Deuterated inhibitors of bruton's tyrosine kinase

Abstract

The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising the compound; and methods of treating the indications disclosed herein.

Description

DEUTERATED INHIBITORS OF BRUTON'S TYROSINE KINASEFIELD OF THE DISCLOSURE

[0001] Described herein are a deuterated compound and pharmaceutically acceptable salts thereof, methods of making the same, pharmaceutical compositions and medicaments containing such compound, and methods of using such compound and compositions to inhibit the activity of Bruton’s Tyrosine Kinase (BTK).BACKGROUND

[0002] BTK, a member of the Tec family of non-receptor tyrosine kinases, is a signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. BTK plays a well-documented role in the B-cell signaling pathway linking cell surface B-cell receptor stimulation to downstream intracellular responses. BTK is also a regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, BTK exerts a physiological effect through other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediate TNF-a production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. BTK has an ATP -binding pocket with high similarity to Src-family kinases, such as lymphocyte-specific protein tyrosine kinase (Lek) and Lyn.

[0003] BTK also plays a central role in other immunological processes such as cytokine production by neutrophils, mast cells and monocytes, degranulation of neutrophils and mast cells as well as differentiation / activation of osteoclasts.SUMMARY

[0004] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

[0005] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of Formula (I) and a pharmaceutically acceptable carrier.

[0006] In another aspect, the present disclosure provides a method of treating or preventing indolent systemic mastocytosis (ISM) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present disclosure provides a method of treating or preventing eosinophilic esophagitis (EoE) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present disclosure provides a method of treating or preventing mast cell activation syndrome (MCAS) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present disclosure provides a method of treating or preventing a food allergy in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a method of treating or preventing an ophthalmic condition in a human subject in need thereof comprising topically administering to an eye of the human subject a pharmaceutical composition comprising the compound of Formula (I). In some embodiments, the ophthalmic condition is dry eye disease (DED), allergic conjunctivitis (AC), or geographic atrophy (GA).

[0011] In one embodiment, the compounds and pharmaceutical composition thereof described herein are for the treatment of cancer such as brain, lung, colon, epidermoid, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, uterine, rectal, esophageal, testicular, gynecological, thyroid cancer, melanoma, hematologic malignancies such as acute myelogenous leukemia, multiple myeloma, chronic myelogenous leukemia, myeloid cell leukemia, glioma, Kaposi's sarcoma, or any other type of solid or liquid tumors.

[0012] The disclosure also relates to the use of compounds for the preparation of a medicament for the treatment of hyperproliferative diseases related to the hyperactivity of BTK as well as diseases modulated by the BTK cascade in mammals, or disorders mediated by aberrant proliferation, such as cancer or hyperactivity of B cells, mast cells, neutrophils and monocytes such in inflammatory conditions.

[0013] In some embodiments, the disclosure relates to a method of treating a malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic graft-versus-host disease (cGVHD), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis in a human subject comprising the step of administering to the human subject a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows that the BTK inhibitor Compound (II) is metabolized to pharmacologically inactive Compound III, primarily by the enzyme aldehyde oxidase 1 (AOX1), and not by more common cytochrome P450 (CYP) isoenzymes.

[0015] FIG. 2 shows that Compound (II) is metabolized by human liver microsomes plus NADPH, however Compound (III) is not appreciably formed (Upper panels). Compound (II) is metabolized by recombinant human CYP3A4, however Compound (III) is not formed (Lowerpanels). Compound (II) metabolism is inhibited by the pan CYP inhibitor aminobenztriazole (ABT) indicating the in vitro formation of metabolites other than Compound (III).

[0016] FIG. 3 shows that Compound (II) is metabolized to Compound (111) by human liver S9 containing cytosolic AOX1 (top panels) and by recombinant human AOX1 (lower panels) and Compound (II) metabolism and Compound (III) formation is inhibited by the AOX1 inhibitor icotinib.

[0017] FIG. 4 shows mean plasma concentration versus time data for Compound (II) and Compound (III) in healthy subjects (N=26) that received a 150 mg dose of Compound (II) with a low fat meal shows that the mean plasma exposure of the inactive metabolite, Compound (III), is higher than Compound (II).

[0018] FIG. 5 shows relative in vitro activity of Compound (II) and Compound (III) against the BTK target showing more than 1000-fold lower potency of Compound (III).DETAILED DESCRIPTION

[0019] While preferred embodiments of the disclosure are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the disclosure. Various alternatives to the described embodiments may be employed in practicing the disclosure.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0021] The term “amount effective to” or “effective amount” or “therapeutically effective amount” or “amount sufficient” refers to that amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients as described herein that is sufficient to affect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g. the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, and other factors which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, (e.g. the reduction of platelet adhesion and / or cellmigration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0022] The term “Compound (I)” or “Compound I” refers to the compound of Formula (I); “Compound (II)” or “Compound II” refers to the compound of Formula (II); “Compound (III)” or “Compound III” refers to the compound of Formula (III).

[0023] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of signs or symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0024] The terms “QD,” “qd,” or “q.d.” means quaque die, once a day, or once daily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day, or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die, three times a day, or three times daily. The terms “QID,” “qid,” or “q.i.d.” mean quater in die, four times a day, or four times daily.

[0025] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0026] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, and absorption delaying agents. The use of such media and agents for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional media or agent is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients can also be incorporated into the described compositions.

[0027] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that “consist of’ or “consist essentially of’ the described features.

[0028] The effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI etal., J Pharm Sci, 1975, 64:367- 91; Foster, AB, Adv Drug Res 1985, 14: 1-40; Kushner, DJ el al., Can J Physiol Pharmacol 1999, 79-88; Fisher, MB etal., Curr Opin Drug Discov Devel, 2006, 9: 101-09). The reported results of those studies measuring deuterium substitution's effect on overall metabolic stability are variable and unpredictable. For some compounds, deuteration decreased metabolic clearance in vivo. For others, there was no change in metabolic clearance. Still others demonstrated increased metabolic clearance. The variability in phenotypic outcomes related to deuterium isotope effects in drug candidates has led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting a particular metabolic pathway.

[0029] Thus, deuterium isotope effects on a drug's metabolism are not predictable, even when deuterium atoms are incorporated at known sites of metabolism. Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug. Clearly, there are other factors that can combine to influence whether a deuterium modification results in tangible benefits in the metabolism of the deuterated drug product, relative to the protonated molecule. Only by preparing and testing a deuterated drug can one determine if and how much the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto JM, etal., J. Med. Chem. 1991, 34, 2871-76.

[0030] It is estimated that more than half of the marketed drugs are metabolized by enzymes in the cytochrome P450 (CYP) family (Di Martino, et al., Nat Rev Drug Discov 22, 562-584

[2023] ). Further, Evobrutinib, an analogue of the compound of Formula (II), lacking the piperidine fluoro substituent, is primarily metabolized by the microsomal cytochrome P450 (CYP) family of enzymes, not by cytosolic aldehyde oxidase 1 (Scheible et al., Xenobiotica, 2023, 53[8-9]:547-558). Accordingly, during in vitro metabolism studies of Compound (II), it was anticipated that the compound is metabolized more likely by the microsomal cytochrome P450 (CYP) family of enzymes. Unexpectedly, the major human metabolite, Compound (III), was not formed by CYP enzymes (FIG. 2) and it was instead discovered that Compound (II) was metabolized primarily by cytosolic aldehyde oxidase 1 (FIG. 3) to produce Compound (III).

[0031] As the metabolism of Compound (II) to Compound (III) is the dominant metabolic pathway in the overall in vivo human disposition of Compound (II), a deuterium isotope effect on metabolism of Compound (I) by AOX1 would lead to higher pharmacokinetic exposure and possibly a longer half-life of Compound (I), that can in turn decrease the therapeutically effective dose, or dose frequency, and improve the overall therapeutic efficacy and safety of Compound (I).

[0032] With modern targeted, highly selective, potent, covalent kinase inhibitor drugs like Compound (I), a key factor will be the extent of deuteration necessary to elicit the desired metabolic switch away from an inactive, or nonselective major metabolite. Some drug molecules have metabolism at sites that require multiple deuterium atoms to alter metabolism, such as the - OCDs groups of deutetrabenzazine, that may be subject to O-demethylation in the non-deuterated compound (Di Martino 2023). Physicochemical changes associated with multiple deuterium atoms have the potential to decrease target potency or selectivity in the finely tuned covalent interaction of a targeted covalent drug with its kinase target. Compound (I) has the effective minimum number of deuterons necessary (one) to elicit a metabolism change without a detrimental physicochemical effect of multiple deuterons on potency or selectivity at the BTK target.

[0033] A key factor in discerning the overall impact of a deuterium isotope effect on drug metabolic clearance in vivo is the importance of metabolism at the site of interest, relative to the sum of metabolism at all the other competing sites (Sharma, et al., Drug Metab Dispos.40[3] :625-34

[2012] ). To be rate limiting in drug clearance in vivo, metabolism at the potential site of deuteration also has to be favored over other pathways, as indicated by the abundance of the metabolites from that pathway in plasma relative to the parent drug. Since Compound (III) is the most abundant metabolite of Compound (II) in human plasma and exceeds plasma concentrations of the parent drug, (FIG. 4), replacing the proton with deuterium at the site of metabolism of Compound (II) to Compound (III), has better potential to improve Compound (I) pharmacokinetics and pharmacodynamics in vivo.

[0034] Another key factor in discerning the overall impact of a deuterium isotope effect on drug clearance is whether the metabolite formed from the protonated compound is pharmacologically active or not. Decreased production of a major pharmacologically active metabolite due to a deuterium isotope effect may not result in a meaningful improvement in the efficacy of the compound. However, limiting the production of an inactive or nonselective metabolite and boosting the plasma concentrations of the active parent drug may improve efficacy (Mullard 2022, Nat. Rev. Drug Discov. 21, 623-625). Compound (III) is >1000 fold less active against the BTK target in vitro (FIG. 5), indicating that decreased or slower production of Compound (III) from deuterated Compound (I) will not result in a loss of pharmacological activity at the BTK target.

[0035] The benefit of a deuterium isotope effect on metabolism is an improvement in parent drug PK, which can manifest as a longer half-life ( t’A), and / or an increase in area under the curve (AUC) and maximum concentration (Cmax) of Compound (I) in plasma, relative toCompound (II). Improved parent drug PK is expected to result in a lower dose and / or dose frequency or other benefits that improve overall safety and efficacy in patients.

[0036] In one aspect, the present disclosure provides a compound of Formula (1):or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of Formula (I) and a pharmaceutically acceptable carrier.

[0038] In another aspect, the present disclosure provides a method of treating or preventing indolent systemic mastocytosis (ISM) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0039] In another aspect, the present disclosure provides a method of treating or preventing eosinophilic esophagitis (EoE) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0040] In another aspect, the present disclosure provides a method of treating or preventing mast cell activation syndrome (MCAS) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0041] In another aspect, the present disclosure provides a method of treating or preventing a food allergy in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0042] In another aspect, the present disclosure provides a method of treating or preventing an ophthalmic condition in a human subject in need thereof comprising topically administering toan eye of the human subject a pharmaceutical composition comprising the compound of Formula (I). In some embodiments, the ophthalmic condition is dry eye disease (DED), allergic conjunctivitis (AC), or geographic atrophy (GA).

[0043] In one embodiment, the compound of Formula (I) and pharmaceutical composition thereof described herein are for the treatment of cancer such as brain, lung, colon, epidermoid, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, uterine, rectal, esophageal, testicular, gynecological, thyroid cancer, melanoma, hematologic malignancies such as acute myelogenous leukemia, multiple myeloma, chronic myelogenous leukemia, myeloid cell leukemia, glioma, Kaposi's sarcoma, or any other type of solid or liquid tumors.

[0044] The disclosure also relates to the use of compound Formula (I) for the preparation of a medicament for the treatment of hyperproliferative diseases related to the hyperactivity of BTK as well as diseases modulated by the BTK cascade in mammals, or disorders mediated by aberrant proliferation and inflammatory cell trafficking, such as cancer or hyperactivity of B cells, mast cells, neutrophils and monocytes in inflammatory conditions.

[0045] In some embodiments, the disclosure relates to a method of treating a malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic graft-versus-host disease (cGVHD), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis in a human subject comprising the step of administering to the human subject a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.EXAMPLES

[0046] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to theseexamples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.Example 1: l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl-2-d)amino)methyl)-4- fluoropiperidin-l-yl)prop-2-en-l-one (Formula (I))

[0047] The manufacturing process involves five steps: (1) Exchange of the pyrimidine 1 hydrogen atom with a deuterium atom by reaction with an iridium catalyst; (2) Nucleophilic displacement of a chloride atom on compound 2 by amine 3; (3) Suzuki coupling between chloropyrimidine 4 and boronic acid 5; (4) acidic cleavage of BOC- protective group on compound 6; and (5) A -acylation of compound 7 by using acryloyl chloride 8 to form Formula (I) as shown in Scheme 1.Scheme 1. Synthetic Steps to Formula (I)Step 1: Preparation of Compound 2

[0048] The iridium catalyst is weighed out and dissolved in dry tetrahydrofuran. Pyridine and tricyclohexylphosphine (PCys) and compound 1 are added to the solution. The reaction mixture’s temperature is lowered with liquid nitrogen and is slowly elevated. After warming to ambient temperature, the reaction is stirred under a deuterium gas atmosphere for 4 hours. The reaction mixture is fdtered to afford compound 2.Step 2: Preparation of Compound 4

[0049] Pyrimidine compound 2 and piperidine compound 3 are suspended in 1,4-di oxane and demineralized water. After the addition of potassium carbonate, the reaction is heated to a temperature of 120 ° C. After in-process testing confirms the reaction is complete, the reaction mixture is cooled to an internal temperature of 60°C. Maintaining an internal temperature of at least 50°C, acetonitrile and demineralized water is added and the reaction mixture is cooled to 20°C and is stirred for one hour. The solid-liquid separation of the suspension is carried out and the filter cake is washed with a mixture of deionized water and acetonitrile. The crystals are dried in a vacuum at 50°C to afford compound 4.Step 3: Suzuki Coupling - Preparation of Compound 6

[0050] Chloropyrimidine 4, boronic acid 5 and potassium hydrogen carbonate are suspended in dioxane and deionized water and are heated at a temperature of 120 °C for 60 minutes. The reaction mixture then is cooled to 25 °C and the catalyst Pd(amphos)Ch is added at a temperature of 25 °C. The reaction mixture is heated at 120 °C and kept at reflux for 12 hours when a sample is taken to determine reaction completeness by HPLC.

[0051] Once complete the reaction is cooled to 60 °C, and the organic phase is separated and concentrated. The organic phase is mixed with toluene, demineralised water, potassium hydrogen carbonate and A-acetylcysteine (ACC) and is stirred. The aqueous phase is separated off. The organic phase is stirred again with demineralised water and the aqueous phase is separated off. The organic phase is passed through a 0.2 pm candle filter at 70 °C, and is rinsed with toluene. The filtrate is completely dissolved at 80 °C and is cooled to 35 °C, and is then stirred for 30 minutes. Seed crystals of compound 6 is added and stirring is continued for 60 minutes. The temperature is cooled further to -10 °C for crystallization. After the final crystallization temperature has been reached, the mixture is stirred for at least 30 minutes. The suspension isfiltered using aNutsch Dryer, washed with toluene and dried under vacuum at 50 °C to afford compound 6.Step 4: Protective Group Cleavage - Preparation of Compound 7

[0052] Pyrimidine compound 6 is suspended in water and tetrahydrofuran (THF) in the reaction apparatus. Sulfuric acid is added to the suspension, and the reaction mixture is distilled at reflux until compound 6 has completely reacted by HPLC analysis. The reaction mixture is quenched with sodium hydroxide solution and the aqueous phase is separated off. The organic phase is washed with aqueous sodium chloride solution and then is diluted with THF, and the crude THF solution of compound 7 is used in Step 4 without further purification.Step 5: A-Acylation Reaction - Preparation of the Compound of Formula (I)

[0053] Diisopropylethyl amine (DIPEA) is added to the tetrahydrofuran (THF) solution and the reaction mixture is cooled to -20 °C. A previously prepared solution consisting of THF, DIPEA and acryloyl chloride, which is kept a -35 °C, is added. After metering and subsequent stirring time, the reaction mixture is quenched and is warmed up with sodium chloride solution and the aqueous phase is separated off. Phenothiazine is added to the organic phase as a stabilizer. The organic phase is concentrated by vacuum distillation and then is diluted with ethyl acetate and is filtered through two columns filled with silica gel. In the receiver apparatus, the solution is concentrated by vacuum distillation. Ethyl acetate and water is added and separated. The organic phase is distilled off again under vacuum till the crystallization starts. The resulting suspension is cooled, and the crystals is isolated using a Nutsche filter and is washed with ethyl acetate. The washed crystals is dried under vacuum on the Nutsche filter to afford the compound of Formula (I) with IUPAC name l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl-2- r7)amino)methyl)-4-fluoropiperidin- 1 -yl)prop-2-en-l -one.

Claims

CLAIMS1. A compound of F ormula (I) :or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

3. A method of treating or preventing indolent systemic mastocytosis (ISM) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

4. A method of treating or preventing eosinophilic esophagitis (EoE) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

5. A method of treating or preventing mast cell activation syndrome (MCAS) in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

6. A method of treating or preventing a food allergy in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

7. A method of treating or preventing an ophthalmic condition in a human subject in need thereof comprising topically administering to an eye of the human subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the ophthalmic condition is dry eye disease (DED), allergic conjunctivitis (AC), or geographic atrophy (GA).

9. A method of treating a malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic graft-versus-host disease (cGVHD), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis in a human subject comprising the step of administering to the human subject a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Images