Wild type kit inhibitors

Abstract

Disclosed are Compounds (1), (2), and (3) or a pharmaceutically acceptable salt thereof: Compounds (1), (2), and (3) Compounds (1), (2), and (3) are useful for inhibiting wild type c-kit kinase and for treating disorders and diseases mediated by wild type c-kit kinase in humans or non-humans.

Description

WILD TYPE KIT INHIBITORSRELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 656,477, filed on June 5, 2024, the entire teachings of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The disclosure relates to novel compounds and their use as selective inhibitors of wild type c-kit kinase, a cell surface receptor that acts as the master survival and functional regulator of mast cells.BACKGROUND OF THE INVENTION

[0003] 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.

[0004] 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 forchronic urticaria, and all currently recommended treatment options are intended only to control and prevent the symptoms of chronic urticaria.

[0005] 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.SUMMARY OF THE INVENTION

[0006] Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which are useful for inhibiting wild type c-kit kinase and for treating diseases or disorders mediated by wild type c-kit kinase. The compounds of the disclosure are potent inhibitors of c-kit kinase. Some compounds of the disclosure are orally bioavailable, selective over other kinases such FLT3 kinase and PDGFR and have minimal CNS penetration to reduce CNS side effects.

[0007] One embodiment of the disclosure is a compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 1

[0008] One embodiment of the disclosure is a compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 2

[0009] One embodiment of the disclosure is a compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 3

[0010] Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the composition is for treating a disease or disorder mediated by wild type c-kit kinase. In another aspect, the composition is for inhibiting wild type c-kit kinase in a subject in need thereof.

[0011] Another embodiment 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 administrating to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0012] Another embodiment of the disclosure is a method of inhibiting wild type c-kit kinase in a subject in need thereof. The method comprises administrating to the subject in need thereof an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0013] Another embodiment of the disclosure is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure 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.

[0014] Another embodiment of the disclosure is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure 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.

[0015] Another embodiment of the disclosure is a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier or excipient for the treatment of a medical condition mediated by wild type c-kit kinase.

[0016] Another embodiment of the disclosure is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition comprising a compound of the disclosure 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

[0017] Fig. 1 is the XRPD of a crystal form of Compound 1.

[0018] Fig. 2 is the XRPD of an amorphous form of Compound 3.DETAILED DESCRIPTION OF THE INVENTION

[0019] An object of this disclosure is to provide novel compounds and compositions with highly selective, potent activity against wild type c-kit kinase for the safe and effective treatment of mast cell associated disease in a subject. For example, the IC50 values for inhibition ofphospho kit provided in Table 2 demonstrate that these compounds are potent inhibitors of c-kit. The term “KIT” or “kit” refers to a human tyrosine kinase that may be referred to as mast / stem cell growth factor receptor (SCFR), proto-oncogene c-kit, tyrosine-protein kinase kit or CD117.

[0020] In treating these mast cell associated diseases, especially chronic disorders such as urticaria and asthma, any new therapy should be well-tolerated. The compounds of the disclosure aim to provide treatments having desirable efficacy, safety, and pharmaceutical properties for the treatment of c-kit mediated diseases. In some aspects, compounds of the disclosure are orally administered. In some aspects, compounds of the disclosure are selective inhibitors of c-kit kinase. Selective inhibitors selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target, which leads to an increased probability of clinical success in comparison with a non-selective inhibitors. In some aspects, compounds of the disclosure have low CNS penetration, which is a desirable property for reducing and minimizing side effects of chronic treatment. Compounds with low CNS penetration often have high levels or active transport out of the brain, z.e., high efflux ratios from the CNS. In some aspects, compounds of the disclosure have improved solubility, which is advantageous for administration.

[0021] Compounds of the disclosure are selective c-kit inhibitors. As used herein, a“selective c-kit inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that has the ability to selectively inhibit c-kit kinase over other targets. More specifically, a selective c-kit inhibitor has the ability to selectively inhibit c-kit over another kinase. In some aspects, compounds of the disclosure are selective for c-kit over FLT3 kinase and PDGFR kinase. A selective c-kit inhibitor has the ability to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. The ability to selectively target c-kit with a compound of the disclosure or pharmaceutically acceptable salt thereof provides advantages in terms of improved potency, less off-target activity and an increased probability of clinical success in comparison with a non-selective compound or salt.

[0022] Some compounds of the disclosure are inhibitors of KIT exon 9 and / or 11. Mutations in exon 9 and 11 of KIT are primary driver mutations in -10% of gastrointestinal tumors, and high dose imatinib, a KIT ex9 / l 1 inhibitor, has been shown to be an effective treatment option.

[0023] In a first aspect, the compound or a pharmaceutically acceptable salt thereof of the disclosure isCompound 1

[0024] In a second aspect, the compound or a pharmaceutically acceptable salt thereof of the disclosure isCompound 2

[0025] In a third aspect, the compound or a pharmaceutically acceptable salt thereof of the disclosure is:Compound 3

[0026] The present disclosure is directed to i) novel crystalline forms of Compounds (I)-(III), including unsolvated forms, solvated forms, amorphous forms, and crystalline forms and ii) methods of use and preparation of the crystalline forms of Compounds (I)-(III).

[0027] As used herein, “crystalline” refers to a solid having a crystal structure wherein the individual molecules have a highly homogeneous regular three dimensional configuration.

[0028] In one aspect, the present 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.

[0029] 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 present disclosure.

[0030] 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.

[0031] Crystalline Forms of Compound (I)

[0032] In one embodiment, the present disclosure provides a crystalline form of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.0°, 12.2°, and 20.5° ± 0.2 in 29.

[0033] In another embodiment, the present disclosure provides a crystalline form of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.0°, 9.6°, 12.2°, 16.1°, 20.5°, 25.3°, and 25.8° ± 0.2 in 29.

[0034] In another embodiment, the present disclosure provides a crystalline form of Compound (I), which is characterized by an X-ray powder diffraction pattern which comprises peaks at 4.0°, 9.6°, 10.3°, 12.2°, 13.1°, 16.1°, 20.5°, 25.3°, 25.8° and 26.8° ± 0.2 in 29.

[0035] As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit / risk ratio.

[0036] Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0037] Compounds having one or more chiral centers can exist in various stereoisomeric forms, z.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0038] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by 7?" or “S”) or structure (e.g, the configuration is indicated by “wedge”bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%

[0039] ‘Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0040] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or 7?". the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0041] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0042] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0043] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0044] 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.

[0045] 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. Non-limiting 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, granulocytemacrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor a (TNFa), and chemokines including CCL-2, CCL-3, CCL-5, and CXCL8.

[0046] Compounds 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, burningwheals 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.

[0047] 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.

[0048] 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 diarrheaprominent 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.

[0049] 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.

[0050] Compounds 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.

[0051] Compounds of the disclosure can be administered in combination with another agent. In one aspect, compounds 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, compounds of the disclosure are administered in combination with one or more asthma agents such as montelukast and zafirlukast.

[0052] In another aspect, compounds 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, compounds of the disclosure can be administered with anti-IgE monoclonal antibodies such as ligelizumab and UB-221 . Compounds 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 compound of the disclosure and agent can be coadministered or administered in alternating regimen. In some aspects, compounds of the disclosure can be administered with antihistamines. 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, andrupatadine. In some aspects, compounds of the disclosure can be administered in combination with an MRGPRX2 inhibitor. Examples of MRGPRX2 inhibitors are EP-262 and EVO-756.

[0053] In some aspects, compounds of the disclosure are administered to a subject in need thereof. In some aspects, compounds of the disclosure are administered as a pharmaceutical formulation, wherein the compound is combined with one or more pharmaceutically acceptable excipients or carriers. Thus, in some aspects, disclosed herein are compositions comprising at least one entity compound of the disclosure and pharmaceutically acceptable salts thereof and optionally further comprising at least one pharmaceutically acceptable excipient.

[0054] The compounds of the disclosure or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

[0055] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, 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.

[0056] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;(13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0057] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0058] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the disclosure, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0059] Suspensions, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0060] Ointments, pastes, creams and gels may contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0061] Powders and sprays can contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0062] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount ofcompound of the disclosure or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0063] Dosage forms for the topical or transdermal administration of a compound of this disclosure or pharmaceutically acceptable salts thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The compound of the disclosure may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0064] When the compounds of the disclosure or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of compound of the disclosure in combination with a pharmaceutically acceptable carrier.

[0065] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracap sularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

[0066] Actual dosage levels of the compounds of the disclosure 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.

[0067] The term “effective amount” means an amount when administered to the subject (or more specifically, a 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 compound or pharmaceutically acceptable salt thereof 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 compound of the disclosure 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 determineappropriate 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 a compound of the disclosure or a pharmaceutically acceptable salt thereof 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 the compounds of the disclosure 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.

[0068] In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0069] 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.

[0070] 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.

[0071] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of compound of the disclosure 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 salinesolutions, 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, hydroxymethy cellulose, 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 compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0072] 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.

[0073] The compounds of the disclosure can be prepared according to the synthetic methods.

[0074] The invention is illustrated by the following examples, which are not intended to be limiting in any way.EXEMPLIFICATIONAbbreviationsAbbreviations and acronyms used herein include the following:Aq. means aqueous;Boc means tert-butoxy carbonyl;Bu2Sn(OAc)2 means dibutyltin diacetate;CS2CO3 means caesium carbonate;CU(OAC)2 means copper diacetate; d means doublet; dd means doublet of doublets;DCM means di chloromethane;DMAP means N,N-dimethylpyridin-4-amine;DMF means N,N-dimethylformamide;DMSO means dimethylsulfoxide;DMSO-de means trideuterio(trideuteriomethylsulfinyl)methane;EDCI means l-Ethyl-3-(3 ' -dimethylaminopropyl)carbodiimide;EtOAc means ethyl acetate;EtOH means ethanol;HPLC means high performance liquid chromatography;LCMS means liquid chromatography mass spectrometry;LiHMDS means lithium bis(trimethylsilyl)amide; m means multiplet;MeCN means acetonitrile;MeOH means methanol;MS m / z means mass spectrum peak;NaOH means sodium hydroxide;NaOMe means sodium methoxide;Na2SC>4 means sodium sulphate;NHs means ammonia;NMR means nuclear magnetic resonance;PE means petroleum ether;Pd(dppf)C12 means 1 1 J '-bis(diphcnylphosphino)fcrroccnc |dichloropalladiiim(II):PVP-VA64 means copolymer of 1 -vinyl -2 -pyrrolidone and vinyl acetate in a ratio of 6:4 by mass; rt means room temperature; s means singlet;SFC means supercritical fluid chromatography; t means triplet; tt means triplet of triplets;TFA means trifluoroacetic acid;THF means tetrahydrofuran;TLC means thin layer chromatography;TMEDA means tetramethylethylenediamine;TMSNs means trimethylsilyl azide;Preparation of IntermediatesIntermediate 1

[0075] methyl (S)-5-(l-(2-hydroxy-3-methoxypropyl)-3-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carboxylate (Intermediate 1)

[0076] Step 1: Synthesis of (S)-l-methoxy-3-(3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxahorolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol compound and (S)-l-methoxy-3-(5-methyl-4- ( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxahorolan-2-yl)-lH-pyrazol-l -yl)propan-2-ol:A mixture of 3 -methyl -4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (10.0 g, 48.1 mmol), (S)-2-(methoxymethyl)oxirane (5.1 g, 58 mmol) and CS2CO3 (15.6 g, 48.1 mmol) in DMF (80 m ) was stirred at 100°C for 3 h. The solvent was evaporated and the residue was purified by silica gel column eluting with 5% MeOH in DCM to afford the title compounds (10.4 g, 73.1 %) as a yellow solid. LCMS: m / z = 297 [M+H]+.

[0077] Step 2: Synthesis of methyl (S)-5-(l-(2-hydroxy-3-methoxypropyl)-3-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylate and methyl (S)-5-(l-(2-hydroxy-3- methoxypropyl)-5-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylate:A mixture of (S)-l-methoxy-3-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propan-2-ol compound and (S)-l-methoxy-3-(5-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol (10.4 g, 35.29 mmol), methyl 5- bromopyrazolo[l,5-a]pyridine-3-carboxylate (9 g, 35.29 mmol), Pd(dppf)C12 (256 mg, 0.35 mmol), CS2CO3 (11.5 g, 35.29 mmol) in dioxane (100 mb) and H2O (20 mb) was stirred at 100°C for 3 h. Concentrated to dryness. The residue was purified on silica gel column to afford title compounds (9.7 g, yield: 80%) as a yellow solid. LCMS: m / z = 345 [M+l],

[0078] Step 3: Synthesis of methyl (S)-5-(l-(2-hydroxy-3-methoxypropyl)-3-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylate (Intermediate 1):The mixture of products from step 2 was purified by prep achiral SFC (Torus 2-PIC OBD, 3* 15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeCN:MeOH=4: 1 (20 mM NHs.MeOH) at 60 mL / min; Gradient: isocratic 16% B, to afford, Peak 1, methyl (S)-5-(l-(2-hydroxy-3- methoxypropyl)-5-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylate LCMS m / z = 345 [M+H]+; 'HNMR (400 MHz, DMSO-de) 5 8.86 (d, 1H), 8.42 (s, 1H), 8.00 (d, 1H), 7.90 (s, 1H), 7.28 (dd, 1H), 5.18 (d, 1H), 4.23 - 3.95 (m, 3H), 3.84 (s, 3H), 3.42 - 3.27 (m, 5H), 2.51 (s, 3H) and title compound, 2.8 g and Peak 2, the title compound (2.5 g) as an off-white solid.LCMS m / z = 345 [M+H]+; 'H NMR (400 MHz, DMSO-de) 58.84 (d, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.30 (dd, 1H), 5.20 (d, 1H), 4.19 - 4.09 (m, 1H), 4.00 (q, 2H), 3.84 (s, 3H), 3.30 (d, 4H), 3.17 (d, 1H), 2.44 (s, 3H).Intermediate 2

[0079] 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoroaniline (Intermediate 2)

[0080] Step 1: Synthesis of 5-(4-chloro-2-fluorophenyl)-2H-tetrazole:A mixture of 4-chloro-2 -fluorobenzonitrile (280 g, 1.8 mol) and «-Bu2Sn(OAc)2 (632 g, 1.80 mol) in toluene (1.4 L) was degassed and purged with N2. Using a flow chemistry system with Erida and / or Rongbai pumps, this mixture was pumped at 6.8 mL / min and combined with a pumped solution (flow rate 6.8 mL / min) of TMSN3 (415 g, 3.6 mol) in toluene (1.4 L). The combined solution was reacted in a PFA reactor (136 m , 3.18 mm coil) at 65 °C with a residence time of 10 mins. The reaction solution was collected, maintained at 65°C overnight, then cooled to 20°C and diluted with water (100 m ). The mixture was filtered and the filter cake washed with toluene (3 x 450 mb). The filter cake was dried under vacuum to afford the title compound as a white solid, 300 g, 83.5%. LCMS m / z = 192 [M+H]+

[0081] Step 2: Synthesis of 5-(4-chloro-2fluorophenyl)-2-cyclopropyl-2H-tetrazole:For an initial batch, cyclopropylboronic acid (69.21 g, 0.705 mol), followed by sodium methoxide (21.8 g, 0.403 mol), trimethylethylene diamine (117 g, 1.01 mol) and CU(OAC)2 (36.6 g, 0.201 mol) were added sequentially to a solution of the compound from step 1 (40.0 g, 0.201 mol) in dioxane (0.4 L) and the reaction mixture stirred at 80°C for 12 h. The mixture was cooled to room temperature, additional cyclopropylboronic acid (17.3 g, 0.20 mol) was added and the reaction mixture stirred for 12 h at 80°C. The mixture was cooled to room temperature, additional cyclopropylboronic acid (17.3 g, 0.20 mol) was added and the reaction mixture stirred for 24 h at 80°C before cooling to room temperature. For a second batch, cyclopropylboronic acid (302 g, 3.5 mol), followed by NaOMe (109 g, 2.01 mol), TMEDA (585 g, 5.04 mol) and Cu(OAc)2 (183 g, 1.01 mol) were added sequentially to a solution of the compound from step 1 (200 g, 1.01 mol) in dioxane (2.0 L) and the reaction mixture stirred at 80°C for 12 h. The mixture was cooled to rt, additional cyclopropylboronic acid (43.2 g, 0.5 mol) was added and the reaction mixture stirred for 12 h at 80°C. The mixture was cooled to rt, additional cyclopropylboronic acid (43.2 g, 0.5 mol) was added and the reaction mixture stirred at rt for 24 h. The mixture was filtered, the filtrate diluted with water (1.5 L) and the mixture extracted with EtOAc (2 L x 3). The combined organic extracts were washed with IM NaOH (2 L), dried over Na2SC>4, filtered and the filtrate evaporated in vacuo to afford the title compound, crude, 350 g as a brown solid. The crude was dissolved in EtOH (1 L), water (560 mb) was added dropwise and the mixture stirred for 1 h. The mixture was filtered and the filter cake dissolved in DCM (2 L). The aqueous solution was dried over Na2SC>4, filtered and the filtrate evaporated under reduced pressure to give the title compound, 153 g as a brown solid, 41.2%. LCMS m / z = 239 [M+H]+

[0082] Step 3: Synthesis of 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-2H-tetrazole:A solution of the compound from step 2 (153 g, 641 mmol) was dissolved in H2SO4 (765 mL) at 20°C. Using a flow chemistry system with Erida and / or Rongbai pumps, this solution was pumped at 6.8 mL / min and combined with a pumped solution (flow rate of 6.8 mL / min) of KNO3 (68. 1 g, 673 mmol) and H2SO4 (765 mL) at 20 °C. The combined solution was reacted in a PFA reactor (68 mL, 3.18 mm coil) at 25°C, with a residence time of 5 min. The reaction solution was collected and poured into ice / water (2 L) at 0°C. The resulting mixture was fdtered, the fdter cake washed with water (200 mL x 2) and then dissolved in DCM (3 L). This organic solution was dried over Na2SC>4, fdtered and the fdtrate evaporated under reduced pressure to give the title compound (160 g, 85%). LCMS m / z = 284 [M+H]+.

[0083] Step 4: Synthesis of 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4fluoroaniline (Intermediate 2): 4,4'-Bipyridine (441 mg, 2.82 mmol) was added to a solution of the compound from step 3 (160 g, 564 mmol) in DMF (1.12 L) at 20°C. Using a flow chemistry system with Erida and / or Rongbai pumps, this mixture was pumped at 11.8 mL / min and combined with a pumped solution of tetrahydroxydiboron (152 g, 1.69 mol) in DMF (2.08 L) (flow rate of 15.4 mL / min) at 20°C. The combined solution was reacted in a PFA reactor (136 mL, 3.18 mm coil) at 20°C, with a residence time of 5 min. The completed reaction solution was diluted with H2O (IL) and half-saturated NaHCCf solution (2 L) and the mixture stirred for 10 min and allowed to stand for 15 min. The layers were separated, the aqueous phase was extracted with EtOAc (2 L), the combined organic phases were washed with brine (2 L x 2) and concentrated in vacuo. The resulting brown solid (160 g) was suspended in EtOH (500 mL), the mixture warmed to 60°C, and the solution stirred for 30 min, then cooled to rt. The mixture was triturated with EtOH for Ih, fdtered and the fdter cake dried under reduced pressure to give the title compound as a brown solid, 102 g, 62.7%. LCMS m / z = 254 [M+H]+Example 1

[0084] (S)-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)-5-(l-(2 -hydroxy-3-methoxypropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (Compound 1)

[0085] To a mixture of Intermediate 1 (1.1 g, 3.18 mmol) and Intermediate 2 (1.6 g, 6.36 mmol) in toluene (80 mL) was added LiHMDS (12.7 mL, 12.7 mmol, 1 M in THF) at 0°C and the reaction mixture was stirred at 25 °C overnight. The mixture was quenched with water (50 mL), extracted with EtOAc (3x50 mL) and the combined organic phase was washed with brine. The organic layer was dried over Na2SC>4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (883 mg, 46%) as a light pink solid. LCMS: m / z = 566 [M+H]+; 1H NMR (4OO MHz, DMSO-de) 5 9.93 (s, 1H), 8.83 (dd, 1H), 8.77 (s, 1H), 8.30 (d, 1H), 8.26 (dd, 1H), 8.22 (s, 1H), 7.85 (d, 1H), 7.28 (dd, 1H), 5.19 (d, 1H), 4.52 (tt, 1H), 4.19 - 4.08 (m, 1H), 4.05 - 3.92 (m, 2H), 3.36 - 3.23 (m, 5H), 2.41 (s, 3H), 1.47 - 1.34 (m, 2H), 1.34 - 1.25 (m, 2H). The XRPD of Compound 1 is shown in Figure 1. The 20 (two theta) angle of Compound 1 is listed in Table 1.Instrument type: Bruker D2 Phaser X-ray diffractometer Detector: PSD LynxEye X-ray wavelength: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°Table 1Example 2

[0086] (S)-l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)carbamoyl)pyrazolo [ 1 ,5 -a]pyridin-5 -y 1) -3 -methyl- IH-pyrazol- 1 -yl)-3 - methoxypropan-2-yl dihydrogen phosphate (Compound 2)

[0087] Step 1: Synthesis of (S)-dibenzyl (l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5- yl)-4fhiorophenyl)carbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-3-methyl-lH-pyrazol-l-yl)-3- methoxypropan-2-yl) phosphate:Dibenzyl diisopropylphosphoramidite (1.62 g, 4.68 mmol) was added to a solution of (S)-N-(2- chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)-5-(l -(2 -hydroxy-3 -methoxypropyl)- 3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (883 mg, 1.56 mmol) and 5- methyl-lH-tetrazole (394 mg, 4.68 mmol) in DCM (25 mb) at 0°C and the reaction mixture was stirred at rt for 10 h. The reaction was quenched with H2O2 (6 mL, 30% aq) and the mixture stirred at 25°C for 2 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mLx2), the organic layer was dried with Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column (10% MeOH in DCM) to afford the title compound (600 mg, 46%) as an off-white solid. LCMS m / z = 826 [M+H]+

[0088] Step 2: Synthesis of ((S)-l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)carhamoyl)pyrazolo[l,5-a]pyridin-5-yl)-3-methyl-lH-pyrazol-l-yl)-3- methoxypropan-2-yl dihydrogen phosphate:Pd / C (60 mg) was added to a solution of the compound from step 1 (600 mg, 726 pmol) in MeOH (15 mL) and the reaction mixture was stirred at 25°C overnight under H2. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC with DCM: MeOH= 30: 1 and the product then re -crystallized from DCM:MeOH:MTBE (1: 1:3) to afford the title compound (165.3 mg, 35%) as an off-white solid. LCMS: m / z = 646 [M+H]+; 1H NMR (400 MHz, DMSO-de + DC1) 5 8.85 - 8.73 (m, 2H), 8.37 - 8.22 (m, 2H), 8.18 (s, 1H),7.86 - 7.80 (m, 1H), 7.28 (d, 1H), 4.60 - 4.56 (m, 1H), 4.51 - 4.47 (m, 1H), 4.36 - 4.22 (m, 2H), 3.49 - 3.33 (m, 2H), 3.29 (s, 3H), 2.42 (s, 3H), 1.38 (m, 2H), 1.31 (m, 2H).Example 3

[0089] (S)-l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)carbamoyl)pyrazolo [ 1 ,5 -a]pyridin-5 -y 1) -3 -methyl- IH-pyrazol- 1 -yl)-3 - methoxypropan-2-yl L-valinate (Compound 3)

[0090] Step 1: Synthesis of (S)-l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fhiorophenyl)carbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-3-methyl-lH-pyrazol-l-yl)-3- methoxypropan-2-yl ( tert-butoxycarbonyl) -L-valinate :EDCI (65.6 mg, 423 pmol) and DMAP (51 .6 mg, 423 pmol) were added slowly to a mixture of (S)-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)-5-(l-(2-hydroxy-3- methoxypropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (200 mg, 353 pmol) and (tert-butoxycarbonyl)-L-valine (91.9 mg, 423 pmol) in DCM (20 m ) at 0°C.The reaction mixture was stirred at 25°C for 3 h. The resulting solution was diluted with water (8 m ), the mixture extracted with DCM (2x20 mb) and the combined organic extracts washed with brine (10 mb). The organic layer was dried over Na2SC>4 and concentrated in vacuo. The crude product was purified by prep-TLC with PE: EtOAc = 1: 1 to give the title compound (150 mg, 56%) as a yellow solid. LCMS m / z = 765 [M+H]+

[0091] Step 2: Synthesis of (S)-l-(4-(3-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)carbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-3-methyl-lH-pyrazol-l-yl)-3- methoxypropan-2-yl L-valinate:

[0092] TFA (1.5 mb) was added to a solution of the compound from step 1 (150 mg, 196 pmol) in DCM (20 mb) and the reaction mixture was stirred at 25°C for 3 h. The resulting solution was concentrated in vacuo, the residue was diluted with DCM (20 mb) and water (5 mb), and the pH adjusted to 7 with NH3.H2O. The mixture was extracted with DCM (2x20 mb), the combined organic extracts washed with brine (10 mb), dried over Na2SC>4 and concentratedin vacuo. The crude product was purified by prep-HPLC: XBridge Prep OBD C18 Column, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCC>3+0.05% NH3H2O), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 42% B to 72% B in 10 min; to give the title compound (63.9 mg, 49%) as a white solid. LCMS m / z = 665 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 9.93 (s, 1H), 8.84 (dd, 1H), 8.77 (s, 1H), 8.33 - 8.23 (m, 3H), 7.85 (d, 1H), 7.26 (dd, 1H), 5.33 - 5.24 (m, 1H), 4.54 - 4.52 (m, 1H), 4.35 (dd, 1H), 4.29 (dd, 1H), 3.55 - 3.43 (m, 2H), 3.28 (s, 3H), 2.39 (s, 3H), 1.86 - 1.69 (m, 2H), 1.47 - 1.34 (m, 2H), 1.37 - 1.25 (m, 2H), 0.76 (t, 6H). The XRPD of Compound 3 is shown in Figure 2.Example 4 - Compounds of the Disclosure Inhibit Wild Type c-Kit in a Biochemical Phospho c-Kit Inhibition Assay

[0093] The ability of compounds of the disclosure (described herein as test compounds) to inhibit autophosphorylation of wild type c-kit was measures using either a PathScan phospho c- kit (Tyr719) sandwich ELISA (CST#7298).

[0094] For the PathScan phospho c-kit (Tyr719) sandwich ELISA: 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 uL per well using a multichannel pipet. The plate was allowed to incubate at 37°C in a humidified tissue culture incubator for 4 hours.

[0095] After 4 hours of incubation, each well was dosed with 6.25 uL 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 uL / 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 uL / 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.

[0096] 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 uL / well of reconstituted Detection Antibody was added to each well, the plate sealed with an adherent cover, and incubated at 37°Cfor 1 hour. The wash procedure was repeated and 100 uL / 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 uL / 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 uL / 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.

[0097] 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 IC50 was calculated using a 4-parameter logistic nonlinear regression. The results are shown in Table 2.Example 5 - Compounds of the Disclosure Have Various Levels of Solubility in a FaSSIF Assay

[0098] The ability of compounds of the disclosure to dissolve in Fasted State Simulated Intestinal Fluid (FaSSIF) was measured using the following protocol.

[0099] FaSSIF was prepared by dissolving 0.420 g of NaOH, 3.438 g of NaftPCL and 6.186 g of NaCl into about 900 mL ultrapure water and adjusting the pH of the solution to 6.5 with 1 N NaOH or 1 N HC1. The solution was diluted with ultrapure water to 1000 mL at room temperature to create buffer A.

[0100] To 500 mL of buffer A was added 2.240 g of FaSSIF powder and the suspension was stirred until the powder is completely dissolved. This solution was diluted with another 1000 mL of buffer A at room temperature to give the final FaSSIF solution used for solubility experiments.

[0101] Procedure for Apparent Solubility Determination: 30 pL of stock solution (10 mM) of each sample was placed in order into their proper 96-well rack. 970 pL of FaSSIF was added into each vial of the cap-less solubility sample plate. The assay was performed in duplicate. One stir bar was added to each vial and sealed using a molded PTFE / Silicone plug. The solubility sample plate was then transferred to the Eppendorf Thermomixer Comfort plate shaker and shaken at 25 °C at 1100 RPM for 2 hours. After completion of the 2 hours, the stir bar was removed using a big magnet and the samples were transferred from the solubility sample plate into the filter plate. Using the Vacuum Manifold, all the samples were filtered. An aliquot of 10 pL was taken from the filtrate followed by addition of 990 pL of a mixture of H2O and acetonitrile containing aninternal standard (1: 1). The dilution factor could be changed according to the solubility value and the LC / MS signal response.

[0102] Preparation of 3 uM Standards (STD): From the 10 mM DMSO STD plate, 30 pL was transferred into the remaining empty plate, 970 pL of DMSO was added to that plate to achieve an STD concentration of 300 pM. From the 300 pM DMSO STD plate, 10 pL was transferred into the remaining empty plate, and 990 pL of a mixture of H2O and acetonitrile containing internal standard (1: 1) was added to that plate to have a final STD concentration of 3 pM. The concentration of the standard sample could be changed according to the LC / MS signal response.

[0103] Data Analysis: All calculations are carried out using Microsoft Excel. The samples were analyzed and quantified against the standard of known concentration using LC / MS / MS. The solubility of the test compound was calculated as follows:

[0104] [Sample] = Area Ratio sample x DF sample x [STD] / Area Ratio STD

[0105] DF is defined as the dilution factor. DF is 100. [STD] is 3 pM. Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated. The results are shown in Table 2.Example 6 - Compounds 2 and 3 Convert Into Compound 1 Following Oral Dosing

[0106] In order to effectively orally administer Compound 2, the phosphate prodrug must be formulated such that Compound 1 releases at a rate that does not result in significant in vivo precipitation. Specifically, after oral administration, Compound 1 is released from Compound 2 through the intestinal metabolic cleavage of the phosphate moiety of Compound 2. The in vivo rate of release of Compound 1 relative to its intestinal absorption rate was not known. If the release of Compound 1 occurs too rapidly, it may result in significant undesired precipitation of Compound 1 before the compound can be absorbed.

[0107] To assess the release rate of Compound 1, Compound 2 was evaluated in two different formulations: (1) phosphate buffered saline (PBS) only and (2) PBS with 5% (v / v) Vitamin E TPGS (D-a-Tocopheryl Polyethylene Glycol 1000 Succinate). The use of PBS uniformly dispersed Compound 2 in both formulations, which helped to facilitate consistent dosing of the compound. The addition of 5% (v / v) Vitamin E TPGS in formulation (2) can be used to reduce the risk of precipitation in vivo| If the exposure is greater from the Vitamin E TPGS formulation (2) than formulation (1), then a precipitation resistant formulation is recommended for effective administration of Compound 2.

[0108] The in vivo rat PK results following oral administration of Compound 2 demonstrated that a precipitation resistant formulation is indeed recommended, as the AUClast of Compound 1 in the Vitamin E TPGS containing formulation (2) of 786 h*ng / mL per mpk was greater than the AUClast of Compound 1 in the PBS only formulation ( 1) of 481 h*ng / mL per mpk. Thus, these results confirm the need for a precipitation resistant formulation.

[0109] A follow up experiment was designed and conducted to determine whether: i) a formulation containing less than 5% Vitamin E TPGS could provide higher oral exposure than the PBS only formulation, and ii) a formulation containing PVP-VA64 could provide higher oral exposure than the PBS only formulation. Compound 2 was dosed orally in rats in a PBS with 1% (v / v) Vitamin E TPGS formulation as well as in a PBS with 1% (w / v) PVP-VA64 formulation. The PBS with 1% (v / v) Vitamin E TPGS formulation gave a Compound 1 AUClast of 557 h*ng / mL per mpk whereas the PBS with 1% (w / v) PVP-VA64 formulation gave a Compound 1 AUClast of 548 h*ng / mL per mpk. These in vivo rat PK results demonstrate that lower levels of either Vitamin E TPGS or PVP-VA64 in the formulation provide higher oral exposure of Compound 1 than the PBS only formulation when administered as the phosphate prodrug Compound 2. In other work related to the formulation optimization for Compound 2, Vitamin E TPGS was found to lower in vivo exposure compared to a PBS only formulation, therefore in consideration of applications for other doses, use in other species and translation to a solid oral formulation, 1% (w / v) PVPVA-64 in PBS was selected as the optimal vehicle for dosing Compound 2 and Compound 3.

[0110] The ability of Compounds 2 and 3 to convert into Compound 1 following oral dosing was assessed by running pharmacokinetic experiments.

[0111] Animals: Male Sprague-Dawley rats (6-8 weeks old, body weight 200-300 g) were kept in plastic cages with free access to standard rodent diet (Keaoxieli, Beijing, China) and water. The animals were maintained at a temperature of 20-25 °C with a 12-hour light / dark cycle and relative humidity of 40%-70% before the experiment.

[0112] Pharmacokinetics in rats: The cannulation of the jugular vein was performed before the study. Test compound dissolved in a suitable formulation (e.g. 10% dimethylsulfoxide, 10% Solutol and 80% “(2-Hydroxypropyl)-P-cyclodextrin (20%HP-[3-CD) in water” or phosphobuffered saline with 1% poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64)) was administered orally via oral gavage for the oral (PO) arm, and test compound dissolved in a suitable formulation (e.g. 10% dimethylsulfoxide, 10% Solutol and 80% “(2-Hydroxypropyl)-[3- cyclodextrin (20%HP-P-CD) in water”) was injected to the tail vein for the intravenous (IV) arm.

[0113] Blood samples (approximately 0.2 mL each) were collected from the jugular vein at 0 min (as a pre-dose), 5 min (only for IV administration), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h post dose. Following dosing serial blood samples (approximately 0.2 mL blood into tubes containing potassium EDTA as anticoagulant) were collected up to 24 h after the start of dosing via a surgically implanted jugular vein cannula. At the end of the study, the rats were euthanized by inhalation of rising concentrations of carbon dioxide. Blood was centrifuged to yield plasma. Plasma samples were stored at -75°C prior to analysis.

[0114] Plasma sample analysis: Plasma samples (50 pL for rat) were extracted using protein precipitation with 200 pL of acetonitrile containing an analytical internal standard. An aliquot of the supernatant was analyzed by reverse phase LC-MS / MS. Samples were assayed against calibration standards prepared in control plasma and the assay was qualified through inclusion of quality control (QC) samples. When Compounds 2 3 were used in an experiment, the concentration of both the Compounds 2 and 3 and the desired Compound 1 were analyzed.

[0115] Data analysis: Standard methods were used to calculate the pharmacokinetic parameters, such as the total area under the plasma concentration-time curve from time 0 to infinity (AUCO-t) and terminal half-life, using non-compartmental analysis (WinNonlin). The peak plasma concentration (Cmax) and time to reach Cmax (Tmax) were determined directly from the experimental data.

[0116] Animal care: All the procedures related to animal handling, care, and the treatment in these in vivo studies were performed according to Animal care and Use Application (AUP) approved by an Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). IACUC policies were in compliance with laws and regulations of the local government for animal research, and also in compliance with the guidelines of the Guide for the Care and Use of Laboratory Animals.

[0117] Table 2 shows the activity of the exemplified compounds in the pKIT assay according to the ELISA assay and solubility in the FaSSIF assay described herein.Table 2

[0118] Table 3 shows the total area under the plasma concentration-time curve in rats derived from pharmacokinetic experiments described herein calculated for Compound 1 from time 0 to infinity (AUCO-t) upon dosing compounds described herein.Table 3Example 7 - Inhibition of Exon 11 by Compound 1

[0119] 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 was 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 is used to assess levels of phospho KIT. Data was normalized to 0% and 100% inhibition controls and the IC50 is calculated using Four Parameter Logistic IC50 curve fitting.Compound 1 has an IC50 = 0.4 nM.

Claims

CLAIMSWhat is claimed is:

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 12 A compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 23 A compound or a pharmaceutically acceptable salt thereof, wherein the compound isCompound 34. A pharmaceutical composition comprising a compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

5. The pharmaceutical composition of claim 4 comprising a compound of claims 1 or 2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.6 The pharmaceutical composition of claim 5, comprising at least one pharmaceutically acceptable carrier that is PVP-VA64.7 A method of treating a subject suffering from a disease or disorder mediated by wild type c- kit kinase, comprising administrating to the subject an effective amount of a compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 4-6.8 The method of claim 7, 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.9 The method of claim 8, wherein the disease or disorder is chronic urticaria.10 The method of claim 9, wherein the chronic urticaria is chronic spontaneous urticaria (CSU).11 The method of claim 10, wherein the subject is resistant to antihistamine treatment (i.e., the subject remains symptomatic despite antihistamine treatment).12 A method of inhibiting wild type c-kit kinase in a subject in need thereof, comprising the step of administrating to the subject an effective amount of a compound of any one of claims 1-3or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 4-6.

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