Fluorinated phenylamino compounds and pharmaceutical compositions

Abstract

The present disclosure relates to fluorinated phenylamino compounds, pharmaceutical compositions thereof, and methods of treating a tumor or cancer selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), pancreatic ductal adenocarcinoma (PDAC), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis (TSC), Langerhans cell histiocytosis (LCH), brain tumor, and cancer metastasized to the brain of a patient, comprising administering these pharmaceutical compositions to a patient in need thereof.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 321,043, filed March 17, 2022, which is incorporated herein by reference.

[0002] The present disclosure relates to fluorinated phenylamino compounds, pharmaceutical compositions thereof, and methods of treating a tumor or cancer selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), pancreatic ductal adenocarcinoma (PDAC), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis (TSC), Langerhans cell histiocytosis (LCH), brain tumor, and cancer metastasized to the brain of a patient, comprising administering these pharmaceutical compositions to a patient in need thereof. [Background technology]

[0003] In the tumors and cancers listed above, there is a need to find better treatments because objective responses are rarely complete and disease recurrence after completion of treatment is common. Summary of the Invention

[0004] The following compound [ka] or a pharma- ceutically acceptable salt thereof provided herein.

[0005] The following compound [ka] or a pharma- ceutically acceptable salt thereof provided herein.

[0006] The following compound [ka] or a pharma- ceutically acceptable salt thereof provided herein.

[0007] In one embodiment, the compound is (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester or a pharma- ceutically acceptable salt thereof (e.g., (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester). In another embodiment, the compound is (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester or a pharma-ceutically acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester). In yet another embodiment, the compound is (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester or a pharma- ceutically acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester).

[0008] Provided herein is a pharmaceutical composition comprising a compound selected from the group consisting of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxy-propyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester, and pharma- ceutical acceptable salts thereof.

[0009] The following compound [ka] Provided herein is a pharmaceutical composition comprising (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester or a pharma- ceutical acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester or a pharma- ceutical acceptable salt thereof (e.g., (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester).

[0010] The following compound [ka] Provided herein is a pharmaceutical composition comprising (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester or a pharma- ceutical acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester).

[0011] The following compound [ka] Provided herein is a pharmaceutical composition comprising (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester or a pharma- ceutical acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester or a pharma-ceutical acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester).

[0012] The pharmaceutical composition may further comprise an additional MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutical acceptable salt thereof. In one embodiment, the pharmaceutical composition of any of the embodiments described herein further comprises mirdametinib.

[0013] A method for treating one or more tumors or cancers selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), pancreatic ductal adenocarcinoma (PDAC), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis complex (TSC), Langerhans cell histiocytosis (LCH), brain tumors, and cancers metastasizing to the brain of a patient, comprising administering to a patient in need thereof a pharmaceutical composition as set forth above.

[0014] One embodiment is a method of treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN) in a patient in need thereof by administering a pharmaceutical composition as described herein. The pharmaceutical composition can be administered orally. Another embodiment is a method of treating NF1-PN in a patient in need thereof by orally administering to the patient an effective amount of one or more pharmaceutical compositions as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] I. Definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0016] Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0017] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one," may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single." In other embodiments, the term "a" or "an" includes "two or more" or "multiple."

[0018] Furthermore, as used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, whether or not the other is present. Thus, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" when used in expressions such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0019] The term "mirdametinib" refers to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0020] "mg / m 2 The term "body surface area" refers to the area per square meter of the patient's body surface area. 2 This refers to the dose in milligrams per serving.

[0021] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject.

[0022] As used herein, the terms "treat", "treated" and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of a condition, disorder, or disease; stabilization (i.e., not worsening) of a condition, disorder, or disease; delay in onset or slowing of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of a condition, disorder, or disease state; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or improvement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0023] In certain embodiments, if a patient shows one or more of the following: reduction in tumor size; mitigation of one or more symptoms related to a particular tumor; reduction in tumor volume; improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progression (PD), increase in time to progression (TTP), or any combination thereof, the subject is successfully "treated" with tumor according to the methods described herein.In some embodiments, the nationally or internationally accepted standard of therapeutic outcome in a given tumor can be used to determine whether the effective amount of active ingredient meets any of these specific endpoints (e.g., CR, PFS, PR).

[0024] In certain embodiments, a subject is successfully "treated" with cancer (e.g., lung cancer or ovarian cancer) according to the methods described herein if the patient shows one or more of the following: reduction or complete absence of cancer cell count; mitigation of one or more symptoms associated with a particular cancer; reduction in morbidity and mortality; improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progression (PD), increase in time to progression (TTP), or any combination thereof.In some embodiments, the effective amount of active ingredient can be determined to meet any of these specific endpoints (e.g., CR, PFS, PR) using nationally or internationally accepted standards of therapeutic outcome in a given cancer.

[0025] The terms "pharmaceutical acceptable carrier", "pharmaceutical acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutical acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0026] The term "pharmaceutical acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of Compound A or Compound B. These salts can be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound of the present invention in its free base form with a suitable organic or inorganic acid and isolating the salt formed during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19).

[0027] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

[0028] In certain embodiments, the compounds of the present invention may contain one or more acidic functional groups, and therefore can form pharma-ceutically acceptable salts with pharma-ceutically acceptable bases. The term "pharma-ceutically acceptable salts" in these instances refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example, Berge et al., supra).

[0029] The term "about" or "approximately" refers to the tolerance of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0030] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are to be interpreted inclusively rather than exclusively, and are used with the express understanding that Applicant intends each of these terms to be so interpreted in interpreting this patent, including the claims which follow.

[0031] II. Compounds and Pharmaceutical Compositions The following compound [ka] or a pharma- ceutically acceptable salt thereof is provided herein. In one embodiment, the compound is (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester or a pharma- ceutically acceptable salt thereof (e.g., (R)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxypropyl ester).

[0032] The following compound [ka] or a pharma- ceutically acceptable salt thereof is provided herein. In one embodiment, the compound is (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester or a pharma- ceutically acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxypropyl ester).

[0033] The following compound [ka] Or a pharmaceutically acceptable salt thereof is provided herein. In one embodiment, the compound is (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester or a pharmaceutically acceptable salt thereof (e.g., (S)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester).

[0034] Provided herein is a pharmaceutical composition comprising a compound selected from the group consisting of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 2,3-dihydroxy-propyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester, and pharma- ceutical acceptable salts thereof.

[0035] In some embodiments, the pharmaceutical composition comprises 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2,3-dihydroxy-propyl ester. In some embodiments, the pharmaceutical composition comprises 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester. In some embodiments, the pharmaceutical composition comprises 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester.

[0036] The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments, the compound is administered at a concentration of from about 1 μg to about 10 mg, from about 1 μg to about 9 mg, from about 1 μg to about 8 mg, from about 1 μg to about 7 mg, from about 1 μg to about 6 mg, from about 1 μg to about 5 mg, from about 1 μg to about 4 mg, from about 1 μg to about 3 mg, from about 1 μg to about 2 mg, from about 1 μg to about 1 mg, from about 1 μg to about 950 μg, from about 1 μg to about 900 μg, from about 1 μg to about 850 μg, from about 1 μg to about 800 μg, from about 1 μg to about 750 μg, from about 1 μg to about 700 μg, from about 1 μg to about 650 μg, from about 1 μg to about 60 The compound is present in an amount of about 0 μg, about 1 μg to about 550 μg, about 1 μg to about 500 μg, about 1 μg to about 450 μg, about 1 μg to about 400 μg, about 1 μg to about 350 μg, about 1 μg to about 300 μg, about 1 μg to about 250 μg, about 1 μg to about 200 μg, about 1 μg to about 150 μg, about 1 μg to about 100 μg, about 1 μg to about 75 μg, about 1 μg to about 50 μg, about 1 μg to about 25 μg, about 1 μg to about 20 μg, about 1 μg to about 15 μg, about 1 μg to about 10 μg, or about 1 μg to about 5 μg. In some embodiments, the compound is administered at about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1.5 mg, about 1 mg, about 950 μg, about 900 μg, about 850 μg, about 800 μg, about 1000 μg, about 15 ... The compound is present in an amount of about 1 μg, about 750 μg, about 700 μg, about 650 μg, about 600 μg, about 550 μg, about 500 μg, about 450 μg, about 400 μg, about 350 μg, about 300 μg, about 250 μg, about 200 μg, about 150 μg, about 100 μg, about 75 μg, about 50 μg, about 25 μg, about 20 μg, about 15 μg, about 10 μg, about 5 μg, or about 1 μg.

[0038] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutically acceptable salt thereof.

[0039] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib. In some embodiments, the pharmaceutical composition further comprises mirdametinib. In some embodiments, the pharmaceutical composition further comprises binimetinib. In some embodiments, the pharmaceutical composition further comprises cobimetinib. In some embodiments, the pharmaceutical composition further comprises trametinib. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0040] In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises mirdametinib.

[0041] In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutical acceptable salt thereof.In some embodiments, the pharmaceutical composition further comprises binimetinib.

[0042] In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib fumarate. In some embodiments, the pharmaceutical composition further comprises cobimetinib.

[0043] In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises trametinib dimethylsulfoxide. In some embodiments, the pharmaceutical composition further comprises trametinib.

[0044] In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib sulfate. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0045] The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the compound is administered at a concentration of from about 1 μg to about 10 mg, from about 1 μg to about 9 mg, from about 1 μg to about 8 mg, from about 1 μg to about 7 mg, from about 1 μg to about 6 mg, from about 1 μg to about 5 mg, from about 1 μg to about 4 mg, from about 1 μg to about 3 mg, from about 1 μg to about 2 mg, from about 1 μg to about 1 mg, from about 1 μg to about 950 μg, from about 1 μg to about 900 μg, from about 1 μg to about 850 μg, from about 1 μg to about 800 μg, from about 1 μg to about 750 μg, from about 1 μg to about 700 μg, from about 1 μg to about 650 μg, from about 1 μg to about 60 The compound is present in an amount of about 0 μg, about 1 μg to about 550 μg, about 1 μg to about 500 μg, about 1 μg to about 450 μg, about 1 μg to about 400 μg, about 1 μg to about 350 μg, about 1 μg to about 300 μg, about 1 μg to about 250 μg, about 1 μg to about 200 μg, about 1 μg to about 150 μg, about 1 μg to about 100 μg, about 1 μg to about 75 μg, about 1 μg to about 50 μg, about 1 μg to about 25 μg, about 1 μg to about 20 μg, about 1 μg to about 15 μg, about 1 μg to about 10 μg, or about 1 μg to about 5 μg. In some embodiments, the compound is administered at about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1.5 mg, about 1 mg, about 950 μg, about 900 μg, about 850 μg, about 800 μg, about 1000 μg, about 15 ... The compound is present in an amount of about 1 μg, about 750 μg, about 700 μg, about 650 μg, about 600 μg, about 550 μg, about 500 μg, about 450 μg, about 400 μg, about 350 μg, about 300 μg, about 250 μg, about 200 μg, about 150 μg, about 100 μg, about 75 μg, about 50 μg, about 25 μg, about 20 μg, about 15 μg, about 10 μg, about 5 μg, or about 1 μg.

[0047] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib. In some embodiments, the pharmaceutical composition further comprises mirdametinib. In some embodiments, the pharmaceutical composition further comprises binimetinib. In some embodiments, the pharmaceutical composition further comprises cobimetinib. In some embodiments, the pharmaceutical composition further comprises trametinib. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0049] In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises mirdametinib.

[0050] In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutical acceptable salt thereof.In some embodiments, the pharmaceutical composition further comprises binimetinib.

[0051] In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib fumarate. In some embodiments, the pharmaceutical composition further comprises cobimetinib.

[0052] In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises trametinib dimethylsulfoxide. In some embodiments, the pharmaceutical composition further comprises trametinib.

[0053] In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib sulfate. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0054] The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the compound is administered at a concentration of from about 1 μg to about 10 mg, from about 1 μg to about 9 mg, from about 1 μg to about 8 mg, from about 1 μg to about 7 mg, from about 1 μg to about 6 mg, from about 1 μg to about 5 mg, from about 1 μg to about 4 mg, from about 1 μg to about 3 mg, from about 1 μg to about 2 mg, from about 1 μg to about 1 mg, from about 1 μg to about 950 μg, from about 1 μg to about 900 μg, from about 1 μg to about 850 μg, from about 1 μg to about 800 μg, from about 1 μg to about 750 μg, from about 1 μg to about 700 μg, from about 1 μg to about 650 μg, from about 1 μg to about 60 The compound is present in an amount of about 0 μg, about 1 μg to about 550 μg, about 1 μg to about 500 μg, about 1 μg to about 450 μg, about 1 μg to about 400 μg, about 1 μg to about 350 μg, about 1 μg to about 300 μg, about 1 μg to about 250 μg, about 1 μg to about 200 μg, about 1 μg to about 150 μg, about 1 μg to about 100 μg, about 1 μg to about 75 μg, about 1 μg to about 50 μg, about 1 μg to about 25 μg, about 1 μg to about 20 μg, about 1 μg to about 15 μg, about 1 μg to about 10 μg, or about 1 μg to about 5 μg. In some embodiments, the compound is administered at about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1.5 mg, about 1 mg, about 950 μg, about 900 μg, about 850 μg, about 800 μg, about 1000 μg, about 15 ... The compound is present in an amount of about 1 μg, about 750 μg, about 700 μg, about 650 μg, about 600 μg, about 550 μg, about 500 μg, about 450 μg, about 400 μg, about 350 μg, about 300 μg, about 250 μg, about 200 μg, about 150 μg, about 100 μg, about 75 μg, about 50 μg, about 25 μg, about 20 μg, about 15 μg, about 10 μg, about 5 μg, or about 1 μg.

[0056] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the pharmaceutical composition further comprises a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib. In some embodiments, the pharmaceutical composition further comprises mirdametinib. In some embodiments, the pharmaceutical composition further comprises binimetinib. In some embodiments, the pharmaceutical composition further comprises cobimetinib. In some embodiments, the pharmaceutical composition further comprises trametinib. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0058] In some embodiments, the pharmaceutical composition further comprises mirdametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises mirdametinib.

[0059] In some embodiments, the pharmaceutical composition further comprises binimetinib or a pharma- ceutical acceptable salt thereof.In some embodiments, the pharmaceutical composition further comprises binimetinib.

[0060] In some embodiments, the pharmaceutical composition further comprises cobimetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises cobimetinib fumarate. In some embodiments, the pharmaceutical composition further comprises cobimetinib.

[0061] In some embodiments, the pharmaceutical composition further comprises trametinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises trametinib dimethylsulfoxide. In some embodiments, the pharmaceutical composition further comprises trametinib.

[0062] In some embodiments, the pharmaceutical composition further comprises selumetinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises selumetinib sulfate. In some embodiments, the pharmaceutical composition further comprises selumetinib.

[0063] III. Treatment method A method for treating one or more tumors or cancers selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis (TSC), pancreatic ductal adenocarcinoma (PDAC), Langerhans cell histiocytosis (LCH), brain tumors, and cancers metastasizing to the brain of a patient, comprises administering (e.g., orally) to a patient in need thereof a pharmaceutical composition as set forth above. In one embodiment, the method comprises administering (e.g., orally) an effective amount of one or more pharmaceutical compositions described herein.

[0064] In some embodiments, the tumor or cancer is a plexiform neurofibroma (PN).

[0065] In some embodiments, the tumor or cancer is plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN).

[0066] In some embodiments, the tumor or cancer is cutaneous neurofibroma (cNF).

[0067] In some embodiments, the tumor or cancer is high-grade glioma (HGG).

[0068] In some embodiments, the tumor or cancer is a low-grade ovarian cancer.

[0069] In some embodiments, the tumor or cancer is tuberous sclerosis complex (TSC).

[0070] In some embodiments, the tumor or cancer is pancreatic ductal adenocarcinoma (PDAC).

[0071] In some embodiments, the tumor or cancer is Langerhans cell histiocytosis (LCH).

[0072] In some embodiments, the tumor or cancer is a brain tumor.

[0073] In some embodiments, the tumor or cancer is a cancer that has metastasized to the patient's brain. EXAMPLES

[0074] Example 1: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2,3-dihydroxy-propyl ester [ka] The synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2,3-dihydroxy-propyl ester was carried out according to scheme 1 shown below. Starting from a fluorinated phenyl amino acid, the primary alcohol ester of glycerol and acid was obtained by reaction with solketol (1A). Since only one free hydroxyl group is present, esterification can only occur via this hydroxyl group to give compound 2A. Acetonide deprotection using acidic DOWEX resin gave the desired compound 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 2,3-dihydroxy-propyl ester. The structure of this compound was confirmed by NMR, which showed a characteristic peak from the methylene protons of the ester at a chemical shift of 4.4 ppm. The methine protons on the secondary carbon are observed as a multiplet at 4.05 ppm, and the methine protons on the alcohol are observed as two doublets at 3.8 and 3.65 ppm.

[0075] Scheme 1: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2,3-dihydroxy-propyl ester [ka]

[0076] Example 2: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester [ka] The synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester was carried out according to Scheme 2 shown below. The acetonide group of the starting material was deprotected using Dowex acid resin in methanol to obtain diol (1). The diol intermediate was purified by column chromatography before proceeding to the next step. The coupling reaction of the diol with acid gave compound 2. The deprotection of compound 2 was completed with ammonium hydroxide in toluene at 40°C.

[0077] The progress of the reaction was monitored by LCMS, which indicated a very clean reaction, giving compound 3 in high yield. The product was also characterized by 1H NMR, which confirmed that the ester bond was formed through the primary alcohol. Compound 3 is highly reactive and readily forms Schiff bases with aldehydes and ketones. Reaction of formaldehyde (36% solution in water) with compound 3 in the presence of catalytic acetic acid in THF gave the desired compound 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxypropyl ester.

[0078] Scheme 2: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester [ka]

[0079] Example 3: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meth-(E)-ylideneaminooxy]-2-hydroxy-propyl ester [ka] Based on the scheme 3 shown below, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester was synthesized. 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester was synthesized according to the same process as 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester. Compound 3 was reacted with glyoxylic acid in the presence of a trace amount of acetic acid to obtain 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester.

[0080] Using column purification and crystallization in a mixture of 10% EtOAc in heptane, 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 3-[1-carboxy-meth-(E)-ylideneaminooxy]-2-hydroxy-propyl ester was obtained in greater than 95% purity.

[0081] Scheme 3: Synthesis of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meth-(E)-ylideneaminooxy]-2-hydroxy-propyl ester [ka]

[0082] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0083] While the invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modifications, and that this application is intended to cover any variations, uses, or adaptations of the present disclosure, including departures from the present disclosure that may be applied to the essential features set forth above, which generally follow the principles and come within known or customary practice in the art to which the invention pertains, and which comply with the scope of the claims.

[0084] In addition to the various embodiments described herein, the present disclosure includes the following embodiments, numbered E1 through E39, which are provided as an exemplary list and the application is not limited to these embodiments.

[0085] E1. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0086] E2. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0087] E3. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0088] E4. A pharmaceutical composition comprising a compound selected from the group consisting of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2,3-dihydroxy-propyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 3-[1-carboxy-meta-(E)-ylideneaminooxy]-2-hydroxy-propyl ester, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxy-propyl ester, and pharma- ceutical acceptable salts thereof.

[0089] E5. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0090] E6. The pharmaceutical composition of E5, wherein the compound is present in an amount of about 1 μg to about 10 mg.

[0091] E7. The pharmaceutical composition of E5, wherein the compound is present in an amount of about 1 μg to about 8 mg.

[0092] E8. The pharmaceutical composition of E5, wherein the compound is present in an amount of about 1 μg to about 1 mg.

[0093] E9. The pharmaceutical composition of E5, wherein the compound is present in an amount of about 1 μg to about 500 μg.

[0094] E10. The pharmaceutical composition of E5, wherein said compound is present in an amount of about 1 μg to about 250 μg.

[0095] E11. The pharmaceutical composition of E5, wherein said compound is present in an amount of about 1 μg to about 100 μg.

[0096] E12. The pharmaceutical composition of E5, wherein said compound is present in an amount of about 1 μg to about 50 μg.

[0097] E13. The pharmaceutical composition of E5, wherein said compound is present in an amount of about 1 μg to about 25 μg.

[0098] E14. The pharmaceutical composition of E5, wherein said compound is present in an amount of about 1 μg to about 10 μg.

[0099] E15. The pharmaceutical composition of any one of E5 to E14, further comprising a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutical acceptable salt thereof.

[0100] E16. The pharmaceutical composition of any one of E5 to E14, further comprising mirdametinib.

[0101] E17. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0102] E18. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 10 mg.

[0103] E19. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 8 mg.

[0104] E20. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 1 mg.

[0105] E21. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 500 μg.

[0106] E22. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 250 μg.

[0107] E23. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 100 μg.

[0108] E24. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 50 μg.

[0109] E25. The pharmaceutical composition of E17, wherein said compound is present in an amount of about 1 μg to about 10 μg.

[0110] E26. The pharmaceutical composition according to any one of E17 to E25, further comprising a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutically acceptable salt thereof.

[0111] E27. The pharmaceutical composition of any one of E17 to E25, further comprising mirdametinib.

[0112] E28. The following compound [ka] or a pharma- ceutically acceptable salt thereof.

[0113] E29. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 10 mg.

[0114] E30. The pharmaceutical composition of E28, wherein said compound is present in an amount from about 1 μg to about 8 mg.

[0115] E31. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 1 mg.

[0116] E32. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 500 μg.

[0117] E33. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 250 μg.

[0118] E34. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 100 μg.

[0119] E35. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 50 μg.

[0120] E36. The pharmaceutical composition of E28, wherein said compound is present in an amount of about 1 μg to about 10 μg.

[0121] E37. The pharmaceutical composition of any one of E28 to E36, further comprising a MEK inhibitor selected from the group consisting of mirdametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharma- ceutically acceptable salt thereof.

[0122] E38. The pharmaceutical composition of any one of E28 to E36, further comprising mirdametinib.

[0123] E39. A method of treating a tumor or cancer selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), pancreatic ductal adenocarcinoma (PDAC), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis complex (TSC), Langerhans cell histiocytosis (LCH), brain tumor, and cancer metastasized to the brain of a patient, comprising administering to a patient in need thereof a pharmaceutical composition described in any one of E4 to E38.

Claims

1. Compounds selected from the group consisting of the following: 【Chemistry 1】 and its pharmaceutically acceptable salts.

2. (a) Compounds selected from the group consisting of the following: 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 2,3-dihydroxypropyl ester, 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 3-[1-carboxymeth-(E)-ylideneaminooxy]-2-hydroxypropyl ester, 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid 2-hydroxy-3-methyleneaminooxypropyl ester, and The pharmaceutically acceptable salt, and (b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

3. The composition is 【Chemistry 2】 The pharmaceutical composition according to claim 2, comprising a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 3, wherein the compound is present in an amount of about 1 μg to about 10 mg.

5. The pharmaceutical composition according to claim 3, further comprising a MEK inhibitor selected from the group consisting of mildametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, wherein the MEK inhibitor is mildametinib.

7. The composition is 【Transformation 3】 The pharmaceutical composition according to claim 2, comprising a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, wherein the compound is present in an amount of about 1 μg to about 10 mg.

9. The pharmaceutical composition according to claim 7, further comprising a MEK inhibitor selected from the group consisting of mildametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, wherein the MEK inhibitor is mildametinib.

11. The composition is 【Chemistry 4】 The pharmaceutical composition according to claim 2, comprising a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, wherein the compound is present in an amount of about 1 μg to about 10 mg.

13. The pharmaceutical composition according to claim 11, further comprising a MEK inhibitor selected from the group consisting of mildametinib, binimetinib, cobimetinib, trametinib, and selumetinib, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, wherein the MEK inhibitor is mildametinib.

15. A method for treating a tumor or cancer selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), cutaneous neurofibroma (cNF), pancreatic ductal adenocarcinoma (PDAC), high-grade glioma (HGG), low-grade ovarian cancer, tuberous sclerosis (TSC), Langerhans cell histiocytosis (LCH), brain tumors, and cancers that have metastasized to the brain of a patient, the method comprising administering the pharmaceutical composition described in claim 6 to a patient in need thereof.

16. A method for treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN) in a patient in need thereof, the method comprising administering the pharmaceutical composition according to claim 6 to the patient.

17. A method for treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN) in a patient in need thereof, the method comprising administering the pharmaceutical composition according to claim 10 to the patient.

18. A method for treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN) in a patient in need thereof, the method comprising administering the pharmaceutical composition according to claim 14 to the patient.

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