC) thermogram of crystalline Form A of Compound (I).

[0022] FIG 2A shows the X-ray Powder Diffraction (XRPD) pattern of crystalline Form O of Compound (I).

[0023] FIG 2B shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of crystalline Form O of Compound (I).

[0024] FIG 2C shows the coupled Thermogravimetric Analysis-Differential Scanning Calorimetry Analysis (TGA / DSC) thermogram of crystalline Form O of Compound (I).

[0025] FIG 3 shows the X-ray Powder Diffraction (XRPD) pattern of the amorphous form of Compound (I).

[0026] FIG 4 shows the X-ray Powder Diffraction (XRPD) pattern of crystalline Form N of Compound (I).

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] The disclosure is directed to: i) novel crystalline forms of Compound (I), including unsolvated forms, solvated forms, amorphous forms, and crystalline forms and ii) methods of use and preparation of the crystalline forms of Compound (I).

[0029] As used herein, “crystalline” refers to a solid having a crystal structure wherein the individual molecules have a highly homogeneous regular three dimensional configuration.

[0030] In one aspect, the disclosure provides crystalline forms of Compound (I). The form of Compound (I) can be crystalline and can exist as one or more polymorph forms. These polymorphic forms can be solvated or unsolvated forms. These polymorphic or crystalline forms differ with respect to their X-ray powder diffractions (XRPD) patterns, spectroscopic, physicochemical, and pharmacokinetic properties, as well as their thermodynamic stability.

[0031] For the crystalline forms of Compound (I) disclosed herein, at least a particular percentage by weight of Compound (I) is in a particular crystalline form. Particular weight percentages include 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a weight percentage of 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, 70-80%, 80-90%, 90-100% by weight of Compound (I) is in a particular crystalline form. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed by the disclosure.

[0032] When the crystalline form of Compound (I) is defined as a specified percentage of one particular crystalline form of Compound (I), the remainder is made up of amorphous form and / or crystalline forms other than the one or more particular forms that are specified. Examples of particular crystalline forms include Form A and Form O, each of which are characterized by one or more properties as discussed herein.

[0033] As used herein, an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms are the same ± 0.2 °20. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (°20) referred to herein) generally mean that value reported ± 0.2 degrees 20 of the reported value, an art-recognized variance discussed above.

[0034] Crystalline Forms of Compound (I)

[0035] Form A

[0036] In one embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 5.5°, 11.0°, 20.7°, 24.9°, and 26.3° ± 0.2 in 29.

[0037] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 5.5°, 9.5°, 11.0°, 13.3°, 15.9°, 20.7°, 24.9°, and 26.3° ± 0.2 in 29.

[0038] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises at least six peaks chosen from 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 29. In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises at least seven peaks chosen from 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 20.

[0039] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises at least eight peaks at 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 20.

[0040] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises at least nine peaks chosen from 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 20.

[0041] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 29.

[0042] In another embodiment, Form A is characterized by an X-ray powder diffraction pattern substantially similar to Figure 1A.

[0043] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by a differential scanning calorimeter (DSC) with a peak phase transition temperature of 180.1 ± 2 °C.

[0044] In another embodiment, the disclosure provides a crystalline Form A of Compound (I), which is characterized by a differential scanning calorimeter (DSC) with an onset temperature of 174.3 ± 2 °C.

[0045] In another embodiment, Form A is characterized by a differential scanning calorimetry analysis (DSC) thermogram substantially similar to Figure IB.

[0046] In another embodiment, Form A is characterized by a coupled TGA / DSC thermogram substantially similar to Figure 1C.

[0047] In one embodiment, crystalline form A of Compound (I) is an anhydrate.

[0048] In another embodiments, at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) is in crystalline Form A.

[0049] Representative XRPD peaks are tabulated in Table 1. The XRPD patterns and peaks are shown in Figure 1 A. The Differential Scanning Calorimetry Analysis (DSC) thermogram is shown in Figure IB. The coupled thermogravimetric analysis- differential scanning calorimetry analysis (TGA / DSC) thermogram is shown in Figure 1C. Table 1. Representative XRPD peaks of crystalline Form A of Compound (I)

[0050] Form O

[0051] In one embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray diffraction pattern which comprises peaks at 8.0°, 16.1°, 19.3°, 23.1°, and 26.9° ± 0.2 in 20.

[0052] In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 8.0°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 20.

[0053] In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction which comprises at least six peaks chosen from 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 20.

[0054] In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction which comprises at least seven peaks chosen from 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 29.

[0055] In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction which comprises at least eight peaks chosen from 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 29. In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction which comprises at least nine peaks chosen from 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 29.

[0056] In another embodiment, the disclosure provides crystalline Form O of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 26.

[0057] In another embodiment, Form O is characterized by an X-ray powder diffraction pattern substantially similar to Figure 2A.

[0058] In another embodiment, the disclosure provides a crystalline Form O of Compound (I), which is characterized by a differential scanning calorimeter (DSC) with a peak phase transition temperature of 195.9 ± 2 °C.

[0059] In another embodiment, the disclosure provides a crystalline Form O of Compound (I), which is characterized by a differential scanning calorimeter (DSC) with an onset temperature of 194.0 ± 2 °C.

[0060] In another embodiment, Form O is characterized by a differential scanning calorimetry analysis (DSC) thermogram substantially similar to Figure 2B.

[0061] In another embodiment, Form O is characterized by a coupled TGA / DSC thermogram substantially similar to Figure 2C.

[0062] In one embodiment, crystalline form O of Compound (I) is an anhydrate.

[0063] In another embodiments, at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) is in crystalline Form O.

[0064] Representative XRPD peaks are tabulated in Table 2. The XRPD patterns and peaks are shown in Figure 2A. The Differential Scanning Calorimetry Analysis (DSC) thermogram is shown in Figure 2B. The coupled thermogravimetric analysis- differential scanning calorimetry analysis (TGA / DSC) thermogram is shown in Figure 2C.

[0065] Table 2. Representative XRPD peaks of crystalline Form O of Compound (I)

[0066] Pharmaceutical Compositions

[0067] Some embodiments of the disclosure relate to a pharmaceutical composition comprising a crystalline Form of the disclosure and a pharmaceutically acceptable carrier. Some embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient and crystalline Form A of Compound (I). Other embodiments of the disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient and crystalline Form O of Compound (I).

[0068] Crystalline forms of the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiments, the crystalline form included in the pharmaceutical compositions may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

[0069] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, polymorphs, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0070] Examples of pharmaceutically acceptable carriers / excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., corn starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;

[0071] (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar;

[0072] (14) buffering agents, such as, e.g., magnesium hydroxide and aluminum hydroxide;

[0073] (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;

[0074] (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins, such as, e.g., Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0075] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, and the like) can include one or more pharmaceutically acceptable carriers, such as, e.g., sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as, e.g., starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, e.g., carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as, e.g., glycerol; (4) disintegrating agents, such as, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as, e.g., paraffin; (6) absorption accelerators, such as, e.g., quaternary ammonium compounds; (7) wetting agents, such as, e.g., cetyl alcohol and glycerol monostearate; (8) absorbents, such as, e.g., kaolin and bentonite clay; (9) lubricants, such as, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0076] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, e.g., water or other solvents, solubilizing agents, and emulsifiers, such as, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (such as, e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0077] Suspensions, in addition to Form A or Form O of Compound (I), may contain suspending agents as, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0078] Ointments, pastes, creams and gels may contain, in addition to Form A or Form O of Compound (I), excipients, such as, e.g., animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.

[0079] Powders and sprays can contain, in addition to Form A or Form O of Compound (I), excipients such as, e.g., lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as, e.g., chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as, e.g., butane and propane.

[0080] A crystalline Form of the disclosure can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (such as 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0081] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

[0082] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0083] The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day. The precise amount of Form A or Form O of Compound (I) administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of Form A or Form O of Compound (I) being used by following, for example, dosages reported in the literature and recommended in the Physician ’s Desk Reference (57th ed., 2003). A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of Form A or Form O of Compound (I) employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0084] In general, a suitable daily dose of Form A or Form O of Compound (I) will be that amount of the polymorph form that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0085] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.

[0086] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[0087] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the crystalline Forms provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with Form A or Form O of Compound (I) disclosed herein.

[0088] A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, the patient is an adult human.

[0089] Methods of Treatment

[0090] The c-kit kinase inhibitors described herein are useful for treating diseases and disorders mediated by wild type c-kit. In some aspects c-kit mediated diseases and disorders include mast cell related disorder, an eosinophil related disorder, cancer, asthma, an inflammatory condition, rheumatoid arthritis, an allergic inflammation, inflammatory bowel disease, a gastrointestinal disorder, or fibrosis.

[0091] Wild-type KIT plays a central role in mast cell survival, proliferation, and activation. Specifically, inhibitors of c-kit are useful for the inhibition and / or depletion of mast cells and thus are useful for treating mast cell related disorders. As used herein, the term "mast cell related disorder" or "mast cell related disorders" or “mast cell mediated disorder” or “mast cell mediated disorders” refers to disorders where mast cell activity contributes to the pathology and / or mast cells are found in abnormal amounts, such as above-normal amounts or below-normal amounts, in various parts of the body. For example, mast cell related disorders can exhibit accumulation of pathological mast cells and / or can be characterized by mast cells that are aberrantly activated in potentially any or all organs and tissues and / or aberrant release of one or more mast cell mediators such as inflammatory mediators. Nonlimiting examples of inflammatory mediators released by mast cells include any of (i) granule-associated mediators, including histamine, serotonin (5-hydroxytryptamine), and a variety of proteases such as tryptase and chymase) and peptidases; (ii) eicosanoids such as prostaglandin D2 (PGD2) and leukotriene C4 (LTC4); and (iii) cytokines including interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, granulocyte-macrophage colonystimulating factor (GM-CSF), and tumor necrosis factor a (TNFa), and chemokines including CCL-2, CCL-3, CCL-5, and CXCL8.

[0092] Form A or Form O of Compound (I) of the disclosure are useful for treating chronic urticaria. Chronic urticaria includes chronic spontaneous urticaria (CSU), chronic idiopathic urticaria and chronic induced urticaria (i.e., chronic inducible urticaria (CIndU). In certain aspects, the mast cell related disorder is CSU. In certain aspects, the mast cell related disorder is CindU. Chronic inducible urticarias are forms of urticaria that have an attributable trigger associated with them, typically resulting in inflammation of the skin characterized by wheals (hives) or angioedema. Complications of both CSU and CindU include swelling / hives in inopportune sites (mouth, airway, genitals) and anaphylaxis. Sleep disruption, stress, & anxiety due to severe itching are major contributors to disease burden. In a specific aspect, the chronic inducible urticaria is cold urticaria (ColdU). People afflicted with cold urticaria experience symptoms like itching, burning wheals and angioedema when their skin is exposed to temperatures below skin temperature. In another aspect, the chronic inducible urticaria is symptomatic dermographism (SD). Symptomatic dermographism is characterized by the development of a wheal and flare reaction in response to stroking, scratching or rubbing of the skin and usually occurs within minutes of the inciting stimulus. In another aspect, the chronic inducible urticaria is cholinergic urticaria. Cholinergic urticaria is triggered by the body’s sweating response to active or passive body warming and is characterized by small (1-4 mm) wheals surrounded by bright red flares. Common triggers include exercise, hot baths / showers, fever, occlusive dressings, eating spicy foods and emotional stress. In another aspect, the chronic inducible urticaria is heat urticaria. In another specific embodiment, the chronic inducible urticaria is delayed pressure urticaria. In another aspect, the chronic inducible urticaria is solar urticaria. In another specific embodiment, the chronic inducible urticaria is vibratory urticaria. In another aspect, the chronic inducible urticaria is contact urticaria. In one aspect, the vibratory urticaria is characterized by a missense mutation in EMR2. In another aspect, the chronic inducible urticaria is aquagenic urticaria.

[0093] Other mast cell related disorders and diseases include dermatosis, including: atopic dermatitis and allergic contact dermatitis; idiopathic angioedema; idiopathic anaphylaxis; asthma, including allergic asthma; hereditary alpha tryptasemia (HAT); idiopathic mast cell activation syndrome (MCAS); monoclonal MCAS; neurofibromatosis; idiopathic pulmonary fibrosis; bullous pemphigoid; and prurigo nodularis.

[0094] Additional diseases with mast cell involvement include: age-related macular degeneration; allergic conjunctivitis; allergic rhinitis; non-allergic rhinitis; alpha-1 antitrypsin deficiency; Alzheimer’s disease; amyotrophic lateral sclerosis (AML); bronchiectasis; Celiac disease; chronic graft verse host disease; chronic rhinosinusitis with nasal polyps; allergic fungal rhinosinusitis; aspirin-exacerbated respiratory disease; allergic broncho pulmonary aspergillosis; colorectal cancer; dermatitis herpetiformis; irritable bowel syndrome (IBS), including diarrhea-prominent IBS; fibromyalgia; fibrosis, including hepatic fibrosis, pulmonary, and cardiac fibrosis; food allergies, including Igf-mediated food allergies and peanut allergies; insect venom allergy; drug allergy; insulin-dependent diabetes mellitus; mast cell leukemia; migraine; multiple sclerosis; Parkinson’s disease; psoriasis; and rheumatoid arthritis.

[0095] Other diseases modulated by c-kit include pulmonary arterial hypertension (PAH); inflammatory bowel disease (IBD), cholestatic pruritis; uremic pruritis; chronic pruritis of unknown origin; pulmonary fibrosis; scleroderma; dermatosis; dermatitis herpetiformis; melanoma; gastrointestinal stromal tumor; mast cell tumor; anaphylactic syndrome; idiopathic anaphylaxis; diabetes, type I or type II, eosinophilic esophagitis (EoE); eosinophilic gastritis & duodenitis; interstitial cystitis / bladder pain syndrome, chronic prostatitis / chronic pelvic pain syndrome; endometriosis; and mastocytosis, including cutaneous mastocytosis and systemic mastocytosis.

[0096] Form A or Form O of Compound (I) of the disclosure are useful for treating gastrointestinal stromal tumor (GIST). GISTs are the most common malignant subepithelial lesions of the gastrointestinal tract, and the most common symptoms of GISTs are gastrointestinal bleeding, acute melena (dark feces containing blood), hematemesis (vomiting of blood) with anemia, weakness, and abdominal pain and distension. Nearly 80% of metastatic GISTs have a primary activating mutation in either the extracellular region (exon 9) or the juxtamembrane (JM) domain (exon 11) of KIT. Imatinib is a standard therapy used to treat GIST. Side effects of imatinib include mild stomach upset, diarrhea, muscle pain, and skin rashes. There is a need for new therapies for the treatment of GIST.

[0097] Form A or Form O of Compound (I) of the disclosure can be administered in combination with another agent. In one aspect, Form A or Form O of Compound (I) of the disclosure are administered in combination with one or more antihistamine agents such as loratadine, cetirizine, fexofenadine, cimetidine, famotidine or diphenhydramine. In another aspect, Form A or Form O of Compound (I) of the disclosure are administered in combination with one or more asthma agents such as montelukast and zafirlukast.

[0098] In another aspect, Form A or Form O of Compound (I) of the disclosure can be administered in combination with one or more other agents that are used in the treatment of urticaria. For example, compounds of the disclosure are administered in combination with omalizumab, dupilumab, reslizumab, mepolizumab, and benralizumab. In some aspects, Form A or Form O of Compound (I) of the disclosure can be administered with anti- IgE monoclonal antibodies such as ligelizumab and UB-221. Form A or Form O of Compound (I) of the disclosure can also be administered with a monoclonal antibody to Siglec-8 (AK002), Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), a spleen tyrosine kinase inhibitor, and dupilumab. The polymorph forms of the disclosure and agent can be co-administered or administered in alternating regimen. In some aspects, Form A or Form O of Compound (I) of the disclosure can be administered with antihistamines.

[0099] Examples of antihistamine agents include Classic Hl antihistamines with sedation as a side effect including chlorpheniramine, hydroxyzine, and diphenhydramine, nonsedating second generation Hl antihistamines including loratadine, cetirizine, terfenadine, and mizolastine, second generation Hl antihistamine derivatives including desloratadine, levocetirizine, and fexofenadine, and H2 antihistamines including cimetidine, ranitidine, famotidine and nizatadine. Other antihistamine agents include bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and rupatadine. In some aspects, Form A or Form O of Compound (I) of the disclosure can be administered in combination with an MRGPRX2 inhibitor. Examples of MRGPRX2 inhibitors are EP -262 and EVO-756.

[0100] EXEMPLIFICATION OF THE INVENTION

[0101] Abbreviations:

[0102] Abbreviation Solvent Abbreviation Solvent

[0103] ACN Acetonitrile MeOH Methanol

[0104] PE Petroleum ether DMF Dimethylformamide

[0105] EDTA Ethylenediaminetetraacetic MtBE / MTBE tert-Butyl Methyl acid Ether

[0106] DCM Dichloromethane THF Tetrahydrofuran

[0107] EtOH Ethanol MEK Methyl Ethyl Ketone

[0108] EtOAcZEA Ethyl Acetate TFA Trifluoroacetic Acid

[0109] DMSO Dimethyl sulfoxide DCE 1,2-dichloroethane

[0110] Units

[0111] Full Name Abbreviation

[0112] Celsius C

[0113] Degrees0

[0114] Equivalents eq.

[0115] Gram g

[0116] Hour h

[0117] Kelvin K

[0118] Liters L

[0119] Milligrams mg Milliliters mL

[0120] Microliters pL

[0121] Minute min

[0122] Milliamp mA

[0123] Nanometer nm

[0124] Millivolt mV

[0125] Relative Humidity RH Room temperature RT Second s

[0126] Weight Percentage wt.%

[0127] Analysis Conditions (unless noted otherwise in the Example)

[0128] Differential Scanning Calorimetry (DSC):

[0129] DSC was performed using a TA Discovery DSC. The sample (1-5 mg) was weighed directly in a 40 pL hermetic aluminum pan without a pinhole and analyzed according to the parameters below:

[0130] Parameters

[0131] Method Ramp

[0132] Sample size 1-5 mg

[0133] Heating rate 10.0 °C / min

[0134] Temperature range 30 up to 300 °C

[0135] Method gas N2 at 50.00 mL / min

[0136] Dynamic Vapor Sorption (DVS):

[0137] DVS was performed using a Q5000SA. The sample (5-15 mg) was loaded into an aluminum sample pan, suspended from a microbalance, and exposed to a humidified stream of nitrogen gas. Weight changes were relative to a matching empty reference pan opposite the sample, suspended from the microbalance. The sample was held for a minimum of 10 min at each level and only progressed to the next humidity level if there was < 0.002 % change in weight between measurements (interval: 5 s) or 45 min had elapsed (for 5-65 % RH) or 2 h had elapsed (for 80 and 95 % RH). The following program was used:

[0138] Equilibration at 50 % RH

[0139] 50 % to 5 %. (50 %, 35 %, 20 %, and 5 %)

[0140] 5 % to 95 % (5 %, 20 %, 35 %, 50 %, 65 %, 80 %, and 95 %)

[0141] 95 % to 5 % (95 %, 80 %, 65 %, 50 %, 35 %, 20 %, and 5 %)

[0142] 5 % to 50 % (5 %, 20 %, 35 %, and 50 %) High Performance Liquid Chromatography (HPLC):

[0143] HPLC was conducted using an Agilent 1220 Infinity LC. Flow rate range was 0.2-5.0 mL / min, operating pressure range was 0-600 bar, temperature range was 5 °C above ambient to 60 °C, and wavelength range was 190-600 nm. The HPLC method is shown below:

[0144] Parameters

[0145] Mobile Phase A 0.1% TFA in distilled water

[0146] Mobile Phase B Methanol

[0147] Diluent ACN:water:TFA (50:50:0.1 vol)

[0148] Injection Volume 5 pL

[0149] Monitoring Wavelength 246 nm

[0150] Column Atlantis T3, 4.6 x 150mm, 3.0 pm

[0151] Column Temperature 40 °C

[0152] Time (min) %A Flow Rate (mL / min) 0 95 0.7

[0153] J5.0 50 0.7

[0154] Gradient Method 20.0 5 0.7

[0155] 22.0 85 0.7

[0156] 22.5 95 0.7

[0157] 29.0 95 0.7

[0158] Karl Fischer (KF) Titration:

[0159] KF titration for water determination was performed using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell with a diaphragm, and a double-platinum-pin electrode. The range of detection of the instrument is 1 ppm to 5 % water. Aquastar™ CombiCoulomat fritless reagent was used in both the anode and cathode compartments. Samples of approximately 0.03-0.10 g were dissolved in the anode compartment and titrated until the solution potential dropped below 100 mV. Hydranal 1 wt. % water standard was used for validation prior to sample analysis.

[0160] Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC)

[0161] TGA and DSC were performed on the same sample simultaneously using a Mettler Toledo TGA / DSC 3+ Protective and purge gas was nitrogen at a flowrate of 20-30 mL / min and 50-100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed according to the parameters below: Parameters

[0162] Method Ramp

[0163] Sample size 5-10 mg

[0164] Heating rate 10.0 °C / min

[0165] Temperature range 30 up to 300 °C

[0166] X-Ray Powder Diffraction (XRPD):

[0167] XRPD was performed using a Bruker D8 Advance equipped with LYNXEYE detector in reflection mode (i.e. Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for XRPD methods used are listed below:

[0168] Parameters for Reflection Mode for High Resolution Scans

[0169] X-ray wavelength Cu Kai, 1.540598 A,

[0170] X-ray tube setting 40 kV, 15 mA

[0171] Slit condition 1.25 ° div., Ni kp filter, 0.3 mm rec.

[0172] Scan mode Continuous

[0173] Scan range (°20) 4 - 40

[0174] Step size (°20) 0.05

[0175] Dwell time (s / step) 1.25

[0176] Spin No

[0177] Example 1: Synthesis of Amorphous Compound (I):

[0178] Intermediate 1 : 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0179] Step 1: Synthesis of 4-jluoro-2-methyl-5-(2H-tetrazol-5-yl)aniline

[0180] To a solution of 5-amino-2-fluoro-4-methylbenzonitrile (5 g, 33.2 mmol) in DMF (50 mL) was added BusSnNs (33.2 g, 99.6 mmol) and the reaction mixture was stirred at 100 °C for 12 h. The mixture was diluted with EtOAc (500 mL) and water (500 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3^200 mL) and the combined organic phase was washed with brine (300 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by a silica gel column with PE:EtOAc = 3: 1 to give the title compound (2.6 g, 41% yield) as a yellow solid. LCMS m / z = 194 [M+H]+. Step 2: Synthesis of 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-jluoro-2-methylaniline

[0181] A mixture of 4-fluoro-2-methyl-5-(2H-tetrazol-5-yl)aniline (260 mg, 1.34 mmol), K2CO3 (553 mg, 4.01 mmol), [CuOH(TMEDA)]2C12 (124 mg, 0.268 mmol), and cyclopropylboronic acid (171 mg, 0.268 mmol) in DCE (8 mL) was stirred at 60 °C for 24 h under O2 and then cooled to room temperature (10 reactions were run in parallel on this scale and combined for workup and purification). The mixture was filtered and the collected solid was washed with a solution of DCM:MeOH = 10: 1. The filtrates were combined and concentrated under vacuum. The crude product was purified by silica gel column with PE:EtOAc = 2: 1 to give the title compound (460 mg, 15% yield) as a yellow solid. LCMS: m / z = 234 [M+H]+.

[0182] Compound (I): N- 5- 2-cvclopropvl-2H-tetrazol-5-vl)-4-fluoro-2-methvlphenyl)-5- l- 2- hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0183] Step 1: Synthesis of 2-methyl-l-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)propan-2-ol and 2-methyl-l-(5-methyl-4-( 4, 4, 5, 5 -tetramethyl- 1 , 3, 2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol

[0184] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.5 g, 26.3 mmol), 2, 2-dimethyl oxirane (1.90 g, 31.6 mmol) and CS2CO3 (8.6 g, 26.3 mmol) in DMF (70 mL) was stirred at 100 °C for 3 h under N2. The solvent was evaporated and the residue was purified by silica gel column with DCM:MeOH 19: 1 to afford the title compound (5.4 g, 73 % yield) as a yellow solid. LCMS: m / z = 281 [M+H]+. Step 2: Synthesis of methyl 5-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4- yl)pyrazolo [ 1 ,5-a]pyridine-3-carboxylate and methyl 5-(l-(2-hydroxy-2-methylpropyl)-5- methyl-lH-pyrazol-4-yl)pyrazolo[ 1, 5-a]pyridine-3-carboxylate

[0185] A solution of the mixture of compounds from step 1 (3.4 g, 12.1 mmol), methyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate (3.1 g, 12.1 mmol), CS2CO3 (7.9 g, 24.2 mmol) and Pd(pddf)C12 (940.3 mg, 1.1 mmol) in dioxane (40 mL) and water (4 mL) was stirred at 100 °C for 3 h under N2. The solvent was removed under vacuum and the residue was purified on a silica gel column with DCM:MeOH 19: 1 to give the mixture of the title compounds (3.0 g, 75% yield) as a yellow solid. LCMS m / z = 329 [M+H]+.

[0186] Step 3: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fhioro-2-methylphenyl)-5-(l-(2- hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0187] To a stirred solution of the mixture of compounds from step 2 (600 mg, 1.83 mmol) and Intermediate 1 (460 mg, 2.0 mmol) in toluene (8 mL) was added MesAl (1.9 mL, 3.8 mmol, 2M in toluene) at 0 °C. The reaction mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The mixture was concentrated under vacuum and purified by a silica gel column with DCM:MeOH = 10: 1 to give 200 mg as a white solid. The crude product was purified by prep-SFC using following condition: Column: Green Sep Basic 3*15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: ACN:MeOH = 4: 1 (20 mM NH3 in MeOH); Flow rate: 75 mL / min; Gradient: isocratic 30% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; Run Timel(min): 6.15; Sample Solvent: MeOH; Injection Volume: 1.5 mL; Number of Runs: 8.0, to afford the title compound (67.7 mg, yield: 6.4 % yield) as a white solid. LCMS: m / z = 530 [M+H]+. An XRPD of the obtained product is shown in FIG 3. (Instrument type: Bruker D2 Phaser X-ray diffractometer, Detector: PSD LynxEye, Slit condition: 1.0 mm divergence slit, 2.5° seller, Scan mode: Continuous PSD fast scan, Scan range (2 theta): 3.00-40.00°, Scan step (2 theta): 0.02°.^ NMR (400 MHz, DMSO ) 8 9.72 (s, 1H), 8.81 (d, 1H), 8.73 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.06 (d, 1H), 7.40 (d, 1H), 7.26 (dd, 1H), 4.74 (s, 1H), 4.49 (tt, 1H), 3.98 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 1.41 (q, 2H), 1.29 (td, 2H), 1.10 (s, 6H). (Only a trace of N-(5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-(l-(2-hydroxy-2-methylpropyl)-5- methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was isolated). Example 2: Inhibition of Wild Type c-Kit in a Biochemical Phospho c-Kit Inhibition Assay

[0188] Compound (I) is shown to inhibit autophosphorylation of wild type c-kit and was measured using a PathScan phospho c-kit (Tyr719) sandwich ELISA (CST#7298). These studies were carried out as follows.

[0189] M-07e cells were resuspended at 2 x 106cells / mL in phenol red free, serum-free, GM- CSF-free Iscove's Modified Dulbecco's Medium (IMDM) media with 1% Penicillin- Streptomycin. The cells were then dispensed into the wells of a U-bottom, 96-well plate at 50 pL per well using a multichannel pipet. The plate was allowed to incubate at 37 °C in a humidified tissue culture incubator for 4 hours.

[0190] After 4 hours of incubation, each well was dosed with 6.25 pL of test compound at a final DMSO concentration of 0.25% for 60 min at 37 °C to generate an 8-point dose concentration series of test compounds in duplicate. Cells were then incubated for 1 hour at 37 °C in a humidified tissue culture incubator. Next, human SCF at 500 ng / mL was added to the appropriate wells at 6.25 pL / well and the plate was shaken at 450 rpm at room temperature for 10 minutes. AlphaLISA 5X Lysis Buffer supplemented with IX protease and phosphatase inhibitor was then added at 16 pL / well. The plate was sealed with an adherent cover and shaken at 4 °C at 600 rpm for 30 minutes. After this period of lysis, the plate was stored at -80 °C.

[0191] When the 96-well plate containing M07e lysates was ready to be processed, the plate was brought to room temperature and 40 pl from each well was transferred to the wells of a PathScan Phospho-c-Kit (Tyr719) Sandwich ELISA plate (CST, Catalog #7298). The ELISA plate was sealed with an adherent cover and incubated for 2 hours at 37 °C. Next, the wells were washed 4 times with the provided IX Wash Buffer, and 100 pL / well of reconstituted Detection Antibody was added to each well, the plate sealed with an adherent cover, and incubated at 37 °C for 1 hour. The wash procedure was repeated and 100 pL / well of reconstituted HRP -Linked secondary antibody was added. The plate was sealed with an adherent cover and incubated at 37 °C for 1 hour. The wash procedure was repeated and 100 pL / well of TMB Substrate was added. The plate was incubated for 10 minutes at room temperature or until the positive reaction elicited a blue color in the appropriate wells. 100 pL / well of STOP solution was added and shaken gently for a few seconds a microplate reader or conventional spectrophotometer e.g., a Perkin Elmer Envision multimode plate reader, part #2105-0010. The raw data was normalized using the values derived with 10 pM staurosporine as 100% inhibition of c-kit phosphorylation and DMSO as 0% inhibition of c-kit phosphorylation. An pKIT IC50 of 0.3 nM was calculated for Compound (I) using a 4- parameter logistic nonlinear regression.

[0192] Some compounds of the disclosure are substrates of the human P-glycoprotein (P-gp). The potential for compounds prepared according to the examples to be substrates of P-gp was evaluated using in vitro on Multi drug Resistance Mutation 1-Mardin-Darby Canine Kidney (MDCK-MDR1)) (Mardin-Darby Canine Kidney) cell monolayers overexpressing P-gp grown on permeable supports. A higher efflux ratio of P-gp means that the compound is pushed out of the brain tissue by the transporter.

[0193] Preparation for cell seeding: MDCK-MDR1 cell culture medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) with high glucose and L-glutamine supplemented with: 10% FBS, 0.1 mg / mL of streptomycin, 0.6 pg / mL of Kanamycin sulfate and 100 units of penicillin was prepared. 50 pL of culture medium was added to each well of the Transwell insert. The Transwell insert was removed from the reservoir and 25 mL of culture medium was added. After incubation at 37 °C, 5% CO2 for 1 hour, the plates were ready for cell seeding. The cells were cultivated in T-75 flasks in a cell culture incubator set at 37 °C, 5% CO2, 95% relative humidity until they reached 80-90% confluence before detaching and splitting. The cultivated cells were rinsed in T-75 flasks with 5 mL PBS and aspirated off, and then 1.5 mL trypsin / EDTA was added and incubated at 37 °C for approximately 5 to 10 minutes or until the cells detach and float. The trypsin / EDTA was inactived by adding excess serum containing medium. The cell suspension was transferred to a conical tube and the cells pelleted by centrifugation at 120 x g for 10 minutes. The cells were resuspended in seeding medium at a density of 1.56xl06cells / mL. This cell concentration was used to seed 5.45xl05cells / cm2.

[0194] Seeding and feeding of MDCK-MDR1 cells into transwell plates: 50 pL of the above cell suspension was added to each well of a previously prepared Transwell plate and the plate was incubated for 4-8 days, replacing the medium every other day beginning no sooner than 48 hours after initial plating. The medium must be replaced on the day before conducting the experiment, and the procedure for medium changes was carried out as follows. The plate was removed from the incubator and placed in a hood. The medium was aspirated from a reservoir and each Transwell was inserted. 100 pL of culture medium was added to each well of the Transwell inserts and 25 mL of culture medium to reservoir tray. The plate was returned to the incubator.

[0195] Assessment of cell monolayer integrity: When the 4-day cultured MDCK-MDR1 cells reached confluence and were differentiated, the medium was removed from the reservoir and Transwell inserts. 100 pL of prewarmed culture medium was added to each transwell insert and 25 mL was added to the reservoir tray. The electrical resistance across the monolayer was measured using a Millicell Epithelial Volt-Ohm measuring system. The electrical resistance for each well was measured and then the plate was returned to the incubator. TEER values were calculated using this formula: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm cm2). Any monolayer with a TEER value < 42 ohms- cm2, indicating poor monolayer formation, was discarded.

[0196] Performing the drug transport assay: The MDCK-MDR1 plate was removed from the incubator and the monolayer was washed, exchanging the volume two times using prewarmed HBSS (Hank’s balanced salt solution) (10 mM HEPES, pH 7.4). The plate was then incubated at 37 °C for 30 minutes. A 1 pM compound working solution was prepared as follows: Added 2 pL of stock solution (10 mM in DMSO) of test compound and control compounds (Metoprolol, Prazosin and Imatinib) in one 96 well plate, then added 98 pL of DMSO into the same well to obtain 0.2 mM stock solutions (note a stock solution was further diluted 1 : 10 for eventually making a 0.1 pM compound working solution). Transferred 3 pL of 0.2 mM solution into 597 pL of transport buffer in one 96 well plate to prepare the 1 pM compound working solution. The plate was shaken at 1000 rpm for 10 min. The final concentration of DMSO in the incubation system was 0.5%. The rate of drug transport in the apical to basolateral direction was carried out as follows: Added 125 pL of the 1 pM working solution to the Transwell insert (apical compartment), and transferred 50 pL of sample immediately from the apical compartment to 250 pL of quenching solvents in a new 96-well plate as the initial donor sample (A-B). The plate was shaken at 1000 rpm for 5 minutes. The wells in the receiver plate (basolateral compartment) were filled with 235 pL of transport buffer.

[0197] The rate of drug transport in the basolateral to apical direction was carried out as follows: Added 285 pL of the 1 pM working solution to the receiver plate wells (basolateral compartment), and transferred 50 pL of sample immediately from the basolateral compartment to 250 pL quenching solvents in a new 96-well plate as the initial donor sample (B-A). Filled the Transwell insert (apical compartment) with 75 pL of transport buffer. The plate was shaken at 1000 rpm 5 minutes.

[0198] The multiwell insert plate was placed into the basolateral receiver plate and the plate was placed into the incubator, incubating at 37 °C for 2 hours. At the end of the transport period, 50 pL of samples was transferred from donor sides (apical compartment for Ap— >B1 flux, and basolateral compartment for Bl— >Ap flux) to 250 pL quenching solvents in a new 96-well plate. 50 pL was removed directly from receiver sides (basolateral compartment for Ap— >B1 flux, and apical compartment for Bl— >Ap flux) and transferred to new 96-well plates with 250 pL quenching solvents. The samples were vortexed at 1000 rpm for 5 minutes and then centrifuged at 4,000 rpm for 20 minutes. An aliquot of 100 pL of the supernatant mixed with 100 pL of pure water was used for LC / MS / MS analysis. All incubations were performed in duplicates. To determine the Lucifer Yellow leakage after 2-hour transport period, stock solutions of Lucifer yellow in water were prepared and diluted with HBSS containing 25 mM HEPES, pH 7.4 to reach the final concentration of 100 pM. 100 pL of the Lucifer yellow solution was added to the Transwell insert (apical compartment) and the wells in the receiver plate (basolateral compartment) were filled with 300 pL of HBSS containing 25 mM HEPES, pH 7.4., incubating at 37 °C for 30 mins. 80 pL was removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to new 96 wells plates. Lucifer Yellow fluorescence was measured (to monitor monolayer integrity) in a fluorescence plate reader at 485 nM excitation and 530 nM emission.

[0199] Data calculations: All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The Lucifer yellow leakage of MDCK- MDR1 cell monolayers was calculated using the following equation: LY Leakage= {IacceptorxQ.3} / { / acceptorx0.3+ / donorx0.1 })x l00%, where lacceptor is the fluorescence intensity in the acceptor well (0.3 mL), and Idonor is the fluorescence intensity in the donor well (0.1 mL) and expressed as % leakage. Any monolayer that produces a Lucifer yellow leakage > 1%, indicating poor monolayer formation, was excluded from the evaluation.

[0200] The apparent permeability (Papp), in units of centimeter per second, was calculated for MDCK-MDR1 drug transport assays using the following equation: Papp= V A / ( Area time)} {[drug]acceptor} / { [drug]initial, donor}, where VA is the volume (in mL) in the acceptor well (0.235 mL for Ap— >B1 flux and 0.075 mL for Bl— >Ap flux), Area is the surface area of the membrane (0.143 cm2 for HTS Transwell-96 Well Permeable Supports), and time is the total transport time in seconds.

[0201] The efflux ratio was determined using the following equation: Efflux Ratio=Papp (B~A) / Papp (A-B), where Papp (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B) indicates the apparent permeability coefficient in apical to basolateral direction.

[0202] The recovery rate was determined using the following equation: Recovery%= {[drug]acceptorx VA+[drug]donorxVD} / {[drug]imtial,donorxVD})x lOO, where VA is the volume (in mL) in the acceptor well (0.235 mL for Ap— >B1 flux, and 0.075 mL for Bl— >Ap), VD is the volume (in mL) in the donor well (0.075 mL for Ap— >B1 flux, and 0.235 mL for Bl— >Ap).

[0203] At 1 pM concentration of compound or 0.1 pM, Compound (I) demonstrated a Pgp Efflux Ratio of 13.2.

[0204] Example 3: Compound (I) inhibits Exon 11 KIT

[0205] Exon 11 HMC1.1 autophosphorylation assay: 50,000 HMC1.1 cells were incubated in 50 pl culture media (phenol-red free IMDM, no iron, no serum) in each well of a 96-well plate and serum starved 4 hours in a tissue culture incubator (5% CO2, 37°C). An 8-point dose concentration series of compound were then added to the cells in a volume of 7 pl to each well. After 90 minutes, 14 pl of 5X AlphaLISA Lysis Buffer (Perkin Elmer) supplemented with a protease and phosphatase inhibitor cocktail (Cell Signaling Technologies) was added to each well and shaken at 2500 xg for 5 minutes at 4°C. Phospho- Y719 c-KIT ELISA kit from Cell Signaling Technology was used to assess levels of phospho KIT. Data was normalized to 0% and 100% inhibition controls and the IC50 was calculated using Four Parameter Logistic IC50 curve fitting.

[0206] Compound (I) demonstrated an IC50 of 0.9 nM. Example 4: Preparation and Characterization of Crystalline Form A

[0207] 4, 1 Synthetic Procedure to Prepare Form A of Compound (I)

[0208] Intermediate 1 : 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0209] Step 1: Synthesis of 5-(2-jluoro-4-methylphenyl)-2H-tetrazole

[0210] To a solution of 2-fluoro-4-methylbenzonitrile (250 g, 1.85 mol) and (25)-pyrrolidine-2- carboxylic acid (532 g, 4.62 mol) in DMF (2000 mL) was added TMSN3 (853 g, 7.40 mol, 973 mL) at room temperature and the reaction mixture stirred at 120 °C for 24 h. The mixture was cooled to room temperature and poured into water (15 L). The mixture was filtered and concentrated under vacuum to afford the title compound (750 g, 75% yield) as a yellow solid which was used directly in the next step. LCMS m / z = 179 [M+H]+.

[0211] Step 2: Synthesis of 2-cyclopropyl-5-(2-fluoro-4-methylphenyl)-2H-tetrazole

[0212] To a mixture of the product of step 1 (100 g, 561 mmol) and cyclopropylboronic acid (191 g, 2.25 mol) in dioxane (3.00 L) was added TMEDA (65.2 g, 561 mmol), K2CO3 (553 mg, 4.01 mmol), and Cu(OAc)2 (102 g, 561 mmol) at room temperature. The mixture was degassed and replenished with O2 3 times and then stirred at 100 °C for 16 hours. The mixture was cooled to room temperature. (6 reactions were run on this scale and combined for workup and purification). The combined mixtures were filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column with PE:EtOAc = 30: 1 to 5: 1 to give the title compound (206 g, 27% yield) as a yellow solid. LCMS: m / z = 219 [M+H]+.

[0213] Step 3: Synthesis of 2-cyclopropyl-5-(2-fluoro-4-methyl-5-nitrophenyl)-2H-tetrazole

[0214] The product of step 2 (200 g, 916 mmol) was added to H2SO4 (1.0 L) at 20 °C, and then KNO3 was slowly added at 0 °C. The mixture was stirred at 0 °C for 1 hour and then was poured into ice water (3.0 L) at 0 - 5 °C. The resulting mixture was extracted with EtOAc (500 mL x 3), and the combined organic layers were combined and washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (240 g, 99% yield) as a yellow solid which was used directly in the next step. LCMS: m / z = 264 [M+H]+.

[0215] Step 4: Synthesis of 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-jluoro-2-methylaniline

[0216] To a mixture of the product of step 3 (240 g, 912 mmol), acetic acid (1.08 L), ethanol (1.44 L), and water (720 mL) was added iron (255 g, 4.56 mol) in small portions at 30 - 40 °C. The mixture was stirred at 50 °C for 1 hour and then cooled to room temperature before filtering. The pH of the filtrate was adjusted to pH 8-9 with sodium carbonate. The aqueous layer was extracted with ethyl acetate (1.0 L x 3) and the combined organic layers were combined and washed with brine (1.0 L x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was triturated with PE:EtOAc = 5: 1 (300 mL) for 16 hours and this mixture was filtered. The resulting solid was again triturated with PE:EtOAc = 5: 1 (300 mL) for 16 hours and this mixture was filtered to provide the title compound (181 g, 84% yield) as a yellow solid. LCMS: m / z = 234 [M+H]+.

[0217] Intermediate 2: Ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine-3 -carboxylate

[0218] To a solution of ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate (22.0 g, 81.8 mmol) and bis(pinacolato)diboron (24.9 g, 98.1 mmol) in dioxane (250 mL) was added Pd(dppf)C12 (5.98 g, 8.18 mmol) and KOAc (24.1 g, 245 mmol). The mixture was stirred at 100 °C for 2 hours under N2. On completion, the mixture was filtered and washed with THF (100 mL), and the filtrate was concentrated under vacuum. The residue was purified by a silica gel column with PE:EA= 60: 1 to 20: 1 to afford the title compound as a yellow solid. LCMS m / z = 317 [M+H]+.1H-NMR (400 MHz, CDCI3): 8 ppm 8.65 (s, 1H), 8.49 (d, 1H), 8.40 (s, 1H), 7.25 (d, 1H), 4.41 (q, 2H), 1.47 - 1.40 (m, 3H), 1.37 (s, 12H). Intermediate 3 : Ethyl 5-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carboxylate

[0219] Step 1: Synthesis of l-(4-bromo-3-methyl-lH-pyrazol-l-yl)-2-methylpropan-2-ol

[0220] To a mixture of 4-bromo-3 -methyl- UT-pyrazole (40.0 g, 249 mmol) in DMF (800 mL) was added CS2CO3 (202 g, 621 mmol) and l-chloro-2-methylpropan-2-ol (53.9 g, 497 mmol, 51.0 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (1500 mL) and water (200 mL). The organic phase was separated, washed with brine (200 mL x 3), dried over ISfeSCU, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (column: Welch Ultimate XB-SiOH 250*70* lOum; mobile phase: [97:3 Hexane:EtOH (0.1% NH3.H2O)] to give the title compound (21.0 g, 34% yield) as a white solid. 'H-NMR (400 MHz, CDCI3): 8 ppm 7.37 (s, 1H), 3.95 (s, 2H), 2.24 (s, 3H), 1.16 (s, 6H).

[0221] Step 2: Synthesis of ethyl 5-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4- yl)pyrazolo[ 1, 5 -a ]pyridine-3-carboxylate

[0222] A mixture of the product of step 1 (13.0 g, 55.8 mmol), Intermediate 2 (21.2 g, 67.0 mmol), and K3PO4 (23.7 g, 112 mmol) in THF (130 mL) and water (26 mL) was added cataCXiumAPdG3 (4.06 g, 5.6 mmol). The mixture was stirred at 70 °C for 2 hours under N2. The reaction mixture was cooled to room temperature and partitioned between EtOAc (300 mL) and water (60 mL). The organic phase was separated, washed with brine 120 mL (60 mLx2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by a silica gel column (DCM:MeOH = 10: 1 to 9: 1) to give the title compound (16.0 g, 82% yield) as a gray solid. 'H-NMR (400 MHz, CDC13): 5 ppm 8.52 - 8.47 (m, 1H), 8.39 (s, 1H), 8.21 - 8.16 (m, 1H), 7.69 (s, 1H), 7.04 - 6.99 (m, 1H), 4.40 (q, 2H), 4.06 (s, 2H), 2.53 (s, 3H), 1.43 (t, 3H), 1.23 (s, 6H). Crystalline Form A ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-(l-

[0223] (2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3- carb oxami de

[0224] Two reaction batches were run separately. Batch 1 : To a solution of Intermediate 3 (4.30 g, 12.6 mmol) and Intermediate 1 (3.22 g, 13.8 mmol) in toluene (86 mL) was added AlMes (2.0 M, 18.8 mL) at 0 °C under N2. The mixture was stirred at 100 °C for 2 hours under N2. Batch 2: To a solution of Intermediate 3 (9.60 g, 28.0 mmol) and Intermediate 1 (7.19 g, 30.8 mmol) in toluene (192 mL) was added AlMes (2.0 M, 42.1 mL) at 0 °C under N2. The mixture was stirred at 100 °C for 2 hours under N2. The reaction mixtures were cooled to room temperature, combined, and quenched with 3N HC1 (200 mL), and then the pH was adjusted to pH=12 with 4 NNaOH. The mixture was extracted with DCM:MeOH = 10:1 (800 mL), and then the organic phase was separated, washed with brine (150 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column (DCM:MeOH = 1 :0 to 50: 1) to obtain the title compound; the pure fractions were combined to yield 12.4 g, and the impure fractions were combined to yield 8.6 g. The impure 8.6 g was triturated with EtOAc:PE twice to give 7.2 g, which was further purified by silica gel column (DCM:MeOH = 1 :0 to 50: 1) to give 4.8 g (99% purity) and 1.1 g (91% purity). The 4.8 g of product was suspended in EtOAc:PE (15mL:45 mL) and the mixture was stirred at room temperature for 30 minutes before the solid was collected by filtration. The filter cake was dried under vacuum to afford the title compound (4.47 g) as a white solid.1H-NMR (400 MHz, CDCI3): 8 ppm 8.50 (d, 1H), 8.43 - 8.36 (m, 2H), 8.26 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.14 (d, 1H), 7.07 (dd, 1H), 4.27 (tt, 1H), 4.03 (s, 2H), 3.90 (s, 1H), 2.51 (s, 3H), 2.40 (s, 3H), 1.58 - 1.52 (m, 2H), 1.31 - 1.26 (m, 2H), 1.21 (s, 6H).

[0225] 4,2 Preparation of Crystalline Form A of Compound (I): Large Scale

[0226] To an agitated reactor was charged crude Compound (I) (1 kg) and a previously prepared mixture of methylethylketone (MEK) and deionized water (12 L, v / v = 95:5). The mixture was heated to 60-70 °C and polish filtered. The filtrate was distilled at atmospheric pressure to 5 L, followed by continuous distillation with MEK until the water content was not more than 1%-w / w. The mixture was cooled to 70-80 °C and EtOH (2 L) was charged to the reactor. The solution was cooled to 62-66 °C, then seeded with Form A. The resulting mixture was cooled to 40-50 °C, followed by addition of methyl tert-butyl ether (MTBE, 9 L). The resulting slurry was further cooled to 0-10 °C, aged and filtered. The wet cake was washed with MTBE and dried to give Form A of Compound (I) as a crystalline solid, with a yield of -90%.

[0227] Select characterization data for crystalline Form A of Compound (I) is presented below.

[0228] Note. Decomp., decomposition.

[0229] Example 5: Preparation and Characterization of Crystalline Form O of Compound (I). 5, 1 Initial Generation of Form O:

[0230] Crystalline Form O of Compound (I) was first observed as a mixed pattern with crystalline Form A of Compound (I) during a competitive slurry experiment. First, a saturated solution of crystalline Form A of Compound (I) was prepared at 45 °C. To make the solution, crystalline Form A of Compound (I) was added to 1 mL of MEK:EtOH (3:7) already stirring at 45 °C. Once a thin slurry was observed, the sample was left to equilibrate overnight. After holding overnight, the stir bar was removed and the solid was allowed to settle and 600 mL of supernatant was pipetted into a clean 2 mL vial containing a stir bar.

[0231] The supernatant was then left to stir for an additional 15 min prior to adding seed (1 spatula tip, ~20mg) of crystalline Form A of Compound (I) and crystalline Form N of Compound (I). The sample was plated for XRPD analysis immediately after seeding. Postseeding, crystalline Form A of Compound (I) was observed. After 1 day, crystalline Form O of Compound (I) was observed. The ratio of crystalline Form O of Compound (I) appeared to increase after slurring for 4 days. Crystalline Form N of Compound (I) was obtained as the wet cake from amorphous Compound (I) slurries in EtOH, at both RT and 50 °C. FIG 4 shows a characteristic XRPD for crystalline Form N of Compound (I). A peak listing for Crystalline Form N of Compound (I) is shown in Table 3.

[0232] Table 3. Representative XRPD peaks of crystalline Form N of Compound (I)

[0233] 5,2 Preparation of Form O. Vial-Scale

[0234] Crystalline Form A of Compound (I) (2.13 g) was placed in a 20 mL scintillation vial with a 10 mm stir bar and 5 vol MEK with seed of Form O (~10 mg) and placed on a hotplate overnight at 70 °C. The solids were confirmed as Form O by XRPD the following day. The solids were filtered and dried at 50 °C under active vacuum overnight and approximately 2 g of Form O recovered.

[0235] 5,3 Preparation of Form O (with seeding):

[0236] Crystalline Form A of Compound (I) (30 g) was weighed into a 400 mL EasyMax vessel with a 5.0 cm PTFE retreat curve impeller. MEK (250 mL) was added to the vessel and the solids suspended with a stir rate of 300 rpm. The beige slurry was heated to 60 °C (controlled by reactor temperature) and held for 30 min before seeding with a slurry of Pattern O in MEK. After 24 h, partial conversion to crystalline Form O of Compound (I) was observed and the temperature control was switched to the jacket over the weekend. After 72 h, full conversion to crystalline Form O of Compound (I) was observed. Following filtration, solids were dried at 50 °C under active vacuum.

[0237] Select characterization data for crystalline Form O is presented below.

[0238] Note. Decomp., decomposition.

Claims

CLAIMSWhat is claimed is:

1. Crystalline Form A of Compound (I):characterized by an X-ray powder diffraction pattern which comprises peaks at 5.5°, 11.0°, 20.7°, 24.9°, and 26.3° ± 0.2 in 20.

2. The crystalline Form A of Compound (I) according to claim 1, characterized by an X- ray powder diffraction pattern which comprises peaks at 5.5°, 9.5°, 11.0°, 13.3°, 15.9°, 20.7°, 24.9°, and 26.3° ± 0.2 in 20.

3. The crystalline Form A of Compound (I) according to claim 1, characterized by an X- ray powder diffraction pattern which comprises peaks at 5.5°, 9.5°, 11.0°, 13.3°, 14.8°, 15.9°, 20.7°, 24.9°, 25.1°, and 26.3° ± 0.2 in 20.

4. The crystalline Form A of Compound (I) according to any one of claims 1-3, characterized by a differential scanning calorimeter (DSC) with an onset temperature of 174.3 ± 2 °C.

5. Crystalline Form O of Compound (I):characterized by an X-ray powder diffraction pattern which comprises peaks at 8.0°, 16.1°, 19.3°, 23.1°, and 26.9° ± 0.2 in 29.

6. The crystalline Form O of Compound (I) according to claim 5, characterized by an X- ray powder diffraction pattern which comprises peaks at 8.0°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 20.

7. The crystalline Form O of Compound (I) according to claim 5, characterized by an X- ray powder diffraction pattern which comprises peaks at 8.0°, 9.1°, 11.3°, 12.7°, 16.1°, 18.6°, 19.3°, 23.1°, 26.6°, and 26.9° ± 0.2 in 20.

8. The crystalline Form O of Compound (I) according to any one of claims 5-7, characterized by a differential scanning calorimeter (DSC) with an onset temperature of 194.0 ± 2 °C.

9. A pharmaceutical composition comprising the compound of any one of claims 1-8, and a pharmaceutically acceptable carrier.

10. A method of treating a subject suffering from a disease or disorder mediated by wild type c-kit kinase, comprising administering to the subject an effective amount of a compound of any one of claims 1-8, or a pharmaceutical composition of claim 9.

11. The method of claim 10, wherein the disease or disorder is selected from urticaria, dermatosis, idiopathic anaphylaxis, asthma, hereditary alpha tryptasemia (HAT), neurofibromatosis, idiopathic pulmonary fibrosis, bullous pemphigoid, prurigo nodularis, age-related macular degeneration, allergic conjunctivitis, allergic rhinitis, alpha- 1 antitrypsin deficiency, Alzheimer’s disease, amyotrophic lateral sclerosis (AML), bronchiectasis, Celiac disease, chronic graft verse host disease, chronic rhinosinusitis with nasal polyps, colorectal cancer, dermatitis herpetiformis, irritable bowel syndrome (IBS), fibromyalgia, fibrosis, food allergies, insulin-dependent diabetes mellitus, mast cell leukemia, migraine, multiple sclerosis, Parkinson’s disease, psoriasis, rheumatoid arthritis, pulmonary arterial hypertension (PAH), inflammatory bowel disease (IBD), scleroderma, dermatosis, dermatitis herpetiformis, melanoma, gastrointestinal stromal tumor, mast cell tumor, anaphylactic syndrome, idiopathic anaphylaxis, eosinophilic esophagitis and mastocytosis.

12. The method of claim 11, wherein the disease or disorder is chronic urticaria.

13. The method of claim 12, wherein the chronic urticaria is chronic spontaneous urticaria (CSU).

14. The method of claim 13, wherein the subject is resistant to antihistamine treatment (i.e., the subject remains symptomatic despite antihistamine treatment).

15. A method of inhibiting wild type c-kit kinase in a subj ect in need thereof, comprising the step of administering to the subject in need thereof an effective amount of a compound of any one of claims 1-8, or a pharmaceutical composition of claim 9.

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